Respiratory System consists of following:

Gas exchanging organ (Alveoli in lungs & Pulm

capillaries)
Ventilatory pump (chest wall, diaphragm, areas in brain
that control respiration)
1.
2.
3.
4.

Respiration involves 4 distinct processes:

Pulm Ventilation Inflow & outflow air btwn atmosphere &
lung alveoli
Diffusion of Oxygen & Carbon dioxide btwn alveoli & blood
in pulm capillaries
Transport Gases via circulation
Regulation of Ventilation

Cell

Lung Gross Anatomy

The Pleurae
Pleura: thin, doublewalled serosa
surrounding lungs;
consists of 2 layers
- Parietal pleura
- Visceral pleura

Space btwn 2
pleurae is pleural
cavity

WHAT IS PLEURAL EFFUSION??

BLOOD SUPPLY:
- Pulm As (Deoxygenated blood)
- Bronchial as supply conducting
airways
- Pulm BF is CO of RV,
delivered to lungs via pulm a
Venous Drainage: (Oxygenated
blood) in lungs via Pulm &
Bronchial vs
Brochial vs drains in to Pulm vs,
Azygous & Hemiazygous vs.
INNERVATION:
Parasymp: bronchoconstrict
Symp: Bronchodilate via 2
receptors
- 2 adrenergic agonists:
Epinephrine, Isoproterenol
Terbutaline & Albuterol) dilate
airways in tx of Bronchial
Asthma

Primary Bronchi
Secondary
Bronchi
Tertiary Bronchi
Terminal
Bronchiole

(no cartilage, hence

where lung collapse can occur)

Respiratory
Bronchiole
Passages w/dm of
<1mm are called
Bronchioles
All conducting airways

 2 main zones in
respiratory system:
A) CONDUCTING ZONE
- transports gases
B) RESPIRATORY ZONE
takes pt in gas
exchange; areas of
respiratory system
w/Alveoli (scattered
thin-walled air sacs)

Respiratory Zone:

spiratory zone begins from Respiratory bronchioles.

spiratory bronchioles continue as alveolar ducts which
ad into Alveolar sacs.

Alveolar epithelium has 2 cell

types Type I and II Pneumocytes
Type I alveolar cells
(Type I Pneumocytes):
large flat cells that form
pt of thin gas diffusion
barrier
Make type II
Type II alveolar cells
(Type II Pneumocytes):
produce Surfactant,
substance that reduces
surface tension in alveoli
thereby preventing them
from collapsing

Functions of the lungs

1) GAS EXCHANGE most imp func of lungs
2) Lung defense mechanisms
3) Metabolic & Endocrine functions

GAS EXCHANGE function of the

lungs
O from air enters into venous blood & CO moves out
2

from blood into exhaled air

Air mixes w/gas in alveoli by SIMPLE DIFFUSION (Gases
diffuse from area of high to low partial pressure of that
particular gas)
O2 enters blood in Pulm capillaries & CO2 enters alveoli
Exchange occurs at blood gas interface called

RESPIRATORY MEMBRANE:

Alveolar + Capillary membranes form

Respiratory membrane . It has gas on
1 side & blood on other

Respirator
y
Membran
e:

How such an enormous

surface area for diffusion
is present inside a limited
Thoracic cavity????
- This is b/c of coiling of
pulmonary capillaries
around numerous
small air sacs called
ALVEOLI

Diffusion of gases across respiratory

membrane depends on Ficks Law
Ficks Law of Diffusion states that: net rate of
diffusion
of gas
across a of
fluid-memb
is directly
The net rate
of diffusion
a gas across
a fluid
proportional
partialproportional
pressure differences
membrane istodirectly
to partialacross
memb
& surface
areaacross
available
for diffusionand
&
pressure
differences
the membrane
inversely
proportional
to thickness
of memb
area available
for diffusion
and inversely
(diffusion
distance)
proportional
to thickness of the membrane
Rate
of diffusion
= Surface area X Partial pressure
(diffusion
distance)
difference x solubility of gas
Rate of diffusion = Surface area X Partial pressure
Distance (Thickness) X MW
difference

Ex: diffusion of O2 from alveolarDistance

air into pulm capillaries
depends
partial
pressure
for Ocapillaries
2 btwn alveolar
Diffusion
of on
O2 from
alveolar
air differences
into pulmonary
air
& capillary
bloodpressure differences for O between
depends
on partial
2

alveolar air & capillary blood

Clinical implications on diffusion of gases

across Respiratory Membrane (RM)
In healthy lungs, gas exchange efficient as
respiratory memb only 0.5-1.5 m thick & surface
area enormous.
In Pneumonia, thickness of Respiratory memb ^due
to consolidation (filling alveoli & small airways
w/inflammatory exudates)
How will this affect the efficiency of gas exchange?
Diffusion of gas across respiratory memb decreases
in Pneumonia
Hypoxia hypoxemia

Clinical implications on diffusion of gases across

Respiratory Membrane (RM)
What happens to diffusion of gases in Emphysema?
In Emphysema, theres destruction of alveoli which
decreases surface area thereby diffusion of gases
across Respiratory memb is decreased
What happens to diffusion of gases in Pulmonary
Edema?
In Pulm edema, accumulation of fluid in interstitial
space. So diffusion distance ^, thereby decreasing net
rate of diffusion
What happens in Bronchial asthma?
In Bronchial Asthma, bronchioles constricted. Partial
pressure gradient is decreased which will decrease rate
of gas diffusion.

b/c youre not diffusing

Other Functions of lungs Lung defense

mechanisms

Respiratory tract Humidify inspired air so that by time it

reaches alveoli it is ~equal to body temp
Removal of foreign particles by Respiratory tract:
Hair in nostrils (Trap particles >10m)
Reflex bronchoconstriction & coughing (Trap particles
2-10 m in dm)
Ciliary escalator (ciliated respiratory epithelium cilia
beat in co- ordinated manner) helps removal of foreign
particles

Other functions of lungs

Particles <2 m in dm reaching alveoli are ingested by Pulmonary

alveolar macrophages (PAM / Dust cells) via Phagocytosis
Bronchial secretions have secretory IgAs Helps resisting
infections
Pulmonary epithelium also has PGE2s protective to epithelial
cells
Metabolic & Endocrine functions of the lungs:
Lungs synthesize
Surfactant
Prostaglandins causes bronchodilation
Histamine causes bronchoconstriction

ACE in Lungs activate Angiotensin I to Angiotensin II

Central Airways
(Trachea & larger bronchi)

Peripheral airways
(Bronchioles)

Have cartilaginous
support which make
No cartilage. Have
them semi-rigid
smooth ms & quite
(Stiff)
compliant
Velocity of air greater
Parallel arrangement
- Turbulent airflow
therefore lesser
resistance
Velocity of air
decreasesTherefore maximum resistance
to airflow is found
in Large Central airways likeLess
Trachea
& theairflow
turbulent
bronchi when compared to peripheral airways like

A 65-year-old man presents with productive cough and

difficulty in breathing. His sputum culture is positive for
encapsulated gram-positive pneumococci diagnostic of
pneumonia. The primary cause of dyspnea in this patient is
due to:

1. Inadequate perfusion
2. Inadequate
ventilation
3. Increased airway
resistance
4. Increased lung
compliance
5. Poor oxygen diffusion

1.

2.

3.
4.
5.

Concerning airflow in the lungs

which of the following statements
is true?
Flow is more likely to be
turbulent in the small
airways than in trachea
Large central airways offer
maximum resistance to
airflow
Velocity increases towards
the peripheral airways
Peripheral airways are
stiffer
Larger central airways are
more compliant

Some important values you should

remember:
Respiratory rate = 12- 15 breaths / min
Anatomic Dead Space = 150 ml
Tidal volume = 500 ml (0.5 Liter)
Vital capacity : 4500 ml (4.5 Liters)

Remember.

Formula to calculate:
IC, FRC, VC or FVC & TLC
Dead Space
Ventilation Rate Minute & Alveolar
ventilation
Alveolar ventilation equation

PULMONARY FUNCTION TESTS:

SPIROMETRY

LUNG VOLUMES
A) Tidal volume (TV): volume of air inspired or expired w/each normal breath; normal value: 500ml (0.5 L)
B) Inspiratory reserve volume (IRV): volume of air inspired w/maximal inspiratory effort; air amt inspired in excess of tidal
volume
C) Expiratory reserve volume (ERV): volume of air expelled w/forced expiratory effort; volume of air expired after tidal
expiration
D) Residual volume (RV): volume of air in lungs at end of maximal forced expiration; amt of air that can be never expelled
from lungs; helps preventing Atelectasis (Collapse of lungs)

LUNG CAPACITIES
A) INSPIRATORY CAPACITY (IC): total volume of air inspired w/maximal
inspiratory effort (TV + IRV)
B) FUNCTIONAL RESIDUAL CAPACITY (FRC): volume of air in lungs at
end of quiet, passive expiration (ERV + RV); indicates Equilibrium
point of Respiratory system. No muscular effort required; stays
normal in pt w/generalized weakness of skeletal ms
C) Vital capacity (VC) / Forced vital capacity (FVC): volume of
air forcibly expired after maximal inspiration (TV + IRV + ERV) :
Normal value: 4500 ml (4.5 Liters)
D) Total lung capacity (TLC): volume of air in lungs after a maximal
inspiration (TV + IRV + ERV + RV)
) Most Lung volumes & Capacities can be measured by Spirometry
EXCEPT Residual volume (RV) & any Capacity containing RV ie; TLC,
FRC
) FRC can be measured by Helium dilution technique
) Peak Expiratory Flow rate (PEFR): expiratory flow rate at peak of
FVC. (Normal: 400-500L/min); simple bedside test done using peak
flow meter. PEFR is markedly reduced in OBSTRUCTIVE AIRWAY

DEAD SPACE (DS)

Dead space: space where no gas exchange
occurs. There are 3 types of DS
1. ANATOMIC DEAD SPACE: Volume of
conducting airways (ends at lvl of
terminal bronchioles). ~150ml
2. ALVEOLAR DEAD SPACE: Includes nonfunctional alveoli or alveoli containing air
but w/out BF in surrounding capillaries

3. PHYSIOLOGIC DEAD SPACE:

volume of lungs that does not participate in gas
exchange i.e. total dead space in lungs
(Anatomic + Alveolar dead space)
VD = VT X PaCO2 PE CO2
PaCO2
Where,
VD Physiologic dead space (ml)
VT Tidal Volume (ml)
PaCO2 PCO2 of arterial blood ( mm Hg)

PE

CO2

- PCO2 of expired air (mm Hg)

Ventilation rate:

1) Minute ventilation (MV) / total

ventilation: total volume of air
moving in / out of respiratory system
per minute
Minute ventilation (MV) = Tidal volume x
breaths / minute

MV= 500ml X 15 breaths / min =

7500ml/min

2) ALVEOLAR VENTILATION ( AV): volume of

air delivered to respiratory zone (alveoli)
per minute
1st 150ml of each inspiration does not
contribute to alveolar ventilation WHY??? Stays in conducting zone
Because of Anatomic Dead Space
ALVEOLAR VENTILATION =
(TIDAL VOLUME DEAD SPACE ) X Breaths/min
( 500 150 ml ) X 15 = 350 mlX15
= 5250 ml / min

Increased depth of breathing

(Hyperventilation)
Increases Total and
Alveolar ventilation
Increased Rate of breathing
Increases
total ventilation but not Alveolar ventilation

Alveolar Ventilation Equation

Describes inverse relnship btwn alveolar ventilation (VA)
& alveolar PCO2 (PACO2)
Expressed as:
VA = VCO2 x K
PACO2

or rearranging, PACO2 = VCO2 x K

VA
Where,
VA= Alveolar ventilation (mL /min)
VCO2 = Rate of CO2 production (mL /min)
PACO2 = Alveolar PCO2 (mm Hg)
K= Constant
If CO2 production is constant, PACO2 & VA have inverse relnship
Eg: Increase in alveolar ventilation causes decrease in PA CO2 & vice versa
As seen during strenuous exercise, if CO 2 production doubles, in order to
maintain normal PACO2 (40mm Hg), Alveolar ventilation should also double

Alveolar or arterial Pco2 as a function of alveolar ventilation.

he relationship is described by alveolar ventilation equation. When CO 2 production doubles

rom 200 mL/min to 400 mL/min, alveolar ventilation also must double (5L/min to 10 L/min)
to maintain the PACO2 and PaCO2 at 40 mm Hg

Pleural Effusion is accumulation of excessive amounts

of fluid in pleural cavity

Which side is the Pleural

Effusion???

Chest x-ray of a pleural effusion.

arrow A shows fluid layering in R pleural cavit
B arrow shows normal width of lung in cavity

A question now
Inflammation of central pt of diaphragmatic pleura produces referred pain to
shoulders Why???
-

Innervated by Phrenic ns originating at cervical roots C 3,4,5

-ve intrapleural pressure increases too much causing collapsed lung

Pneumothorax

Pneumothorax occurs when air

leaks from inside lung to space
btwn lung & chest wall (pleural
cavity). Lung then collapses
Commonly due to chest trauma, or
underlying lung dis COPD, Asthma,
CF, TB
Hyperlucency & absent vascular
markings is DARK AREA; hence
collapsed lung

Muscles of Inspiration:
Diaphragm most imp
Respiratory muscles:
inspiratory m
- When diaphragm
contracts, abdominal
contents pushed downwds,
ribs lifted upwd & outwd,
thereby ^vol of thoracic
cavity
As thoracic volume s,
lung volume also ^^
causes lung pressure to
Now Palv is <Patm so airll flow
down its pressure gradient &
enter lungs.
Inspiration ends when
Palv=Patm

Rib movements which ^thoracic dms

are...
A) Pump handle movement where ribs move upwds & forwds. This movement ^anteroposterior dm of rib cage

B) Bucket handle movement: ribs move upwards & outwards

(laterally) thereby ^lateral dimension (Transverse dm) of rib cage

What happens during exercise?

External intercostals & Accessory muscles
of inspiration will contract & help in
inspiration.
- These ms not used during normal, quiet
breathing

Muscles of Expiration:
Expiration passive process b/c both lungs & chest wall
are elastic structures that return back to their resting
poss after inspiration
Expiratory ms mainly used during exercise or lung diss
like Asthma where theres increased airway resistance
Imp Expiratory ms are.
Abdominal ms contract to compress abdominal cavity
push diaphragm upwards, pushing air out lungs
Internal intercostal ms contract to pull ribs downwards &
inwards, vol thoracic cavity which aids in expulsion of
air outside

Inspiration

Expiration

X-ray of chest in full expiration (left) & full inspiration (R). Dashed
white line on right is an outline of lungs in full expiration.

Important Pressures
Atmospheric pressure (Patm):
pressure exerted by air
surrounding body; total
atmospheric pressure is 0
Intrapulm/Intra-alveolar
pressure (Palv): pressure w/in
alveoli of lungs; rises & falls during
breathing but always equalizes
w/atmospheric pressure
Intrapleural pressure (Pip):
pressure w/in pleural cavity.
(Esophageal pressure is index of
intrapleural pressure); always
lower than both Palv & Patm
Transmural pressure: difference
btwn alveolar pressure (inside
lungs) & intra-pleural pressure
(outside lungs)

What causes lungs to expand & collapse??

When pressure surrounding lungs (intra-pleural
pressure) is ve, Transmural pressure gradient
(Intra-alveolar-Intrapleural pressure) is +ve. This
expands alveoli & air from outside will enter lungs.
Lungs expand more & lung volume ^
If pressure surrounding lungs +ve, Transmural
pressure gradient is ve. Lungsll collapse & lung vol
decreases

Volumes and Pressures during

Normal Cycle

Pressure becomes -5 to -8 as lung expan

At rest ( Before inspiration begins)

Alveolar pressure = Atmospheric pressure = 0

Intrapleural pressure is negative -5 cm of H2O
Lung volume is at FRC
At equilibrium Intrapleural pressure is ve/
sub atmospheric Why???
intrapleural fluid in btwn lungs firmly pushes
lung to chest wall (like suction cup)
2 opposing forces (of lung & chest wall) which
are equal & opp like a syringe w/2 plungers
being pulled in 2 opp directions

During inspiration.
Inspiratory muscles contract Increases volume
of thorax
Intrapleural pressure becomes more ve
Greater pressure gradient causes alveoli to
expand
Alveolar volume increases, thereby decreasing
alveolar pressure

Alveolar pressure decreases to less than

atmospheric pressure i.e., becomes negative

Air moves from higher pressure to lower pressure

& this causes air entry into lungs

At the end of inspiration..

Lung expands until recoil force increases to equal intrapleural pressure
Alveolar pressure returns back to 0
Intrapleural pressure is more negative (-8 Cm of H2O)
Lung volume increases by 1 Tidal volume i.e.,
Lung volume at end of inspiration is : FRC + TV

During Expiration..
Alveoli undergoes elastic recoil. Alveolar volume
decreases, thereby increasing alveolar pressure
Alveolar pressure becomes greater than
atmospheric pressure i.e., becomes positive
Pressure gradient reverses & air flows out of lungs
Intrapleural pressure returns to resting lvls during
normal, passive expiration
Alveolar pressure returns back to 0 at end of
expiration & Lung volume returns to FRC
During forced expiration, intrapleural pressure
becomes +ve

Pressures during normal

breathing cycle:
#s over yellow arrows give
magnitude of
transmural pressures.
Wide blue arrows show airflow
into & out of lungs.
A Rest
B half-way thru inspiration;
C end of inspiration;
D halfway thru expiration.

Pressures across alveoli & conducting airways

during forced expiration in normal person and a person with
chronic obstructive pulmonary disease (COPD)
Trans-mural pressure being +ve, keeps lung open & from collapsing

Force vital capacity decreases in these pts b/c collapsed air

When trans-mural pressure becomes ve

What happens in a person w/COPD???

In COPD, lung compliance increases b/c of loss of elastic

fibers. During forced expiration, intrapleural pressure is
raised to same value as in normal person, +20 cm H 2O
Alveolar pressure & airway pressure are lower than in
normal person b/c structures have diminished elastic recoil
Transmural pressure gradient across lungs remains +ve
expanding pressure, +5 cm H2O, & alveoli remain open
However, large airways collapse b/c transmural pressure
gradient across them reverses, becoming ve (collapsing)
transmural pressure of -5 cm H2O
If large airways collapse, resistance to airflow increases &
expiration is more difficult
Persons with COPD learn to expire slowly w/pursed lips,
which raises airway pressure, prevents reversal of
transmural pressure gradient across large airways, &, thus,
prevents their collapse

Pursed lip breathing in Emphysema

What happens during Valsalva

Maneuver?

Glottis is closed
Expiratory ms contract vigorously,
causing +ve pressure in thoracic cavity
Large +ve intrapleural pressure &
ncreased force of recoil
This creates a +ve alveolar pressure

The following information was obtained from a 23 year old patient during a
complete workup in a pulmonary function laboratory by a direct Spirometry:
Inspiratory Reserve volume (IRV) = 4500 ml
Residual Volume (RV) = 1500 ml
Tidal Volume = 500 ml
Functional Residual capacity (FRC)= 3000 ml
Expiratory Reserve volume in this patient would be:

1.
2.
3.
4.
5.

1100
2000
1500
4000
5000

ml
ml
ml
ml
ml

Compliance of Respiratory System

= distensibility of lungs & chest wall

Compliance: distensibility of lungs & chest wall

= V / P *Normal
value is 0.2L/cm H2O
= change in lung volume (Tidal volume) for given change in surrounding
pressure (pressure difference across pulmonary structures ie; (Transmural
pressure)
Compliance is inversely related to Elastance
Elastance: depends on amt of elastic tissue; measure of recoiling
tendency of hollow organ
To understand this, compare a thick & thin rubber band

Compliance of the Lungs alone

Depends on the stretchability of elastic fibers in lungs
Also depends on presence of surfactant which decreases surface tension
in alveoli
This elasticity tends to move lungs inwards during recoil

Compliance of the chest wall alone.

Depends on elastic tissue of the chest wall

Elasticity tends to move chest wall outwds during recoil

Compliance of the lungs + chest wall..

Compliance of combined lungs + chest wall system is less than

compliance of lungs / chest wall when considered independently (shown

by flatter slope shown in graph):

Compliance of lungs, chest wall, & combined lung & chest-wall

system. Equilibrium pos is at FRC, where expanding force on chest wall is
exactly equal to collapsing force on lungs.
When volume < FRC, Less volume in lungs (collapsing pressure is smaller),
but Expanding force is greater. Combined lung & chest wall wants to expand.
When volume > FRC, collapsing force on lung is greater than expanding
force of chest wall and lung + chest wall want to collapse.

Combined lung chest wall system at

equilibrium
At rest lung volume is at FRC
Pressures in airways & lungs =
Atmospheric pressure = Zero
At rest, there is a collapsing force on the
lung & expanding force on chest wall
which are equal & opposite
Therefore at rest, there is no collapse ,nor
expansion

What happens in
Pneumothorax ????
Air enters into the intrapleural
space
Intrapleural pressure =
Atmospheric pressure
Equilibrium is disturbed Lungs
will collapse & chest wall springs
outwards

Factors affecting Lung Compliance

A)

Lung size: Man or Mouse- lung compliance

^w/^lung size
B) Old age : lung compliance ^due to loss of
elasticity. FRC & RV remains normal
C) lungs diss: In Fibrosis, theres decreased
lung compliance b/c elastic tissue in lungs is
replaced by stiffer* fibrous tissue
A) ^tendency of lungs to collapse which is
greater than tendency of chest wall to
expand. In order to balance 2 opposing
forces, lung-chest wall system seeks
new, lower FRC
B) At lower FRC, collapsing force is lesser,
(see compliance graph), thus making 2
forces equal again
What happens in Emphysema??? = destruction
of alveolar walls w/loss of elastic recoil of
lungs
) Lung compliance increases, thereby tendency
of lungs to collapse reduces becoming much
lesser than tendency of chest wall to expand.
) To balance 2 opposing forces, lung-chest wall
system seeks higher FRC ^collapsing
force, (see compliance graph), making 2
forces equal again. This in turn results in
chronically overinflated lungs leads to
Barrel Shaped Chest deformity in these pts

Barrel Shaped chest

seen in Emphysema

Surface
Tension of
Alveoli

Surface tension results from attractive forces btwn molecules of liquid lining
alveoli (intermolecular attraction)
Creates a collapsing pressure which is directly proportional to Surface tension
& inversely proportional to alveolar radius ( Laplace Law)
Surfactant & its role in reducing Surface tension
Surfactant: detergent like chemical which interferes w/cohesion of water
molecules; mixture of Phospholipids & Apoproteins Dipalmitoyl phosphatidyl
choline (DPPC)
Secreted by Type II alveolar cells
Lines alveoli
Surfactant disrupts intermolecular attraction of liquid molecules surrounding
alveoli, thereby decreases Surface tension, prevents collapse of small alveoli.
Therefore increases alveolar compliance

Laplace Law states that..

Tension (T) in wall of an organ is equal to product of
pressure surrounding it and its radius ( r)
T= Pr
P=T/r

Effect of alveolar size and surfactant

Large Alveolus
Small AlveolusSmall
Alveolus
With
Surfactant

Therefore, large alveoli have large radius, low collapsing pressure so easy
to be kept open
Small alveoli have small radius, high collapsing pressure so more difficult
to be kept open

In Fetus.
Surfactant synthesis takes place btwn 28
35 weeks of gestation.
Lecithin: Sphingomyelin ratio 2:1 in
amniotic fluid rflx mature surfactant lvls
Lack of surfactant in infants leads to life
threatening disorder known as Neonatal
Respiratory Distress Syndrome

Infant Respiratory Distress Syndrome /

Hyaline Membrane Disease:
in premature Infants because of lack of surfactant; Infant shows
- Atelectasis (lung collapse)
- Due to lack/def Surfactant, ^surface tension which results in
dec lung compliance
Surfactant also decreases capillary filtration forces. Therefore
absence of surfactant, gives rise to Pulm edema
Cellular debris & proteinaceous exudates lines ]alveoli, which on
histo looks like Hyaline cartilage (hyaline=transparent) Therefore
also known as Hyaline Membrane Dis
Ex: A prematurely born infant of 27 weeks gestation who exhibits
noisy breathing, is presented to pediatrician. On exam, child has
very high respiratory rate, accessory ms of respiration acting,
appears bluish (cyanosis). CXR w/collapse of lungs. ^blood CO 2

Pathogenesis of Infant Respiratory

Distress Syndrome / Hyaline Membrane
Disease.

Premature birth
Immature lung
structures

Decreased Surfactant
Atelectasis /
Collapse of lungs
Hyaline membrane
formation

Hypoxia

Changes in
Compliance
in
Emphysema
& Fibrosis

These are 2 radiographs taken in 2

different infants..Comment????

Pressure, Airflow and Resistance

How are these related???
This relationship is given by the following
equation :

Q= P/ R
Q= Airflow (ml/min or L/min)
P= Pressure gradient ( Cm H2O )
R = Airway resistance ( cm H2O / L / sec)

Airway Resistance
Resistance of airways was
described by famous
French Physician
Poiseuille
He framed Poiseuilles
Law which is as stated
below:
R = 8l / r
R = Resistance
= Viscosity of inspired gas
l = Length of airway
r = Radius of airway

Resistance 1/(radius)4
If airway r by factor of
4,then resistance by
factor of (4) 4
ie; 256 & therefore airflow
by factor of 256

Exception to Poiseuilles Law

Medium sized Bronchi offer maximum resistance
to airflow compared to smaller peripheral airways
Why???
Larger Bronchi are Stiffer less compliant,
turbulent airflow
Smaller airways have no cartilage rings, have
smooth ms which are more compliant & have
parallel arrangement

Factors affecting Airway resistance

A) Type of flow: Laminar or Turbulent flow.
Turbulent flow offers greater resistance to airflow, thereby airflow
B) State of Bronchial smooth ms: Whether in contracted or relaxed state?
) Altering radius of airways, changes airway resistance
) Parasymps (+) , Irritants (cigarette smoking), Asthma, Histamine
injection - constrict airways/bronchoconstrict, radius, thus resistance
to airflow
) Symp (+) & Symp agonists ( adrenergic agonists Albuterol,
Isoproterenol) relax bronchial SMs/Bronchodilate, r, thereby
resistance to airflow
) This is basis for using agonists (esp 2 agonists) in txing
Bronchial Asthma
C) Viscosity & density of inspired air
) viscosity & density of air leads to resistance to airflow
) That is why, in deep sea diving, theres resistance to airflow
) Breathing low density gas like Helium, resistance to airflow

A 40 yr old male, who is a chronic smoker, presents to the

physician with chronic cough & difficulty in breathing. On
exam, his respiratory rate was 26/min. He appeared
bluish. Lung function tests revealed:
Vital capacity = 3.0 Lts
FEV1 = 1.50 Lts
FEV1/FVC = 50%
Interpret above findings & what is your probable
diagnosis?
FEV1/FVC = 50% (b/c <80% know its obstructive lung
disease type), usually see chronic productive cough in
smokers w/chronic bronchitis (not emphysema b/c of

Forced Expiratory Volume (FEV) & Equal pressure

FEV/Timed Vital capacity: determinespoint
amt of air(EPP)
expelled during

specific time intervals of FVC test

For ex, volume exhaled during 1st second of forced maximal
expiration is FEV1. Ppl w/healthy lungs can exhale about:
80% of FVC in 1st second - FEV1
95% in 2nd second FEV2
97% by 3rd second- FEV3
FEV1/ FVC = 80/100=0.8 or 80%

Normally, ppl can exhale only 80% of VC in 1 st sec b/c, during forced expiration,
intrapleural pressure becomes +ve & airways are compressed (known as Dynamic
compression of airways) which limits expiratory flow rates . This is explained by
concept of Equal pressure point (EPP) due to dynamic compression of airways
Equal pressure point (EPP): point where Intrapleural pressure & Alveolar / intraairway pressures are equal.
In forced expiration, both intrapleural pressure & (intra)-alveolar pressure will
increase. BUT alveolar pressure will decrease along length of airway until pressure
of 0 at mouth, whereas intrapleural pressure will remain same
Therefore therell be point where intra-pleural pressure will be equal to pressure
inside airway known as EPP
Beyond this point, intra-pleural pressure will be greater than airway pressure &
can cause compression of airways known as Dynamic compression of airways.
If EPP occurs in larger cartilaginous airways, airway remains open. However, if EPP
is in smaller airways, it will collapse.
Increasing force of expiration does not overcome EPP since itll increase both
alveolar & intra-pleural pressure.
EPP moves distally as expiration progresses b/c as air leaves alveolar unit,
pressure in alveoli decreases hence pressure in airway decreases as well.
Clinical significance: Problem may arise in pt w/COPD, in which equal pressure
point shifts twds smaller airways & they tend to collapse making expiration more
difficult

FVC & FEV1 in normal subjects

Subjects inspired maximally & then expired
FEV1 = 4 L
forcibly.
FVC = total volume that is forcibly expired FVC = 5 L (# from top)
FEV1/FVC = 80% (4/5) norm
FEV1 = volume expired in first second
Pulmonary func tests help differentiate
btwn Obstructive & restrictive pulmonary

Obstructive airway disease

Pts w/obstructive lung disease have difficulty
exhaling all air from lungs. B/c of damage to
lungs or narrowing of airways inside lungs,
exhaled air comes out more slowly than
normal. At end of full exhalation, abnormally
high amt of air may still linger in lungs
MCCs of obstructive lung disease are: COPD,
which includes Emphysema & chronic
bronchitis
Chronic Bronchitis: persistent cough
w/sputum production for atleast 3 months
in at least 2 consecutive yrs (3/2 rule)
Hyper-secretion of mucus due to chronic injury
(smoking, dust, etc)
Enlargement & increased secretory activity of
mucus secreting glands in trachea & large
bronchi &
Hyperplasia of goblet cells secretions that fill
bronchi & bronchioles, also resulting in
thickening of bronchial walls

Bronchial Asthma:

Obstructive airway disease

Emphysema
Emphysema: abnormal , permanent
enlargement of air spaces distal to
terminal bronchioles with destruction
of their walls
Causes are:
A) Hereditary deficiency of -1
Antitrypsin (major protease inhibitor &
normally inhibits Elastase activity)
B) Tobacco smoking inactivates -1
Antitrypsin. Tobacco smoking also
causes increased release of Elastase
by activating alveolar MOs &
Neutrophils
Pathogenesis: suppression of -1
Antitrypsin activity & increased
Elastase activity which digests Elastic
tissue of lungs. Lung loses elastic
tissue, there is a decreased recoil
force which results in over-distension

Obstructive Airway diseases

Examples are
Emphysema,
Chronic Bronchitis,
Bronchial Asthma

nflammation in red
Mucous becomes hard mucous plugs & thick secretions in ASTHMA!

Restrictive Lung diseases

( Pulmonary Fibrosis,
Interstitial Lung Disease)
Fibrosis, or scarring of lung
tissue, impairs gas exchange
processes
Air sacs, as well as lung tissue
btwn & surrounding air sacs, &
lung capillaries, are destroyed by
formation of scar tissue
Occurs due to Occupational
& enval exposures. Many jobs
esp coal mining or jobs
w/exposure of workers to
asbestos or Silica - can damage
lungs & cause pulmonary fibrosis
Tumors in lung & pleural
effusions also have restrictive
pattern

Restrictive Lung Diseases

(Pulmonary Fibrosis)

2/3 = <80%
obstructive

3/3 = 100%
>80% restrictive
More FVC expired in 1st sec itsel
Hence ratio is increased

FVC and FEV1 in normal subjects and patients with lung disease:

Subjects inspired maximally and then expired forcibly.

A-C, The graphs show the phase of forced expiration.
he total volume that is forcibly expired is called the Forced vital capacity (FVC
The volume expired in the first second is called FEV1

In obstructive lung diseases

( Emphysema, Chronic
Bronchitis & Bronchial
Asthma)
Obstructive ventilatory pattern:
Increased Airway resistance
Decreased expiratory flow rates
FVC reduced
FEV1 reduced more than FVC due
to greater expiratory problem in
pts
FEV1/FVC ratio reduced (<0.8/
80%)
Lungs hyper-inflated (b/c
increased RV & FRC)
Gives rise to Barrel shaped chest

In Restrictive lung diseases

(Pulmonary Fibrosis &
Interstitial Lung Disease)

Restrictive
ventilatory
pattern:
FVC greatly reduced
FEV1 slightly low or
maybe normal b/c no
problem w/expiration
FEV1/FVC Ratio
NORMAL or increased

Flow Volume Loops

Normal pt:

Expiratory Flow volume loops help in

differentiating btwn OBSTRUCTIVE & RESTRICTIVE
lung diseases

In a normal lung, expiration starts at total lung capacity &

continues to residual volume

Comment on
graphs A & B
Gas transport - Oxygen transport
USMLE requires u to know.
Different forms of oxygen in blood
What is hemoglobin?
Oxygen carrying capacity
Hemoglobin-Oxygen dissociation curve
- Significance of sigmoid shape
Factors affecting Hb O2 dissociation
- Shift of curve to R Increased PCO2 / decreased pH, Increased temp & 2,3 DPG/BPG conc.
- Bohr Effect
- Shift of curve to L Decreased PCO2 / increased pH, decreased temp, decreased 2,3 DPG conc.,
Fetal Hb (HbF), CO poisoning
- Effect of Polycythemia & Anemia on dissociation curve Hypoxia & Hypoxemia

O2 Transport

Molecular oxygen in blood is either dissolved in plasma (1.5%) or bound to hemoglobin w/in RBCs
(98.5%)
Dissolved form of Oxygen is responsible for PO2 & diffuses to tissues (not bound O2 to Hb)
Each Hb can bind 4 molecules of O2 & this binding is quite reversible.
Hb containing O2 is Oxyhemoglobin & Hb w/out O2 is Deoxyhemoglobin (reduced Hb).
Each subunit of Hb has heme which contains Iron in Ferrous form which can bind to oxygen
If Fe is in Ferric form (Methemoglobin) Cannot bind to O 2
Normal adult Hb has 22 PP chains. Fetal Hb has 22 PP chains
Oxygen capacity (O2): maximum amt of oxygen that can bind to Hb; measured at 100% saturation;
dependent on [Hb] in blood [Normal Hb] = 15 g/100ml; aka (1) Hb conc (2) saturation of Hb & (3)
PO2; ie. Thus, O2 carrying capacity decreases in Anemia & increases in Polycythemia
1 gm of Hb can bind to 1.34ml of O2. If avg Hemoglobin is 15g/dl (100 mL). Then, O2 binding
capacity of blood = 15 g/100 mL 1.34 mL O2/g hemoglobin = 20.1 mL O2/100 mL blood
Loading & unloading of O2 is given by a simple reversible eqn:
Hb4 + O2 Hb4O2
Hb4O2 + O2 Hb4O4
Hb4O4 + O2 Hb4O6
Hb4O6 + O2 Hb4O8
O2 binding is Positive cooperativity: binding of 1st O2 molecule causes Hb to change its shape,
exposes more binding sites on it, which makes it easier for 2 nd O2 to bind. Binding of 2nd O2 makes it
easier for 3rd & binding of 3rd makes it easier for 4th
When Hb has 4 bound O2 molecules its Saturated. When it has 1,2, or 3 its Unsaturated
Oxygen-Hemoglobin dissociation curve: when saturation of Hb is plotted against PO2
88

Hemoglobin O2 dissociation curve

Hb-O2 dissociation curve is

Sigmoidal. Why?
B/c of +ve cooperativity
(increased affinity of Hb for each
successive O2 molecule)
curve has a Steep part & a Flat
portion. What is the significance
of this?
Flat portion indicates binding of
O2 in lungs & Steep portion
indicates unloading of O2 at
tissues
With reference to the graph
Even if PO2 falls from 100 to 60
mmHg , theres not much
change in % saturation of Hb
This is useful in ppl at high
altitudes
At pressures <60 mmHg, %
saturation of Hb falls rapidly,

75

40

P50 is partial pressure of O2

89
at which hemoglobin
is 50% saturated.

Various values obtained.

At PO2 of 100 mmHg ( e.g., Arterial blood) Hb is 100%
saturated.O2 is bound to all 4 heme groups
At PO2 of 40 mmHg (e.g., mixed Venous blood) Hb is
75% saturated. O2 is bound to 3 heme groups
At PO2 of 25 mmHg Hb is only 50% saturated O2 is
bound to 2 heme molecules
PO2 at 50% saturation is called P50 , Normally its at 25
mmHg
90

Hemoglobin saturation as a function of PO2

in systemic arterial blood and mixed venous blood
91

Factors affecting O2 binding

As cellular metabolism proceeds, CO2, acids, & heat are all

generated Example is during exercise
As Pco2, Plasma [H+], & temp , affinity Hb has for O2 will .
All these factors shift the Hb-O2 dissociation curve to the right.

92

Effect of
temperature

93

13

Bohr Effect
Increased PCO2
Increases H+ - decreases
O2 affinity of Hb ( as H+
has more affinity for
deoxygenated Hb) Releases O2 to tissues &
shifts O2- Hb dissociation
curve to right

94

Graph showing effect of 2,3 DPG

Effect of 2,3 Diphosphoglycerate
( 2,3 DPG)/2,3 BPG
On Oxygen Hb dissociation curve

Decreased 2,3 DPG

Shift to left

2,3 DPG present in RBC binds to chain of deoxy Hb decreasing

Normal

affinity of Hb for O2 - more oxygen is

liberated.
Therefore 2,3 DPG shifts curve to
right (ie. In higher altitudes)
Therefore any factor shifting curve to
right favors release of O2 to tissues
by decreasing saturation of Hb w/O 2

Increased 2,3 DPG

Shift to right

People living at high altitudes show

synthesis of 2,3 DPG Justify this???
At high altitudes there is decreased PO2
As an adaptation to chronic Hypoxemia, there is
synthesis of 2,3 DPG
This 2,3 DPG will bind to Hb, prevent binding of O 2 to Hb
therefore O2 released to tissues

96

Factors shifting O2 Hb dissociation curve

to left
PCO2 , temp, Increased pH ( H+)***,
decreased 2,3 DPG Shift curve to left
Other factors are Fetal Hb
- Carbon Monoxide
Shift of curve to the left indicates less release
of O2 & greater saturation of Hb w/O2

What favors O2 delivery from

mother to the fetus?

Fetal Hb has 22 chains

Due to poor binding of 2,3 DPG to chain

Therefore theres increased affinity of Fetal Hb

for O2 than adult Hb & curve shifts to left

This favors O2 delivery from mother to fetus

In a person w/Carbon Monoxide poisoning there

is severe tissue hypoxia..
Carbon Monoxide (CO) competes for
O2 binding sites on Hb
Affinity of Hb for CO is 250 X more
than its affinity for O2
CO binds to Hb, decreases O2
binding at that site only*
In addition, binding of CO to Hb,
increases affinity of remaining* sites
for O2 (reduced RELEASE of
oxygen), causing shift of curve to L,
thereby decreasing O2 release to
tissues, thus worsening tissue
hypoxia (no hypoxemia!!!)
Carbon monoxide reduces # of sites
available for O2 binding to hemoglobin
99
and causes a shift of O -hemoglobin dissociation curve to left

To summarize
Factors shifting Hb O2
dissociation curve to
right Release O2 to
tissues
PCO2, H+,
temperature, 2,3 DPG

Factors shifting Hb O2
dissociation curve to
left
- Do not release O2 to
tissues
PCO2, H+,
temperature, 2,3 DPG
HbF
CO

100

Efx of Hb concentration on dissociation curve

In Polycythemia
(higher than normal
[Hb] in blood):
Increased O2 carrying
capacity of blood
In Anemia (Reduced
[Hb] in blood):
decreased O2
carrying capacity of
blood
P50 remains same
(~25 mmHg)
20 ml O2 /100 ml of blood

Increased P50

Decreased P50

Hypoxemiais reduced oxygen in arterial blood

Causes for Hypoxemia: High altitudes, theres a decreased
barometric pressure, In Hypoventilation theres decreased
alveolar PO2
Arterial PO2 is decreased in both above conditions

Hypoxia.is reduced O2 supply to the tissues

Causes: Decreased CO resulting in decreased BF
Anemia- decreased [Hb], PO2 maybe normal b/c dissolved form of Oxygen is
not affected
CO poisoning decreases O2 binding capacity of Hb
Cyanide poisoning decreased O2 utilization by tissues
27

Carbon dioxide transport (in dissolved,

carbamino & bicarbonate form)
Forms of CO2 transport Dissolved, Carbamino & Bicarbonate form
Chloride shift In tissues & at lungs
CO2 from tissues carried to lungs via venous blood in 3 forms :
A) Dissolved form ~5%; CO2 is 24X more soluble in blood than O2
Therefore even though PCO2 in blood is 40-46 mmHg, 5% of total CO2 is
carried in dissolved form
B) Carbamino compounds (5%): CO2 reacts w/terminal Amine groups of protein
to form Carbamino compounds Here, protein is Hb, therefore forms
Carbaminohemoglobin
C) Bicarbonate form (HCO3-): 90% of CO2 carried as plasma HCO3- CO2
generated in tissues diffuses freely into venous plasma & then into RBCs

Carbonic Acid Formation

Carbonic acid forms abundantly in RBC when Carbonic
anhydrase (which is absent in plasma) stimulates water to
combine quickly w/carbon dioxide. summarized as follows:

Carbonic anhydrase

CO2 + H2 0

Unit 1 - Objective 6

H2 CO3

105

Bicarbonate Ion Formation

Bicarbonate ion also forms abundantly in RBC where
carbonic acid breaks down to release a hydrogen ion &
bicarbonate; summarized as follows:

H2 CO3

H+ + HCO3_

32

Chloride Shift in Tissue Capillaries

Tissue Capillary

When RBCs move thru tissue capillaries, they take in carbon dioxide & release bicarbonate. As bicarbonate is
released, chloride
shifts into
107 charge balance in RBC.
Unit 1 (-1)
- Objective
4 RBC to replace ve bicarbonate (-1). This preserves

Overall reaction..

108

Chloride Shift in Pulmonary Capillaries In lungs reverse rxns occur

When RBCs move thru pulmonary capillaries (in lungs), they take in bicarbonate & release carbon dioxide.
As bicarbonate (-1) shifts into RBC, chloride (-1) shifts out of RBC. This also preserves charge balance in
RBC

Pulmonary Capillary

Unit 1 - Objective5

109

38

In the case of Carbon- monoxide

poisoning, P50 is:
1.
2.
3.
4.
5.

Increased & Hb has lesser

affinity for O2
Increased and Hb has greater
affinity for O2
Decreased and Hb has
greater affinity for O2
Decreased and Hb has lesser
affinity for O2
Remains normal and Hb has
lesser affinity for O2

110

Normally, as the alveolar PO2 is increased from

110 to 950 mmHg, the amount of oxygen:
1. Dissolved in plasma increases, amount associated with
Hb remains almost constant
2. Dissolved in plasma increases, amount associated with
Hb decreases
3. Dissolved in plasma remains constant, amount
associated with Hb increases
4. Dissolved in plasma remains constant, amount
associated with Hb remains constant

111

Which compartment normally has the

highest O2 partial pressure?
1. Alveolar gas
2. Arterial blood
3. The first 25% of inspired
air after it enters the
mouth /nose
4. The last 25% of inspired
air after it enters the
mouth /nose
5. Mixed expired gas

112

Shunts
Shunt: portion of CO that takes diverted route in
circulation
This portion may not follow normal routine
routes of circulation
This portion may or may not take pt in gas
exchange
Types of Shunts:
Physiologic- present in all normal individuals
Pathologic- present in disease states

113

Physiologic
= amt systemic blood
that directly enters L side of heart w/out undergoing gaseous
shunt
exchange

Consists of bronchial circulation & pt of coronary circulation

Constitutes 2% of CO

This blood dilutes oxygenated blood returning to L heart (there is admixture of

oxygenated & deoxygenated blood)

Therefore, Systemic arterial PO2 is 5 mmHg less than Alveolar PO2 & Hb saturation is
0.5% less

114

Pathologic shunts
Occur in disease states
Are of 3 types:
Left-to-right shunt (less dangerous)
Right-to-left shunt (dangerous)
Shunt due to respiratory diseases (dangerous)

Systemic venous
40 mmHg

Pulmonary venous
100 mmHg

Right Atrium
(PO2 in mmHg)
40

Left Atrium
(PO2 in mmHg)
100

Right Ventricle
(PO2 in mmHg)

Left Ventricle
(PO2 in mmHg)

40

100

Pulmonary arterial
40 mmHg

Systemic arterial
100 mmHg
116

Left-to-right shunts

Blood flowing directly from left side to right side

of heart
Examples: VSD, ASD
There is additional (oxygenated) blood going to
pulmonary circulation
There is no hypoxia w/normal lungs
PaO2 is normal, (A-a) gradient is normal
Note: (A-a)= alveolar & arterial PO2 difference
which is normally ~5 mmHg
117

118

Right-to-left shunts
Blood flowing directly from right side to left side
of heart without being circulated to lungs
Examples: Pulmonary Stenosis, Fallot tetralogy
Since blood does not go to lungs, no
oxygenation
Hypoxia is always the feature
PaO2 is always low, widening of (A-a) gradient
PaO2 will not improve by breathing 100% oxygen

119

Shunt due to respiratory diseases

Occurs when parts of lung do not have
ventilation
Eg: Complete or partial airway
obstruction
Since blood flow is normal,
ventilation is poor, no gas
exchange takes place
Leads to ventilation-perfusion
mismatch
120

Factors affecting pulmonary blood flow are - Hypoxia,

Pulmonary vascular resistance & Gravity

A) Hypoxia one of main factors affecting pulmonary blood flow

In lungs, for ex. if a bronchus/bronchiole is obstructed leads to
hypoxia b/c of under ventilation of alveoli hypoxia causes local
vasoconstriction redirects blood from poorly ventilated, hypoxic
regions of lungs twds well ventilated regions. It is an adaptive
mechanism

B) Effect of Pulmonary vascular resistance:

Constriction of pulmonary blood vessels, increases pulmonary
vascular resistance, increases work load on R side of heart &
constriction of pulmonary v, increases pulmonary capillary pressure

121

What happens in the fetus???

122

Fetal pulmonary vascular resistance is very high.

Why??
Fetus is subjected to hypoxic conditions in mothers
womb (in utero).
Fetal lungs are without air & no PAO2
This causes generalized hypoxic vasoconstriction
This causes increased pulmonary vascular resistance
in the fetus. Therefore BF thru fetal lungs is very low

123

What happens with the first cry of the

newborn ??
First cry of a newly born
baby opens up lung
& alveoli
Alveoli of neonate
are oxygenated
Pulmonary vascular
resistance decreases
Pulmonary blood flow
increases
124

Factors affecting pulmonary blood flow.

C) Effect of gravity:

Pulmonary Blood flow depends on posture

It is Uniform in supine posture, Uneven in upright/standing due to

effect of gravity on pulmonary arterial pressure

Accordingly, lungs are divided into: Zone1, Zone2, Zone3

In upright position, upper part of lung (Apex) is above the level of

the heart, lower part of the lung (Base) lies below heart

Less blood flow in apex of lung as it is against gravity & there

is increased pulmonary vascular resistance at apex of lungs

Greater blood flow towards base of the lung, as it is towards

gravity & there is decreased pulmonary vascular resistance

126

Blood flow is against gravity & increased

Pulmonary vascular Resistance

Zone 1
127

Zone 2
128

Flow is towards gravity & decreased

Pulmonary Vascular resistance

Zone 3
129

In upright position, ventilation per unit lung volume

is greater at base than at apex. why???
This is b/c, Intra-pleural pressure
is less ve at base
( -2.5 cm H2O) than apex. Hence
there is a smaller expanding force
on alveoli at base. Alveoli at base
are small & more compliant
Intrapulmonary Intrapleural
pressure difference is less at the
base. Therefore the lung is less
expanded
Due to all these factors, during
inspiration, alveoli at base have
greater tendency to expand, thereby
increasing ventilation
130

ventilation

131

At the apex of the lung..

Intrapleural pressure is more ve at apex (- 10 cm H2O)
Hence there is a large expanding force on alveoli
Alveoli at apex are large & contain more air
Intrapulmonary-Intrapleural difference is more. Therefore
lung & alveoli are more expanded at apex
Due to all these factors, during inspiration, alveoli at
apex are already expanded & have lesser tendency to
expand. Therefore ventilation at apex is lesser compared
to the base of the lung

132

Differences in ventilation & blood flow

(perfusion) in different parts of the lungs.

133

Ventilation Perfusion ratio ( V/Q)

ratio of alveolar ventilation (V) to pulmonary blood flow (Q)
Indicates effectiveness of O2 & CO2 exchange
In a normal individual, under resting conditions V/Q ratio is
approximately 0.8 ( 4/5=0.8)
This V/Q ratio ( 0.8) results in, Arterial PO2 = 100 mmHg
Arterial PCO2= 40 mmHg
pH = 7.4
If V/Q < 0.8 under ventilation,PaCO2, PaO2, pH
If V/Q > 0.8 over ventilation,PaCO2, PaO2, pH

V/Q ratios in different parts of the lung

At apex of lung, both ventilation & perfusion are less, but
blood flow is much lesser compared to the ventilation. So
ventilation is in excess of blood flow (Over-ventilation)
Greater V/Q ratio at the apex, PO2 is highest & PCO2 is
lowest at the apex due to over-ventilation
At the base of the lung, there is increased ventilation &
blood flow. But blood flow is much greater than
ventilation & ventilation is not adequate (Underventilation)
Lower V/Q ratio at the base of the lung. PO2 is lowest,
PCO2 is highest.

135

136

27

Blood flow is against gravity & increased

Pulmonary vascular Resistance

Zone 1
137

Zone 2
138

Flow is towards gravity & decreased

Pulmonary Vascular resistance

Zone 3
139

Why is Tuberculosis cavity more often seen

at the apex of the lungs???
Tubercle
Bacilli is an
Aerobic
Organism.
As Apex of Lung is
over-ventilated,
it favors growth of
organisms

140

Clinical implications of V/Q ratio

A) In Airway obstruction: If airways completely blocked,
ventilation is Zero
Perfusion is normal, V/Q = Zero
Represents Shunt blood is not
getting oxygenated
No gas exchange in a lung that is
perfused, but not ventilated
PO2 (40mmHg)& PCO2(47 mmHg)
is that of mixed venous blood
Alveolar-arterial (A-a) gradient
This condition also seen in
Foreign body in trachea
collapse of lungs
141

B) V/Q in Pulmonary Embolism

BF to lungs completely blocked by

embolus occluding Pulm a
BF to lungs is 0
Ventilation is normal
V/Q is Infinite Represents Dead
Space air present is not undergoing
gas exchange
no gas exchange in lung which is
ventilated, but not perfused
PO2 (150mmHg), PCO2 (0mmHg) is
equal to that of inspired air

When V & Q
Are matching

When
V<Q

When
Q<V

143

What is Decompression Sickness?

When a diver breathing 80% Nitrogen ascends from dive, alveolar PN 2 falls.
N2 diffuses from tissues into lungs
If he ascends rapidly N2 escapes from soln & forms bubbles in tissues &
blood leading to Decompression sickness / Bends / Caissons Disease
N2 bubbles in:
pulmonary capillaries leads to Dyspnea
Coronary arteries causes Myocardial infarction
Around jts causes severe jt pains (known as Bends)
In blood vessels of brain & spinal cord are fatal - may lead to death

144

Integrated responses of respiratory

system
A)

During Exercise : Increased ventilatory rate

Increased O2 consumption & CO2 production in body

Capillary dilatation & increase in # of active capillaries

During exercise, jt & m receptors are activated, this stimulates

breathing, thereby increasing respiratory rate

Arterial PO2 & PCO2 does not change

Arterial pH does not change in moderate exercise, but decreases

in strenuous exercise (b/c of lactic acid accumulation)

) Venous PCO2 increases due to excess CO 2 produced by exercising

ms which are carried to lungs in venous blood
) Increased CO causes increased Pulmonary BF
) Increased V/Q ratio
145

Adaptation to high altitude (Acclimatization)

146

During Acclimatization Changes

aka Physiological changes when ind ascends high altitudes
Acute Changes:
Alveolar PO2 decreases at high altitudes
Arterial PO2 also decreases (Hypoxemia)
Hypoxemia stimulates peripheral chemoreceptors, which further stimulate Respiratory
centers & cause increased ventilation (Hyperventilation)
Hyperventilation leads to decreased PCO 2 causing Respiratory Alkalosis
Chronic Changes:
Increased 2,3 DPG conc., shifts Hb- dissociation curve to right decreases affinity of Hb
for O2- facilitates release of oxygen to tissues
Hypoxemia stimulates renal production of Erythropoietin which increases RBC production
(Polycythemia) & increases Hematocrit value, increases [Hb], increases O2 carrying
capacity & total O2 content of blood, increased capillary density, increased mitochondria
Hypoxia causes pulmonary vasoconstriction- increases pulmonary vascular resistance
increases work load on right side of heart as they have to pump against higher resistance
leads to Rt. Ventricular hypertrophy
147

What is to be remembered in Regulation of Respiration??

Central control Medullary centres DRG,VRG
Chemoreceptor control Central & Peripheral chemoreceptors,
their location, Stimuli to which they respond
Lung stretch receptors (Hering Breuer Reflex)
Breath holding
Yawning
Medullary respiratory centers
DRG (Dorsal Respiratory Group/Inspiratory center) - sends
impulses to diaphragm
Acts both in quiet & forceful inspiration- D for Diaphragm
VRG (Ventral Respiratory Group/Expiratory center) - sends
impulses to accessory respiratory ms
Acts only in forceful respiration (both forceful inspiration &
148
expiration)

149

B) Control of respiration via

Chemoreceptors
Chemoreceptors are the receptors which respond to
chemical changes in the body
They respond to pH, PCO2 & PO2 changes in the body
Based on their location, they can be classified as:
- Central Chemoreceptors
- Peripheral Chemoreceptors

150

Central Chemoreceptors
Are located on the surface of Medulla
Main stimulus for these receptors are:
CSF [H+] & CO2
Blood Brain Barrier (BBB) is freely permeable to CO 2 as
it is lipid soluble. Arterial [H+] passes very slowly across
the BBB which is considered negligible. Therefore
central chemoreceptors are not sensitive to arterial
[H+]
CO2 diffuses across BBB, enters the CSF,CO 2+H2O
forms H+ + HCO3- .This is the source of [H +] in CSF
There are no central chemoreceptors for changes in
PO2
Increased PCO2 & [H+] in CSF, stimulate central
Chemoreceptors, which in turn stimulate respiratory
centers, produces an increase in breathing rate
Hyperventilation CO2 is washed out & PCO2 comes
back to normal
151

Peripheral Chemoreceptors

Based on their location, theres 2 types:

A) Carotid Bodies located at the bifurcation
of Common Carotid a. Carry afferents to
CNS via Glossopharyngeal (IX cranial)
nerve
B) Aortic Bodies located above & below the
aortic arch. Carry afferents to CNS via the
Vagus (X cranial) nerve
) Most imp stimulus is decrease in arterial PO2
) PO2 must fall below 60mmHg for peripheral
chemoreceptors to stimulate breathing
) When PO2 decreases, Peripheral
Chemoreceptors are stimulated, which in turn
stimulate Respiratory centers, causing
increase in respiration & increase PO2 back to
normal.
) Increase in arterial PCO2 can also (+)
peripheral chemoreceptors, but resp is less
effective compared to central
Chemoreceptors
) Increased arterial [H+] also stimulates the
carotid body peripheral chemoreceptor

152

Why is there hyperventilation in Metabolic

acidosis?
This is because, in metabolic acidosis, for ex. in DKA,
increased arterial [H+], stimulates carotid body peripheral
chemoreceptor, which in turn causes increased
breathing & hyperventilation

153

Response to increased plasma PCO2

154

Comparison between Central & Peripheral

chemoreceptors
Central chemoreceptors
Location Medulla
Stimuli - CSF [H+],
PCO2
Long acting & more
effective in controlling

Peripheral chemoreceptors
Location Carotid &
Aortic bodies
Stimuli - PO2 - less than
60mmHg (main stimulus)
PCO2, pH

alveolar ventilation
155

Other types of receptors for control of

breathing
Lung stretch receptors: Hering Breuer Reflex

Located in smooth muscles of airways

Distension of lungs stimulates lung stretch receptors

which inhibit Inspiratory centers & they produce reflex
decrease in inspiration

Clinical significance of this is,

- Limits degree of inspiration, thereby preventing
overinflation of lungs
- esp useful in Infants & during exercise, when theres
an increase in tidal volume

156

Try to do this..

How long can u hold your breath?

Time duration for which a person can hold his/her breath is called
Breath Holding Time

Point at which a person can no longer hold the breath is called

Breaking Point. This occurs because of increased PCO2 &
decreased PO2 , which stimulate chemoreceptors & bring about
respiration

CO2 retention causes cerebrovascular dilatation & may cause

dizziness (light headedness) - CO2 is a cerebral vasodilator &
increases cerebral blood flow & decreases cerebral vascular
resistance
157

Joint & muscle receptors

During exercise, one notices an increase in breathing rate.
Why???
During exercise, the joint & muscle receptors are
activated during movement of the limbs
These receptors cause stimulation of respiratory centre

What is yawning?????
Yawning occurs due to an increased CO2 & decreased
O2 which leads to underventilation. Increased CO2
stimulates Central Chemoreceptors
It causes a deep inspiration & increased intake of air
158

SV X HR = CO (amt of blood ejected out of each ventricle /min!

Organization of cardiovascular system

oxygenated
Resistance kills
pressure; so RA
pressure is 0 mm Hg
At lvl of capillaries, oxygen diffuses from alveoli into capillary, where CO2 is
eliminated from atmosphere; blood becomes oxygenated

5 mm Hg

MV/BICUSPID
LV pressure <L

Pulmonary circulation

AV opens when
LVP > AP

Opens via RV pressure goes above> pulmonary a

At 15 mm Hg

Mean/avg arterial pressure in

aorta during cardiac cycle is
100 mm Hg

Systemic circulation carrying

oxygenated blood to tissues,
that extract O2 & return it as
deoxygenated via SVC & IVC
(which eventually drain into R
side of <3)

Systemic vs carry deoxygenated blood

Pulmonary circuit (5l/min)

15 mm Hg

5 mm Hg

Right heart

Left heart

0 mmHg

100 mm Hg

Systemic circuit (5 l/min)

Organization of cardiovascular system

Organization of cardiovascular system

Consists of
2 pumps (L & R ventricles)
2 circuits (systemic & pulmonary)
Connected in series thus blood flow equal in both circuits
Pressure & resistance are diff
Composition of:
Systemic arterial blood (sampled here)= Pulm. venous blood
Syst. mixed venous blood=Pulm. art. blood

When the two circulations have the

same flow (5 L/min), what causes the
pressure differences in them?
systemic circulation has greater resistance than pulmonary
circulation. Therefore as per eqn, pressure difference in
systemic circulation is greater.
Pressure gradient (S)
Flow= -------------------------Resistance (S)
Pressure gradient (P)
Flow= -------------------------Resistance (P)

Pathway of blood circulation

in CVS

Lower
body

Pulmonary circulation

Systemic circulation

Pressures in the Pul. Circulation

Pressures in the Sys.Circulation

R.Ventricle

25/0 mmHg

L.Ventricle 120/0 mmHg

Pul. Artery

25/8 mmHg

Aorta 120/80 mmHg

Mean Pul. Artery 15 mmHg

Mean arterial
Blood pressure

Capillary

Capillary: skeletal 30 mmHg (lower b/c all these

vessels offer resistance)
Renal Glomerular 50 mmHg (btwn afferent &
efferent as; higher due to arterioles on each side,
this is to favor filtration)

Pul . Venous
Left Atrium

7-9 mmHg

5 mmHg
5 - 10 mmHg

~100 (93) mmHg

Peripheral Veins 15 mmHg

Right Atrium 0 mmHg

Pressure gradient 15 5= 10 mmHg Pressure gradient 93-0= 93 mmHg

Tabulate 3 differences betn. 2 circuln.

Higher pressure
Higher resistance
Higher capillary
pressure (30)

Lower pressure
Lower resistance
Lower capillary
pressure (8)

ALL IN SYSTEMIC
C.

ALL IN
PULMONARY C.

Arteries
Include large, medium & small as
Contain large amt of elastic tissue hence have wonderful property of
recoil when stretched
When blood flows into these vessels, theyre stretched & undergo
recoiling that compresses blood in their lumen (putting this blood
under high pressure)
Hence BV contained in these as is stressed blood volume (vs.
unstress blood volume in vs)
Elastic recoil helps in 2 ways:
1. helps to maintain high pressure in as
2. helps to maintain flow of blood in vessels even when <3 is relaxing
(during ventricular diastole)

Arterioles (Most resistant vessels!)

Arteries continue as arterioles: vessels w/thick layer of circular smooth ms

Contraction of smooth ms cause decrease in dm of lumen (vasoconstriction)
Highest resistance for blood flow in entire CVS (highest/most resistant vessels)
smooth ms innervated by postganglionic symp ns (NE to -1 receptors, not -2)
At rest, few impulses travel thru these ns & keep smooth ms partially contracted
If symp ns stimulated, large # of impulses travels thru these ns & stimulates smooth
ms to contract strongly & result in intense vasoconstriction
Vasoconstriction raises resistance to blood flow in CVS (thus dm, r, blood flow)
If symp ns inhibited, no impulse travels thru these ns & thus, smooth ms undergo
relaxation, resulting in vasodilatation
Low lvls of NE & E from adrenal medulla bind to -2 adrenergic receptors in
arterioles of skeletal m, when activated cause vasodilation
Vasodilatation reduces resistance to blood flow in CVS (thus dm, r, blood flow)
Thus, site of highest resistance in vasculature & also site where resistance can be
changed by altering symp n activity, by circulating catecholamines & by other
vasoactive substances ie. Angiotensin II, NO, Vasopressin

Capillaries aka Exchange

Vessels:
Thin vessels as single layer of endothelial cells resting on
basement memb
Capillary wall is permeable to almost all substances in plasma
except plasma proteins
site where fluid moves in & out btwn blood & tissue space in organ
Along w/fluid, smaller substances such as glucose, AAs,
electrolytes, metabolic wastes also move btwn plasma & interstitial
space in organ
Therefore, capillaries called, exchange vessels
Ie. 3 layers of epithelial cells in glomerular capillaries that have
long processes of podocytes

Venous Compartment/System:
Venules & vs aka capacitance/highest
COMPLIANT vessels!

venules & vs make venous system

Venules = thin-walled vessels
walls of vs are thin-walled having large inner dm (lumen) & contain
modest/less smooth m & less elastic tissue in their walls compared to as
major charac feature of venous system: large capacity to hold blood w/low
pressure hence, blood contained in vs called unstressed blood
volume
Vs also called, capacitance vessels due to their high capacity to store
blood in CVS. At rest, ~70% of total BV present in venous system alone.
smooth ms lining walls of vs also innervated by postganglionic symp ns
Stimulation of symp ns causes narrowing of their lumen & decreases their
capacity to hold blood that in turn improves/increases venous blood return to
<3
In addition, larger vs have valves that help blood flow twds <3
Carry back deoxygenated blood to <3 & can store some blood

Organization of the systemic

vessels
85% goes back to circulation thru here
Remaining 15% is taken back thru lymphatics

Atrium

Continue to form vs

Pressure profile in systemic

circuit
Pressure drop along circuit from aorta to R
atrium
Pressure dissipates to overcome resistance
Pressure drop proportional to resistance of that
segment
Small pressure drop in major as
LARGEST pressure DROP across ARTERIOLES
Small drop in major vs

Pressure profile along systemic circulation

Aorta &
Arterioles
Arteries

Capilry

120

80

Venous
Right
comprtmnt heart

Systolic diastolic pressure = PULSE PRESSURE (PP)

When increases = widening of PP

40

= (avg pressure during cardiac cycle) often closer to

diastolic pressure ~80 mm Hg b/c spend more time
relaxing vs contracting

CIRCUIT
120 80
120 0
Greatest pressure loss b/c
offer greater resistance

Cross-Sectional Area (CSA) in circuit:

Aorta w/largest dm has smallest CSA

As aorta brs, CSA of ind vessels decreases; but collective CSA increases
Max. CSA in highly brd capillaries
CSA decreases thru venous system

From L R CSA increases

Aka Aorta to Capillaries

AORTA
(least CSA)

VEINS
Arteries
Capillaries
(highest/max CSA)

Identify the region of the circuit with LEAST & HIGHEST CSA

CSA

CIRCUIT

Velocity of blood flow (v):

Velocity: distance fluid travels in unit time in cm/sec or cm/min
velocity of blood flow: blood flows w/certain speed in diff
blood vessels
velocity of blood flow is reld to quantity of blood flowing in that
blood vessel per unit time & area of cross section of that blood
vessel. Relnship is mathematically shown as formula:
Velocity (V) = Q/A;
Where,
Q= Flow rate (in mL/sec or mL/min)
A= Total cross-sectional area of blood vessel (in cm 2)
Velocity is inversely proportional to CSA; thus, greatest in Aorta;
Least in capillaries & increases along venous system
Low velocity in capillaries favors continuous & effective
exchange of dissolve substances b/w plasma & tissues
(nutritional flow)

Identify the region of the circuit with LEAST & HIGHEST

Velocity of blood flow

velocity

CIRCUIT

Biophysics of haemodynamics
Poiseuille eqn describes relnship btwn
FLOW (Q)
PRESSURE GRADIENT (P1-P2)
RESISTANCE (R)
P1- P2
Q= ---------P2
P1
R

FL

RESISTANCE

Determinants of resistance
Radius of blood vessel (r); only changing 1 to
be able to change resistance & thus blood
flow
Length of blood vessel (L)
Viscosity of blood () = internal resistance of
blood to flow (aka hematocrit)
8L
R= -------r4

1. Radius of blood vessel

Resistance inversely proportional to 4th power of radius
Small changes in radius cause large changes in resistance
Most imp factor regulating resistance & blood flow in body
If radius is decreased by half, resistance increases 16 fold thus
flow decreased by 16 folds
If radius double, resistance decreases to 1/16 of original thus flow
increased by 16 fold
Radius altered by many neurohumoral factors
Vasodilatation (radius double) causing blood flow to
increase 16 X.
Therefore, radius of blood vessels is single most imp factor
in determining vascular resistance as well as blood flow in
cardiovascular system.
small change in r makes sig change in resistance & blood flow

2. Vessel length
Greater length = greater resistance
If length doubles, resistance doubles.
If length decreases by half, resistance decreases by
half
Mostly constant; not physioal factor reging resistance
& flow
Long blood vessels seen in kidney (Vasa recta) have
high resistance & sluggish blood flow

3. Viscosity of blood

measure of internal resistance to flow

Greater viscosity = greater resistance
Primary determinant of viscosity is hematocrit
Severe anemia (low hematocrit) causes
decreased vascular resistance & increased blood
flow (High cardiac output)
Polycythemia seen in ppl w/chronic hypoxia, COPD,
smokers increased RBCs by bone marrow
higher viscosity higher resistance reduced flow

Laminar v/s Turbulent blood

flow

Laminar

Turbulent

Probability of turbulence
Reynolds number gives probability of
turbulence in blood vessels
(diameter) (velocity) (density)
R # = -----------------------------------------Viscosity
Greater R# = greater probability of turbulence
R >2000 = Turbulent flow
R <2000 = Laminar flow

Normal blood flow is

laminar
Turbulent flow is likely to occur when
velocity of flow is very high
viscosity of blood is very low (ex: severe anemia)
Following may also promote turbulence
Vessel branching
Narrow orifice (severe stenosis) due to increased
velocity
Turbulent flow causes sounds
ex: flow murmurs in severe anemia, Korotkoffs sounds,
murmurs in valvular stenosis/regurgitation & Bruit in
carotid a. (or femoral a)

Series & parallel circuits:

Dependent flow = hence same

Independent flow = hence

diff in each vessel

Vascular resistances are also arranged in series &

parallel manner in our body

Vascular resistances in series

RTotal = R1 + R2 + R3 + R4 + R5

A major feature: flow must be equal at

all points in a series system
If flow changes it changes equally at
all points in a series system

Vascular resistances in series

In any organ, diff types of blood vessels are connected in
series btwn feeding a & draining v

total vascular resistance (Rtotal) is sum of ind

resistances:

RTotal = R1 + R2 + R3 + R4 + R5
Total is always greater than of ind resistances.
-Adding resistor in series increases resistance of system
-Connecting resistors in series results in high-resistance system
Since flow is same through all resistances, greatest fall in pressure
occurs in arterioles which offer max resistance

What would happen to the pressure if the arteriolar

resistance is suddenly increased by constriction of the
vessel?

Pressure downstream decreases

P1

P2

P1

P2

pressure upstream in as
increases (b4 area of
vasoconstriction)

Flow decreases at capillary lvl, more

resistance, pressure in capillaries
decreases (goes below 30 mm Hg)

P=120

P=0
R1

R2

R3

In the above circuit, if Pin & Pout are kept constant, & if
R2 increases,
What would happen to the Flow through the
series system?
Decreases equally at all points
If the flow is kept constant what would happen to
Pressure immediately downstream from R2 ?
decrease
Pressure immediately upstream from R 2 ?
increase

P=120

P=0
R1

R2

R3

In the above circuit, if Pin & Pout are kept constant, & if R2 decreases,
What would happen to the Flow through the
series system? Less resistance & more flow downstream
Increase equally at all points
If the flow is kept constant what would happen to
Pressure immediately downstream from R2 ?
increases
Pressure immediately upstream from R2 ?
decreases

Flow through a single nephron

AA (100 mmHg, offers resistance,

decreasing following pressure) GC (50
mmHg; filtration) EA PTC (8 mmHg;
reabsorption/reclaiming back from blood
vessels)
If AA further CONSTRICTED, resistance
increases, decreasing GC pressure further
& its filtration abilities & decreasing PTC
pressure & reabsorption abilities; same
vice versa if AA dilated.
If EA CONSTRICTED, everything after it
will have DECREASED pressure, but
everything before it will have INCREASED
pressure so blood flow thru nephron will
DECREASE (as total resistance still
increases), filtration & reabsorption will
INCREASE
All connected in series, so blood flow thru
nephron decreases

Problem:
The blood flow to an organ = 500 ml/min
The pressure difference between the feeding artery and
draining vein = 100 mm Hg
The resistance of arteries R1 = 0.05 mm Hg/ml/min
The resistance of capillaries R3 = 0.03 mm Hg/ml/min
The resistance of veins R4= 0.02 mm Hg/ml/min
What is the resistance offered by the arterioles in the
organ?
Solution:
Total resistance = R1+R2+R3+R4
P
100
Total resistance = ------- = ------- = 0.20 mm Hg/ml/min
Q
500
R2 = 0.20 (0.05+0.03+0.02) = 0.10 mm Hg/ml/min

Vascular resistances in PARALLEL CIRCUIT:

Total vascular resistance (Rtotal) is calculated by:

If resistances are connected in parallel, reciprocal of total

resistance is sum of reciprocals of ind resistance.
total resistance is always LESS than any of ind resistances
ADDING another resistance DECREASES total resistance in
circuit
By ADDING resistor to parallel system, total RESISTANCE
DECREASES; VS. REMOVING resister, INCREASES
resistance!

Vascular resistances in parallel

Addition of parallel circuits (obesity) decrease total peripheral resistance

(Flow) ? (CO)? (BP)?
Increased, increased, INCREASED.
Hypertension
Addition of placenta (??? TPR, FLOW, PRESSURE)
Increased, increased, INCRE
Removal of placenta (? TPR, FLOW, PRESSURE)
increased RESISTANCE, decrease flow, CO & BP
Removal of a kidney (? TPR, FLOW, PRESSURE)
increased RESISTANCE, decrease FLOW, CO & BP
Removal of a limb (? TPR, FLOW, PRESSURE)
Increased RESISTANCE, decrease FLOW, CO & BP
Total resistance in parallel system (systemic) = Total peripheral resistance

Independent BF reg

P1

P2

If one of the resistances (R2) changes, What would happen

to the flow in the remaining parallel circuits?

NO CHANGE
In parallel circuits, flow can be independently
regulated by changing ind resistances
OVERALL FLOW? ONLY THIS CHANGES

Vascular resistances are arranged in both

series and parallel pattern
BRAIN

HEART
SERIES

PARALLEL
SKIN

Problem:
R=1

R=2

R=3
In the above diagram, the blood flow in the three organs arranged in
parallel are indicated. What could be the total resistance in these vascular
beds?
A. 9
B. 6/11
Solution:
C. 11/6
1/RTot = 1+1/2+1/3 = 11/6
D. 3
RTot = 6/11
E. 6

Problem- Two organs, 1 & 2 are connected in parallel,

each receiving a flow of 300 mL/min & 450 mL/min
respectively. The input pressure is 100 mm Hg & the
outflow pressure is 10 mm Hg. Calculate the resistances of
organ 1 & 2.

organ 1 (300ml/min)

100 mmHg
10mmHg
organ 2 (450ml/min)

Solution:

Pressure gradient
Flow in organ 1= 300= ------------------------- =
Resistance

100 10
------------R

R= 90/300 = 0.3 mm Hg/ml/min

Pressure gradient
Flow in organ 2= 450 = ------------------------- =
Resistance

100 10
------------R

R= 90/450 = 0.2 mm Hg/ml/min

Organ 1 offers a higher resistance & gets less blood supply than
organ 2, even though the pressure gradient for both the organs is
the same.

Laplace law
Relates
Internal pressure (P)
Wall tension (T) = force trying to break open vessel wall
Radius (r)
Applicable to a hollow viscus/blood vessel

T=P r
Can be applied to ventricular organ
as well
Complication of hypertension in
aneurysm; most likely seen in
vessel w/greatest radius AORTA
; aneurysms fate is to rupture
eventually due to wall tension

Clinical application of Laplace

law
Aortic aneurysm (Dilated portion of aorta)- Dilated portion
has greater wall tension; likely to burst w/further increase
in radius
Dilated <3 (ex: in HF)- Places greater tension on failing
heart since chamber is dilated & has ^radius, further
reducing performance

b/c decreases FOC in dilated chamber (greater

length of sarcomere FOC decreases b/c # of
cross-bridges can cycle); more preload, more
distension, more strength but to further point aka
beyond optimal length FOC decreases

Vessel compliance
Compliance is change in volume per unit
over change in pressure = how easily you
can stretch a vessel
V
Compliance = -------P
Veins are most compliant vessels, containing large
% of blood volume w/small changes in pressure
Noncompliant = stiff vessels

4 Characs of systemic veins:

Highly compliant (20 X more compliant than systemic
as)
Hold large volume of blood (70% of systemic BV)
Small change in pressure
large change in volume
Larger vs innervated by symp ns that change
venomotor tone by altering dm, leading to reduction
in stored BV
Symp stimulation decreases v compliance thus
reducing stored amt of blood increasing venous return
to <3

Clinical application
In hemorrhage, decreased venous pressure
body reacts by.
causes sig constriction of vs leading to decreased
stored BV (Due to decreased compliance). This
volume of blood contributes to circulating BV.

Associated symp venoconstriction adds to

above effect.

3 Characs of systemic
Arteries:
1. Less compliant vessels; show pressure
fluctuations during cycle of cardiac activity
1. Compliance decreases as you go distally from
1. Aorta Femoral a Popliteal a Dorsalis pedis a;
WHY? b/c amt of smooth m INCREASES

2. Pressure rises to max. of 120 mm Hg (Systolic

pressure) & falls to min of 80 mm Hg (Diastolic
pressure); difference is Pulse pressure
3. Mean arterial pressure (MAP) is pressure avgd
during cycle of cardiac activity

Arterial Pressure (Pressure pulse)

in systemic circulation

Arterial pressure (mm Hg)

Pulse pressure (PP)

Systolic pressure (SP)

Mean arterial pressure(MAP) =

Diastolic pressure (DP)

Pulse pressure = Systolic pr Diastolic pr

Mean arterial pressure = Diastolic pr + 1/3 Pulse pressure

Factors affecting SBP & DBP:

Systolic pressure determined by:
Stroke volume of <3 (amt of blood
ejected out each ventricle w/each
systole); thus SV = SYSTOLIC PR

Ie. Hyperthyroidism b/c FOC due to more

b1 stimulation (sensitivty of their receptors
increases too) so get high systolic pr)
Also increased by increased BV
Ie. Hypovolemia losing BV decreases
SV decreases FOC present
w/hypotension due to reduced SV
Aortic regurgitation: SV increases
Aortic stenosis: SV decreases

Arterial compliance; reduced

increases

Diastolic pressure determined by:

Peripheral resistance: increases
DIASTOLIC pr
Stroke volume increases DIASTOLIC pr
Arterial compliance reduced
decreases DIASTOLIC pr

Arteriosclerosis: when elastic tissue in as

decrease & become fibrosed, arterial
compliance decreases if aorta stiffens,
cannot expand; when ventricle ejects blood
w/pressure, lumen of aorta may not be able
to accommodate all that blood, so its systolic
pr in aorta will increase

What factors affect Pulse pressure? Following will increase (widen) PP

Stoke volume of heart

Arterial compliance

Pressure pulse for Aorta & Femoral artery

AORTA
More compliant

FEMORAL ARTERY
Stiff & less compliant; large PP

Which of the above is the compliant

vessel & which is the stiffer one?

Answer
Aorta is more compliant artery than
femoral artery b/c peripheral as are more
muscular & less compliant.
compliant artery has a small pulse
pressure
femoral artery is stiff & less compliant &
has a large pulse pressure

Arterial pulse in health & diseases:

Normal

Patient with
arteriosclerosis

Arteries are
stiff and less
Compliant
= increased PP!

Patient with
aortic stenosis

Stroke volume
Is less
= decreased SBP
= decreased PP!

b/c aortic valve is acting as

So pressure & flow decrea

Factors affecting Mean Arterial pressure:

You have to now recollect the Poisseulles eqn as
applicable to systemic circulation
P1- P2
Q= ---------R

In systemic circulation,
P1 is mean arterial pressure, (beginning of systemic circulation)
P2 pressure at entrance of R atrium, (~0); Q is cardiac output;
R is total peripheral resistance
Poiseuille equation can be rewritten as
Mean arterial pressure (MAP)
(CO) Cardiac output = ---------------------------------------------Total peripheral resistance (TPR)

Effect of gravity on
circulation
When a person goes from supine to upright posture,
Pressure in dependent vs increases
Blood volume in dependent vs increases (vs are
very compliant)
Cardiac output decreases
MAP decreases
Gravity decreases VR

Do we have mechanisms to
overcome the efx of gravity?
Answer is YES
Immediate neural reflex (Baroreceptor
reflex) mechanism returns MAP to near
normal
HR Increases
TPR increases

Venous
pressure

Arterial
pressure

-ve pressure
In head & neck
Air embolism if cut /inject in neck

(~0)

2 mm Hg

100 mm Hg

Effect of
Gravity

82 mm Hg

180 mm Hg

Gravity effect
Above heart lvl systemic arterial pressure
progressively decreases
Venous pressure at heart level is zero
Venous pressure above heart becomes subatmospheric (-ve)
Surface vs above heart cant maintain sig
pressure below atmospheric
Deep vs & those inside cranium can maintain
pressure thats sigly below atmospheric (Eg:
Mean pressure in Saggital sinus is -10 mmHg)
As consequence of preceding is that
severed/punctured v above heart lvl has potential
for introducing air into system Air embolism

Electrophysiology of <3: Cardiac m cells

CARDIAC ACTION POTENTIALS
217

Components of conducting system

1. Sinoatrial node
2. Atrial internodal
pathways carry
impulses btwn SA & AV
node

Bachmanns bundle (after AV node)

3. Atrioventricular node (lower pt of R atrium)

4. Bundle of His
5. Bundle
branches (R&L) &
pass IV septum

6. Purkinje fibers terminate on

ventricular n fibers by carrying
AP; endo then to epi side
218

Components of conducting system

219

Heart has 2 types of m cells:

A. Conducting cells:
1 to 6
not contract
BUT
can generate
APs & conduct
APs
Make conducting
system of heart
SAVE HIS BUNDLE
OF PURKINJE
Major characs:
automaticity &
rhythmiticity

B. Contractile cells

Do

1
2

Working cardiac
cells
Able to contract
Develop force for
pumping blood

3
4

Conducting system of heart

Specialized cardiac m cells
Connected to each other & w/contractile cells by low resistant gap juncs (in
intercalated discs)
Ions can flow & allow whole m to contract in syncitium
Consists of 6 diff components
Have ability to generate APs w/out external stimulus
Conduct cardiac APs to all pts of <3 (working myocardial cells) in specific sequence

Components of conducting system

Sinoatrial node (SA node): pacemaker of <3; initiates APs in human <3; has
highest intrinsic frequency; 60-100 beats/min
Atrioventricular node (AV node): conduction is slowest!!! (b/c less gap juncs &
smaller size lower velocity conduction), creates AV delay, delay allows time for
ventricular filling & helps <3 to func as sequential pump; acts as 2nd pace maker when
SA node fails; 40-60 beats/min
Atrial internodal pathways: conduct cardiac APs from SAN to AVN; help to spread
APs to both atria simultaneously
Bundle of His: carries APs from atria to ventricles; ONLY electrical connector btwn
atria & ventricles
Bundle branches: off shoots of bundle of His; 2 separate bundle branches run in R &
L ventricles
Purkinje fibers: continuation of bundle brs, run in substance of working ventricular
221 gap juncs); 20-40
ms; fastest conducting component among all (largest fibers, more

1. Impulse originates at SA node

Sequence of spread
of cardiac APs:

4. Spreads rapidly
over both
ventricles from
apex to base
thru Purkinje fibers
(Endocardial to
Epicardial surface)

2. Conducted to atria &

AV node rapidly
AV delay occurs for
ventricular filling
At same time spreads
over atria slowly

3. Spreads rapidly to
apex thru bundle of
His & bundle brs

base
base

Apex

3.1) L bundle br
gives off to IV
222 septum

Two types of Cardiac APs:

A. Fast resp type: AP in working cardiac ms
B. Slow resp type: AP of SA node (Pacemaker)
& AV node

223

5 PHASES of FAST resp type AP (of ventricular fiber):

Phase 1
Phase 2

s
Pha

Phase 0

e3

Membrane potential (mV)

5 phases
Duration:150-300 ms

RMP is
stable at
- 85 mV

Phase 4

100

200

300

Time (ms)
224

Membrane Channels
Ungated potassium channels:
Always open
Efflux of potassium (unless memb potential
reaches equilibrium potential of K+)

225

Voltage gated Sodium Channels

closed under resting condition
Under Memb depolarization quickly
open & close
Fast Channel
Same as VGNa+ channels in neuron
Once closed, will not respond to 2 nd
stimulus until cell repolarizes
226

Voltage Gate Calcium channels (L-type):

Closed under resting conditions (when memb highly
ve)
Depolarization open (they open more slowly than
sodium channels
Calcium entered thru these channels will participate in
contraction
All open during plateau phase
Phase 2 most channels open w/max calcium conduction

Voltage-gated potassium channels:

several types of voltage gated channels, 2 most imp:
1. Inward rectifying channels, ik1
Open under resting conditions (-ve memb potential)
Depolarization close
Closing during depolarization phase & ALL closed in main pt plateau phase
Reopen during repolarization (late plateau to early repolarization)
2. Delayed rectifying channels, Ik:
Control more like potassium channels in n,
Open w/depolarization; SLOW TO CLOSE, SLOW TO OPEN
However very slow to open (delayed); open late in plateau phase of AP to
speed repolarization. (most/ALL during mid-repolarization)
close very slowly; remain open in to resting potential & contribute to
extended relative refractory period (by prolonging relative refractive period
prevent developing 2nd AP in cardiac tissue too quickly preventing
arrythmias)
All closed in later pt of RMP

Ionic basis of phases of fast resp:

Phase 0

Phase zero (0):

Rapid depolarization
Opening VG Na+ channels
Inward sodium current
MP reaches +20 mV

Ventricular
M memb

Ion
current

229

Ionic basis of phases of fast response:

Phase 1

Phase 1: Initial, brief repolarization

Closure of VG Na+ channels &
Outwd K+ current due to high
electrochemal gradient for K+

Ion
current

230

Ionic basis of phases of fast resp:

Phase 2

Phase 2: Plateau phase

Long, stable depolarization at ~0 mV
Opening VG slow (L-type) Ca2+ channels
Slow inward Ca+2 current balances outward K+
current (ungated channels)

Ion
current

Role of calcium
Ca2+ entering ventricular
m cell in plateau phase
participates in
contraction by releasing
additional Ca2+ from SR
(Ca2+ dependent Ca2+
release)
IC Ca2+ = major
determinant of force
during contraction
CCBs reduce Ca2+
entry during this phase
Catecholamines ^Ca2+
entry & ^cAMP
activating PKA
phosphorylates VG Ca2+
channels release
more Ca2+ from SR into
cell ^FOC of cardiac
contraction (+ve
inotropic effect)

Ionic basis of phases of fast response:

Phase 3:Rapid repolarization
Opening VG K+ channels (delayed Rectifier)***
VG Ca+2 channels start closing
Strong outward K+ current takes MP to RMP
se 3
Pha

Ion
current

232

Ionic basis of phases of fast response:

Phase 4: Resting phase
VG Na+ & Ca2+ channels
closed
Delayed rectifier K+
channels gradually close

Phase 4

Ion
current

233

Summary of ionic basis of phases of fast response

Phase 1
Phase 2

se 3
Pha

Phase 0

Phase 4

Q R S
Ion
current
K

234

Action Potential of SA node (slow response):

Three phases
Has unstable resting phase
(Phase 4)
Membrane potential (mV)

0
Phase 0

Phase 3
Threshold

- 65

e
Phas

235

Ionic basis of AP of SA node:

Phase 0:
Slow depolarization (upstroke)
Due to opening VG (L-type) Ca+2 channels &
inward Ca+2 current
a
Ph
se
3

Phase 0

Membrane potential (mV)

Phase 3:
Slow repolarization
Due to opening VG K+ channels &
outward K+ current
236

Ionic basis of AP of SA node:

Phase 4 (UNSTABLE resting phase) b/c +ve charges coming in & less
charges going out!
Most ve value of MP is 65 mV
MP doesnt remain at this value; theres gradual depolarization taking MP to threshold
due to
1. Opening Na+ (funny) channels & inwd Na+ current (^in Na+ conductance)
1. Also opening of T type Ca2+ channels (^Ca2+ conductance)
2. Decreasing K+ conductance* (closure in potassium channels)
. This is called pacemaker potential or prepotential
. responsible for automaticity of SA node (DUE TO UNSTABLE PHASE 4)

mV
- 65

Threshold
e4
Phas

e4
Phas
237

Effect of stimulation of autonomic ns on conducting system of <3:

A. Stimulation of sympathetic ns:

i) On SA node: increases <3 rate called +ve chronotropic effect
Mechanism: NE binds w/beta1 receptors in SA node increases cAMP lvls
Activation of beta1 receptors increases slope (rate of rise) of phase 4 due to
more funny sodium current going, potassium channels close faster (reduced
potassium conductance) & T calcium channels open faster (increased
calcium conductance)
Drugs stimulating b1 receptors: DA, NE, E, Dobutamine

Normal heart rate

al
Norm

Heart rate after

sympathetic nerve
stimulation
238

A. Stimulation of symp ns:

ii) On AV node:
. Increases velocity of conduction in AV node
. AV delay decreases (less ventricular filling)
. Causing faster conduction of impulses from atria to ventricles
Known as +ve dromotropic effect
Increased HR, increased CV, decreased DBP?
PR segment also decreases (AV Delay line smaller, travels
faster)

Drugs that block beta receptors decrease <3 rate

Ex: Propranolol (a beta blocker)
Beta blockers used to reduce <3 rate in tachycardia &
conduction velocity to treat atrial fibrillation
Ie. In hyperthyroidism tachycardia & high SBP; given beta
blockers to lower <3 rate, conduction velocity & thus
239
tachycardia

Effect of stimulation of autonomic ns on conducting system of <3:

B. Stimulation of parasymp ns:
i) On SA node: decreases <3 rate known as ve chronotropic effect
Mechanism: ACh binds w/muscarinic receptors in SAN
& causes - Decrease in rate of rise of phase 4
- Hyperpolarization (increase in K+ of pacemaker cells &
decrease in inwd sodium current)

al
Norm

Normal <3 rate

<3 rate after parasymp n

stimulation
240

B. Stimulation of parasymp ns:

ii) On AV node:
Decreases velocity of conduction in AV node
AV delay increases aka more ventricular filling (duration of
Diastole increases, PR segment increases/prolonged)
Slower conduction of impulses from atria to ventricles
Known as ve dromotropic effect
Intense stimulation causes complete blockage of impulses from
atria to ventricles

Drugs that block muscarinic receptors increase <3 rate. Ex:

Atropine tx for symptomatic* bradychardia; increase phase 4
Increase in muscurrinic receptors

241

Refractory period in ventricular action potential

2 types: Absolute refractory period (ARP)
Relative refractory period (RRP)
Contractile response
RRP
ARP

Advantage of long refractory period:

Ventricle does not undergo sustained contraction (recollect
genesis of tetanus) & acts as intermittent pump
242

Cardiac muscle:
Striated
Involuntary
Highly brd
Rectangular m fibers
Single nucleus
Funcal syncytium
B/C of intercalated
discs that have gap
funcs

243

Intercalated disks that act as low resistance bridges make

cardiac m a Functional syncytium
Nucleus
Intercalated
disk

Single
muscle
fiber

cell adhesion
structure

cell 1

cell 2

Gap junction

Action
potential
244

Structure of ventricular muscle:

Myofilaments, sarcomere, banding pattern, contractile proteins are all same as in skeletal ms

Thin filament

Thick filament

2.2 um = optimal length

well devd T tubules & SR as in skeletal ms

T tubule
ECF

Excitation-Contraction coupling in cardiac m:

Spread of APs thru T tubules
Entry of Ca2+ from ECF ICF during plateau phase
Ca2+ induced Ca2+ release from terminal cisternae
Increase in IC [Ca2+]
Binding of Ca2+ w/Troponin-C of troponin complex
Exposing active site of actin filament & cross-bridge cycling!
Sliding of thin filaments on thick filaments
M contraction (shortening of sarcomeres) Develop ACTIVE
tension in cardiac m during contraction

Muscle relaxation:
Occurs when IC [calcium] decreases (& moves to SR & ECF)
Calcium moves to:
A. SR by Ca+2-ATPase pump regd by phospholambin
B. ECF thru Na+-Ca+2 exchanger
Ca+2

Sodium-calcium exchanger

Na+
Sarcoplasmic
reticulum

ATP

Calcium

Calcium ATPase
pump

Sarcolemma of
ventricular
muscle cell

Systolic performance:
Overall FORCE generated by ventricular m during systole;
determined by # of cross-bridges cycling during contraction
Greater # of cross-bridges cycling = greater FOC
# of cross-bridge cycling determined by 2 independent factors:
amt of PL on m & lvl of contractility
If contractility is gone, only thing that can try to bring
back systolic performance is amt of preload
MI = hypoxic injury, w/decreased myocardial FOC (loss
of CT, NOT PRELOAD), thus preload of ventricle will
increase to stretch myocardium & compensate for loss
of contractility
248

Factors that affect systolic performance of <3:

Preload = END DIASTOLIC VOLUME
Load that acts b4 ventricle begins to contract (relaxed state aka
diastole/ventricular filling)
Load or pre-strech on ventricular m at end of diastole
Force that decides ventricular fiber length at end of diastole
Preload for ventricle is end diastolic volume (EDV) / end diastolic
pressure (Best Indices)
Less reliable indices are LAP, PVP, PCWP
LAP (Left atrial pressure), PVP (Pulmonary venous
pressure), PCWP (Pulmonary capillary wedge pressure)
Increase in preload increases ventricular performance

249

 Myocardial contractility: ability of myocardial cells to develop force at

given m length (given PL)
Acute changes in CT due to IC changes in calcium dynamics.
Factors/ drugs that Increase CT provide more Ca2+ to contractile machinery
more cross-bridge cycling (Increased FOC); known as +ve inotropic
effect: increase in myocardial CT; occurs by +ve inotropic agents:
Symp n stimulation increase b receptors cAMP
Circulating catecholamines
Cardiac glycosides digitalis, Oubain, digitalis in <3 failure to
increase FOC
Mechanism: all these elevate IC [free calcium] in cytoplasm

250

Mechanism involved in +ve inotropic effect

by symp n stimulation:
There is increase in peak (maximal) tension devd
Symp n stimulation releases NE

NE binds to beta1 receptors in m

Activation of G protein & formation of cyclic AMP

More Ca+2 entry in plateau of AP

&

More Ca+2 release from storage site

Increase in IC Ca+2 & hence increase in tension

251

Positive inotropic effect by circulating catecholamines:

1. Symp n stimulation to adrenal medulla
2. Release catecholamines (E & NE) from adrenal medulla into
circulation
3. Catecholamines reach <3 & bind w/beta1 receptors
4. Produce efx similar to direct stimulation of symp ns to heart

Catecholamines
Blood

252

Positive inotropic effect by cardiac

Sodium-potassium ATPase
Sodium-calcium Exchanger
glycosides
ECF

ICF

Ex: Digitalis

Ventricular muscle cell

Mechanism of action:

1.
2.
3.
4.
5.
6.

Drug inhibits sodium-potassium ATPase pump

Increased IC [Na+]
Decreased Na+ gradient across ventricular memb
Decreased activity of sodium-calcium exchanger
Accumulation of Ca2+ inside myocardium
Increase in myocardial CT

.Cardiac glycosides increase ventricular performance & so very useful in cardiac

failure

Effect of PL on cardiac performance

Frank-Starlings curve
Increased contractility

Cardiac output
or
Stroke volume

NORMAL

Decreased contractility

PRELOAD OR
End diastolic volume (EDV) or
Right atrial pressure (RAP) or
Central venous pressure (CVP)

254

Indices of contractility

Rate of pressure devt during contraction (dp/dt)

Peak ventricular pressure ^
Rate of relaxation ^
Systolic interval decreases

Ejection fraction: (SV/EDV); ^w/^CT

EF = SV/EDV = ie. 70/100 = .70 = 70%

Normally btwn 55-70%
If ind w/EF 20% after MI = abnormal SIG LOST of ejection fraction
Rmr SV = EDV ESV
ESV = end systolic volume blood volume left out in ventricle (not ejected)
Formula can also be rewritten as: EF = (EDV ESV) /EDV

255

L VENTRICULAR PRESSURE CURVE DURING CARDIAC CYCLE:

2
contractility

1
120 = Systole

Normal
contractility

4
0 = Diastole
Systolic interval Diastolic interval

Changes induced by increased contractility

Other factors that affect systolic performance of <3:

Afterload: force against which ventricle must contract (to pump blood)
Afterload for ventricle is pressure in great vessels
Afterload for L ventricle: Pressure in aorta, ie. Aortic stenosis, systemic
HYPERTENSION; = AORTIC PRESSURE;
Afterload for R ventricle: Pressure in pulmonary a & ie. Pulmonic stenosis
(pulmonic valve), pulmonary HYPERTENSION; = PULMONARY
PRESSURE
Chronic increase in afterload decreases ventricular performance
Concentric hypertrophy = occurs in pt who has increased afterload; high BP for
long time (lumen gets smaller)
Sudden INCREASE in AFTERLOAD = amt of blood ejected out ventricle
DECREASES = SV DECREASES; body overcomes this afterload by increasing
thickness (HYPERTROPHY)
MCC of L VENTRICULAR FAILURE IS SYSTEMIC HYPERTENSION
Increasing AFTERLOAD by constricting arteroles
Reduce AFTERLOAD by dilating arterioles
257

258

Cardiac cycle
Cardiac cycle: period of time from beginning of 1
ventricular beat to beginning of next
Length of 1 cardiac cycle is measured by:
a. ECG recording ; R-R interval
b. Calculated when HR is known by formula:
60
Cardiac cycle length = ------------------------------Heart rate (beats/min)
As HR increases, cycle length decreases
. 2 main phases:
Systole: when heart chamber is contracting
Diastole: when heart chamber is relaxing
. Atrial phases: Atrial systole & diastole
. Ventricular phases: Ventricular systole & diastole

Events during cardiac cycle

Electrical events: depolarization (systole) & repolarization (relaxation/diastole) of cardiac

chambers (cardiac APs)
Mechanical events: events due to cardiac m contraction include: pressure changes in chambers,
volume changes in chambers. valvular closure making heart sounds & pressure changes in
great vessels

Phases of cardiac cycle

7 phases in cardiac cycle w/respect to ventricular phases:
3 phases occur during ventricular systole
4 phases occur during ventricular diastole
Ventricular systole: requires depolarization (QRS?) (120 mm Hgwhere?)
1. Isovolumetric ventricular contraction: no change in volume but ventricle is contracting b/c
valves connected are close so no blood in/out of ventricles
2. Rapid ventricular ejection: as valves open, blood ejected out ventricle into large vessel; rapid
b/c pressure rapidly increases & most of SV ejected during this (~70%)
3. Reduced ventricular ejection: 30% of blood ejected, pressure of vessels decreasing as most of
SV already ejected
Ventricular diastole: requires repolarization (T wave devt) (80 mm Hgwhere?)
4. Isovolumetric ventricular relaxation: no change in volume, b/c all valves in chambers closed
5. Rapid ventricular filling: ventricles mostly filled due to opening AV valves, blood accumulated in
ventricles immediately
6. Reduced ventricular filling (diastasis): remaining blood pushed into ventricles more slowly
7. Atrial systole: atria contracts; note: other than this phase, atria remains in relaxed state rest of
time
260

Left ventricular
& aortic
pressure changes

ction
a
r
t
con
r
t
n
e
ction jection axation g
illing
e
j
f
Iso v
e
r
l
t
e
n
d
e
n
i
r
li
Rap
ucedo ventr ventr filuced ve systole
d
e
l
R
Is
id
Red
Atria
Rap

1
1

3
4

Heart sounds
261

Ventricular diastole:
Atrial systole; FOCUS ON L SIDE!

LA
RA
LV
RV

Last pt of ventricular diastole

Spread of next cardiac impulse
causes depolarization of atria
marked by P wave in ECG
Both atria contract
Ventricular volume reaches
EDV at end of this phase
Ventricles ready for next systole
(when impulse goes out of AV
node into ventricular m)

Ventricular systole:
1. Isovolumetric ventricular contraction

marked by Mitral
Valve closure (start) & aortic valve opening (end, step #2)
Aorta

Pul artery

LA
RA
LV
RV

Ventricles filled w/blood

volume aka EDV
Depolarization of ventricles is
seen by QRS in ECG
Ventricles begin to contract
Rise in pressure closes atrioventricular valves (AVV)
producing 1st heart sound(S1)
Ventricular pressure rises
sharply but volume remains at
EDV
MITRAL VALVE CLOSURE
MARKS BEGINNING OF THIS
STEP! (S1)
263

Ventricular systole:
2. RAPID VENTRICULAR EJECTION marked by opening of
AORTIC valve

LA
RA
LV
RV

Ventricular pressure exceeds

pressure in great vessels
Semilunar valves (SLV) open
Blood gets ejected rapidly
Most of blood ejected during this
phase (~70% of SV)
Ventricular pressure reaches
maximal lvl (120 mm Hg) along
w/aortic pressure while aortic valve
open
Pressures in great vessels also
increase
Ventricular volume decreases*

Ventricular systole:
3. Reduced ventricular ejection ends w/aortic valve
closure & pressure drop

LA
RA
LV
RV

L Ventricular pressure starts falling

as large volume is ejected during
previous phase
Ventricles continue to eject at lower
rate (30% of SV)
Pressures in great vessels also start
falling as blood moves to peripheries
End systolic volume (ESV) of blood
remains in ventricles at end of this
phase
Last phase of ventricular systole
Atrial filling continues
Aortic valve closes at end,
producing S2 sound (due to L
ventricular pressure going below
aortic pressure)

Ventricular diastole:
4. Isovolumetric ventricular relaxation

beginning marked
by aortic closure & end marked by mitral valve opening

LA

RA

LV
RV

Ventricles start relaxing

Ventricular pressure falls below
that of great vessels
SLVs close producing 2nd <3 sound
(S2) due to rapid fill
LVP falls very steeply *close to 0
(hence becomes <LAP
causing opening of MV)
Ventricular volume remains same
at ESV

Ventricular diastole:
5. Rapid ventricular filling marked by MV opening
(high pressure in Atriums!)

LA
RA
LV
RV

VPs fall <APs

AV valves open causing blood to
flow to ventricles
Blood flow rapid due to high
pressure gradient
Rapid flow produces 3rd <3
sound (S3)
Maximal filling occurs &
ventricular volume increases
Ventricular pressures remain low
as ventricles are relaxing
267

Ventricular diastole:
6. Reduced ventricular filling (diastasis): longest!

LA
RA
LV
RV

Ventricular filling continues

Amt of blood flow less as
pressure gradient btwn atria &
ventricles is lower
longest phase
At higher HR, phase will be
reduced to make sure remaining
of ventricular filling phases not
much affected
Atrial & ventricular pressures
become equal at end of this
phase
268

Ventricular diastole:
7. Atrial systole

LA
RA
LV
RV

Last pt of ventricular diastole

Spread of next cardiac impulse
causes depolarization of atria
marked by P wave in ECG
Both atria contract
Small volume of blood fills into
ventricles producing 4th <3 sound
(S4; not audible normally)
Ventricular volume reaches EDV at
end of this phase
Ventricles ready for next systole
269

Left ventricular
and aortic
pressure changes

ction
a
r
SV)
t
f
n
o
o
c
(70%tion
entr
v
n
ion
t
o
o
i
a
illing
t
c
f
x
Is
c
e
r
a
j
g
e
l
t
j
e
n
e
le
ven
ed
filli
tr r
id e
Rap Reduc Iso ven d ventreduced ial systo
i
R
Atr
Rap

80

Heart sounds
270

270

normal

271

272

272

Identify the volumes?

Changes in duration of cardiac cycle at high <3

rates:

At high HRs, duration of cardiac cycle decreases

Both systolic & diastolic times decrease
Diastolic time is reduced to greater extent than systolic time
Phase of Diastasis is reduced most
Moderate increase in HR (ie. exercise) doesnt not affect filling (since
filling least in diastasis)
Very high rates (ie. ventricular tachycardia) encroach on diastole & filling
is reduced, resulting in decreased SV (may lead to hypotension)
Just b/c your <3 is moving faster, doesnt mean your filling more blood

274

 Stroke Volume (SV) = volume of blood ejected by each ventricle in a

beat; difference btwn EDV & ESV;
SV = (EDV ESV) ml per beat
SV increases w/increase in EDV; SV Increased w/contractility & preload
When both ^in EDV & decrease in ESV occur, SV ^^maximally.
Ejection Fraction (EF) = fraction of end diastolic volume ejected in 1
beat; = SV/EDV
index of myocardial contractility; Decrease in arterial compliance, increases
EF
Increase in EF indicates +ve inotropic effect
Decrease in EF indicates ve inotropic effect
MI, CHF = reduced EF
Measuring ejection fraction when pt comes in w/MI to assess tissue
damage.thromboletics/angioplasty (must do w/I 90 mins<90mins=
ischemia/loss CT/damaging myocardial cells death from chf)
Cardiac output (CO) = vol blood ejected by each ventricle per min = (SV
x HR) ml/min
CO depends on stroke volume and heart rate
Increase in SV and/or HR increase/s CO
Decrease in SV and/or HR decrease/s CO

275

Heart Sounds
Heart sounds are due to vibrations produced by
closure of valves or flow of blood
4 heart sounds:
First, Second, Third & Fourth heart sounds
First and second heart sounds heard well
w/stethoscope
First heart sound (S1):
Due to closure of both atrioventricular valves
Has mitral and tricuspid components but heard
as a single sound
Mitral occurs just before tricuspid component
Low pitched, soft sound: lub
Becomes loud in mitral stenosis
276

276

Heart
Sounds
Second heart sound (S2):
Due to closure of both semilunar valves
Has aortic & pulmonary components but
heard
as single sound
Aortic occurs just before pulmonary
component
Higher pitched, sharp sound: "dupp
Becomes loud in systemic hypertension

 3rd <3 sound (S3): low pitched; due to rapid ventricular

filling when AV valves open; heard w/bell of at apex, following
S2
Normally heard in children & young adults below <35 yrs age
not heard in normal adults
Indicates: LV failure or **volume over load** (on ventricle)
Better heard in mitral area in L lateral decubitus pos

278

 4th heart sound (S4): Low pitched; due to ventricular

filling by atrial systole, not audible in normal ppl
Heard best w/bell at apex, preceding S1
Reflects atrial contraction into noncompliant L ventricle
Increase in afterload (high pressure in aorta): Found in
Aortic stenosis, systemic hypertension, hypertrophic
cardiomyopathy = IV septum gets thickened, lumen gets smaller; smaller
ventricular chamber, compliance of ventricle decreases

Pressure overload conditions leads to CONCENTRIC

hypertrophy M thickness increases
Better heard in mitral area in L lateral decubitus pos
279

Valvular heart disease:

a. Mitral stenosis

Narrowing
of mitral
valve

Mitral stenosis: narrowing or

obstruction at opening of MV
Impairs emptying of LA into L
ventricle during diastole
L atrium enlarges & LAP
builds up
pressure gradient btwn L
atrium & L ventricle thru out
diastole
Diastolic murmur appears
PTS PRESENT
W/DYSPHAGIA, due to large
L atria. Pressures of L
recurrent larengeal n=
hoarseness of voice
280

Mitral stenosis

281

Mitral stenosis

Pressure gradient
between LVP
and LAP throughout
ventricular filling
Diastolic Murmur

282

Mitral Insufficiency (M. Regurgitation)

incompetent (leaky) MV causes

blood to regurgitate from LV to LA
during ventricular systole (when
LV contracts & some blood flows
backwd into LA)
^LA volume & pressure +^LV volume
& pressure during ventricular systole
no pressure gradient btwn LA & LV
thru out ventricular filling
*PAN/Holosystolic (pansystolic)
murmur (same intensity in entire
systole)
^in intensity during expiration
Best heard in mitral area aka apex
Keep steth. in axilla to hear LA!!
Large V wave in LAP curve due to
incompetency
Lumen on ventricle chamber ^,
thickness of m ^= ECCENTRIC
hypertrophy !!!! When both lumen &
m size ^
MCC is ischemia/infarction of
myocardium of papillary ms
attached to MV

Aortic pressure

Left ventricular pressur

elevated LAP i
systole w/no
gradient btwn
LAP during
ventricular dia

Left atrial pressure

Systolic Murmur

c. Aortic stenosis:

Narrowing around aortic valve (AV)

AV normally acts as major resistance for flow
during ejection ( AL)
LVP rises to very high lvls during systole (but mean
aortic pressure in N range, due to this theres
pressure gradient btwn LV & aorta during systole)
LV hypertrophy (CONCENTRIC)
Systolic murmur appears
MCC is calcification of AV &/OR bicuspid AV in
elderly
LVP > AP during systole in pressure curve
During reduced ejection, murmur decreases
in intensity crescendo-decrescendo best
heard in aortic area, radiates to neck/carotids
SP in aorta decreases; decreased PP

Aortic stenosis
Pressure gradient btwn LVP &
AP during ejection

Systolic Murmur

284

d.Aortic insufficiency (A.

regurgitation):
incompetent (leaky) AV (doesnt close
properly) allows blood to regurgitate from
aorta to LV during ventricular diastole
^^LV EDV & pressure ( preload) (due to
backward flow of blood thru leaky valve)
LV & aortic systolic pressures
Decreased aortic diastolic pressure
SIGLY* due to backflow
aortic PP; diastolic murmur appears
(early diastolic murmur best heard at L
sternal border ~3/4th ICS, radiates to
mitral area (L ventricle)

285

Aortic Insufficiency
(Regurgitation)
SP

High LVP & AP during systole

Low AP during diastole
High PP in Aorta

DP

Aortic pressure (AP)

Left atrial pressure
Left ventricular pressure (LVP)
Diastolic Murmur
286

Jugular venous pulse:

IC

Filling
of R
atrium

AS

TCV
opens
-ve wave
=Y
descent

X-descent
due to
atrial
relaxation /
diastole

+ a-wave - atrial contraction

+ c wave: caused by bulging
of TCV into RA during early
isovolumetric ventricular
contraction
+ v wave: arises from
pressure produced when
blood filling RA comes up
against closed TCV (during
ventricular systole)
X-descent: decreased RAP
due to relaxation
y-descent: opening of TCV
287

Abnormal JVP

In atrial fibrillation (quivering; lack

of contraction & relaxation), a waves
will be absent, also note no x descent.

No a wave b/c no atrial contraction

In tricuspid regurgitation, c wave & x

descent missing & replaced by large
+ve wave & also in ASD (atrial septal
defect)
Mitral insufficiency/regurgitation: large
v wave of L atrial pressure curve
Tricuspid stenosis, pulmonary
stenosis: Large a wave.
288

SYSTEMIC ARTERIAL BLOOD PRESSURE (BP)

BP is lateral pressure exerted by flowing blood on vessel wall
Arterial BP is of 2 types:
Systolic pressure (SP) & diastolic pressure (DP)
Normal expression of arterial BP: BP = SP/DP in mm Hg

BP apparatus:
Sphygmomanometer

Normal BP in adults:
120/80 mm Hg
289

SYSTEMIC ARTERIAL BLOOD PRESSURE (BP)

Mean arterial pressure (MAP): avg arterial pressure during
single cardiac cycle; calculated by formula:
MAP = Diastolic pressure + 1/3 Pulse pressure
Normal MAP = 80+(1/3x40) = 93.33 mm Hg (~to 100 mm Hg)
driving force for blood flow to organs
Relnship btwn MAP, cardiac output (CO) & total peripheral
resistance (TPR):

MAP = CO x TPR
CO!
Note:
Since CO & TPR not independent factors, doubling TPR will not double MAP
in body; same w/changes in
290

Reg of systemic arterial BP:

Normal MAP is maintained at value of ~100 mm Hg (this
constant value is set point value of MAP determined by BP
regulatory centers in brain stem (Medulla))
Any disturbance that tries to change BP from this set point
value is strongly resisted by BP regulatory systems in body
Resps offered by BP regulatory systems bring MAP back to set
point value. This is called arterial pressure reg
2 major BP regulatory systems exist in human:
a. Baroreceptor reflex mechanism short term control
b. Renin-angiotensin-aldosterone system long term

291

A. Baroreceptor reflex mechanism of reg of

arterial BP:
rapid, short term BP regulatory mechanism
reflex mechanism mediated thru NS
Components of baroreceptor reflex:
Stimulus: Changes in mean arterial pressure
Receptors (sensors): baroreceptors (stretch receptors)
in carotid sinus & aortic arch
Afferent (input) path: Sinus n (IX N), vagus n (X N)
Integrating center: Brain stem BP regulatory centers
Efferent (output) path: Symp ns to <3 & blood vessels (ALL pts);
parasymp ns to <3 (via X N; only SA node, AV node & Atrium)
Effector organs: Heart, arterioles, vs
Resp (effect): changes in CO & TPR
Purpose: To maintain MAP at set point value
292

Baroreceptor are mechanoreceptors

that detect arterial BP:
Increase in MAP

Stretching of carotid sinus &

aortic arch

Increased firing rate of

Baroreceptors (stretched
depolarization)

APs travel via IX N & X N

CV regulatory centers in brain

stem
293

Baroreceptor response to increase in BP

Increase in baroreceptor impulses to cardiovascular regulatory centers
Decrease in symp n activity
& increase in parasymp n (vagal tone)
activity to <3

Decrease in HR &
decrease in contractility

Decrease in symp n
activity to vs & arterioles

Dilatation of
arterioles

Decrease in
venous return

EDV decreases
Decrease in CO
(CO = HR x SV)

Decrease in
TPR

Decrease in arterial BP
(MAP = CO x TPR)
294

Baroreceptor resp to decrease in BP

Ex: Hemorrhage

Fall in arterial BP

Decrease in baroreceptor impulses to cardiovasc. regulatory centers

Increase in symp n activity
& decrease in parasymp n
activity to heart

Increase in symp n activity to vs

& arterioles
a1

Increase in HR (reflex tachycardia) &

contractility

Increase in CO
(CO = HR x SV)

a1

Increase in
venous return
contributing to
SV

Vasoconstriction
of arterioles

Increase in
TPR

Increase in arterial BP
(MAP = CO x TPR)

295

Reg of BP by RAAS mechanism:

long term mechanism of reg of BP since system takes hrs to days to

become effective (LONGER)
b/c mechanism mediated by lipid soluble hormones
Decreased renal blood flow SINGLE MOST INITIATING FACTOR FOR
RELEASE OF RENIN (by JG cells in walls of afferent arterioles monitoring
BP)
mechanism regulates BP by regulating BV
activation of system in resp to low BP produces resps to increase BV

Blood
volume

Cardiac
output

Arterial
BP

Blood volume is altered by altering salt & water in body

296

Reg of BP by Renin-angiotensin-aldosterone
mechanism:
Decrease in BV
Decrease in arterial BP
Decrease in blood flow to kidneys******
Sensed by juxtaglomerular cells of afferent arterioles &
they secrete enzyme, renin into circulation
Renin converts angiotensinogen to angiotensin I in plasma
Angiotensin I is converted to angiotensin II (in lungs) as blood flows thru
lungs & kidneys by ACE (in endothelial cells of lungs)
Continued to next slide..
297

Regulation of BP by Renin-angiotensinaldosterone mechanism

Hormone, Angiotensin II
Angiotensin II (POTENT vasoconstrictor)
acts on ZG of adrenal cortex

Angiotensin II acts on
hypothalamus

Secretion of hormone,
Aldosterone by adrenal cortex

Increases thirst &

Secretion of hormone, ADH

Aldosterone increases
sodium reabsorption in kidneys

ADH increases water

reabsorption in kidneys

Retention of salt & water in body increases BV

Increase in arterial BP!!!
298

Regulation of arterial BP by
Renin-angiotensin-aldosterone mechanism
Retention of Salt and
Water increases plasma
volume, Cardiac output
and Blood Pressure

Increase in TPR and

Blood Pressure

299

HYPERTENSION:
Hypertension: sustained elevation of systemic arterial pressure
Normal: Systolic <120 mm Hg, diastolic < 80 mmHg
Prehypertension: Systolic 120-139 mm Hg, diastolic 80-89 mm Hg
Stage 1: Systolic 140-159 mm Hg, diastolic 90-99 mm Hg
Stage 2: Systolic 160 mm Hg or greater, diastolic 100 mm Hg or greater
May be
Primary OR Essential/Idiopathic (90-95%), which may develop as result of enval or
genetic causes, (thus no known cause) OR
Secondary (2-10%), has multiple etiologies renal, vascular & endocrine causes
Pathophysioal basis for hypertension: either increase in BV or TPR or
both!
Any disease that increases these factors produces elevation of arterial
pressure
Salt & water retention increases BV & increases BP
Examples:
Renal diss: chronic pyelonephritis, primary glomerulonephritis,
tubulointerstitial nephritis& renal a stenosis (Renal vascular causes)
Release of renin increases aldosterone hypertension

Endocrine diss: Conns, Cushings, pheochromocytoma & CAH

JNC-7, JNC-8: only change in management & criteria

Reflex Changes for Specific Maneuvers

Condition

Afferent
activity

Parasymp
Activity

Symp
Activity

BP increase

BP decrease

BP

HR

Carotid occlusion (proximal

to carotid sinus)

Lack of
baroreceptor
signals

Carotid massage
(tricks brain to think you
have high BP, so brain will
lower HR & BP) = fall down
w/syncable attack & wake
up after few mins; best for
SVT supraventricular
tachycardia

Cut afferents

<20 SBP, <10

DBP

toward
normal

toward
normal

Lying to Stand
Orthostatic hypotension
Fluid Loss
Volume load
Weightlessness

MICROCIRCULATION,
REG OF REGIONAL BLOOD FLOW

Microcirculation: funcs of smallest blood vessels capillaries

Capillaries called exchange vessels b/c exchange of nutrients,
metabolic wastes & fluid btwn vascular & interstitial
compartments takes place thru them
Blood flow to capillaries depends on degree of vasoconstriction
(decreases blood flow) or relaxation of arterioles & precapillary
sphincters (connected in series)
Not all capillaries are open in organ all the time
Clinically:

Lymphatic obstruction can lead to edema

Dilate arterioles increases blood flow thru capillaries = more

blood to tissues ie. NO, lowering angiotensin II, local metabolites
in tissues

Constriction of arterioles decreases flow thru capillaries = less

blood to tissues ie. Symp activity, ADH/vasopressin, DA

Exchange of substances across capillary wall

Solutes & gases cross by simple

diffusion
Lipid soluble substances diffuse thru
endothelium
i.e. Oxygen, CO2, steroid
hormones
Water soluble substances diffuse thru
intercellular gaps
i.e. Glucose, AAs, electrolytes
Bigger molecules like proteins
generally do NOT cross

Fluid exchange across capillaries by

Starlings forces:
fluid movement btwn vascular & interstitial
compartments across capillary wall governed
by osmotic & hydrostatic pressures in 2
compartments
fluid movement driven by these
pressures/forces described by: Starlings eqn
Jv = Kf [(Pc - Pi) (c i)]
Where
= Net (filtration) pressure = sum of hydrostatic
& oncotic pressure across capillary membs
Jv = Rate of fluid movement (ml/minute)
Kf = Water permeability of capillary (Filtration
coefficient) product of surface area & permeability of
capillary memb ***
Pc = Capillary hydrostatic pressure (mm Hg)
Pi = Interstitial hydrostatic pressure (mm Hg)
c = Capillary oncotic pressure (mm Hg)

Starlings forces (pressures):

PC
Arteriolar
end

Venular
end

Pi
Fluid movement
into capillary
is called

Fluid movement
out of capillary
is called

Absorption

Filtration

i
c
Algebraic sum of these pressures is called net pressure

Starlings pressures
Pressure favoring filtration has plus/+ (+ve)
sign
Pressure favoring absorption has minus/ (-ve)
sign
If net pressure has +ve sign: fluid is
getting filtered
If net pressure has ve sign: fluid is getting
absorbed

Water permeability of capillary wall (Kf ) aka Filtration

coefficient: varies from type of capillaries in tissue
Ie. more in fenestrated capillaries than in continuous
capillary
Injury to capillary wall increases permeability & also Kf :
i.e. burns & inflammation
Greater permeability = greater movement of fluid

2 Hydrostatic pressures (P)

1. Capillary hydrostatic pressure (Pc): force w/which blood flows in

capillaries; this pressure favors filtration (has plus sign)
Value determined by arterial & venous pressures (2 ends of capillaries)
Ie. MORE at arterial end & LESS at venous end
Obstruction to as or decrease in MAP decreases this pressure
(+arteriolar constriction or dilation of vs)
Obstruction at vs increases this pressure
Increase in pressure of vs (venous pressure) can lead to hydrostatic
pressure (b/c increases pressure upstream MORE FILTRATION)
Ie. DVT no properly BF thru that v, pressure in capillaries ^,
pt presents w/edema; ^in capillary hydrostatic pressure
RESPONSIBLE FOR THIS
2. Interstitial hydrostatic pressure (Pi): fluid pressure in tissues; this
pressure favors

absorption (has minus sign); normally its negligible

2 Oncotic pressures ()
1. Capillary oncotic pressure (c) aka plasma colloid
osmotic pressure: contributed by [plasma protein]; favors
absorption (has minus sign)
If [plasma protein] is low, its also low
When this pressure is low, more fluid moves to interstitial
space & less fluid is absorbed back
fluid accumulation in tissues causes edema
2. Interstitial oncotic pressure (i): force created by
proteins present in interstitial space; favors filtration (has plus
sign); this pressure is negligible under normal conditions

Movement of fluid in tissue capillaries:

At arterial end of capillary:
net pressure = (+37-1-25+0) = +11 mm Hg
net pressure favors filtration of fluid
At venous end of capillary:
net pressure = (+17-1-25+0) = -9 mm Hg
net pressure favors reabsorption of fluid
Arteriolar
end

PC=37

c=25

Pi=1

i=0

PC=17

c=25

Venular
end

Pi=1

Movement of fluid in tissue capillaries:

As blood moves in capillary, fluid leaves capillary near
arteriolar end & reenters to capillary near venous end
Theres constant movement of fluid in & out in most of
tissues of body except kidneys (ie. Glomerular capsule for
filtration & PTC for absorption)
~24 liters/day of fluid is filtered thru capillaries
~85% of it is absorbed into capillaries
remainder returns to circulation via lymphatics

Capillary hydrostatic pressure

decreases along length of
capillary; all other pressures
remain same

Problem:
In a skeletal muscle capillary, the following Starling
pressures were measured:
Pc = 30 mm Hg ; Pi = 2 mm Hg
c = 25 mm Hg; c = 3 mm Hg
The Kf is 0.5 ml/min.mm Hg.
What is the direction and magnitude of fluid
movement
across this capillary?
Solution:
The net pressure = [(30-2) (25-3)] = [28-22]
= +6
Since net pressure is positive, it favors filtration.
The magnitude of fluid movement = Kf x net
pressure
= 0.5 x 6 = 3 ml/min

Question:
At arteriolar end of capillary in an organ:
Hydrostatic pressure is 35 mm Hg;
Colloid osmotic pressure of plasma is 25 mm Hg;
Hydrostatic and colloid osmotic pressures in
interstitial space are zero mm Hg.
The net movement of fluid will be:
A. From capillary to interstitial space
B. From interstitial space to capillary
C. Zero
D. Called reabsorption of fluid at the capillary
E. Called secretion at the capillary
Correct answer : A

Question:
n a tissue capillary, the interstitial hydrostatic pressu
s 2 mm Hg, the capillary hydrostatic pressure is
5 mm Hg, and the interstitial oncotic pressure is
mm Hg. If the net pressure across the capillary wall
s 4 mm Hg favoring filtration, what is the capillary
ncotic pressure?
A. 20 mm Hg
B. 22 mm Hg
C. 24 mm Hg
D. 26 mm Hg
E. 28 mm Hg

Correct answer : D

Cause

Causes and Examples of Edema

formation
Examples

Pc (capillary
hydrostatic pressure)

Arteriolar dilation
Venous constriction
Increased Venous pressure
Heart failure

Extracelluar fluid volume expansion (pt. giv

3L of normal saline)
Capillary oncotic
pressure
Causes generalized
edema = ANASARCA

Decreased [plasma protein] concentration *

Severe liver failure (failure to synthesize

protein
MCC is cirrhosis of liver (via alcohol!) (henc
alcohol cirrhosis/liver failure generalize
edema down osmotic pressure ascites
portal hypotension)
Protein malnutrition (Koshiarkor)

If concentration of PP
increases, capillary oncotic
pressure increases
If capillary oncotic pressure
DECREASES

Nephrotic syndrome (loss of protein in urine

increased loss of protein in kidneys
VS> nephritic syndrome also causes loss o
protein in urine, but NEPHROTIC CAUSES
INCREASED PROTEIN LOSS (aka >3.5 g prote

Causes & Exs of Edema formation

Cause

Examples

Kf (Increased
hydraulic
conductance)

Burn (capillaries open more filtration

edema) b/c SA increases

Impaired lymphatic
drainage

Standing for long time (lack of skeletal m

compression of lymphatic's)

Inflammation
Permeability of capillaries will increase in
both situations^*

Removal or irradiation of lymphatic's (ie. Tx

in breast cancer, removal of axillary lymph
nodes so harder to drain fluid in interstitial
compartment permanent edema!)
Parasitic infection of lymph nodes
Ie. Elephantiasis due to parasite infection
(parasite Wuchereria bancrofti (Larve form)
lymphatic obstruction initially get pitting
edema & then later on becomes NONPITTING
EDEMA!

Factors that Alter Capillary Flow and Pressure

Resistance

Capillary
Flow

Capillary
Pressure

Examples

Arteriole dilation

-adrenergic agonist, adrenergic blocker (normally a1

constricts), decreased symp NS
activity, metabolic dilation, ACE
inhibitors, ARBs, NO

Arteriole constriction

-adrenergic agonist, 2adrenergic blocker, increased

symp NS activity, angiotensin II

Venous dilation

Increased metabolism of tissue

Venous constriction

Physical compression, increased

symp activity

Increased arterial
pressure (MAP when
more SV & CO)

Increased CO, volume expansion

Decreased arterial
pressure

Decreased CO, hemorrhage

dehydration

Increased venous
pressure

Congestive <3 failure, physical

compression

Decreased venous
pressure

Hemorrhage, dehydration

2 ways of Reging blood flow to organs:

1. Intrinsic regulation (inside control/autoreg, ie.
Brain 100%, <3 95%, skeletal m during
exercise)
2. Extrinsic regulation
.
.
.

Basic mechanism of both is changes in arteriolar dm

(constriction/dilation)
Mechanisms afx smooth m of arterioles
Changes in dm afx resistance & thereby flow thru
capillaries of organ (w/pressure gradient being
same)

Intrinsic regulation (Autoregulation):

Mechanisms entirely w/in organ itself

What is regd is flow by changing resistance
No ns or circulating substances are involved
2 main theories
Metabolic theory: Tissue metabolites regulate flow increase BF
Vasodilators dilate arterioles & increase flow when organ is metabolically
more active (ex: Adenosine in coronary circulation) increases ATP
breakdown to ADP!
Major metabolic vasodilators: adenosine, lactic acid, hydrogen ions,
hypoxia (lungs constrict, everything else dilates)
Myogenic theory: to keep flow constant in spite of increased perfusion pressure
1. Increased perfusion pressure (which tends to increase flow) causes
stretching of arteriolar wall & smooth m
2. Stretched smooth m contracts due to its intrinsic property
3. Arteriolar radius decreases
4. Increased precapillary resistance & maintenance of flow
1.

ie. Kidneys regulate MAP btwn 60-160 mm Hg

Blood Flow

Autoregulation

Autoregulatory range

60
Mean arterial pressure

160

Blood flow in most cases is proportional to tissue metabolism

Blood flow is independent of nervous reflexes
Autoregulating tissues include:
cerebral circulation
coronary circulation (adenosine causes dilation)
Skeletal m vasculature during exercise (lactic acid), NOT RESTING
renal circulation

EXTRINSIC REG by nervous & humoral factors

originating outside organ:

These 3 constrict vessels:

1. Symp stimulation
2. NE (on - receptors)
3. Angiotensin II (AT 1
receptors) constricts
arterioles & raises TPR

These 2 dilate vessels

W/drawal of symp
activity
Epinephrine (on receptors)

EPINEPHRINE REVERSLE EFFECT:

At high lvls, circulating E has
vasoconstrictor effect thru alpha
adrenergic receptor; Ie. Txing
pheochromocytoma
mechanisms:

2 Circulations regd by extrinsic

1. Cutaneous circulation only regd by symps & 100% EXTRINSIC REG
2. Skeletal m circulation (resting flow) EXTRINSIC ONLY WHEN RESTING
FLOW

Control of flow in exercising muscle

Mainly Via vasodilator metabolites (along
w/increase in CO)
E via -receptor activation can contribute to
increase in flow
No effect of increased symp activity on
exercising ms (b/c alpha receptor do not
respond to NE during exercise as long as lactic
acid is elevated)

Coronary circulation:

5% of CO (250 mL/min) at rest

L coronary flow subjected to severe mechanical compression of intramyocardial blood
vessels
Very little if any flow occurs during systole; Most of flow during diastole***
R ventricular contraction causes modest mechanical compression on intramyocardial
vessels:
Sig blood flow occur during systole

Greatest/most of flow during diastole (both coronary as get MAX blood flow)

Cardiac m extracts maximum O2 from flowing blood (A-V difference) at rest

venous PO2 is extremely low (entire CVS in a resting ind)
Any increase in O2 demand has to be met w/increased blood flow
In coronary circulation flow must match metabolism
Coronary blood flow closely reld to myocardial O2 consumption
Coronary flow (ml/min) determined by pumping axn, or stroke work X HR
Increased pumping axn means increased metabolism, which releases vasodilatory metabolites
such as adenosine, which in turn increases blood flow
Increased pump func occurs w/:
- mild moderate Exercise : increased volume work, ONLY increases contractility*
severe exercise: increased venous return to <3, ventricular diastolic pressure increases,
preload increases & contractility increases causing SV to increase SIGLY*
- Increased arterial pressure (Hypertension): Increased pressure work
ie. LVP, adenosine lvls increase, increased coronary blood flow in myocardium
If demand not met w/(less supply due to narrowing coronary vessels) ISCHEMIA

Cerebral circulation:
~15% of CO (750 mL/mib), 100% Autoregulated
Flow proportional to arterial PCO2 tension
Normally, ARTERIAL PCO2 is main factor reging Cerebral flow*
(abnormal below, PO2 regulates)
Increased **PaCO2 increases cerebral blood flow***
Decreased Pa**CO2 decreases cerebral blood flow***
As long as PO2 is normal/>normal, cerebral blood flow will be regd via
arterial PCO2
If normal person switches from breathing room air to 100% oxygen, no
change to cerebral flow
ONLY large decrease in arterial PO2 will increase cerebral blood flow
Under these conditions, its low PO2 thats determining flow.

Baroreceptor reflexes DONT affect flow

Intracranial pressure can affect CBF
Chemoreceptors are found on carotid body metabolites that regulate

Cutaneous circulation:

Almost entirely controlled via adrenergic ns

Large venous plexus innervated by symps
A-V shunts innervated by symps
Symp stimulation to skin will cause:
Constriction of arterioles & decrease in BF
Constriction of venous plexus & decrease in BV in skin
Increase in velocity of blood flow (decrease in CSA)
Symp activity to skin varies mainly w/bodys need for heat exchange w/env
Ie. When exposed to cold, core body temp decreases, temp regulatory center
increases symp activity to skin for heat exchange
Parasymps stimulate: increased skin temp directly causes vasodilatation, which
increases heat loss/dissipation

Renal Circulation:

small change (mild-moderate) in BP will invoke auto-regulatory resp to

maintain renal blood flow.
Thus, undernormal conditions renal circulation demonstrate autoregulation
In conditions like large increase in symp activity (Hypotension; severe
change in BP) usually cause vasoconstriction & decrease in blood flow (thus
no longer autoregd)

A1 receptors constrict in afferent arterioles

D1 receptors cause vasodilation
Thus both constriction & dilation occur!
Kidney also produces prostaglandins increase BF dilate
Angiotensin II constrict

Renal circulation is greatly over perfused in terms of O2 & nutrition

requirements, w/increase in symp activity, venous PO2 is high (b/c of less
O2 extracted from renal circulation).

Cadiovascular changes in EXERCISE:

HEART

Larger increase in HR

Increase in SV

Large increase in CO

Increase in preload ONLY in heavy exercise *(VS. mild-moderate DOESNT increase preload)

Increased FOC, increased EJ & decreased ESV

Pulmonary circuit (very compliant so easily distended)

Increase in CO, produce rise in pulmonary pressures

B/c of compliant nature of circuit, resp to rise in pressure is vessel dilation!

Large decrease in pulmonary vascular resistance consequently, theres slight increase in pulmonary a pressure

Increase in pulmonary BV

#of perfused capillaries increase

(perfused = flow)

Increase in capillary surface area (increased perfusion matching ventilation)

Base of lungs has most O2 filtration b/c of gravity (top of lungs have little ventilation, BUT during exercise, more O2 gets here)
Systemic circuit (Arterial system)

Large increase in blood flow

Slight increase in mean arterial pressure (Increase in SBP; fall in DBP)

Large decrease in peripheral resistance (Dilation of skeletal muscle beds)

No significant change in PO2 & PCO2

No change or slight decrease in pH (b/c no sig change b/c ventilation also increases)
Systemic circuit Venous system

Increase in venous return (large in heavy exercise, hence also increase PRELOAD)

Decrease in venous compliance (symp axn)

Decrease in PO2 (100 in as 20 in vs once thru skeletal m) & increase in PCO2, uptake of O2 by skeletal m

Decrease in pH
Exercising ms

Increase in blood flow

Decrease in vascular resistance (symp vasodilation more stretch)

Increase in capillary pressure & filtration

Increase in lymph flow

Decrease in venous PO2

increased oxygen extraction

Cutaneous blood flow

Increases to dissipate heat

Coronary blood flow

Increased (due to increased volume work of <3)

Cerebral blood flow: no sig change
GI blood flow

Slight decrease

<3 AS PUMP- Cardiac output & Venous return:

Cardiac output (CO) = Amt of blood ejected by each
ventricle in min; avg value in adult = 5000 ml/min (5L)
CO of R ventricle = to CO of L ventricle
Factors that determine cardiac output
CO = SV x HR
Increase in SV/HR or both increases CO
Decrease in SV/HR or both decrease CO
SV is determined by
KNOW THEIR EFX*
1. PRELOAD
2. CONTRACTILITY
3. AFTERLOAD
HR influenced by many neurohumoral factors, reflexes,
body temp (ie. Fever, temp^ & CO^), pain, drugs etc.

Factors that determine stroke volume (SV)

a. Preload:
Increase in preload increases SV Ex: Increased venous return
Decrease in it decreases SV Ex: hypovolemia
b. Afterload:
Sustained increase in afterload decreases SV/ Increases
myocardial O2 consumption to maintain SV
Ex: Hypertension

c. Myocardial contractility:
Positive inotropic agents increase SV e.g: digitalis, symp
stimulation, catecholamines

Negative inotropic agents decrease SV Ex: Loss of myocardial

tissue as in pt w/MI decreases stroke volume; beta blockers, calcium
channel blockers

PRELOAD & Frank-Starling relationship

Frank-Starling law of heart: Volume of blood ejected by
ventricle depends on volume of blood in ventricle at end of
diastole
Stroke volume (SV) End diastolic volume (EDV)
Greater ventricular filling greater SV & CO;
Lesser the ventricular filling less SV & CO
plot of SV/CO against EDV is called Frank-Starlings curve or
Cardiac func curve
EDV also substituted by R atrial pressure (RAP) or Central
venous pressure (CVP)
EDV = preload on ventricles

Cardiac output
or
Stroke volume

Frank-Starlings curve or Cardiac function

curve

End diastolic volume (EDV) or

Right atrial pressure (RAP) or
Central venous pressure (CVP)

Preload on ventricles

Mechanism of Starlings relationship

Increase in VR (blood returning to heart)

Increase in ventricular filling & EDV

Stretching ventricular m fibers

Increase initial length of m fibers

More # of cross bridge formation during contraction

Increase in myocardial tension devd

Increase in SV & CO

Effect of contractility on cardiac func curve:

Increase in contractility:
Curve shifts to L &

upwards
+ve inotropic agents like
digitalis, catecholamines,
symps
Normal control

Decrease in contractility:
Curve shifts to R & down
-ve inotropic agents like
cardiac depressant drugs
(beta blockers, CCBs) or in pt
w/MI
or CVP

Venous return (VR)

Venous return = amt of blood received by R atrium per min
In normal person, it is same as CO (5 L/min)
pressure gradient btwn R atrium & peripheral vs is driving
force for VR
Higher the gradient = greater will be the venous return;
Lower the gradient = less will be the venous return
Factors that increase this gradient improve VR
Factors that increase venous return are:
-ve intrathoracic pressure (thoracic pump; more BF IN R
side of <3 during INSPIRATION)
Increase in total blood volume (ie. Administer saline)
Contraction of skeletal ms (skeletal pump)
Increased venomotor tone (ex: symp stimulation)
Lying posture (lack of gravity effect)

Vascular function curve

Venous return or C.O. (L/min)

= plot btwn venous return (or CO) & right atrial pressure
inverse relationship exists
between RAP and VR in
range 0 to 7 mm Hg of RAP

Collapse
during
ve
pressure

Normal
point

No further increase in VR occurs

when RAP < 0 mm Hg as vs
collapse at ve pressures

Mean circulatory (mean

systemic) filling
Pressure
= 5 L at +7 mmHg
Right atrial pressure (mm Hg)
>+2 venous return decreases

+7 = VR becomes 0

Effect of changing total BV on vascular func curve

Increased blood volume:
Curve moves upward & to RIGHT
Mean circulatory pressure rises

N = Normal blood volume

N
Low blood volume:
Curve shifts downward
& to the LEFT
Mean circulatory
pressure falls

Combining cardiac func curve & vascular func curve

Steady state

CO & venous return are

dependent on each other
Interaxn btwn them is best
understood by combining 2
func curves b/c RAP is
common in both
point at which 2 curves
intersect is steady state
(CO=VR)
Combining 2 curves helps
predict changes in CO under
various conditions
In every condition, new steady
state is reached this new
steady state depends on
which curve is primarily
changing due to disturbance

The factors that change the cardiac and

vascular function curves
Factor

Curve that gets

altered

Change in myocardial
contractility
Change in blood volume

Cardiac
function curve
Vascular
function curve

Effect of increasing myocardial contractility

on combined curves:
Positive inotropic agents
E.g.: Sympathetic nerves,
digitalis
Normal

N
N

Effect of increasing total blood volume

on combined curves:

Reach steady state later

N
Normal

Increased blood volume:

E.g.: Infusion of IV fluids

Left ventricular pressure-volume loop

1 to 2 : Isovolumetric ventricular contraction
2 to 3 : Left ventricular ejection
3 to 4 : Isovolumetric ventricular relaxation
4 to 1 : Left ventricular filling

Aortic valve
closes(S2)

Reduced ejection: 30% SV; pressure lowers from 120 mmHg

Rapid ejection: 70% SV; pressure peaks to 120
mmHg

ESV

Isovolumetric relaxation

SV*

Mitral valve
opens
4

Rapid & Reduced Ventricular filling

Aortic valve
opens

Isovolumetric contraction; no change

pressure increases causing AV valve to

Mitral valve
closes(S1)

EDV

Changes in left ventricular P-V loop by:

Increase in preload

Examples: Infusion of normal saline, excess water retention

= increase VR TO <3
Loop A: Normal
Loop B: Increased
preload

SV

EDV increases

SV = EDV - ESV

Changes in left ventricular P-V loop by:

Decrease in preload
Decrease in preload: Hemorrhage, dehydration
SV
is
low

Loop A: Normal
Loop C: Decreased
preload

EDV decreases

Decreased peak LVP!

DECREASED FOC, PL, LVP PE

Changes in left ventricular P-V loop by:

Increase in afterload

Left ventricular pressure

Ex: pts w/systemic HTN, Aortic stenosis, & Clamping

abdominal aorta
Loop A: Normal
Loop B: Increased
afterload

A
B

Left ventricular volume

Increase in ventricular
pressure during systole
Decrease in SV
Increase in ESV

Changes in left ventricular P-V loop by:

Increase in myocardial contractility

Left ventricular pressure

Example: Digitalis, catecholamines, Dobutamine

Loop A: Normal
Loop B: Increased
contractility

A
B

Left ventricular volume

Increase in ventricular
pressure during systole
Increase in SV
Decrease in ESV
Increase in EF

P-V LOOP IN SEVERE EXERCISE

P-V loop in Left ventricular failure

Curve A: Normal
Curve B: Immediate effect of reduced CT no compensation (PL remains same); peak VP decreases, ESV
^, (note: only PL can compensate later seen in curve C)

reduced SV, ^ESV, FOC DECREASES

FOC = vCT * ^PL

Curve C: Compensated LV HF SV partially restored due to ^PL!!!!!, ^LVP peak from B

to C (not as high as N tho) contracting up to optimal length
Curve D: Decompensated LV HF despite ^in PL, SV remains low & <3 over stretched
(beyond optimal length, #crossbridge cycles reduce now) (VOLUME/PRESSURE
OVERLOAD hence hear S3 during rapid filling hence as overfilling)

preload should be same if no compensation

PEAK LVP decreases further b/c stretch occurs beyond optimal length,
decreased BF to organs (esp in renal flow, increase renin angiotensin II
vasconstriction (also by symps) + increased aldosterone thus TPR^ & ^DBP

Progressive changes in cardiac func curves in

Heart Failure (failure of contractility)
See next graph

Immediate effect of reduced CT: (Point B) reduction in CO; This soon

changes due to compensatory changes
Compensated failure: (Point C) BV expansion has partially restored CO by
Starlings mechanism; gradually progresses to massive volume expansion
Decompensated failure: (Point D) as failure progresses, theres severe
reduction in CT despite extreme ^in preload, due to overstretching ventricle.
At this point, increase in PL is harmful to heart!

Tx: diuretics, aldosterone antagonists like ACE Is or angiotensin 1 receptor

blockers (block them due to ^baroreceptor & aldosterone mechanisms as
result of low BP)

Once myocardium damaged, they will eventually die of HF

Progressive changes in Heart Failure

A
B

Pathophysiology of CHF = SYMPS!

Aldosterone ^ PL^
Low BP baroreceptor stretch
Angiotensin II also potent
decreases (short term mechanism)
vasoconstrictor
VASOCONSTRICTION
TPR^ AL^ on ventricles
Symps:
To reduce AL^, give
<3 ^HR, so spends
aldosterone
less time in diastole,
inhibitors/antagonists
thus in given min, <3
(vasodilators), ie. ACE
spends more time in
inhibitors & AG receptor I
systole, so needs
blockers
more ATP & O2, FOC
Nitroglycerin but not life
myocardium ^but not
saving
sigly (just
Also give diuretics
compensated)
To decrease HR (too
Arterioles constricted
high), give beta blockers
(TPR^, AL^ but not
(MAJOR DRUGS AFTER
good so give drugs to
MI!) TO DECREASE O2
dilate vessels
demand prevents
(vasodilators)
recurrent major <3
vs constricted (VR^,
attacks; REDUCE
PL^ good until optimal
Remodeling:
applied
to dilation (other than that due to passive stretch) & other MORTALITY OF PTS
length to term
increase
CO)
slow structural changes that occur in stressed myocardium; may include proliferation W/CHF!!!!!! BY
PREVENTING
of connective tissue cells as well as abnormal myocardial cells w/some biochemal
REMODELING OF <3
characs of fetal myocytes. Ultimately, myocytes in failing heart die at accelerated
rate thru apoptosis, leaving remaining myocytes subject to even greater stress.

Determination of cardiac output by using Ficks principle

O2 taken up by lungs per minute
Cardiac output = -------------------------------------------------------(Pulm. blood flow) (O2 conc. of pulm. Vein - O2 conc. of pulm. artery)
O2 consumed by the whole body per minute
CO = -------------------------------------------------------------------------(sy.Bl.fl) O2 content of systemic artery-O2 content of pulm. artery
Invasive method; requires cardiac catheterization
to obtain a sample of pulmonary artery blood

SAME QUESTION!!!!

etermination of cardiac output by using Ficks princip

Given data:
O2 content of systemic artery (Aorta) = 20 ml/dL=0.20 ml/ml
aka 0.2 mL O2 per 1 mL of blood
O2 content of pulm. artery = 15 ml/dL=0.15 ml/ml
O2 consumption of whole body per minute = 250 ml
Thus were calculating CO of L* heart
250
250
Cardiac output = -------------- = ----------0.20-0.15
0.05
= 5000 ml/minute = 5 L/min

Swan-Ganz Catheter (PCWP):

Balloon at tip for pulmonary a to inflate

SP~25
DP ~0

SP 25
DP 8

Electrocardiography
ELECTROCARDIOGRAM (ECG/EKG)
& ITS APPLICATIONS
Electrocardiogram (tracings on paper) or ECG
or EKG: graphic recing of summated elecal activities
of <3 by surface electrodes
Machine that recds ECG is called
Electrocardiograph; basic pts of it are:354
Electrodes
Main circuit
Recorder

Electrocardiograph:
sophisticated galvanometer, sensitive electromagnet (detect & recd changes in electromagnetic potential)
Has +ve pole & ve pole; wire extension from these poles have electrodes at each end:
- +ve electrode at end of extension from +ve pole
- -ve electrode at end of extension from ve pole

paired electrodes together constitute electrocardiographic lead

When paired electrodes oriented in any particular direction, theoretical straight line joining electrodes is
known as lead. (Eg: Lead 1, RA Ve, LA +ve)

Principle behind ECG recordings

Heart assumed in center of body

Elecal activities produced by <3 spreads to body pts thru body fluids
Electrodes kept at specific sites on body surface pickup these elecal activities
Sequence of depolarization:

SAN ATRIAL & AVN (from AVN) Ventricular

R atrium depolarizes 1st compared to L atrium

If current going from RA to LA (R L) from upper pt of atrium twds lower pt; direction of current will be
for DEPOLARIZATION

For these vector waves, look at direction & magnitude/size of current! Size of current is largest for
ventricle; current always written in terms of vectors

If +ve electrode on L shoulder & atrial depolarization going twds it, see upward P WAVE!

+ve electrode on R shoulder,

L bundle br gives small br to lower pt of !V septum; thus this lower pt of IV septum undergoes
depolarization 1st, then spreads to upper pt (so last pt to undergo depolarization) (L to R; down & up)

Next pt of ventricle that undergoes depolarization is apex (thus endocardial myocardial side)

Thus 1st IV septum, then apex then base; (going from endocardial to myocardial side)

L ventricle is thicker m; HENCE GREATER MAGNITUDE wave, hence larger vector on L side

R bundle br takes depolarization to R ventricle

Note: both ventricles undergo depolarization at same time! Largest wave aka MAJOR is apical
355
depolarization of L ventricle; going in L & downwds!

Sites selected for ECG recording:

Limbs: Right arm (RA), Left arm (LA), Left leg (LL)
Leads connecting limbs are Limb leads view frontal plane
Leads kept on chest wall are Chest/Precordial leads view horizontal plane
Conventionally ECG recd in 12 leads grouped into 3 lead systems are:
- 2 groups of Frontal plane leads (6):
Standard bipolar limb leads (3 in #): Lead I, Lead II & Lead III
Augmented unipolar limb leads (3 in #): aVR, aVL & aVF
- Horizontal plane leads (6): unipolar chest leads (6 in #): V1, V2, V3, V4, V5 & V6

12 LEAD EKG

R-R segment

^Note equiphasic QRS

means current going
perpendicular to that
lead

356

Making ECG

Each lead has new +ve & ve electrodes

This makes each lead vary in shape or
morphology
Correct electrode placement imp to
diagnostic quality of ECG
3 Limb Leads
Placement of electrodes
RA - placed on R wrist
LA - Placed on L wrist
LL - Lateral/Medial aspect of L Malleolus

Precordial Electrodes (six)

V1- 4th ICS, R sternal border

V2- 4th ICS, L sternal border
V3- btwn V2 & V4
V4- 5th ICS, midclavicular (mitral area)
V5- Ant axillary line, same lvl as V4
V6- Midaxillary line, same lvl as V4/5
357

6 Limb Leads:

limb leads view <3 in vertical plane aka frontal plane:

envisioned as giant circle superimposed on pt body.
This circle is marked off in degrees.
limb leads view elecal forces (waves of
depolarization & repolarization) moving up & down &
L&R thru circle
To produce 6 limb leads of frontal plane, each of
electrodes variably designated as +ve or ve (done
automatically by circuitry inside EKG machine)
Each lead has own specific view of <3 aka angle of
orientation
angle of each lead can be determined by drawing
line from ve electrode(s) to +ve electrode(s)
resulting angle then expressed in degrees by
superimposing it on 360 degree circle of frontal
plane

358

Standard Limb Leads:

Lead I:

Lead II:

Lead III:

Direction of

left arm +ve,

right arm ve

legs +ve,
right arm ve.

legs +ve,
left arm ve

Angle of orientation

0.

60.

120.

Augmented Limb Leads:

Lead aVL:

Lead aVR:

Lead aVF:

Direction of current

left arm +ve, other limbs ve.

right arm +ve, other limbs

-ve.

legs +ve other limbs -ve.

Angle of orientation

-30.

-150.

+90.

Theyre called augmented leads b/c EKG machinery must amplify tracings to get
adequate recding.

6 Precordial Leads:

Horizontal plane

Recd elecal forces moving antly

& postly

V1 4th ICS, right of sternum.

V2 4th ICS, left of sternum.
V3 between V2 & V4.
V4 5th ICS, mid-clavicular line.
V5 horizontal to V4 ant axillary line.
V6 5th ICS, mid-axillary line.
NOTE: R ventricle lies antly & medially; L ventricle lies postly &
laterally.
Lead V1 lies directly over R ventricle,
V2 & V3 over IV septum,
V4 over apex of L ventricle,
V5 & V6 over lateral L ventricle.

Each lead views heart from its own

particular angle of orientation

Summary:

Components of Conduction System

Sinoatrial Node
Atrioventricular Node
Bundle of His
Purkinje Fibers
Atrial Myocardium
Ventricular Myocardium

363

Genesis of EKG waves

SA node

P wave:
atrial
depolarization
wave

QRS complex:
3 waves of Ventricular
depolarization wave
Due to changing
direction of wave of
depolarization in
sequence

S
364

Genesis of ECG waves

Ventricles remain in depolarized

state for sometime before they get
repolarized
No potential is recorded
Corresponds to plateau phase of
ventricular AP

T wave: Ventricular repolarization wave

365

PR Interval and Segment

normal PR interval
lasts 0.12 to 0.2 secs.

PR segment is horizontal &

runs along same baseline as
start of P wave

Septal q Waves:

IV septum 1st to depolarize, in LR direction

Normal q-waves: narrow <0.04s & small <25% amplitude of R wave
Septal q waves should not be confused w/pathologic Q waves of MI
Pathological Q waves: 25%or+ of height of partner R wave &/OR greater than 0.04
s in width 1 small square - & greater than 2mm (2 small squares) in depth

>0.20 sec: prolonged PR interval = 1st degree heart block =

-ve dromotropic effect caused by parasymp stimulation
(ACh, M2; beta blockers, calcium channel blockers)

QRS Interval Duration: 0.08-0.10 secs

ST Segment: horizontal or gently up-sloping in all leads; end of ventricular
depolarization to start of ventricular repolarization
T Wave: ventricular repolarization; largely passive w/high energy expenditure;
susceptible to both cardiac & non cardiac influences & thus variable in appearance

Normal ECG tracing

ECG paper: Contains 1 mm x 1 mm boxes
0.1 mV

Voltage (mV)

Paper speed: 25 mm/s

1 mm on x-axis = 1/25 = 0.04 sec

Time in sec
0.04 second

Normal ECG Tracing: Y axis represents voltage, X axis represents time

ECG paper: contains large squares w/25 small squares in each square
Each small square is 1 mm x 1 mm, & on x-axis accounts for 0.04 secs
1 large square has duration of 0.20 sec : 5 small squares horizontally
Each large square = 0.5 mV in voltage; 5 small squares vertically per large square =
1 small square = 0.1 mV
Paper speed is 25 mm per sec; 1 small square = 1 mm
# of small squares/min: 1500 small squares or mm/min
# of large squares/min: 300 large squares/min (1500 small squares/5 =

EKG Paper
The horizontal axis measures time.
Small squares of 1 1 mm; = 0.04 seconds
Large squares of 5 5 mm = 0.2 seconds
The vertical axis measures voltage.
Small square represents 0.1 mV,
Large square, 0.5 mV.

Both waves are 1 large square in duration (0.2 secs), but 2 nd wave is twice voltage of 1st (1 mV compared w/0.5 mV).
Flat segment connecting 2 waves is 5 large squares (5 0.2 secs = 1 sec) in duration.

370

PR interval:
Start of atrial depolarization to
Start of ventricular depolarization.
PR segment:
End of atrial depolarization to
Start of ventricular depolarization.

Naming the Straight Lines

Normal ECG waves, segment

ST segment:
End of ventricular depolarization to
Start of ventricular repolarization.

QRS interval: time of ventricular depolarization.

Voltage

QT interval:
Start of ventricular depolarization to
End of ventricular repolarization.

PR
segment

QRS
interval

PR
interval

Time (sec)

ST
segment

QT inte

Calculate PR, QRS and QT intervals in this ECG

PR interval = 0.04 x 4 = 0.16 sec (Normal: 0.12-0.20 sec)

QRS interval = 0.04 x 2 = 0.08 sec (Normal: 0.08-0.10 sec)
QT interval = 0.04 x 8 = 0.34 sec (Normal: 0.32-0.43 sec)
372

Heart rate can be calculated from ECG

R-R interval

R-R interval gives 1 cardiac cycle length

60
Heart rate = ---------------------- beats per minute
R-R interval (in secs)

60
60
Heart rate of above ECG = ----------- = -------- = 50 beats per minute
30x.04
1.2
373

Analyzing ECG
Assess rate
25mm/sec x 60 secs/min =
1500
Number of boxes
NOB
300, 150, 100, 75, 60, 50 method

374

What is the heart rate of this patient?

R-R interval

Lead II ECG
R-R interval = 23 boxes = 23x0.04 = 0.92 sec
Heart rate = 60/0.92 = 65 beats/min
R-R interval varies inversely with heart rate;
PR interval also varies inversely with heart rate

375

376

Rule of 300:

Take the number of big boxes between neighboring QRS

complexes, and divide this into 300.
The result will be approximately equal to the rate
Although fast, this method only works for regular rhythms

# of big
boxes

Rate

300

150

100

75

60

50

What is the heart rate?

(300 / 6) = 50 bpm

(300 / ~ 4) = ~ 75 bpm

(300 / 1.5) = 200 bpm

10 Second Rule

As most EKGs recd 10 secs of rhythm per page, 1 can simply

count # of beats present on EKG & multiply by 6 to get # of beats
per 60 secs.

This method works well for irregular rhythms.

33 x 6 = 198 bpm

ECG showing sinus tachycardia

Normal sinus rhythm: HR in range 60-100/min; regular

HR in above ECG = 60/20x0.04 = 60/0.8 = 75 beats/min THUS 4 large

squares or 20 small squares

Sinus tachycardia:
Heart rate is greater than 100 beats/min and regular

HR in above ECG = 60/10x0.04 = 60/0.4 = 150 beats/min thus 2 large

squares or 10 small squares
380

ECG showing sinus bradycardia

Normal sinus rhythm:

Heart rate = 60/20x0.04 = 60/0.8 = 75 beats/min

Sinus bradycardia:
Heart rate is less than 60 beats/min and regular

HR in above ECG = 60/35x0.04 = 60/1.4 = 43 beats/min thus ~7 large

squares or 30 small squares
381

How to interpret cardiac rhythm by ECG?

Normal rhythm means regular = means SA node produces
impulses & conducts it thru AV node at regular interval seen in
ECG by R-R interval remaining constant
R-R interval

R-R interval

20 boxes

20 boxes

R-R interval

23 boxes

R-R interval

R-R interval

20 boxes

ECG with regular rhythm

14 boxes

ECG with irregular rhythm

382

QRS Axis
(ventricular depolarization)
QRS axis: represents net overall direction of
hearts elecal activity; abnormal axis indicates
ventricular enlargement, conduction blocks (i.e.
hemiblocks) &/or hearts pos
Normal: btwn -30 to +90 degrees
L Axis Deviation: indicates L ventricular
hypertrophy, LBBB, or seen in pregnant
women; btwn -30 & -90 degrees
Pos of <3 in pregnancy: diaphragm is
raised, <3 is raised, L ventricle is raised:
will see L axis deviation
R Axis Deviation: indicates R ventricular
hypertrophy or RBBB; btwn +90 & +180
degrees
Conduction blocks: RBBB, LBBB
Normal

LAD

RAD

-30 to
+90.

-30 to -90

+90 to +180

The Quadrant Approach

Quadrant Approach: uses Lead I & unipolar augmented limb lead aVF to
calculate QRS axis; examine QRS complex in leads I & aVF, determine if
theyre predominantly +ve or ve
1. Examine QRS complex in leads I & aVF
2. Determine if theyre predominantly +ve or -ve.
3. combination should place axis into 1 of 4 quadrants:
Normal: Both lead I & lead aVF are +ve (upwds!)
LAD: Lead I upright, lead aVF downwards; means current going more twds Lead I
RAD: Lead I downwards, lead aVF upwards; means current going more twds lead aVF

Determining the Axis

Predominantly
Positive

Depolarization;
current twds +ve
electrode

Predominantly
Negative

Repolarization;
current twds ve
electrode

Equiphasic

Under upright &

downwd; normal;
0-90 degrees;
calculate specific angle using equiphasic
approach (next slide)

Equiphasic Approach
for Equiphasic waves, to identify the specific angle of orientation
1. Determine which lead contains most equiphasic QRS complex.
Indicates that net elecal vector (i.e. overall QRS axis) is
perpendicular to axis of this particular lead.
2. Examine QRS complex in whichever lead lies 90 away.
3. If QRS complex in this 2nd lead is predominantly + ve, then
axis of this lead is ~the same as net QRS axis.
4. If QRS complex is predominantly -ve, then net QRS axis lies
180 from axis of this lead.
MEANS current is going 90 degrees to it;
Ie. If its going twds lead I = +ve upright wave
& vice versa
Ie. If its in direction +ve of lead II upright
wave in it; then axis is normal & angle of
orientation is 60 degrees!

AXIS
1) most equiphasic
= AvF
Axis is perpendicular
to this lead!
2) Locate 90 deg
In this case only involves looking at lead 1
Is QRS + or in lead 1.
=positive therefore axis = 0 deg

1) Most equiphasic (isoelectric) = lead AvL

Axis is perpendicular to this lead!
2) Locate 90 deg
In this case lead II
Is QRS + or in lead II.
Positive therefore axis = +60 deg

1) most equiphasic
= lead II
Axis is perpendicular
to this lead!
2) Locate 90 deg
In this case AvL lead
Is QRS + or in lead AvL.
negative therefore axis = +150 deg
= RAD!

Determine the Axis

Lead III is perpendicular to aVR (equiphasic wave)
It is downwrds meaning its twd +120 axis; not in right
direction; opp to this is -60

Equiphasic Example 1.

Lead aVR is smallest & isoelectric lead.

The two perpendiculars are -60

and +120 o.

Leads II and III are mostly negative (i.e., moving away from the + left leg)
The axis, therefore, is -60 o.

).

Lead aVR is closest to being isoelectric (slightly more positive than negative)
The two perpendiculars are -60

and +120 o.

Lead I is mostly negative; lead III is mostly positive.

Therefore the axis is close to +120 o. Because aVR is slightly more positive, the
axis is slightly beyond +120 o (i.e., closer to the positive right arm for aVR

3 Types of heart block

Blocks in conduction pathways!
First degree heart block:
Prolonged PR interval (>0.20 s)
Slowed conduction thru AV node, still conducted from SA node
Second degree heart block:
Some impulses not transmitted thru AV node & dont make it to ventricle, still
conducted from SA node; missing ventricular depolarization & contraction
hence get missed beat/QRS complex
2 types:
Mobitz I: Wenckebach phenomenon- progressive lengthening of PR int. ending in
1 dropped beat; PR keeps getting longer b4 u have missed QRS (missed beat)
Mobitz II: No measurable lengthening of PR interval (remains same) but still
missing QRS complex/ beat

Third degree heart block: complete heart block; no impulses get beyond AV
node (no impulses to ventricular) b/c tissue dead or; so purkinje system takes
over (at 20-40 beats/min), atrial contraction faster (fine) but ventricular
contraction slower & no coordination btwn atria & ventricles

asure PR interval; >0.2 s = 1ST degree heart block

394

Cardiac arrhythmias are diagnosed best by ECG

Diseases characd by irregularity in initiation & conduction of
impulses leading to irregular rhythm of heart are called cardiac
arrhythmias
Example: Heart block:

395

First degree heart block

Wenckebach phenomenon in 2nd degree heart block

P

396

Third degree (complete) heart block

QRS
QRS

See independent P waves & QRS complexes w/no correln

Occasional QRS complexes

No impulses conducted from atria to ventricles

Atria & ventricles beat independently since of intrinsic rhythmicity of Purkinje
fibers/ventricles (slower)
ECG shows no correln btwn P waves & QRS complexes
Frequency of P waves greater than that of QRS complexes
Ie. Stokes Adams syndrome: transient LOC, pt will regain consciousness as ventricle
begins to contract at firing rate of purkinje system
More P waves than QRS complexes!

ECG in Atrial Fibrillation (A-fib)

Mitral stenosis, hyperthyroidism can lead to atrial fibrillation
ECG in atrial fibrillation: multiple foci of impulse generation in atria (from atria & SA
node, normally only SA node); ECG shows multiple, low voltage, irregular P
waves; few impulses reach ventricle producing QRS waves
Atria fails to contract as single unit
Atrial contribution for ventricular filling is zero

QRS complex

QRS complex

MC chronic arrhythmia
Etiologies: ischemia, atrial dilation in MS (valve dis), trauma,
Complications: Embolization
P waves replaced by fine, undulating fibrillatory waves (f waves)
Rx: Rate control, cardioversion w/drugs or electricity

RR Irregularly irregular interval

No P waves - Irregular baseline
R-R interval is irregular
Atrial rate: 350-500 bpm
Ventricular rate: variable
Carotid massage: may slow ventricular rate

(A)Atrial fibrillation w/a slow, irregular

Blood supply to heart

aka the Coronary as! (LAD, RC, & LCC)
1. L ant descending (LAD) coronary a: supplies entire ant portion/wall of LV & ant
2/3rd of IVS; accts for 40-50% of coronary a thrombosis
2. R coronary a: supplies entire post & inf pt of LV, post 1/3rd of IV septum, entire RV, SAN & AVN;
accts for 30-40% of coronary a thromboses
3. L circumflex coronary a: supplies lateral wall of LV; accts for 15-20% of coronary a thromboses

Angina, once they start resting goes

away = exertional/classical angina
Angina can also happen due to spasm
of coronary a

399

ECG in ischemic heart diseases (IHD):

a. ECG changes in angina
IHDs: disorders due to abnormalities in blood supply to heart
(coronary circulation)
Lack of BF produces ischemia & attacks of chest pain called
angina pectoris
ECG changes: Depression of ST segment; T wave inversion
R

Normal ECG

Patients ECG

ST segment
depression

T wave inversion
400

ECG in ischemic heart diseases (IHD):

b. in MI
MI: when blood supply completely stopped, myocardial cells in
that region die; ECG changes show elevated ST segment &
pathologic Q wave
R

T
T

Q S

S
Q

S
Q

Q S

A. Normal ECG prior to MI

B. During acute stage of MI: Marked ST elevation &
shorter/sharp (hyperacute) T wave
C. After few hrs of MI: Pathologic Q waves, less ST elevation
& inverted T wave
D. After many days of MI: Pathologic Q wave alone persists
indicating old infarct (persists for rest of their
401 life!)

ECG in electrolyte imbalance : Hyperkalemia (>5.5 K+ lvls)

Hyperkalemia means elevated plasma potassium lvl
Abnormal slowed down rate of repolarization of myocardium
At extremely higher lvl, myocardium is unexcitable
Heart stops in diastole & fatal
ECG changes: Tall T waves (defective repolarization)* most
imp (b/c taking more time to undergo repolarization)
proLong PR interval (increased AV delay)
Prolonged wide QRS (altered excitability)

402

ECG in
Hyperkalemia

Tall T wave

Flat or low
amplitude T wave
in Hypokalemia
403

LAD supplies ant wall & IV septum; represented by v1, v2, v3, v4
ACUTE ANT WALL MI:
ST segment elevation in Lead I & aVL (little bit)
Lead I, aVL, v2, v3, v4 represent Lateral wall?

Extensive ant wall MI

404

ACUTE Inf wall infarction

e b/c ST segment is elevated, also see depression in V2 ST segment

rocal changes in Lead II, III, aVF elevated ST segments
segment ST depression

below: ST elevation imp!

RCA

405

HYPERTROPHY
ATRIAL ENLARGEMENT

406

LEFT ATRIAL ENLARGEMENT

Greater
than 2.5 mm
wide

SEEN IN PTS w/MS, MR

Note notching here!

RIGHT ATRIAL ENLARGMENT

RIGHT ATRIAL ENLARGEMENT
see P Pulmonale (enlarged P wave!)

MC w/pulmonary stenosis hence called P Pulmonale; or tricuspid

regurgitation & stenosis
Still greater than >2.5 mm but note its wider on R side
408

409

V3 perpendicular to direction of QRS

Big R waves in V4, V5, & V6 = means depolarization current coming twds them!
If L ventricular hypertrophy more current twds L ventricle, R wave will get
bigger in V5, V6 >35 mm!!!!!; V1 & v2 more current going AWAY from it, so S
wave will get deeper
410

Normal chest lead pattern

411

LEFT VENTRICULAR HYPERTROPHY

If L ventricular hypertrophy more current twds L ventricle,

R wave will get bigger in V5, V6 >35 mm!!!!!; V1 & v2 more
current going AWAY from it, so S wave will get412deeper

413

FT VENTRICULAR HYPERTROPHY, S wave Lead I + R wave of Lead V6 = >35

414

415

RIGHT VENTRICULAR
HYPERTROPHY
R wave in Lead v1 + S wave lead V6 = >10
Taller R waves in V1 or V2 (>7)
Deeper S waves in V5 or V6 (>7)

416

Signs & symptoms of renal disorders

Anemia: normocytic, normochomic anemia due to lack of EPO
Haematuria (RBCs in urine)
Proteinuria (protein in urine; albumin in urine = albuminuria; seen in
nephrotic syndrome/nephritic syndrome & diabetics)
Polyuria (large volume of urine, >3L/day, normally 0.5-1.5 L/day)
Oliguria (small volume of urine, <400ml/day)
Anuria (absence of urine; less than 50ml/day)
Anasarca (generalized edema due to renal disease/disorder (ie.
Nephrotic/nephritic syndrome)
Hypertension: high BP in renal a stenosis
Vit D deficiency: inactive form cant be converted to active form
Uremia (accumulation of nitrogenous wastes)
Disorders:
Renal insufficiency (azotemia): means renal failure
Azotemia: accumulated azole groups or nitrogen in blood thus
accumulated urea in blood; azotemia used interchangeably w/renal
insufficiency)
Uremia (end stage renal disease): very severe renal failure w/need
for dialysis; severe urea lvls in blood, worse than azotemia; used

Functional unit of kidney: Nephron

Each kidney contains ~1 mil

nephrons
Each nephron consists of:
a. Renal corpuscle: made of
glomerulus & Bowmans
capsule/space; does
FILTRATION of plasma (from
glomerulus into Bowmans
capsule/space)
b. Renal tubule: proximal tubule,
loop of Henle, distal tubule,
cortical & medullary collecting
ducts; does REABSORPTION
(reabsorbed from tubules into
PTCs) & SECRETION (from
PTCs into tubules)

Nephrons are structural & funcal units of kidney

Different segments of the tubule
Each nephron consists of
Proximal convoluted
Glomerulus- capillary in
Bowmans capsule, glomerular tubule (PCT)
capillary network, afferent &
efferent arterioles
Proximal convoluted tubules:
has convoluted tubule & str8 pt
Straight part
continues as descending
of PCT
limb of LOH continues as
thick ascending limb
continues as early distal tubule
(macula densa cells here btwn
thick ascending & early distal
tubule measure [NaCl]s]
continues as late distal tubule
continues as cortical
Descending limb
collecting duct continues as
of loop of Henle
medullary collecting duct
Loops of Henle- Ascending &
descending loops
Distal convoluted tubule
Collecting duct

Distal
tubule

Thick asc
limb of lo

Colle

419

Thin ascending limb

of loop of Henle

Peritubular capillaries surround tubules

Low hydrostatic
pressure
= CORTICAL
INTERSTITIUM
Proximal convoluted
tubule (PCT)

HIGH hydrostatic
pressure
= MEDULLARY
INTERSTITIUM
Descending limb
of loop of Henle

Thin ascending limb

of loop of Henle

Distal convoluted
tubule (DCT)
Thick ascending limb
of loop of Henle
Collecting duct
Funcs of PTCs:
Carry reabsorbed substances back to
general circulation
Secrete substances into tubules
Provide blood supply like in any other
organ
Help maintain osmotic gradient in
medullary interstitium [maintain higher
osmotic pressures in medullary interstitium
compared to cortical interstitial osmolarity]; has
low hydrostatic pressure = aids in reabsorption

 2 capillary networks & 2

arterioles (glomerular
capillary, peritubular
capillaries, afferent &
efferent arterioles)
AA GC [high hydrostatic
pressure: aids in filtration]
efferent arteriole PTC
[low hydrostatic pressure:
aids in reabsorption]
2 sets of arterioles = allows
for changing resistance
whichll thereby change BF
Renal a divides into
segmental as then
interlobar as arcuate
as interlobular as!
Afferent arteriole arises
from interlobular a***;
afferent arteriole
continues as GC PTC
interlobular v (all
backwds as vs)!

2 types of nephrons
A. Cortical nephrons: most numerous & have
corpuscles near surface of kidney
7/8 of all nephrons
Glomeruli in OUTER cortex
SHORT loops of Henle that descend only till
outer medulla
Tubules in cortex supplied by PTCs (hence,
these essential for tubular transport
(Reabsorption/secretion))
B. Juxtamedullary nephrons: have corpuscles
in inner cortex, near medulla & help in
concentration-dilution of urine
1/8 of all nephrons
Glomeruli at corticomedullary junc (near
inner medulla) as LONG LOH that descend
deep into inner medulla
Have VASA RECTA in addition to PTCs.
Vasa recta: lie parallel to LOH & have
hairpin turn; serve as counter-current
exchangers essential for production of
concentrated urine (by raising osmolarity of
interstitial done by VASA RECTA)

Renal corpuscle funcs in filtration!

Bowmans capsular space
Proximal
convoluted
tubule (PCT)
Podocytes

Glomerular capillaries
Bowmans capsule

Afferent arteriole

Foot processes
of podocytes
Efferent arteriole

Renal corpuscle consists of 2 structures:

a. Interconnected capillary loops, GCs
b. Bowman's capsule surrounds capillary tuft
. Plasma gets filtered into Bowman's space as glomerular filtrate; everything
in blood except proteins & RBCs)
. Bowman's capsule (via space) opens into PCT (proximal convoluted
tubule)

IMP for diagnosing in pathology; know each & their func

JG cells monitor
pressure as
baroreceptors,
secrete renin when
low BP or signal
from macula densa
cells (when low
sodium chloride)

Endothelial cells

3 primary funcs of intraglomerular mesangieal cells: filtration, structural support, & phagocytosis
Filtration & structure :
1. Intraglomerular mesangial cells provide structural support for & regulate BF of GCs by their contractile activity; initiation of contraction of mesangial cells is
424
similar to that of smooth m
2. Contraction of mesangial cells is coupled by that of basement memb of GCs, causing decrease in surface area of basement memb. Thus, decreasing GFR.
When mesangial cells contract, lumen of capillary gets smaller, so surface area for filtration decreases, thus filtration coefficient decreases!!!!!
Phagocytosis: mesangial cells also phagocytize glomerular basal lamina components & immunoglobulins; theyre unusual ex of phagocytic cells derived from

Glomerulus
Function is Ultrafiltration of blood
Filtrate is cell-free & protein-free
FREELY FILTERED substances: [small solutes] in filtrate is
same that in plasma
Glomerulus Receives high BF; forces involved in glomerular
filtration similar to those involved across other systemic
capillaries (Starling forces)
Permeability characs of filtration barrier are diff
Capillary surface area is large
Glomerular filtration rates much higher than filtration rates
across non-renal capillaries

425

The Juxtaglomerular Apparatus (JGA)

Structures very close to glomerulus make juxtaglomerular
(JG) apparatus
JG apparatus is made up of three cell types:
1. Granular cells (or Juxtaglomerular cells) in afferent
arteriole
2. Extraglomerular mesangial cells (or Lacis cells)
3. Macula densa cells are modified epithelial cells of early
DCT

Funcs of JG apparatus:
1.
Secrete renin to initiate renin-angiotensin-aldosterone mechanism of reg of arterial BP
2.
Autoreg of glomerular filtration of single nephron by -Tubuloglomerular feedback
mechanism

427

Glomerular Filtration

GFR: measures glomerular filtration; rate at which plasma is filtered into Bowmans capsules of all funcing
nephrons of both kidneys in mL/min or L/day
~125 mL/min or 180 L/day plasma is filtered in adult; & entire plasma of 3 Ls filtered 60 X/ day
enables kidneys to excrete large quantities of waste products & regulate constituents of ECF very precisely
filtrate is called ultrafiltrate which has all components of plasma except plasma proteins
Ie. Constriction/Obstruction of Ureter: increases hydrostatic pressure of Bowmans Space, decreasing
GFR; doesnt change RPF b/c obstruction only inhibiting urinary flow = FF decreases = renal failure
develops

Layers of Glomerular Filtration memb

Bowmans space

Foot processes

Podocyte

B.M.
N

Glomerular filtration barrier

Filtration occurs thru filtration barrier which has 3 layers:
1. endothelium of GC
2. basement memb (has ve charges, now say they all do)
3. Epithelial cells (podocytes) surrounding GC

3
2
1

Dynamics of Glomerular filtration

Characs of glomerular filtration barrier
Endothelial cells have pores (fenestrated) large enough to allow fluid,
dissolved solutes & plasma proteins to pass thru
-vely charged basement memb repels vely charged large solutes such
proteins (GBM formed by collagen, laminin, other EC matrix proteins such as vely charged
proteoglycans (heparan sulfate))

Filtration slits (smaller than endothelial pores) have selective permeability

Adv of selective permeability of filtration barrier

Prevents loss of plasma proteins (not even smallest protein, albumin doesnt get filtered)
Allows large quantity of fluid to get filtered into Bowmans space

In certain glomerular diseases (Eg: Minimal change disease) - loss of ve charges,

causes leakage of proteins into filtrate resulting in proteinuria, hypoalbuminemia &
edema.
No damage to capillary wall; min change disease can lead to nephrotic syndrome in kids

(Focal segmental glomerulosclerosis & Membranous nephropathy): other 2 causes of

nephrotic syndrome in adults (excretion of proteins in urine >3.5 g/day => exceeds
rate of protein synthesis in liver), oncotic pressure of capillaries in tissues decreases
430
& present w/edema; see loss of ve charges

Dynamics of Glomerular filtration

Glomerular filtration occurs b/c of net outdriving force existing across GC bed at
beginning of capillaries.
These forces (Starling forces) similar to those in any other systemic capillary

GCs ONLY HAVE FILTRATION (& NO absorption of fluid back into capillaries)

Filtration STOPS somewhere at END of GCs b/c of filtration equilibrium (Net

force becomes ZERO)
GFR (Glomerular Filtration Rate): rate at which fluid is filtered into Bowmans space
Starling forces across GCs & formula for calculating GFR

GFR = Kf [(PGC - PBS) (GC BS)]

Where
GFR = Glomerular filtration rate (mL/min)
Kf = Filtration coefficient (hydraulic conductance of filtration barrier)
PGC = Glomerular capillary hydrostatic pressure (mm Hg)
PBS = Hydrostatic pressure in Bowmans space (mm Hg)
431
GC = Glomerular capillary oncotic pressure (mm Hg)
BS = Oncotic pressure of fluid in Bowmans space(mm Hg)

[(PGC - PBS) (GC BS)] = NET FILTRATION

Net filtration pressure & GFR can be

rewritten as
Net filtration pressure = [(PGC - PBS) GC]
AND
GFR = Kf [(PGC - PBS) GC]

432

5 Determinants OF GFR
2. Glomerular capillary hydrostatic pressure (P GC) MAIN FACTOR
THAT DETERMINES GFR
1. Filtration coefficient (Kf ): depends on: (1) water permeability of filtration
barrier & (2) Total surface area of GC bed; Kf for GCs is much more than
that for systemic capillaries (GFR 180 L/day); surface area of GC bed can be altered
by several substances

2. Glomerular capillary hydrostatic pressure (PGC): force favoring

filtration (major outdriving force); main factor that determines GFR;
relatively high (45-60 mm Hg) vs. systemic capillaries; remains constant
along entire length of GC (shows pressure drop in systemic capillaries!);
decreases w/decrease in MAP & vice versa; can change w/changes in
resistance of AA or EA (see later)

433

5 Determinants OF GFR
3. Hydrostatic pressure in Bowmans space (PBS): fluid pressure in
Bowmans capsular space which OPPOSES FILTRATION; ~10
mm Hg; increases w/obstruction to urine flow (ex: ureteric
obstruction by stone or tumors of pelvis) & causes filtration rate to
decrease; Ie. Constriction/Obstruction of Ureter:
increases hydrostatic pressure of Bowmans Space,
decreasing GFR; doesnt change RPF b/c obstruction only
inhibiting urinary flow = FF decreases = renal failure
develops
Ex: Benign prostatic hyperplasia: MC cause in males for renal
tract obstruction, can increase hydrostatic pressure of Bowmans
space; fluid backs up into kidney, kidney enlarges (hydronephrosis), most imply DECREASE in GFR WHICH leads to
post-renal failure thus decreased in FF
4. Glomerular capillary oncotic pressure (GC): determined by
[plasma protein] of GC blood; OPPOSES FILTRATION;
progressively increases as BFs along GC due to filtration of large
quantities of fluid; when increases to certain value, net filtration
pressure becomes 0 & glomerular filtration STOPS (Filtration
Equilibrium; see fig)
5. Oncotic pressure of fluid in Bowmans space (BS): force
created by proteins present in Bowmans space & is NEGLIGIBLE

Dynamics of Glomerular filtration

Due to Starling forces acting at beginning of GC, filtration
occurs, since net filtration pressure is outwd
At end of GC, algebraic sum of Starling forces is ZERO &
filtration stops. (Filtration Equilibrium)
driving force for filtration is net filtration pressure
GFR is 0 if NFP is 0; Filtration stops
GFR alters by alteration in above factors

435

Glomerular Filtration is determined by

Starlings forces
Net filtration
pressure
(NFP) is the
difference
of these forces:
NFP = [(PGC - PBS) GC
Force favoring filtration:
Glomerular capillary hydrostatic pressure (PGC)
Forces opposing filtration:
1. Hydrostatic pressure in Bowmans capsule (PBS)
2. Oncotic pressure in GC (GC)

Beginning
Net filtration
of plasma
occurs due to
outdriving
force all along
GC

END
Filtration STOPS
at efferent end
of GC due to
Filtration
equilibrium (net
pressure = 0)

437

Problem:
Pressures recorded at the glomerulus are
given below:
Glomerular cap hydrostatic pr (PGC) = 45
mmHg
Bowmans capsule hydrostatic pr (PBS) = 10
mmHg
Glomerular capillary oncotic pr (GC) = 25
mmHg
What is the net filtration pressure (NFP)?
What is the direction of fluid flow?

Solution:
NFP = (PGC PBS GC)
= (45 10 25) = +10 mmHg
Since the NFP is positive, filtration is taking

Changes in filtration coefficient (Kf)

alters
GFR coefficient increases GFR; Exs:
Increase
in filtration

Increase in BF to kidney
Agents that relax mesangial cells (eg: ANP, DA)
Inflammation increasing permeability of filtration barrier

Decrease in filtration coefficient decreases GFR; Exs:

Loss of glomeruli (decrease in filtering surface (decreases SA,
decreasing Kf, decreasing GFR) Ie. Diabetes & hypertension; Kf
decreases
Agents contract mesangial cells (A-II, NE, AVP/ADH)
All elevated when you have low BV/BP; want to filter less SA
decreases via mesangial cells contracted
Thickened filtration barrier as in DM, decreasing Kf, gradually we
lose more glomeruli in these pts, GFR decreases & kidney func
gradually decreases until reaching end stage renal failure
kidneys will shut down completely & pts must live on dialysis
unless they get donor for kidney transplant

Increase in hydrostatic pressure (PBC) of

Bowmans capsule decreases GFR
Ex: Renal stones, Ureteric obstruction or
constriction of ureter decrease GFR
Mechanism:
Obstruction to urine flow

Rise in PBC

Decrease in net filtration

pressure

Decrease in GFR
3 types of renal failures:
Renal failure to obstruction of urinary flow is Post-renal failure! (SHOWN
ABOVE)
Intrinsic renal failure if problem/damage w/kidney
If low BP/RV BF decreases kidneys go into PRERENAL failure

Constriction of
afferent arteriole
decreases GC
hydrostatic
pressure & also
renal plasma flow &
thereby GFR

Constriction of
efferent arteriole
increases GC
hydrostatic pressure
& thereby increases
GFR; but decreases
renal plasma flow
If you constrict efferent arteriole nephron flow decreases b/c
youre offering resistance in series renal plasma flow decreases;
hydrostatic pressure in GC increases GFR increases!

441

Regulation of GFR

Normal GFR is ~125 mL per min

GFR is autoregd. i.e., kept constant over wide range, 60-160 mm Hg of MAP,
even though MAP is major factor that determines GC pressure & thus GFR
Autoregd b/c renal BF is autoregd
same theories (Myogenic & juxtaglomerular) that are explained for autoreg of RBF
also apply for autoreg of GFR
Renal BF directly influences GFR independent of Starling forces (i.e., Higher the
flow, higher the GFR)

The following are the pressures recorded at beginning

of glomerular capillaries in an experimental animal.
Glomerular capillary hydrostatic pressure = 50 mm Hg
Hydrostatic pressure in Bowmans space = 10 mm Hg
Glomerular capillary oncotic pressure = 27 mmHg
Oncotic pressure of fluid in Bowmans space = 0 mm
Hg
The net filtration pressure (in mm Hg) is closest to:

1.
2.
3.
4.
5.

13
20
33
47
87

Efx of independent isolated constrictions or dilation

of AAs & EAs

Special features of renal vasculature

Renal vasculature
Renal artery
Afferent arteriole

2 sets of arterioles & 2 sets of capillary beds in series

GC bed has high pressure (due to presence of additional resistance
ahead of it)- For filtration
PTC bed has low pressure (due to presence of additional resistance
behind it)- For reabsorption

Special features of renal vascula

R1
R2
45 mm Hg

Glomerular capillary
FILTRATION

Efferent arteriole
Peritubular capillary
REABSORPTION

Small veins
Renal vein

G.C
FILTRATION
R1 = Afferent arteriole
R2 = Efferent arteriole
444

Per
ar
cap

7-8 mm Hg
REABSORPTIO

Renal blood flow

Receive 25% of CO (1200 ml/min)

Nonuniform in cortex & medulla (large flow to cortex for large amts of filtration at glomeruli; less
flow to medulla to keep high osmolarity of medullary interstitium)
Autoregd
Measured by Fick principle using PAH (all this excreted in urine(
Importance of less BF to medulla = to keep solutes in its vessel; maintaining high solute
concentration/high osmolarity to produce concentrated urine
If medullas BF increases, solutes will be washed out
To produce highly concentrated urine, must reabsorp maximal quantity of water; need high
osmolarity in interstitium (thus must accumulate solutes here; [solute] must be higher)
Thus, when body in need of water (ie. Dehydration), medulla will max its osmolarity to reabsorp
max water
Formula same as Q = change in P/ resistance

Regulation of renal blood flow

Pressure gradient (btwn renal a & v)
Blood flow = -------------------------------Renal vascular resistance (provided by 2 sets of445
arterioles)

Regulation of renal blood flow (RBF)

1.

Symp NS & circulating catecholamines innervate both afferent & efferent arterioles producing
vasoconstriction by activating 1 receptors; far more 1receptors on Afferent arterioles causes
decrease in both RBF & GFR to divert blood circulation twds brain
1.
Only comes into play in extreme conditions, ie. Severe hypotension, severe hypovolemia
2.
Resistance in AA will be greater than in EA hydrostatic pressure in GC decreases!
3.
GFR decreases less than renal BF b/c both arterioles constrict; AA constriction decreases
GFR but constriction of efferent favors GFR slightly (or decreases GFR to lesser extent, b/c EA
constriction tends to raise hydrostatic pressure little bit; imp for filtration fraction)

2.

Angiotensin II potent vasoconstrictor of both afferent & Efferent arterioles. But EAs more
sensitive of AG II efx increase FF!

THUS, LOW LVLs of AG II constricts Efferent arterioles & increases GFR

HIGH LVLs of AG II constricts both afferent & efferent arterioles & decreases GFR
Ie. Renal a stenosis: RBF to kidney decreased hydrostatic pressure of GC decreases GFR
decreases, low pressure sensed by JG cells renin aldosterone AGII increases constrict
EA hydrostatic pressure of GC goes back to normal GFR goes back to normal; THUS AGII
maintains GFR by maintaining hydrostatic pressure by increasing EA constriction! These pts present
w/hypertension due to high lvls of AG II
.Do not give these pts ARBs, ACE inhibitors, AGII receptor blockers (otherwise develop
renal failure!)
3. PGs (PGE2 & prostacyclin locally made) dilates AA to increase RBF by vasodilation (Prostaglandin E2 & I2),
NSAIDS inhibit PG synthesis ( decreasing GFR); tubules primarily synthesize PGE2, while
glomeruli produce both PGE2 & prostacyclin. Renal PGs have imp local funcs but little
systemic activity, since theyre rapidly metabolized in pulmonary circulation
4. DA bind to D1 receptors causing dilatation esp in AAs increases RBF by renal vasodilation, but
constricts skeletal m & cutaneous arterioles by stimulating a1 receptors; used in tx of hemorrhagic
shock
446

Autoregulation of renal blood flow

RBF kept constant over wide range of MAP (60-160 mm Hg)

Renal vascular resistance changes proportionately as MAP changes (recall
Q=P/R)
Afferent arteriole is seat of resistance
Explained by Myogenic & Tubuloglomerular feedback mechanisms
Myogenic hypothesis:
Increase in renal arterial pressure stretches walls of AAs stretch causes
opening of stretch-activated Ca2+ channels in smooth m cell memb causing
reflex contraction of smooth ms of AAs
This increases afferent arteriolar resistance which in turn balances Renal BF
Ie. Hemorrhaging, MAP decreases, renal BF decreases; resp
lower resistance & dilate; AA undergo dilatation to allow more
blood to come into kidney; this is referred to as autoreg??
447

Mechanism of
Tubuloglomerular feedback

1 4
3

Controlled by JGA!

2
1

Renal arterial
pressure RBF
& GFR
Delivery of Na+, Cl- to
JGA
Macula densa of JGA
secretes adenosine, kinins
which cause afferent
arteriolar constriction
(increasing resistance)

RBF GFR
448

Filtration Fraction

Expresses relnship btwn GFR & renal plasma flow (RPF)

GFR
Filtration fraction =
----------RPF
= fraction of renal plasma flow filtered across GCs
Normal FF = 0.15 to 0.20 (15-20%) only 15-20% of plasma that enters
glomeruli is actually filtered
FF depends greatly on total RBF & GFR: When renal BF low, FF increases
if GFR is constant (FF inversely reld w/RPF)

4 Factors affecting FF:

Renal plasma flow: longer fluid remains in GCs greater %age of fluid gets to
be filtered. THUS, as flow decreases, FF has tendency to increase
EA constriction: decreases RPF & increases GFR & thus, increases FF
Symp stimulation: increases FF by vasoconstriction (far more 1receptors on
AAs. Thus decreases both RBF & GFR . Decrease in RPF is more than
decrease in GFR)
Constriction/obstruction of ureter: Increases PBS & decreases GFR, decreases
FF

Increased Plasma protein concentration

- GFR Decreases; FF Decreases

Decreased plasma protein concentration

- GFR Increases; FF - Increases

449

Efx of differential constrictions of AA & EAs on FF

Constriction of Afferent:
Decrease in plasma flow
Decrease in GFR
No change in FF

Constriction of Efferent:
Decrease in plasma flow
Increase in GFR
Increase in FF

Renal tubules modify ultrafiltrate

by reabsorption & secretion
plasma

1. Tubular reabsorption:
movement of substances from
tubular fluid to blood
(Bowmans space PTC)
2. Tubular secretion: movement
of substances from blood into
tubular fluid (PTC
Bowmans space excretion)

URINE: what is remaining in tubular fluid after

these processes & gets excreted
451

Tubular epithelial cells & capillaries are very close to

each other that helps movement of solutes & water
from one to other easily
Transcellular: across ()
across PTC
Paracellular: thru juncs (up
or down btwn cells)

452

Major cells (P & I) in late distal tubule

& collecting ducts
P (principal) cells:
predominate & involved in
sodium & water
reabsorption
I (intercalated) cells:
present in smaller #s &
concerned w/acid
secretion & bicarbonate
reabsorption

453

Measurement of reabsorption & secretion

Filtered Load (FL): rate that substance is filtered into Bowmans
space per unit time (unit: mg/min)
FL = GFR x [substance] in ultrafiltrate
- freely filtered substance: its [ultrafiltrate] & [plasma] are
same; filtered load for freely filtered substance is calculated: FL
= GFR x [substance in plasma] (Psub)***
- Freely filtered substances: Na+, K+, glucose, bicarbonate, urea,
creatinine
- Substances NOT freely filtered: plasma proteins, substances
bound to plasma proteins
- For ex: If GFR is 120 mL/min & [plasma] of freely filtered
substance (ie. Glucose) is 200 mg/dL (2mg/ml), calculate the
filtered load?
- Answer: filtered load is 240 mg/min (120 ml/min X 2 mg/ml)
- Can you calculate the filtered load of Inulin & bicarbonate
454
- Inulin (2mg/ml) & Plasma bicarbonate (24mEq/L)

Measurement of reabsorption & secretion

Excretion rate: amt of substance excreted in final urine per min (unit: mg/min);
= Volume of urine per min x [substance] in urine
Excretion rate = V x Usub
For substance(s) only reabsorbed: amt reabsorbed/min = Filtered load Excretion rate
For substance(s) only secreted: amt secreted/min = Excretion rate Filtered load

Net transport: sign of calculated # will indicate 3 basic categories: (0= no net
transport, + = net reabsorption; - = net secretion)
Net transport rate = filtered load excretion rate = (GFR*plasma conc) (urine vol*urine conc)
Ques: Given following info, calculate reabsorption rate for glucose
GFR = 120mL/min,
plasma glucose = 300 mg/100 mL,
urine flow= 2mL/min,
Urine glucose= 10mg/ml
Answer = 340mg/min
455

Renal handling of 4 hypothetical

substances A, B, C & D

Substance A is ONLY Filtered:

Amt Filtered = amt Excreted
GFR x P = U x V
Ex: Inulin, 120 mL filtered out of 600 mL;
thus clearance of inulin & plasma able to rid of it is 120 mL
FILTERED LOAD = EXCRETION RATE

Substance B is Filtered &

partially reabsorbed:
Amt Filtered > amt Excreted
GFR x P > U x V
Exs: Sodium, chloride

456

Renal handling of 4
hypothetical substances A, B,
C and D
Substance C is Filtered &
completely reabsorbed:
amount Filtered > amount
Excreted
and UxV is zero
Ex: Glucose

Substance D is Filtered & completely secreted:

Amt Excreted > amt Filtered
UxV > GFR x P

Ex: Para amino hippuric acid (PAH)

You only filter 20% of renal plasma; 80% remaining goes into PTCs & secreted by excretion! Ie. PAH; if
you administer PAH & maintain its low concentrations in blood, whatever amt of PAH going into
kidneys, is eliminated from kidneys; 20% eliminated by filtration, 80% by secretion
Amt of PAH cleared by kidney? 100%, by 100% (600 mL), thus clearance of PAH is 600 mL!
(understand term clearance)
Clearance: amt of plasma flowing into kidney that rids of a substance

TUBULAR TRANSPORT OF SOLUTES

Solutes get transported in 2 directions:
a. Reabsorption from tubular fluid to blood; exs: Glucose, Sodium, Potassium
b. Secretion from blood to tubular fluid; exs: Creatinine (some portion also secreted
by kidneys), H+, K+
Solutes get transported by 2 mechanisms:
c. Active transports - Primary or secondary; exs: Sodium, Glucose, AAs
d. Passive transports simple or facilitated diffusion; exs: Urea, Fructose
Solutes follow transport maximum (TM): transport by TM system; exs: Glucose, AAs,
Calcium, PAH
.Transport Max (TM): when substance transported (reabsorbed or secreted) across
renal tubular cells w/help of carrier (transport protein), carrier gets saturated after
filtered load of that substance reaches certain lvl. At this point, max limit of transport
by tubules is reached; max rate that substance is transported across tubules
E.g., When filtered load of glucose reaches beyond certain value, transport max for
glucose [TMG ] is reached. TMG is ~375 mg/min. This occurs in DM w/high plasma
glucose lvl & a large filtered load of glucose. Filtered Glucose in excess of TMG is
excreted. But please note glucose starts appearing in urine even b4 TMG is reached
TM applicable only to transport systems that have high affinity for substrates
w/low back458
leak of substance

Renal clearance

Renal clearance: volume of plasma cleared of substance by kidneys in

mL/min or L/hr or L/day); theoretical volume of plasma from which
substance is removed over unit time
Higher clearance more plasma is cleared of substance
If substance is completely removed from plasma (by kidneys), has highest
clearance
Substance w/low clearance is less removed from plasma (by kidneys)
Substance w/zero clearance will not be removed by kidney (ex: glucose)

Excretion rate of substance

Clearance =
[substance Plasma]
Usub = Concentration of substance in
urine (mg/mL)
V = Volume of urine per minute
(mL/min)
Psub = Concentration of substance in
plasma (mg/mL)

459

For example, if the plasma concentration of substance X is 4

molecules/L & the excretion rate of X is 4 molecules/min, then the
volume of plasma cleared of X (clearance of X) is 1L/min

What happens to the clearance of X???

If the excretion rate of
X decreases to 2
molecules per minute?
ANSWER: 0.5 L/min

If the plasma concentration of X

decreases to 2 molecules per liter
& the excretion rate remains at 2
molecules per minute?
ANSWER: 1 L/min

460

Problem:
Calculate clearance of the following substances, X, Y & Z with the
following data & comment on each:
Urine flow rate = 2 ml/min
Ux = 60 mg/ml & Px = 4 mg/ml
Uy = zero & Py = 100 mg/ml
Uz = 500 mg/ml and Pz = 2 mg/ml
Solution:
Clearance, C = UV/P (all conc.s must be in same unit)
Cx = 60x2/4 = 30 ml/min (small vol of plasma is cleared of X)
Cy = 0x2/100 = Zero (substance Y is not at all cleared)
Cz = 500x2/2 = 500 ml/min (a large volume of plasma is
cleared of substance, Z)

substance having LOW CLEARANCE value = either substance is

REABSORBED highly OR NOT HANDLED by kidneys
substance having HIGH CLEARANCE value = substance is SECRETED
highly & NOT REABSORBED in kidneys

Application of clearance concept:

Clearance of inulin is index of (GFR)
How Inulin clearance is used to measure GFR
Special properties of Inulin:
It is freely filtered; neither reabsorbed; nor secreted
All filtered inulin gets excreted in urine
amt of inulin filtered in unit time =s amt excreted in urine in unit
time
(FL)GFR x Pinulin = Uinulin x V (ER)

Uinulin x V
GFR =

= Clearance of inulin
Pinulin

Problem:
Inulin is infused in a patient to achieve a
steady state plasma concentration of 1.2
mg/ml. A urine sample collected during one
hour has a volume of 120 ml and an inulin
concentration of 60 mg/ml
What is the GFR of this patient?
Solution:
GFR = Cinulin = Uinulin x V/Pinulin
= 60x120/1.2
= 6000 ml/hour or 100 ml/min
463

Inulin clearance is used to predict renal

handling of freely filtered solutes

At value of Inulin clearance or GFR, substance

is neither reabsorbed nor secreted
If clearance of substance is LESS THAN inulin
clearance: means that LESS VOLUME of plasma is
cleared of substance, hence NET REABSORPTION
of substance
If clearance of substance is GREATER THAN inulin
clearance: means that MORE VOLUME of plasma is
cleared of substance, hence NET SECRETION of
464
substance

Creatinine & GFR

Creatinine: endogenous substance freely filtered & not
reabsorbed; but very small amt of it secreted
Creatinine clearance (CCr) is slightly greater than Cinulin(GFR) b/c
small amt secreted too!!!
CCr is clinically considered as ~GFR value
In normal conditions, rate of creatinine: produced, filtered &
excreted are in constant proportion
At constant production of creatinine inside body:
decrease in GFR increases [plasma]
VS.
increase in GFR decreases [plasma]
Estimation of plasma creatinine may be used to assess GFR,
when its produced at constant rate but limitation that its NOT
sensitive measure of reduced GFR b/c increases slightly even
if theres large reduction in GFR!
465

Plasma creatinine as index of renal func

Since all creatinine that is produced is excreted, plasma
creatinine level rises as GFR (CCr) decreases

UCr. V
GFR (CCr) = --------PCr

CONSTANT

Thus plasma creatinine lvl (PCr) can be taken as index of renal

func; but this has limitation since PCr increases slightly even if
theres large reduction in GFR! (see next graph)
Plasma creatinine clinically useful estimate of GFR.
SCr doubles w/each 50% reduction in GFR. Creatine clearance
based on urinary collection considered most accurate method
466

Plasma creatinine, CCr and GFR

sig reduction in GFR can occur w/only

small elevation of plasma creatinine
Hence plasma creatinine NOT
sensitive measure for reduced GFR in
renal diseases
Clinically, measurement of creatinine
clearance (~GFR) is good index vs.
relying only on plasma creatinine

Normal
plasma
creatinine
A normal result is 0.7 to 1.3 mg/dL for men and 0.6 to 1.1 mg/dL for
467
women

Measurement of Effective renal plasma flow

using Ficks Principle & PAH!

Use Fick principle: states that amt of

substance entering kidney (in RA) = amt
of substance leaving Kidney (RV) + amt
excreted in urine
Substance used is Para-aminohippuric
acid (PAH)
Kidneys extract (remove) most PAH from
renal arterial blood by combo of filtration &
secretion
So, almost all PAH entering kidney is
excreted in urine & [PAH] in renal v is ~0
Since no other organ than kidney
extracts PAH, [PAH] in renal a is equal to
[PAH] in any peripheral v ??
20% filtration thru BS
80% secretion thru PTCs/EAs

Handling of
PAH by kidney
Renal vein contains NO
PAH

468

Measurement of Effective renal plasma flow

amt of PAH excreted per min (mg/min)
Effective RPF=-----------------------------------------------------------Renal arterial PAH conc.-Renal~0venous PAH conc.
Urinary PAH conc. (UPAH) x Urine flow rate (V)
Effective RPF=-------------------------------------------------------------Plasma concentration of PAH (PPAH)
= Clearance of PAH (CPAH)

469

Calculation of RBF
Renal Plasma Flow
RBF = ----------------------------1- Hematocrit
Problem: A man with a urine flow rate of 1ml/min has a plasma concentration of PAH of 0.01 mg/mL, a urine
concentration of PAH of 6 mg/mL & a hematocrit of 0.45. What is his RBF?
Urinary PAH conc. (UPAH) x Urine flow rate (V)
Effective RPF = ----------------------------------------------------------Plasma concentration of PAH (PPAH)
6 mg/mL x 1 mL/min
= -----------------------------0.01 mg/mL
= 600 mL/min
Effective RPF
600mL/min
Effective RBF = ---------------------- = --------------------- = 1091 mL/min
1- Hct
1- 0.45

470

Application of clearance concept:

Determination of ERPF (effective renal
plasma flow) by clearance of PAH

Determination of renal plasma flow (RPF)

Clearance of para amino hippuric acid (PAH) gives RPF
PAH is freely filtered, not reabsorbed but large amt secreted in renal tubules
At low [plasma]s, PAH completely removed by kidneys by filtration &
secretion
PAH clearance gives ERPF (effective renal plasma flow)
ERPF = plasma flowing to nephrons, excluding plasma flowing to renal
capsule, fat around kidneys effective b/c not all plasma supplying kidney gets
into PAH, some of it used to supply pts of kidneys (thus excludes plasma
flowing to nephrons & fat around kidneys)
ERPF is only 90% of actual renal plasma flow (ARPF)
UPAH x V
ERPF = PAH clearance =

ml/min
PPAH

PAH Clearance

20% PAH

600 mL/min

PAH has a high extraction ratio

Renal vein [PAH] minimal
or nearly zero

greatest clearance by
kidney is renal plasma flow
(clearance of PAH at low
[plasma]s), 120ml/min by
filtration & 480ml/min by
secretion
At low plasma conc as
such there would be no
PAH in renal venous
blood.
Following saturation not
all of 480mL/min
delivered to PTCs would
be cleared, & clearance
would decrease below
RPF(<600ml/min)

If you completely block secretion of PAH, clearance of PAH will be 120 mL! in reality, as
you raise plasma concentration of PAH, clearance goes below 600 & goes twds 120 mL
but will not reach 120 mL until you block its secretion completely.

Free water clearance (CH2O)

CH20: volume of free water cleared from plasma, & excreted in urine per unit
time
This volume of water excreted in urine DOESNT contain any solutes. This
portion is additional to isosmotic urine volume that contains solutes
CH20 indicates ability of kidney to concentrate or dilute urine (water
conservation or water lost in body)
It is calculated as:
UOsm x V
1 ques!
CH20 = V
POsm
where,
V = Volume of urine in ml/min
Uosm = Osmolarity of urine in mOsm/L
Posm = Osmolarity of plasma in mOsm/L
Ie. More water excreted from body +ve free clearane ie. DI!
Ie. Less water excreted from body -ve free clearance ie. SIADH
(more concentrated urine, more water absorbed & kept in body)
473

 Interpretation of free water clearance: indicates volume of pure water conserved

(added by reabsorption) or lost (removed by not being reabsorbed & being excreted) by
kidneys
free water clearance of 0 means kidney is producing urine thats isosmotic w/plasma
(hence kidney is neither concentrating nor diluting)
value >0 (+ve) = kidney producing dilute urine by excreting additional volume of
solute-free water
value <0 (-ve) = kidney conserving water causing excretion of concentrated urine
Conditions in which CH20 alters
Positive CH2O: Kidneys are excreting dilute urine; LESS Water reabsorption in
kidneys & so body is losing water in urine
Osmolarity of urine is less than that of plasma (hypotonic urine)
Exs: after large volume of water ingestion, DI, conditions of low plasma
ADH
Negative CH2O: Kidneys excreting concentrated urine; HIGH Water reabsorption in
kidneys & so body conserving water by renal reabsorption
Osmolarity of urine is greater than that of plasma (hypertonic urine)
Exs: All dehydration conditions, water deprivation, high plasma ADH
conditions, SIADH, alcohol (inhibits ADH secretion)
production of concentrated or dilute urine depends on circulating lvl of ADH
CH20 used to determine how well ADH funcs in kidney to regulate water balance
in body

Problem: With following data, how will you determine the role of
the kidneys in water balance of the body? Comment on hydration
of the body and plasma ADH level
Plasma osmolarity (POsm) = 300 mOsm/L
Urine osmolarity (UOsm) = 1200 mOsm/L
Urine flow rate (V) = 1 ml/min
Solution:
UOsmV
Free water clearance = V (----------) = 1 - (1200x1/300)
POsm
= 1 - 4 = -3 (negative 3) mL/min
Kidneys are CONCENTRATING URINE by water reabsorption
body is in DEHYDRATED state & water conservation by
kidneys is trying to revive water balance
475

Effect of increasing [plasma] of a substance

on clearance value of that substance
At higher [plasma]s, clearances of substances
start approaching that of inulin (or GFR);
Reason: saturation of carriers & TM
But never become equal to Cinulin b/c some
amt is always being either secreted or
reabsorbed

CInulin or GFR

200 mg/dL (renal threshold)! Where glucose 1 st appears in urine (360 theoretically)
(Concentrations of substances in plasma)

Comment on clearance of each substance as plasma concentration rises

Same graph with out the names of substances

Inulin clearance = GFR (freely filtered; no Reabsorption or secretion)

Always parallel to X-axis
Creatinine clearance = rough GFR estimate & clinically preferred
Slightly greater than inulin clearance since small amts are secreted
endogenously produced
Clearance of glucose = 0 (at low plasma lvls, normally, not in urine)
As plasma lvl rises, renal threshold is reached, once carriers saturated in
some nephrons (glucose gets in urine!) clearance of glucose becomes
+ve value (+ve clearance)
As plasma lvl rises further, clearance increases & approaches that of
inulin, but never becomes equal to it, b/c some glucose always
reabsorbed
If reabsorption of glucose was completely inhibited, clearance of glucose
would equal inulin & GFR
Ie. Flourozine inhibits reabsorption of glucose (increases clearance!)

Clearance of sodium = always +ve clearance (always in urine); flat line!

Aldosterone by increasing reabsorption of Na+ (DECREASES clearance)
ANP by inhibiting reabsorption of Na+ (INCREASES clearance)

477

Representation of transport of diff substances

A. Protein

D.Glucose,
Bicarbonate

B. Inulin

E. PAH

Identify the substances A-F

C. Sodium,
potassium

F. Creatinine
478

To review. Net effects of reabsorption &

secretion
Net transport = Filtered load Rate of excretion

GFR . Px

Ux .V

If value is positive, then substance must have got reabsorbed.

i.e., Filtered load > Rate of excretion
Ex: Sodium, glucose, urea
If value is negative, then substance must have got secreted
i.e., Rate of excretion > Filtered load
Ex: PAH, creatinine
If value is zero, then substance is neither reabsorbed nor secreted
i.e., Filtered load = Rate of excretion
Ex: Inulin

479

Concept of TF/P ratio: ratio of [substance] in tubular fluid to its [plasma] (TF/P)
For all freely filtered substances, TF/P ratio is 1 in Bowmans capsule (in ultrafiltrate)
As substance moves in tubule, its [tubular fluid] changes due its reabsorbtion or secretion in tubules
OR waters reabsorption in tubules This alters TF/P ratio of substance along length of tubule
3 possibilities of TF/P ratio:
A. TF/P of a substance = 1; (same concentration of substance in tubular fluid & plasma)
B. TF/P of a substance is less than 1 (more concentration of substance in tubular fluid > plasma)
C. TF/P of a substance is greater than 1 (less concentration of substance in tubular fluid < plasma)
If TF/P>1 = 3 possible meanings
1. Water reabsorbed in excess of substance (D) ex.
Urea*** (50%) (D) vs. water
2. Substance is neither reabsorbed nor secreted; water
reabsorbed (E) ie. Inulin*** (=3) (at end of PCT becomes
3.0 b/c 2/3rds of water reabsorbed & none of inulin
reabsorbed)
3. Net secretion of substance occurred (F) ie. PAH (secreted
in greater amts) or Creatinine freely filtered, some
secreted, so [TF] higher

If TF/P = 1: Substance is reabsorbed in same

proportion as water (A)
Ie. Na+ in PCT (equally absorbed w/H2O)

D
A
C

Length of PCT

If TF/P<1: Substance is reabsorbed in

excess of water (B & C)****
Ie. Glucose in early PCT (100%
reabsorbed) vs. only 67% of water
reabsorbed (C) (& AAs)
Ie. HCO3- (80-90%) reabsorbed (B) >67%
water reabsorption

TF/Pinulin: marker for water reabsorption along nephron; increases as water reabsorbed; inulin freely filtered, neither reabsorbed

nor secreted but water reabsorbed as TF flows thru nephron; Thus [Inulin] increases along nephron & its [highest] is in tubular
fluid of terminal CDs
following eqn shows how calculate fraction of filtered water thats been reabsorbed:

Fraction of filtered H20 reabsorbed = 1 [1/ (TF/P)Inulin]

1.
2.

For examples,
if 50% water is reabsorbed, the TF/P inulin= 2.0
if TF/Pinulin= 3.0, then 67% of filtered water has been reabsorbed
ie. PAH, creatinine, & inulin

Problem:
Match following substances to their TF/P curve : PAH, Na+, Glucose, Urea,
Bicarbonate

Solution:
PAH : curve A
Sodium: curve C
Glucose: curve E
Urea: curve B
Bicarbonate: curve D
Draw curve for
INULIN

L3: Proximal tubular funcs:

Renal handling of Glucose

Dynamics of glucose transport

Normal Fasting blood glucose: 70-100 mg/dL (3.8-5 mmol/L)
TM for glucose = 375 mg/min (renal tubules can absorb 375
mg/min back to PTCs w/out spilling glucose into urine)
At Normal [Glucose]s amt reabsorbed: 100% of FL & 0%
excreted in urine
Site of reabsorption: Proximal convoluted tubule
Mechanisms:
On luminal surface Secondary active transport by sodium
dependent glucose transporter (SGLT)
On basolateral memb Facilitated diffusion by GLUT1 &
GLUT2
Tubular transport NOT influenced by Insulin
482

Glucose reabsorption in kidney MOSTLY IN

PCT! Via SGLT & GLUT1&2

Apical memb

Tubular
fluid

SGLT

Basolateral memb

GLUT

Peritubular Capillary

Peritubular space

Phlorhizin competitively inhibits glucose binding w/SGLT inhibiting glucose

reabsorption
Most reabsorbed in proximal tubule.
At apical memb, needs Na+/glucose cotransporter (SGLUT) (sodium dependent)!
Crosses basolateral memb via glucose transporters (GLUTs) that
483 dont rely upon Na+

Glucosuria or Glycosuria

Glucosuria/glycosuria: glucose excreted in urine when plasma glucose increases; exs: In DM,
pregnancy
Theoretically, glucose must appear in urine when filtered load of glucose exceeds T M for glucose
In reality, glucose starts appearing in urine when plasma glucose exceeds 200 mg/dL (renal
threshold for glucose)
This can be explained by SPLAY pt of glucose titration curve (see next) b/c in kidney, nephrons
w/shorter PCT have less TM value & reach saturation earlier than longer nephrons (not all
nephrons same length)
Reason
for
splay:
Notshould
all nephrons
Cant rely on
[urinary
glucose],
rely on [plasma glucose]

are equal in dimension

Small nephrons:
Have shorter PCT
Have less carriers
Reach saturation early

Glucose escaping thru small

nephrons responsible for splay

Large nephrons:
Have longer PCT
Have more carriers
Reach saturation late
484

Ex
c

re
te

ed
Fi
lte
r

Amount Filtered or Reabsorbed

or Excreted per minute

Glucose titration curve

A to B:
Reabsorbed = Filtered
& Excreted = Zero

Reabsorbed
B

Spla
y

Beyond B:
Reabsorbed < Filtered
& glucose gets excreted
in the urine

As glucose starts getting in urine b4 FL of glucose reaches TM (on y-axis), splay

occurs
485
Plasma concentration of glucose at point B is Renal threshold

Problem:
Calculate theoretical plasma lvl of glucose at which it
starts appearing in urine. Given data:
GFR = 125 mL/min
TM for glucose = 375 mg/min

Soln: at filtered load (FL) >375, glucose must appear in

urine
[plasma glucose] at FL of 375 =
FL/GFR = 375/125 = 3 mg/mL or 300 mg/dL
>plasma lvl of 300 mg/dL, theoretically glucose starts
appearing in urine, but in reality, it starts appearing in
urine when plasma glucose exceeds 200 mg/dL (renal
threshold)
Ex. UTI very common in females w/glucose in urine b/c

Kidneys Sodium reabsorption & its balance

Na+ amt in ECF determines ECF volume,

which determines BV & BP thus renal
reabsorption of Na+ maintains normal ECF
volume & BP
Na+ balance is func of kidneys
Na+ excretion matched w/dietary Na+
intake
Major sites for Na+ balance in nephron:
late DT & CD (where aldosterone &
ANP act)
Sites of Na+ reabsorption in kidney:
PCT: max %age (67%; 2/3rds)
filtered Na+
LOH: moderate (25%) of filtered Na+
DT & CD (Terminal Nephron): least
(8%) of filtered Na+ (but regd in
order to maintain Na+ balance)
Reabsorption in DCT & CD variable b/c
regd by aldosterone (only 3% but still
sig!) based on bodys need for Na+

%age of filtered
load of Na+
reabsorbed in diff
pts of tubules

487

Na+ must be reabsorbed in order to absorb glucose

& other metabolites into cell!

Low [Na+] drives these molecules in & out

Mechanism of Na+ reabsorption in: EARLY PCT

Epithelial cells of Early PCT

Peritubular space

Symport

Via GLUT1&GLUT2

Antiport

80 90% of filtered
Hco3- is reabsorbed
489
indirectly

Peritubular Capillary

Tubular
lumen

Mechanism of Na+ reabsorption in LATE PCT

In luminal memb: via secondary active transport mechanisms
Cotransporter (symport) coupled w/other solutes Na+-glucose; Na+ -AAs; Na+
coupled w/phosphate/lactate/citrate
Na+-H+ exchange (antiport) (linked to acid-base balance)
In basolateral memb:
Na+ pumped to peritubular space by Na+-K+- ATPase pump
Na+ reabsorption in PCT accompanied by water reabsorption in same proportion
(TF/P for Na+=1); Tubular fluid remains ISOTONIC in PCT.
PCT is site for highest O2 consumption in Nephron
Oxygen consumption in nephron directly proportional to filtered load of Na +

490

Renal Oxygen consumption

Kidneys N consume O2 at 2X rate of brain on

per g weight basis; but have 7X BF
O2 delivered to kidneys far exceeds metabolic
needs
A-V difference for O2 very low

O2 consumption reld to high Na+ reabsorption

rate
Na+ reabsorption in turn reld to GFR &
filtered load of Na+
How to calculate Oxygen consumption in a
tissue? Need parameters: BF & A-V
(arteriovenous) difference in [O2]

O2 consumption

O2 consumption= BF x A-V difference

based on Ficks principle

Calculate renal O2 consumption given, RBF as 1200 mL/min & AV difference as 14 mL02/L (0.014ml 02/ml)
Answer: 16.8 mL/min

Basal oxygen consumption

Na+ reabsorption
What would be the result of admining ouabain that
blocks Na+ K+ ATPase pump?
491

Thin Descending Limb & Thin Ascending Limb

Thin DESCENDING limb: permeable to water & small solutes

such as NaCl & urea
Thin ASCENDING limb: also permeable to NaCl & urea, but
impermeable to water

492

Mechanism of Na+ reabsorption

in
At luminal memb:
Thick ascending limb
of LOH
Na -K -2Cl cotransporter moves 1

Normally reabsorbs ~25% of

filtered Na+.

Na+, 1 K+ & 2 Cl- into cell

In basolateral memb:

K+ leaks back to tubular fluid

causing Ca2+ & Mg2+ to be reabsorbed

Na+ pumps out of cell by Na+-K+ATPase

No water follows Na+ b/c limb
impermeable to water
Hence tubular fluid becomes
hypotonic (urine) (dilution of TF)
Cotransporter inhibited by loop
diuretics
Na+ reabsorption load-dependent

Loop diuretics: anions that BLOCK/attach to Chloride -binding site of Na+K+-2Cl- cotransporter
NaCl reabsorption in thick ascending LOH gets inhibited
Loop diuretics like Furosemide & Ethacrynic acid
At maximal doses can cause excretion of 25% of filtered load of sodium
Side efx: hypocalcemia, hyponatremia
Tx for in malignant hypercalcemia (need to rid of Ca 2+ from body)

Distal Tubule & Collecting Duct (Terminal nephron):

distal tubule & CD (terminal nephron)

together reabsorb ~8% of filtered Na+
Like thick ascending limb, reabsorption in
terminal nephron is load-dependent,
w/capacity to reabsorb extra Na+ that may
be delivered from proximal tubule
mechanism of Na+ transport in early distal
tubule DIFFERS late distal tubule & CD

Early DT: reabsorption of NaCl (5%)

w/out water; impermeable to water;

dilutes tubular fluid (cortical diluting
segment)
PTHs site of axn! stimulates Ca2+
reabsorption

Thiazide diuretics (Eg:

Hydrochlorothiazide, Indapamide
& metolazone) also inhibit Na+- Clco transporter in early DT

Make PTH more active causing side efx of

hypercalcemia

494

Late Distal Tubule & Collecting Duct

Increased K+ Excretion: when ^Na+ reaches late DT P cells ^Na+ entry into cells & then across
Na+-K+ pump at basolateral memb to blood ^K+ excretion (>Na+ delivery causes >K+ loss
HYPOKALEMIA caused by loop diuretics)
2 major cell types interspersed along late distal tubule & CD: principal cells & - intercalated cells

1.
principal cells: FOR Na+ reabsorption, K+ secretion & water reabsorption
2.
-intercalated cells: FOR K+ reabsorption & H+ secretion (bicarbonate reabsorption)

Na reabsorption in Late DT & CD

+

ENaC

Na+

Principal (P) cells of

DCT and CD

At luminal memb, have ENaC

(epithelial sodium channels) that
Na+ diffuses thru w/electrochemal
gradient into P (Principal) cells
In basolateral memb: Na+ moves
out cell by Na+-K+-ATPase
Aldosterone increases # ENaC &
Na+ reabsorption
ANP (Atrial natriuretic peptide) inhibits
Na+ reabsorption
BNP: made from ventricular m; inhibits
Na+ reabsorption in late DT & CDs; 2nd
msngr is cGMP for these; (PHARM Q
FOR PEPTIDE type drugs); ^cGMP &
PKG; used in pts w/CHF where they
already ^but not enough BNP

Potassium sparing diuretics Spironolactone

Cause diuresis, lose aldosterone, cannot secrete K+ (hyperkalemia)
K+ sparing diuretics b/c inhibit K+ secretion by Principal cells
Na+ reabsorption in Principal cells of distal tubule & CDs inhibited by
Potassium sparing diuretics. Eg: Spironolactone, Amiloride &
Triamterene
Spironolactone: aldosterone antagonist; blocks Aldosterone induced
synthesis of ENa+Cs on P cells thereby preventing Na+ reabsorption
Amiloride & Triamterene bind to luminal memb ENaCs & inhibit Aldosterone
induced Na+ reabsorption

Hormones that mediate sodium balance

Hormone

Site of action

Aldosterone

DCT & CD

Atrial natriuretic
peptide (ANP)

DCT & CD

Angiotensin II

PCT

Effect
Increases Na+
reabsorption
Inhibits Na+
reabsorption
Increases Na+
reabsorption
496

Regulation of sodium balance

Response to increased dietary sodium intake:
Increased sodium intake
Increased ECF volume & BV

Increased arterial BP
Decreased symp n activity

ANP
Secretion!

DECREASED
oncotic
pressure in PTC

Decreased renin-angiotensinaldosterone activity

DECREASED sodium reabsorption

DECREASED sodium

in DCT & CDs

reabsorption in PCT

INCREASED sodium excretion in urine

497

Regulation of sodium balance

Response to decreased dietary sodium intake:

Decreased sodium intake

Decreased ECF volume & BV
Decreased arterial BP
INCREASED SYMP N
activity

INHIBITION of ANP

Increased renin-angiotensinaldosterone activity

Increased oncotic
pressure in
So P
peritubular capillary

^Angio II

Aldosterone

Increased sodium reabsorption

in DCT and Collecting ducts

INCREASED sodium
reabsorption in PCT

Decreased sodium excretion in urine

498

Potassium reabsorption & its balance

Kidney & K+ balance: most of total body K+ is in ICF (98%)

small shift of K+ into/out cells can cause large change in ECF [K+]
Potassium balance:

Urinary excretion of K+ must match w/dietary intake

K+ balance done by combo of filtration, reabsorption & secretion by kidneys

In PCT & LOH, K+ is only reabsorbed
DCT & CD responsible for K+ balance: where K+ reabsorption or secretion occurs
depending on need for K+ balance

%age of filtered load of K+ reabsorbed or secreted in diff pts

Reabsorbed of
onlytubules
Secretion of K+ in DCT & CD depends on:
w/low K+ diet

a. Dietary potassium
b. Aldosterone
c. Acid-base status- Alkalosis causes secretion

Maximum fraction of tubular

load is reabsorbed in PCT

Mechanism of K+ reabsorption in DCT & CD

Tubular
lumen

Intercalated (I)
cells of DCT and
CD

H+-K+ ATPase

Occurs only at low K+

diet in I cells

***At luminal memb: H+-K+

ATPase moves K+ in & H+ out
cell

In basolateral memb: K+
diffuses out cell by K+
channels (K+ leaky OR via
Na+-K+ ATPase pump)

Mechanism of K+ secretion in DCT & CD

blood
P cells

-50 mV

Na+

Potassium
channels

lumen

Peritubular Capillary

Tubular
lumen

Secretion occurs in P
cells of DCT & CD

Its net transfer of K+ from

blood into lumen thru K+
channels on both sides of P
cell
Electrochemal gradient for K+
bloodinto lumen
makes it move
Magnitude of K+ secretion
depends on gradients size

Factors INCREASING K+ SECRETION in DCT & CD

a. High K+ diet: ingested K+ increases IC K+ in P cells
b. Aldosterone secretion: aldosterone stimulates K+ secretion & Na+
reabsorption
c. Alkalosis: increase in IC K+ in P cells by shift of K+ into cells when H+ ions
move out in alkalosis (hypokalemia)
Factors DECREASING K+ SECRETION in DCT & CD: low K+ diet, low
aldosterone & acidosis (opp to a, b & c)

Potassium dynamics in acid-base disturbances

(Please use animation to understand!)

ICF

ECF or Plasma
In Acidosis:
Elevated [H+]
H+
K+

ICF

Potassium moves out of

cell resulting in hyperkalemia
in acidosis

ECF or Plasma
In Alkalosis:
Decreased [H+]
H+
K+

Potassium moves in to
cell resulting in hypokalemia
in alkalosis
502

Changes in plasma Potassium can cause

acid-base disturbances
(Please use animation to understand!)
ECF or Plasma
ICF
H+
K+

ICF

ECF or Plasma

H+
K+

In hypokalemia
Potassium moves out &
H+ moves into cell
resulting in ALKALOSIS
(but intracellular acidosis!)
In hyperkalemia
Potassium moves in
& H+ moves out of cell
resulting in ACIDOSIS
(but intracellular alkalosis!)
503

UREA recycling in kidneys:

Urea moves in to thin

ascending limb of LOH
from medullary interstitium
due to [gradient]

DCT, cortical & outer

medullary CDs NEVER
permeable to urea Thus,
no urea leaves DCT,
cortical & outer
medullary CD & gets
concentrated

Inner medullary CD
highly permeable to urea
in presence of ADH

Urea gets [highly]ed as

passes thru CD b/c ADH
induced H2O reabsorption

Urea diffuses to
medullary interstitium
from lumen of inner MCD
along [gradient] IF ADH
PRESENT

Urea cycling sigly imp to

create hypertonic
medulla & to [ ] of urine

Osmotic gradient in inner

medullary interstitium can
reach up to 1200 mOsm/L
in presence of high ADH

Low protein intake (less

urea) decreases kidneys
concentrating ability

Urea reabsorption & recycling in kidney

~50% FL of urea
reabsorbed in
PCT

CCD

MCD (OUT)

Urea gets concentrated

in CCD, as water gets
reabsorbed

Urea gets concentrated

more here, as more
water gets reabsorbed

MCD (INNER)

Urea moves into

medullary
Interstitium (from
MCD) under ADH

~50% Filtered load excreted in urine

Urea recycles
btwn tubular fluid
& medullary
interstitium
Urea recycling
increased by ADH

505

Water filtered: 125 mL/min or 180 L/day ~87% filtered load reabsorbed in all circumstances & ~13%
reabsorbed depending on bodys need for water (for water balance) in DT & CD by ADH (if ADH at max, ALL
13% reabsorbed)
Water reabsorption in diff pts of nephron VIA OSMOSIS:

In PCT : 67% of filtered load (Maximum reabsorption in PCT)

In LOH : 20% of filtered load

In DT & CD : variable - up to ~13% of FL (Least: DT & CD)

87%

Water reabsorption
at diff segments of
nephron

65%

Urine 23L/day
w/out ADH!

2% without ADH

Urine 1.5 L/day

20%
Obligatory urine: amt of
urine required/excreted
to excrete certain solute
amts/day

99%
99.7%

14% with normal ADH

14.7% with max.ADH

Urine 0.5 L/day

Water reabsorption in diff pts of nephron

In PCT, highest amt water reabsorption moves to interstitium due to
osmotic gradient created by movement of solutes

In descending limb, H2O

moves out b/c increasing
osmolarity of medullary
interstitium

400
500

DT & CD impermeable
to H2O in absence of
ADH
Water reabsorption only
when ADH PRESENT
contributes to
concentration of urine

400
500

1200 Osm
Max Osm

Ascending limb, impermeable to water under all

conditions: very imp

ADH increases permeability of DT & CD

If ADH VERY HIGH = SCANTY URINE VOLUME (ie. SIADH)
If ADH DEFICIENT = as seen in DI HIGH & DILUTE URINE VOLUME
Need 2 to make concentrated urine: high ADH & hyperosmolar medullary interstitial

Mechanism of ADH axn in principal cells of DT & CD

Tubular fluid

Tubular
lumen

P cells of DCT & CD

V2 receptors

Adenylyl cyclase
enzyme
2nd messenger
AQP2: aquaporin 2 are
protein water channels
which increase water
permeability of DT & CD

Concentration-Dilution of urine
Water reabsorption in DT & CD contribute to [ ] /dilution of urine
In conditions of low vol in ECF: More water reabsorbed in these regions
due to plasma ADH concentrated urine
In conditions of excess water in ECF: Less water reabsorbed in these
regions & more water lost in urine due to plasma ADH - dilute urine
2 factors contribute to concentration of urine:
A. Osmotic gradient in medullary interstitium
B. Anti-diuretic hormone (ADH)
If anyone of above defective/absent, water reabsorption gets impaired in DT
& CD, resulting in excretion of large vol of hypotonic urine

Dehydrated/water deprivation body resp: ADH keep more water

pass more concentrated urine
VS.
DI: ADH absent or not working (nephrogenic) kidney cant func right
fails to concentrate urine retain less water secrete more diluted/high
volume urine thus kidney cant concentrate urine

A. Osmotic gradient in medullary interstitium of kidne

Numbers indicate osmolarity of medullary interstitium in mOsm/L

Hypertonic: any osmolarity >than

300
- This osmotic gradient in
medullary interstitium of kidney
is created by:
i)
Na-K-2Cl cotransporter in
LOH &
ii) Urea recycling
-) ADH does water reabsorption,
urea recycling & increases Na-K-2Cl
hypertonic osmotic gradient in interstitium of renalcotransporter
medulla due to NaCl
deposition by LOH of
activity
juxtamedullary nephrons
Na+-K+-2Cl- cotransporter in thick ascending limb of LOH & impermeability of this limb to water
create this hypertonic medullary interstitium
Urea recycling also contributes for devt of this osmotic gradient in inner medulla
ADH increases cotransporter activity & urea cycling, resulting in higher gradient this gradient
essential for movement of water from tubular lumen to medullary interstitium by osmosis

Know: As LOHs ascending limb is impermeable to water, tubular fluid leaving thick
ascending limb & GOING TO DT & CD IS ALWAYS HYPOTONIC

Water not leaving, instead, NaCl & K+ moving out; thus, TF becomes hypotonic.
Water remains w/in tubular lumen whereas NaCl constantly being removed out TF

Osmolarity of tubular fluid going to DT/CD

and osmolarity of medullary interstitium

Tubular fluid
from PCT
300
300
300

300

100
150

300
400
500

200

600

300

600

300
800

800
500

1200

1000
1200

cortical medu
line separatin
osmolarity in o
400mOsm/L t
increases in o
point of max A
Osmolarity gr
Na+-K+-2Clurea recyclin
In Descending
driving force f
out is that ins
of 300 mOsm
hyperosmotic
so on, thereby
osmosis into
In Ascending
but, water IS
fluid is hypot
DCT & CD
In DCT & CD
reabsorbed in

Tubular fluid must be hypotonic before reaching DT & CD for water reabsorption

B. Role of ADH in concentration of urine

ADH: made in hypothalamic neurons & secreted by
post pituitary into blood to target Principal cells of DT
& CD
Physioal axns on kidney:
1. Increases water permeability of DT & CD: As TF
flows down DT & CD, its exposed to interstitium
w/higher osmolarity causing water to move out
tubular lumen to interstitium by osmosis
2. Increases Na+-K+-2Cl- cotransporter activity in thick
ascending limb, thereby enhancing countercurrent
multiplication & medullary gradient
3. Increases urea permeability in inner MCDs
enhancing urea recycling & thereby increasing
medullary osmotic gradient size

Water reabsorption in DT
& CD in presence of ADH

Since urea permeability of

medullary CD increased,
medullary osmolarity can
reach 1200-1400 mOsm/L
Reabsorption of H2O
continues thru out CD
Urine osmolarity can go
upto 1200-1400 mOsm/L &
urine volume can be as low
as 0.5 L/day

- Favorable osmolarity for water

reabsorption: 1200-1400 mOsm/L
- In tubular necrosis: tubular lumen lack
osmotic gradient

Cortex

Medulla

200
H2O

250

Formation of dilute
urine

Water reabsorption in DT
& CD in absence of ADH

DT & CD impermeable to water

medullary osmoticgradient is low
due to impermeability of inner
medullary CD to urea
Water reabsorption does NOT occur
in DCT & CD
urine osmolarity is low (~.50
mOsm/L)
urine volume becomes large (as
much as 13% of FL of H2O)
In absence of ADH (i.e. DI): 1. DCT &
CD impermeable to water. 2. poor
medullary gradient is poor
Net result: water reabsorption DOESNT
occur in DCT & CD keep losing water
thus, urine osmolarity very low &
person excretes large volume of urine =
diluted urine increasing plasma
osmolarity stimulating thirst center
polydipsia polyuria

H2O

350
400
H2O
450
500
550
600

H2O

Factors that influence ADH secretion

ADH secretion is
stimulated by:
Increase in
plasma/ECF
osmolarity
Decrease in
plasma/ECF volume
Angiotensin II
Pain/stress

ADH secretion is
inhibited by:
Decrease in
plasma/ECF
osmolarity
Increase in
plasma/ECF volume
ANP
Alcohol

Osmoreceptors and ADH secreting neurons are

located very close to each other in hypothalamus
Hypothalamus: Paraventricular
and Supraoptic nuclei
Osmoreceptors

Posterior pituitary

ADH made predominantly in SupraOptic Nucleus of

hypothalamus & stored in post pituitary
Osmoreceptors stimulated by increase in osmolarity of
ECF/plasma
Osmoreceptors then activate ADH neurons in hypothalamus
Water balance
Water balance means matching of water intake w/water
output; done by kidneys
Kidneys do this by altering reabsorption of water in DCT &
CD under influenced of ADH

Water balance: Body response to water deprivation

Deprivation of water
Increased plasma osmolarity

Decreased plasma volume

Stimulation of osmoreceptors

Activating symp

Stimulation of Thirst

Secretion of ADH

Increased water drinking

Increased water reabsorption

in DCT and CD of kidneys

Increased water intake

Increased water conservation

Decreased plasma osmolarity &

Increased plasma volume

Normal plasma
osmolarity & volume

Water balance: Body response to water drinking

Drink large volume of water: polydipsia
Decreased plasma osmolarity

Increased plasma volume

Activating parasymp

Inhibition of osmoreceptors
Inhibition of Thirst

Inhibition of ADH secretion

Less interest to drink water

Decreased water reabsorption

in DCT and CD of kidneys

Decreased water intake

Increased water loss in urine

Increased plasma osmolarity &

Decreased plasma volume

Normal plasma
osmolarity & volume

Counter-current mechanism of urine

concentration

1. Loops of Henle: counter-current multipliers & establish medullary

osmotic gradient b/c of: anatomical arrangement of loops, differential
permeability of 2 limbs, Na+K+2Cl-Transport, & continuous fluid column
advancement
2. Vasa recta: counter-current exchangers & maintain medullary osmotic
gradient b/c of: sluggish BF & simple exchange of water & solutes

Abnormal water balance due to abnormal ADH secretion

Assessment of water balance in body by estimations of:
Plasma osmolarity
Plasma volume
Urine osmolarity
Urine volume
Free water clearance:
Positive = water loss (hypotonic urine)
Negative = water conservation (hypertonic urine)

ADH deficiency: in Diabetes insipidus (DI); 2 types:

1. Neurogenic/Central DI (ADH is deficient/ absent)
2. Nephrogenic DI (ADH is there, but, its not acting on kidney, b/c kidney has problem)

ADH excess: in Syndrome of inappropriate ADH (SIADH)

1. Neurogenic or Central DI

Lesion in hypothalamus
damaging ADH secreting neurons
(SON & PVN)
NORMAL KIDNEYS
Plasma ADH is low or 0 (key
difference btwn central DI (0) or
nephronic DI )
Water reabsorption in DCT & CD
not possible & large volume of
water is lost in urine
PLASMA OSMOLARITY
becomes HIGH
(b/c no water reabsoption, so
plasma gets concentrated)
PLASMA VOLUME becomes
LOW
Pt passes large volume,
hypotonic urine (as much as
23 L/day)
+ve free water clearance

2. Nephrogenic Diabetes Insipidus

DCT & CD DEFECTIVE in responding to ADH

ADH secreting neurons normal
Plasma volume is LOW but osmolarity HIGH
HIGH Plasma ADH (key difference btwn central
DI or nephronic DI)
Pt passes LARGE volume, hypotonic urine (as
much as 23 L/day) AKA +ve free water clearance
Lithium carbonate: anti-psychotic drug used
to treat Bipolar mood disorders, causes
acquired mutation in expression of apical
water channel, Aquaporin 2, in CDs
results in resistance to ADH axns leading to
Nephrogenic DI; pt might have large urine

volume

Syndrome of inappropriate ADH (SIADH)

abnormally excessive ADH lvls secreted either from
post pituitary or ectopic sites like tumor cells of lungs
ADH secretion is autonomous & not in resp to plasma
osmolarity or volume changes
Excessive H2O reabsorption in DCT & CD
HIGH plasma/ECF volume & LOW plasma
OSMOLARITY
Hypertonic & low volume urine excretion
Negative free water clearance
Very high plasma ADH lvls in DI of nephrogenic origin
& SIADH BUT To differentiate: hypertonic urine =
SIADH; VS. hypotonic urine = DI)

Examples of ADH secretion in certain physiological

and pathological conditions

: Increase or High;

: Decrease or Low

Acid-Base
Physiology
&
disturbance
s

Refer: Kaplan
notes

524

pH of body fluids
pH is expression of [H+] in logarithmic scale: pH = - log10[H+]
B/c [H+] arterial blood 40x10-9 Eq/l, arterial blood pH= - log10 [40 x
10-9]= 7.4

Normal range of arterial pH: 7.38 to 7.42

Increased [H+] reflected by decrease in pH
Decreased [H+] reflected by increase in pH
Sources of acids in body
1. Volatile acid: CO2 produced by aerobic metabolism produces H+
in body fluids by following rxn: CO2 + H2O H2CO3
HCO3- + H+
In lungs: rxns occur in reverse & volatile acid CO2 regenerated
& expired; H+ ions increase in tissues; TAKE CARE OF VOLATILE
ACIDSVS. KIDNEYS TAKE CARE OF NONVOLATILE ACIDS!
2.

Fixed acids or non-volatile acids: sulfuric & phosphoric acids

from catabolism of AAs & phospholipids respectively 50
mmol/day, small amt of keto-acids, lactic acid & acids added to

Principles of buffering:
Buffer: mixture of weak acid & its conjugate base OR weak base & its
conjugate acid; exs: Bicarbonate buffer: Carbonic acid/Bicarbonate,
Buffered soln resists change in pH: addition or removal of H + in buffered
soln changes pH of that soln only minimally
Calculation of pH of a buffered solution
Use Henderson-Hasselbalch eqn:

[A-]
pH = pK + log
[HA]
Where,
[A-] = concentration of the conjugate base (mEq/L)
[HA] = concentration of the weak acid (mEq/L)
pK = negative log of the equilibrium constant
For bicarbonate buffer system:

pH = 6.1+ log [HCO3 ]

[PCO2 ]

Buffers in ECF and Plasma

buffers in ECF/plasma minimize change in pH;
include:
1.Bicarbonate/Carbonic acid (CO2) buffer: most imp
ECF/plasma buffer b/c (1) [bicarbonate] high in ECF, (2)
acid form CO2 easily be altered by respiratory system &
(3) base form bicarbonate easily be altered by kidneys
2. Inorganic Phosphate buffer (HPO4-2/H2PO4-): less imp
buffer b/c of its [low] in ECF
3. Plasma proteins b/c contain basic/acidic groups

Acid-base disorders
Clinical conditions resulting from abnormal [H+] in
blood, reflected by change in pH of blood
Acid-base disorders are of 2 broad types:
a. Acidosis: increase in [H+] or decrease in pH of
arterial blood
b. Alkalosis: decrease in [H+] or increase in pH of
arterial blood
Based on primary disturbance, above disorders are
classified as:
i) Respiratory acidosis & alkalosis
ii) Metabolic acidosis & alkalosis
528

CO2

H + HCO3
+

Respiratory acidosis & respiratory alkalosis

(L side of eqn) due to problems in lungs
originate w/disturbances in CO2 elimination
Metabolic acidosis & metabolic alkalosis (R
side of eqn) due to problems in kidneys (or
others) originate as consequence of direct
change in either H+ or HCO3-

529

Respiratory acid-base disorders

These due to disturbances in CO2 in disorders of respiratory system; include:
1. Respiratory acidosis: in all conditions causing difficulty eliminating CO2 from body
accumulated volatile acid (CO2 retention); exs: all respiratory disorders leading to
decreased alveolar ventilation (hypoventilation) Hypercapnia (Increased arterial PCO2)
causes increased H+ (decreased pH) & slight increase in HCO3Causes of Respiratory Acidosis:
Inhibition of respiratory medullary center: opiates, barbiturates, lesions/trauma of CNS
& central sleep apnea
Disorders of respiratory ms (weakness/paralysis): Guillain-Barre syndrome
(ascending paralysis C. jejuni Gncommabacilli), Poliomyelitis (polio virus), Myasthenia
gravis (ACh receptor), & Amyotrophic lateral sclerosis (degeneration of motor neurons, ms
atrophy)
Disorders of Gas exchange: Acute respiratory distress syndrome (ARDS, type 2
pneumocytes & no surfactant collapsed lung), COPD (due to chronic
bronchitis/emphysema in smokers), Pneumonia & Pulm edema (transudate)
Airway obstruction: acute epiglottitis, aspiration/chocking (caf coronary), obstructive
sleep apnea & laryngospasm
C/F: somnolence, increased intracranial pressure due to cerebral vessel dilation, benign
intracranial HTN, hypoxemia, hypochloremia, hyperkalemia, 2 ndary polycythemia

2. Respiratory alkalosis: in all conditions causing excessive elimination of CO2

(excess removal of volatile acid) aka ^alveolar/hyper-ventilation decreased

arterial PCO2 causes dec in H+ (^pH) & slight decrease in HCO3Causes of Respiratory Alkalosis:
Stimulation of medullary respiratory center
Hysterical hyperventilation
GN septicemia (due to lactic acid production)
Salicylate poisoning
Hypoxemia: low partial pressure of oxygen in arterial blood; can lead to hypoxia
High altitude
Severe anemia
Pulm embolus (tachypnea): seen in DVT, immobilized pts (ie. Traveling >24 hrs
in plane) or women on contraceptives/high estrogen & smoke
Mechanical ventilation
C/F Tetany: hyperventilating
Hyperchloremia: due to IC exchange of Cl- ions for HCO3- entering cells in
non-renal compensation
Hypokalemia: due to H+ ions leaving cells to lower pH & K+ moving into cells to
maintain electroneutrality
Hypophosphatemia: Since alkalosis stimulates glycolysis leading to increased
phosphorylation of glucose
Low Ionised calcium: in presence of a normal total calcium.
531

Metabolic acid-base disorders: disturbances in [HCO3-] in ECF/plasma

1. Metabolic acidosis: conditions causing decreased bicarbonate in ECF due to addition of
non-volatile acids consume bicarbonate
Exs: Diabetic ketoacidosis, lactic acidosis (hypoxic conditions), loss of bicarbonate from body as in severe
diarrhea, chronic renal failure due to inability of kidneys to excrete acids.

Causes of Metabolic acidosis:

Excessive production or ingestion of fixed H+ increased AG!!!!*****
Diabetic ketoacidosis (accumulated beta-hydroxybutyric & acetoacetic acids) increased AG
Lactic acidosis (accumulated lactic acidosis due to hypoxia) Increased AG
Salicylate poisoning, Salicylic acid (also causes respiratory alkalosis) Increased AG
Methanol poisoning: in windshield washer fluid, solvent for paints (converted to formic acid),
increased AG (optic neuritis & permanent blindness)
Ethelene glycol poisoning: antifreeze (Converted to glycolic & oxalic acids) Increased AG
Loss of HCO3 Diarrhea (MCC of metabolic acidosis): GI loss of HCO3-, Normal AG, Hyperchloremia
Type 2 renal tubular acidosis (type 2 RTA)(Proximal): renal loss of HCO3- (failure to reabsorb HCO3-)
due to lowered threshold for HCO3- reclaimation (80-90%, Normal threshold is 24mEq/L), normal AG,
hyperchloremia
Inability to excrete fixed H+
Chronic renal failure: decreased H+ excretion (retension of organic acids like phosphoric acid &
sulfuric acid) & increased AG
Type 1 RTA (Distal): dysfuncal aldosterone mediated H+ ATPase pump in CD; decreased
excretion of H+ & decreased ability to acidify urine
Type 4 RTA: due to JGA destruction low renin & low aldosterone: Hyporenemic
Hypoaldosteronism (MCC is hyaline arteriosclerosis in Diabetic Nephropathy) Hyponatremia,
hyperkalemia & normal AG metabolic acidosis

C/F: Hyperventilation (Kussmauls breathing (deep, rapid respirations)), -ve Inotropic effect on
myocardial tissue, osteoporosis (bone buffers excess H+ ions), warm shock (acidosis vasodilates

2. Metabolic alkalosis: loss of non-volatile acid from body &

increased [ECF/plasma bicarbonate]
Exs: conditions in which there is loss of non-volatile acid from body such as in
severe vomiting; characd by increase in [bicarbonate plasma]
Causes of Metabolic alkalosis
Loss of H+
Vomiting: loss of gastric acid, HCO3- remains in blood, hypokalemia
Primary Hyperaldosteronism: Conns syndrome (11-b or 17-a-hydroxylase)
increased H+ secretion by a-intercalated cells & hypokalemia
Gain of HCO3 Ingestion of NaHCO3 (used to treat acidosis)
Milk-alkali syndrome: ingestion of large amts of HCO3- in conjunc w/renal failure
Volume contraction alkalosis from Loop or Thiazide diuretics: increased HCO3-

reabsorption due to increased AGII & aldosterone (Diuretics: MCC of

Metabolic alkalosis)

Diagnosis of Acid-base disorders

By doing arterial blood gas (ABG) analysis
for:
pH of arterial blood
PaCO2 (arterial partial pressure of CO2)
Bicarbonate concentration of arterial
blood
By plotting above ABG values in
Davenport diagram (see later), one can
diagnose & quantify the disturbance
534

Levels of acid-base disturbances

Whenever acid-base disturbance takes place in body, person
goes to 1 of 3 states:
Uncompensated or acute acidosis/alkalosis:
Happens immediately following disturbance;
Arterial pH is abnormal; & organs (lungs or kidneys) have
not begun to correct imbalance
Partially compensated acidosis/alkalosis:
pH is abnormal but going twds normal b/c organs (lungs
or kidneys) have begun to respond
Completely compensated acidosis/alkalosis: final state of
acid-base disturbance; arterial pH brought back to normal
organ paying compensation is highly active reflected in
highly abnormal values of arterial HCO3- & PaCO2

535

Compensation in acid-base disorders

Compensated state: may be partial or complete; offered by
either respiratory system or
kidneys (renal system)
Rules of compensation:
1. If primary disorder is respiratory (disturbance of CO2),
compensation ONLY by renal adjustments in HCO3- excretion
2. If primary disorder is metabolic (disturbance of HCO3-),
immediate compensation is by respiratory adjustments in CO2
elimination; later by renal adjustments
3. compensation by organ in same direction of original
disturbance: Ex: If acid added, HCO3- also added; & if acid
removed, HCO3- also removed

536

Summary of changes in UNCOMPENSATED state

Type of
disorder

PaCO2
40 mm Hg

pH
7.40

HCO324 mmol/L

Respiratory
acidosis

Respiratory
alkalosis

Metabolic
Acidosis

No
change

Metabolic
alkalosis

No
change

No

No

537

RESPIRATORY system in acid-base balance

occur only in metabolic disturbances & begins almost immediately
By altering removal of CO2, lungs compensate for change in pH of ECF
Lungs work thru bicarbonate/H2CO3 buffer system
Ex 1: In acidosis: Non-volatile acid (Eg:Sulfuric)added to body consumes
bicarbonate; Low pH stimulates respiratory chemoreceptors & stimulates
breathing by chemoreceptor reflex
Result: respiration becomes rapid & deep (hyperventilation); Eliminates
CO2 ; Decreases PCO2; Decreases H+ (Rxn, CO2 H+ + HCO3proceeds to L)
Ex 2: In alkalosis: base buffering requires more CO2 & H+ to be retained in
body
Result: Hypoventilation & increase in PCO2; rxn CO2 H+ + HCO3proceeds to R; More H+ retained & elevated pH (Alkalosis) corrected
Limitation: Lungs compensate only if source of acid/base is other than of
respiratory origin
538

3 Ways Kidneys Compensate In Acid-base Balance:

A. Recovering/reabsorbing filtered bicarbonate ions:
preventing loss of bicarbonate buffer in urine at same time
eliminating H+ in urine (buffered by bicarbonate in tubular
lumen)
B. Formation of NEW bicarbonate ions: Kidneys generate
NEW bicarbonate ions to replenish bicarbonate lost when
buffering fixed acids in body; for every 1 new bicarbonate
made, kidneys secrete 1 H+ into tubular fluid (buffered by
tubular NH3 & phosphate buffers creating titrable acid in
urine (H2PO4- phosphate; not ammonium))
C. Tubular secretion of bicarbonate: in alkalosis to eliminate
extra bicarbonate in urine

539

Proximal Tubule
Tubular fluid

80-90% filtered
bicarbonate
reabsorbed back
into blood here in
PCT!

540

DT and CD -Intercalated cell

541

HOW we form new bicarbonate!!!

542

543

Consequences of renal
compensation in acidosis
Increase in urinary acidity
(decrease in urine pH)
Increased NH4 formation
from ammonia
Increased H2PO4- : HPO42ratio in urine (Titratable
acidity)
Decreased bicarbonate
excretion in urine

Consequences of
renal compensation in
alkalosis
Decrease in urinary acidity
(increase in urine pH)
Decreased NH4 formation
from ammonia
Decreased H2PO4- : HPO42ratio in urine
Increased bicarbonate
excretion in urine

544

544

Lungs & Kidneys alter 2 diff components

Of Bicarbonate/CO2 buffer system
INDEPENDENTLY & thus offer compensation:
Kidneys (Renal system)
alter bicarbonate

pH = 6.1+ log [HCO3 ]

[PCO2 ]
Lungs (Resp. system)
alter PCO2
545

A. What happens when non-volatile acid is added? METABOLIC ACIDOSIS

CO2 + H2O
Lungs
Compensate by:

C.A.

H2CO3

H+ + HCO3-

The CO2 is removed by increased

ventilation (hyperventilation)

B. What would happen if CO2 were increased? RESPIRATORY ACIDOSIS

CO2 + H2O

H2CO3

C.A.
+ HCO3HCO3- synthesis from kidneys will increase
pH = 6.1+ log [HCO3 ]
[PCO2 ]

Kidneys
Lungs

H+
Kidneys

Immediate compensatory changes in various

acid-base disorders
Primary problem

Compensatory
mechanism

Compensation
done

1. Resp. acidosis
(Increased CO2)

New HCO3formed by
kidneys

Elevated plasma
bicarbonate

2. Resp. alkalosis
(Decreased CO2)

Less HCO3Reabsorbed/HCO3secreted by kidneys

Decreased plasma
bicarbonate

3. Metabolic acidosis
(Decreased HCO3-)

More CO2
is removed by
hyperventilation

Decreased arterial
PCO2 & H+

4. Metabolic alkalosis
(Increased HCO3-)

More CO2
is retained by
hypoventilation

Increased arterial
PCO2 & H+
547

Devenport Diagram
A: acute Respiratory acidosis
uncompensated
Bicarbonate high in normal limits
pH high
CO2 low!
If you go higher here, partially
compensated (Z B)
compensation bicarbonate
increases, pH goes twds normal
B C = fully compensated
respiratory acidosis

normal

I: after pH>7.4
acute uncompensated
respiratory alkalosis
Hyperventilating
Low CO2
High pH

F: Acute Metabolic
M = acidosis
Lower than normal bicarbonate
Partially compensated
metabolic & respiratory acidosis
MIXED CONDITION
High CO2 = hyperventilating

Low pH
Low HCO3Normal PCO2

Acidosis side

J: partially compensated respiratory alkalosis

Alkalosis side

Check whether you can identify the various Acid Base status represented by points A to J???

Interpreting acid-base disorder by

using Davenport diagram
(compare this with the table of changes in
uncompensated state)
PCO2=40 mm Hg
Metabolic alkalosis

[HCO3-] mmol/L

32
28

Respiratory
acidosis

24
20
16

Respiratory
alkalosis

Metabolic
acidosis

12
7.1

7.2

7.3

7.4

7.5

7.6

7.7 pH
549

Davenport diagram is the graphic

representation of the relationship between
arterial pH, [HCO3-] and PaCO2
PCO2 =
60 mm Hg

[HCO3-] in mmol/L

32

PCO2 =
40 mm Hg

PCO2 =
20 mm Hg

28

24
20

Blood
Buffer Line

16

N=Normal
point

12
7.1

7.2

7.3

7.4

pH

7.5

7.6
550

7.7 pH

ABG: pH 7.2
PCO2 = 64 HCO3- = 27
PCO2 = 64 mm Hg

35

HCO3-

30

Acid-base disorder:
Acute Respiratory
acidosis
PCO2 = 40 mm Hg

25
20
15

Partial compensation occurs by:

ABG: pH 7.3 PCO2=64
HCO3- =34

10

7.1

7.4

pH

7.7
551

You are following up a patient suffering from severe chronic obstructive

lung disease (COPD), who has periodic exacerbations (worsening) of his
problem. You would expect an impaired gas diffusion & ventilationperfusion imbalance due to the long-standing pathological changes at
his alveoli. Which of the following is likely to be observed in this person
during an acute exacerbation?

A. Elevated arterial pH
B. Elevated PaCO2
C. Elevated PaO2
D. Decreased plasma bicarbonate level
E. Decreased plasma potassium level
552

X = partially compensated met

ABG: pH = 7.5
PCO2 = 40 HCO3- = 32
35

Acid-base disorder:
Acute Metabolic
alkalosis

HCO3-

30
25
20

50
15
10

PCO2 = 40

7.1

Partial compensation occurs by:

ABG: pH = 7.45
PCO2 = 50 HCO3- = 34

7.4
7.7
pH
Compensation = respiratory acidosis

A 30-year-old female is admitted to the emergency

with sudden onset of vomiting due to food poisoning.
She is hypotensive & has signs of dehydration. Which
of the following would most likely be observed in this
patient?

A.Decreased urinary pH
B.Decreased PCO2
C.Increased NH4 formation in renal tubules
D.Increased plasma bicarbonate concentration
E.Hyperkalemia

554

ABG: pH 7.2
PCO2 = 40; HCO3- = 16

Acid-base disorder:
Acute Metabolic
acidosis

35

HCO3-

30

PCO2 = 40 mm Hg

25

30

20
15

Partial compensation occurs by:

ABG: pH 7.3; PCO2=30;
HCO3- =14

10

7.1

7.4

pH

7.7
555

A 25-year-old man with uncontrolled Type I diabetes

mellitus, is admitted to the emergency ward. As you
approach the patient, you smell his acidotic breath & observe
rapid, deep breathing. The plasma glucose is 490 mg/dL, &
his urine is positive for glucose & ketones. When you order
for his ABG analysis & plasma electrolytes, you would most
likely see which of the following findings?

Increased arterial PCO2

Increased plasma bicarbonate level
Decreased arterial pH
Decreased plasma K+ concentration
Decreased plasma anion gap
556

ABG: pH = 7.5;
PCO2 = 30; HCO3- = 22
35

HCO3-

30

Partial compensation occurs

by:
ABG: pH = 7.45;
PCO2 = 25;
HCO3- = 14

25
20
15

PCO2 = 40

Acid-base disorder:
Acute respiratory
alkalosis

30

10

7.1

7.4
pH

7.7
557

When you are doing the regular post-op orthopedic ward rounds,
you see a pt breathing rapidly. Pt was immobilized for 2 weeks
following complicated hip surgery. You suspect

pulm

embolism & arrange for emergency management. PaO2 is 75

mm Hg, PCO2 is 30 mm Hg, plasma HCO3- is 20 mEq/L. Acid-base
disorder that this patient is having now is

A.
B.
C.
D.

Acute respiratory acidosis

Acute respiratory alkalosis
Acute metabolic acidosis
Acute metabolic alkalosis
558

Mixed acidosis
Some times both respiratory & metabolic acidosis
occur together resulting in increased PCO2 &
decreased plasma bicarbonate.
Occurs in severe chronic obstructive lung diseases,
pulmonary disease w/hypoventilation & decreased CO
& tissue perfusion (hypoxia). Hypoventilation causes
elevated PCO2 (respiratory acidosis) & decreased
tissue perfusion causes acidosis (metabolic) due to
accumulation of metabolic acids.

559

Check whether you can identify the various Acid Base status
represented by points A to J???

Plasma Anion gap (PAG)

due to unmeasured anions in plasma
Anion gap = Total cations Total anions
=
(Na+) - (Cl- + HCO3-)
= 140 - (108+24) = 8 mEq/L

Normal range is 10 2 mEq/L

Useful in diagnosing cause of metabolic acidosis.

PAG increases in states w/accumulated organic anions such as lactic acid
(lactic acidosis), ketoacids (ketoacidosis). In these conditions HCO3decreases to neutralize these acids which increases PAG
In diarrhea = loss of HCO3-. But for every HCO3- lost, 1 Cl- reabsorbed in
blood. So PAG DOESNT CHANGE (also in type 2 RTA)
In Hypoalbuminemia = to compensate for loss of proteins, Cl- lvls increase
resulting in DECREASED PAG

561

Acute Kidney Disease (Acute Renal

failure)
rapid loss of kidney func w/in 48 hrs; can be reversed most of time
Causes for Acute renal failure (Azotemia) are classified as:
Prerenal, Intrinsic/Renal & postrenal azotemia.
A) Pre-renal: due to decreased BF to kidneys ie. in low BV
(Hypovolemia), hypotension (cardiogenic shock), heart failure,
renal a stenosis all these result in renal ischemia.
Diagnosis:
BUN:CREATININE ratio of 20:1,
Decreased fractional excretion of Na+ (FeNa<1%)
High specific gravity (>1.010)
High Urine osmolality (>500)

562

Acute Kidney Disease (Acute Renal

failure)
B) Intrinsic:

Damage to glomeruli, renal tubules,

interstitium
Eg: Glomerulonephritis, acute tubular necrosis

563

Acute Kidney Disease (Acute Renal

failure)
C) Post-renal: as result of urinary tract obstruction as
seen in Benign prostatic hyperplasia (BPH),
Nephrocalcinosis (kidney stones) in bladder, renal
malignancy.

Or polyuria depe
564

Acute Renal failure

Criteria for diagnosing ARF:
Decreased urine output (oliguria) - <0.5ml/kg/hr for >6
hrs
Rapid rise in BUN & Serum creatinine over period of
several hrs to days (also weeks eg: Aminoglycoside,
Poststreptococcal Glomerulonephritis)
Complications: Metabolic acidosis due to inability of
kidneys to excrete acids, ECF disturbances
Tx: Treat underlying cause

565

Chronic kidney disease (Chronic renal failure)

progressive loss of renal funcs over months or yrs
Causes for CRF: DM, hypertension, glomerulonephritis
Criteria for diagnosis: GFR less than 60 ml/min for 3 months
Gradual increase in Serum creatinine over months or yrs
Loss of proteins or RBCs in urine
Clinical features:
Hypertension due to increased renal secretion of Renin-A-II & Aldosterone
Metabolic acidosis due to inability of kidneys to excrete acids
Hyperkalemia, Anemia (due to renal EPO secretion), Decreased active Vit
D lvls & hypocalcemia (due to failure of vit D in getting converted to its active
form by 1-hydroxylase in kidneys)
Tx: ACE inhibitors inhibit formation of AG-II, dialysis, renal transplantation (dont
worry about this!)
566

Certain signs & sx of GI disorders:

Difficulty in swallowing (dysphagia)
Heart burn & epigastric pain
Nausea & vomiting
Hematemesis (vomiting blood)
Melena (passing dark tarry stools)
Hematochezia (passing fresh blood in stools)
Abdominal distention
Focal tenderness over abdomen
Diarrhea
Constipation
Steatorrhea (passing fat in stools)
Altered bowel sounds
567

2 processes motility & secretio

aided by these processes in GIT:
A) GI motility
causes mechanical breakdown
of food & propulsion of food thru gut
B) GI Secretionof enzymes, water & ions
GIT funcs regd by
hormones & ns

568

A)

2 components GI Tract Innervation:

Intrinsic component: Enteric Nervous System (ENS): plexus of
neurons & synapses (in GI tracts wall) made of Submucosal & Myenteric
plexuses; motility of GI tract provided by 2 layers of smooth m circular &
longitudinal m
A)

Submucosal plexus (Meissners plexus): btwn submucosa & circular m,

controls GIT secretory funcs
B) Myenteric plexus (Auerbachs plexus): btwn circular m & longitudinal m;
controls GITs motor funcs
Both have NS of GI tract

B)

Extrinsic component: ANS Symp & Parasymp

Serosa
Longitudinal m (outer layer)
Myenteric plexus

Arrangement of GI smooth ms & ns

Circular muscle
(inner layer)

LUMEN

569

Submucous plexus

Submucosa

Mucosa

Arrangement of GI smooth muscles & nerve

plexus
Extrinsic component of n
supply to GI tract by ANS!!!

Monitor pH
Sense stretch of
guts wall

Submucosal
plexus

Myenteric plexus

Parasymp n supply: thru vagus ns (X CN)

& pelvic ns (S2-S4)
Funcs:
i) Efferent parasymp are excitatory

increase GI secretions & motility

ii)

Mechano- & chemoreceptors in GI

mucosa relay afferent info to CNS via
these ns
) Vagal-vagal reflexes:
chemoreceptors detect afferent
&efferent vagus n stimulation in
parasymps myenteric &
submucosal plexus increasing
secretions & motility
) M3 receptors
Symp n supply: from lateral horn cells of
spinal cord, T5-L2;
Funcs:
i) Efferent symp inhibitory decrease GI
secretions & relaxes smooth ms
ii) Afferent inputs from GI tract relayed to
CNS
Autonomic ns control funcing of ENS

Extrinsic innervation of the GIT

ACh - Acetyl choline

NE - Nor epinephrine
571

12

Can you tell????

Injection of atropine (Muscarinic receptor blocker) causes
diarrhea or constipation?
Answer: Constipation Why???
Drugs that block axn of Ach decrease secretion & motility
in GIT
Drugs that block axn of NE increase GI motility
Regulatory substances in GIT:
GIT funcs regd in 3 ways: Hormones, Neurocrines, Paracrines
Regulatory funcs of GIT include:
Contract/relax smooth ms
Secrete digestive enzymes & electrolytes
Trophic (growth) efx on GI tissues
572

Hormones in GIT

GI hormone

Most GI hormones are peptides in nature

all secreted into portal circulation, pass thru
liver & enter systemic circulation
target cells in GIT or glands/organs reld to
GIT
4 major GI hormones are:
1. Gastrin
2. Cholecystokinin (CCK)
3. Secretin
4. Gastric inhibitory peptide (GIP) or GLP
1 & 2 belong to Gastrin family;
3 & 4 belong to Secretin family.

GI hormone

573

GI hormone - Gastrin
Gastrin: GI hormone secreted by G (Gastrin) cells in
stomachs antrum; belongs to Gastrin-CCK fam
Physiological axns:
a) Increases H+ secretion by Gastric parietal cells
b) Stimulates gastric mucosa growth by stimulating protein
synthesis
Reg of Gastrin secretion:
Stimuli increasing Gastrin secretion: stomach distension after
meal, digestion products (peptides & AAs), vagal stimulation
due to release of GRP (Gastrin Releasing Peptide)
Stimuli inhibiting Gastrin secretion: Increased H+ (Low pH) in
stomachs lumen (due to ve feedback)

574

Why????

Anatomic pts of Stomach

Vagal stimulation increases

Gastrin secretion
Its parasymp n which
releases ACh as its NT
Then why does Atropine
(ACh blocker) not block
vagally mediated Gastrin
secretion??????
This is b/c mediator of vagally
induced Gastrin secretion is
Gastrin Releasing Peptide
(GRP) and NOT Acetyl
Choline (ACh for M1 & M3
receptors)
575

Zollinger - Ellison (Z-E) syndrome:

Gastrin secreting tumor/ Gastrinoma (in non--cells of pancreas)
Signs/sx due to high circulating lvls of Gastrin:
A)
B)
C)

Hypertrophy of gastric mucosa (b/c Gastrin stimulates gastric mucosa growth by stimulating
protein synthesis)
Duodenal ulcers caused by increased secretion of H+
Increased H+ secretion inactivates pancreatic lipase (needed for fat digestion) dietary fats
not adequately digested or absorbed fat excreted in stool (Steatorrhea: greasy, foul
smelling, clay colored/pale stools)

Tx:
)
)
)

H2 receptor-blocking drugs: Cimetidine, Ranitidine, Famotidine

PPIs (Proton (H+) pump Inhibitors: Omeprazole, Lanzaprozole, Pantoprazol, Esmoprazol)
Surgical removal of tumor

576

Endoscopy showing Duodenal ulcer

Cholecystokinin (CCK): GI hormone secreted by I cells of

duodenal & jenunal mucosa (gastrin-CCK fam)
Stimuli causing CCK release:
Partially digested fats (monoglycerides & FAs) & proteins
(peptides & AAs) entering in duodenum & jejunum
Note: NOT triglycerides b/c CANT cross intestinal cell membs & thus
CCK: promotes fat digestion & absorption by 4 ways:
i) Contracts gall bladder & relaxes of sphincter of Oddi to eject bile into
small intestinal lumen for lipid digestion
ii) Secretes pancreatic enzymes: pancreatic Amylase, proteases & lipase
iii) Secretion of HCO3- from Pancreas
iv) Slows gastric emptying, ensuring enough time for intestinal digestion &
absorption
577

Secretin: GI hormone secreted by duodenal S (secretin) cells

(secretin-glucan fam) aka Natures Antacid b/c stimulates HCO 3secretion!
3 Stimuli that increase secretin secretion:
(1) [H+] & (2) FAs in duodenums lumen
(3) whenever pH of small intestinal is less than 4.5
3 axns of Secretin:
a) Stimulates HCO3- secretion from pancreas & in bile to neutralize H+ &
increase pH of intestinal contents essential for fat digestion b/c
Pancreatic Lipases inactivated at acidic pH
b) Inhibits H+ secretion from stomach (*likes to ask)
c) Inhibits trophic growth efx of gastrin on gastric mucosa

578

GIP (Gastric inhibitory peptide/Glucose

dependent Insulinotropic peptide):
Source: secreted by K cells of duodenal & jejunal mucosa
Physioal axns:
a) Stimulates insulin secretion by beta cells of pancreas; this
explains why oral glucose is powerful stimulant for insulin
secretion than IV glucose
b) Inhibits H+ secretion from stomach (name implies it)
Reg of GIP secretion: only GI hormone secreted in resp to end
products of digestion of all nutrients, esp, glucose, AAs & FAs

579

Paracrines in GIT

Neurocrines in GIT

Paracrines act locally w/in same tissue that

secrets them; reach target cells by diffusion
in short distances
2 major paracrines in GIT:
1. Somatostatin: peptide paracrine secreted
by D cells of GI mucosa (directly stimulated
by acid D cells then inhibit parietal cells
to decrease acid secretion); inhibitory
axns on GIT (-GI hormones & H+ secretion)
2. Histamine: secreted by ECL
(Enterochromaffin like cells) of stomachs
antral region; along w/Ach & Gastrin,
stimulates H+ secretion by gastric parietal
cells; increases gastrin acid production in
gastric mucosa by binding w/H2 receptors

made in neurons of GIT & released by AP

Substances diffuse across synapse & acts on
target cells, either neurons or non-neuronal cells
Exs:
1) Acetyl choline
2) NE, &
3) Vasoactive intestinal peptide (VIP): increases
intestinal & pancreatic secretions, relaxation of
smooth ms causes secretory diarrhea due to
intestinal infections such as cholera by excessive
chloride secretion by enterocytes
4) Gastrin releasing peptide (GRP): increases
gastrin secretion

Ass for the nigga in VIP cuz hes a G

LOLOLOLOL
whapishhhhh

580

Gastrointestinal Secretions
Principal secretions in GIT are:
Salivary glands - Saliva
Gastric mucosal cells - Gastric secretion
Exocrine pancreas - Pancreatic secretion
Liver Bile
constituents of secretions help in mechanical
& chemical digestion & absorption of food
as well as in protection of mucosa

Mechanism & composition of salivary secretion

Final saliva is hypotonic

Step 1: Initial saliva is isotonic & secreted by acinar cells & has
same electrolyte composition as plasma
Step 2: Ductal cells modify initial saliva by reabsorption of Na+, Cl- &
secretion of K+ & bicarbonate
Final saliva has low Na+, Cl-; high K+, bicarbonate, & is HYPOTONIC
due to reabsorption of NaCl & impermeability of duct to H2O
Other constituents: Salivary amylase, lingual lipase, mucus &
kallikrien protease
Funcs of Saliva

Initial starch digestion by salivary -Amylase (Ptyalin)

Initial Triglyceride digestion by Salivary Lingual Lipase

Lubricate ingested food by mucus for its easy passage thru esophagus

Protection of mouth & esophagus by dilution & buffering ingested foods

Helps articulation & speech by keeping oral cavity moist

Neural reg of salivary secretion

Atropine causes dryness of

mouth by blocking
muscarinic receptors & thus
prevents secretion of saliva

A. Parasymp ns: have dominant role;

increase salivary secretion by increasing
transport processes in acinar & ductal cells &
by causing vasodilatation
Cholinergic receptors on acinar & ductal
cells are Muscarinic receptors
Factors increasing salivary secretion:
food, smell, nausea & conditioned
reflexes
Factors decreasing salivary secretion:
fear, dehydration & anticholinergic drugs
(eg: Atropine)
B. Symp ns: have less influence;
increase salivary secretion thru b-receptors

Source & products of gastric mucosal cells

Fundus
Parietal (Oxyntic) cells:
-in body of stomach
-Secrete HCl & IF
Body

Antrum

Blood
Mucus neck cells:
-in antrum of stomach
-Secrete mucus, bicarbonate

Peptic (Chief) cells:

-in body of stomach
-Secrete pepsinogen

G cells:
-in antrum of stomach
-Secrete hormone, gastrin into
circulation H+ secretion
-Gastrin NOT in gatric juice

G cells are gassy

Mechanism of HCl secretion by gastric parietal cells

Lumen of
stomach

Parietal cell

Blood in
capillary

H+-K+ ATPase
H+
HCl
Cl-

Structure of gastric Oxyntic gland showing various

cell types lining gland

Gastric HCl secretion by PARIETAL cells & its termination

Cells in apical memb (facing lumen) contain H+-K+ ATPase & Chloride channels
Cells in basolateral memb (facing blood) contain Na+-K+ ATPase & Cl--HCO3- exchangers
Parietal cells have carbonic anhydrase that accelerates CO2 hydration
W/max acid secretion, gastric juice will have pH btwn 1 & 2 low pH inhibits gastrin secretion by G cells &
thus terminating gastric HCl secretion (-ve feedback)
alkaline tide in gastric venous blood due to absorption of bicarbonate in HCl secretion (balancing out rxn)
Funcs of Gastric secretion in Gastric Juice:
1.HCl: acidifies gastric contents btwn pH 1-2 which activates pepsinogen to pepsin
2.Pepsinogen: pepsin, active form of pepsinogen partially digests protein into peptides & AAs
3.IF: helps for absorption of vit B12 in terminal pt of ileum; only essential component of gastric
juice
4.Mucus: protects gastric mucosa from acid & lubricates gastric contents for digestion

3 Phases of gastric secretion & their regulation

5.Cephalic phase: gastric secretion influenced by various stimuli before food reaching stomach
6.Gastric phase: gastric secretion influenced by stimuli when food is in stomach
7.Intestinal phase: gastric secretion is influenced by stimuli arising from intestine

Reg of gastric acid secretion during Cephalic phase

Secretion occurs b4 food reaches stomach
Stimuli: smell, taste, chewing & conditioned reflexes
Totally mediated by vagus n
Mechanisms: Direct stimulation of parietal cells OR indirect
stimulation via gastrin
Vagotomy abolishes cephalic
phase of gastric secretion
Why? b/c Stimuli that produce
gastric secretion in cephalic
phase all mediated thru vagus
ns
Cutting vagus ns (vagotomy)
abolishes gastric secretion of
entire cephalic phase
Does muscarinic blocker like
atropine abolish cephalic phase
of gastric secretion completely?
Answer: No; not completely;
partially blocks gastric secretion
of cephalic phase; secretion
mediated thru GRP &
gastrin still continues
- Only inhibits M3 receptors
decreasing* secretion of HCl
from parietal cells

~30% of total gastric secretion

occurs during this phase

Regulation of gastric acid secretion in GASTRIC PHASE

Secretion occurs when food enters stomach
Stimuli for secretion are: Distention,
AAs/peptides
Mediated by vagus nerve & gastrin
Mechanisms: 1 & 2 in the figure

1 Distention
directly stimulates

~60% of total secretion

occurs during this phase
GRP
1

Agents that stimulate and inhibit H+ secretion

+
Vagus/ACh

Gastrin

Histamine

Blocked by
Atropine
M3
receptor

ECL cells

Somatostatin

Prostaglandins

Blocked by
Cimetidine & PGs
Gastrin
receptor

H2
receptor

SR

Gastric
parietal
cell

+ : Stimulation
- : Inhibition

Blocked by Omeprazole
H+ secretion

Gastric
lumen

Agents that stimulate H+ secretion

2
1

All 3 (1, 2 & 3) independently stimulate H+ secretion & also interact

w/each other to POTENTIATE H+ secretion to great extent

Disorders of Gastric H+ secretion

Peptic ulcer disease: ulcerative lesion of
gastric/duodenal mucosa; caused by:
i) Loss of protective mucosal barrier
ii) Excessive secretion of H+ & Pepsin
iii) Combination of i) & ii)
Imbalance btwn protective & damaging factors
leads to peptic ulcer disease

Imbalance between protective & damaging factors on

mucosal barrier leads to peptic ulceration
Lumen

Mucosa of stomach/duodenum
Protective factors:
Mucus, HCO3-,
Prostaglandins,
Mucosal blood flow

Mucosal barrier
Damaging factors:
H+ & Pepsin,
Anti-inflammatory drugs,
Helicobacter pylori (cagA toxin)

PEPTIC ULCER DISEASE

Gastric ulcers mostly due to
defective mucosal barrier

Duodenal ulcers are mostly

due to excess H+ secretion

Patient with Zollinger-Ellison syndrome (gastrinoma) secrete

highest rate of H+ secretion & will have peptic ulcers

A person who takes over dose of non-steroidal antiinflammatory drug (NSAID such as Aspirin &
ibuprofen) will suffer from peptic ulcer disease Why?

Answer:
NSAID damages protective mucosal barrier in
stomach & duodenum LEADING TO PEPTIC ULCER
DISEASE. Ex: Aspirin inhibits COX 1 & decreases
PGs which are protective to Gastric mucosa

Patient with long standing peptic ulcer disease may

be relieved of the disease by tx w/antibiotics - How?

Peptic ulcer seen thru endoscope

H. pylori seen under electron microscope

Answer: Infection w/H. pylori damages mucosal barrier in stomach &

duodenum leading to peptic ulcer. Tx w/antibiotics kills pathogens.
Combo of any 2 antibiotics: Metronidazole, Amoxicillin, Tetracycline,
clarithromycin w/PPIs / Bismuth salicylate
Treatment of Peptic ulcers
A) Avoid spicy foods
B) Use drugs which suppress acid secretion:
i) PPIs: Omeprazole inhibits H+-K+ ATPase & blocks H+ secretion
ii) H2 receptor blockers : Cemitidine reduce acid amt stomach produces by blocking
Histamine, a powerful stimulant of acid secretion
C) Mucosal protective agents - sucralfate

Comparison of Gastric and Duodenal

ulcers

Gastric Ulcer

Duodenal Ulcer

M/F 1/1
Defective mucosal barrier due to
- H.pylori (>75% of cases)
- Mucosal Ischemia (reduced PGE1)
- Bile reflux
- COPD
- renal failure
Location: Lesser Curvature
Complications: Bleed/perforation
C/F- Burning epigastric pain soon
after eating, pain increases w/food.
Relived by antacids

M/F- 2/1
H.pylori (>90% of cases)
decreased HCO3- in mucous
barrier of duodenum
Increased acid production*
MEN-1 (Z-E syndrome)
Location: Ant portion of 1st pt of
duodenum (MC)
Complications: Bleed, perforation
C/F- Burning epigastric pain 1-3
hours after eating. Frequently
relived by antacids or food. Pain
wakes at night.

Forming Secretion from Exocrine Pancreas

Acinar cells secrete all enzymes for digestion of carbs, proteins & lipids
Ductal cells secrete initial aqueous secretion w/same electrolyte
composition as plasma (contributing to isotonicity)
Initial secretion then modified by transport process in ductal cells by
secretion of HCO3- & absorption of Cl- via Cl--HCO3- exchanger in apical
memb
Due to high water permeability of ducts, pancreatic secretion is isotonic
Composition of final pancreatic secretion is: high HCO3- & low Cl-,
w/digestive enzymes & isotonic w/plasma

Formation of Pancreatic secretion

Cl--HCO3Exchanger

Final secretion is ISOTONIC

Regulation of pancreatic secretion

Enzyme & Bicarbonate secretions regd by
2 separate mechanisms:

1.Reg of Acinar cell

(enzymatic) Secretion:
. Vagal stimulation (ACh)
potentiates axn of CCK
. Hormone, CCK
stimulates acinar cells
to secrete large quantity
of enzymes
. Purpose is to digest food

(in duodenal &

jejunal mucosa)

Regulation of pancreatic secretion

2. Reg of Ductal cell
(electrolyte) secretion:
Vagal stimulation (ACh) &
CCK potentiate axn of secretin
Hormone, Secretin stimulates
duct cells to secrete large
quantity of HCO3- & H2O
Purpose is to neutralize acid
coming from stomach

Nature of pancreatic secretion under

influence of different hormones
Under influence of CCK, pancreatic secretion is:
- Rich in enzymes
- Poor in bicarbonate
- Of small volume
Under influence Secretin, pancreatic secretion is:
- Poor in enzymes
- Rich in bicarbonate
- Of large volume

Bile Secretion, Bile Acids/Salts

Bile: made & secreted by liver (hepatocytes), stored in gall bladder;
contains: bile salts major constituent, bile pigments (bilirubin),
cholesterol, phospholipids (mainly Lecithin), electrolytes & water
Bile acids/salts: *for digestion & absorption of lipids in small intestine
Hepatocytes secrete primary bile acids portion of these converted
to secondary bile acids by bacteria in small intestine
Primary bile acids: Cholic acid & Chenodeoxycholic acid
Secondary bile acids: Deoxycholic acid & Lithocholic acid
In liver, above bile acids are conjugated w/AAs, glycine & taurine to
form bile salts which are more water soluble than bile acids in
intestine
bile salts undergo Enterohepatic circulation: circulate btwn
intestine & liver: bile salts secreted from liver into intestine
absorbed into portal circulation taken up by hepatocytes resecreted back into intestine

Bile salts undergo enterohepatic circulation

Gall bladder
During temporary storage in gall
bladder, bile gets concentrated

Bile gets released by axn

of CCK on gall bladder &
sphincter of Oddi

Bile
salts

Duodenum
Secretin stimulates
Secretion of HCO3-

Enterohepatic circulation
economizes bile salt pool

Ileum

Functions of Gall bladder:

stores bile temporarily
concentrates bile: epithelial cells
of bladder absorb ions & water
isosmotically
Ejects bile by contracting bladder

Fatty meal

Secrete CCK by I cells of duodenum & jejunum

Contraction of gall bladder & Relaxation of sphincter of Oddi

Ejection of bile into small intestine

Digestion & absorption of fats

Functions of constituents of BILE

Bile salts: essential for digestion & absorption of lipids
in intestine
Phospholipids help in lipid absorption along w/bile
salts
Both bile salts & lecithin (phospholipid) help solubilize
cholesterol in bile
Bilirubin: bile pigment & metabolic degradation
product of hemoglobin
Bicarbonate in bile provides alkaline media in small
intestine

Gall stones (Cholelithiasis):

Cholelithiasis: gallstones in gallbladder; when [cholesterol] in bile
increases, starts to crystallize & forms stones; Calcium & pigment
also may be incorporated in stone
Predisposing factors: Obesity, females, elderly age group (3 Fs FATTY, FORTY, FEMALE)
Pts exp, Biliary colic described as episodic pain in R upper
abdomen that radiates to R shoulder or back

Gall stones
in ultrasound
scanning

 GI Motility: contraction & relaxation of walls & sphincters of GIT; required for:
A) Mechanical digestion of food: grinding, mixing, fragmenting prepares food for chemal
digestion & absorption
B) Propulsion of food: helps move food along GI tract
Ms of GI tract help in motility:

Smooth ms of GIT: unitary (single

unit) type where cells elecally
connected by gap juncs; func in
syncytium (single mass) & in
circular (inner) & longitudinal (outer)
manner
Contraction of circular: narrows dm of
segment
Contraction of longitudinal: shortens
length of gut in longitudinal
direction; ms continue to contract
even if extrinsic ns sectioned
2 types of GI contractions:
A)
Phasic contractions: for mixing
& propulsion; periodic
contractions followed by
relaxation; in esophagus, gastric
antrum & small intestine
B)
Tonic contractions allow
contents only when needed;
maintain constant contraction
w/out period of regular
relaxation; in all sphincters

Arrangement of GI smooth ms & ns:

Serosa
Longitudinal muscle

Myenteric plexus

Circular muscle

LUMEN

Submucous plexus
Submucosa

Mucosa

 Slow waves (Basal elecal rhythm BER): elecal activity initiating contraction;
via depolarization & repolarization of Memb potentials of smooth m cells
during depolarization, memb potential becomes less ve & if it reaches
threshold, APs occur on top of them
Contractions (tension) follow burst of APs
APs cannot occur w/out slow wave that takes memb potential to
threshold
Slow waves (Basal Electrical Rhythm)

Burst of APs

----------------------------------------------------------------------------- Threshold
RMP

Slow wave

Origin of Slow waves (BER)

Ionic mechanism: depolarizing of slow wave caused by cyclic opening of Ca2+
channels, that produce inwd Ca2+ current/influx that depolarizes cell memb
During plateau of slow wave, Ca2+ channels open inwd Ca2+ current maintains
memb potential at depolarized lvl
Repolarizing phase of slow wave caused by opening of K+ channels produce
outwd K+ current/efflux that repolarizes cell memb

Slow waves originate in interstitial cells of Cajal, abundant in

MYENTERIC PLEXUS
Frequency of slow waves vary along GI tract & ranges from 3-12 waves/min
Stomach has lowest frequency (3/min) VS. Duodenum has highest (12/min)

frequency of slow waves sets frequency of APs therefore frequency of

contractions
Frequency of slow waves not affected by ns or hormones. However, neural &
hormonal activity modulate production of AP & strength of contractions

Movements in GIT
Can be studied under following headings:
Mastication (Chewing)- mixes food w/salivalubricates food, breaks food into small particles
& mixes food w/salivary Amylase which digest
carbs
Swallowing (Deglutition)
Gastric motility
Small intestinal motility
Large intestinal motility

 Swallowing (Deglutition)
reflex: process that food from
Functional anatomy of swallowing
mouth is propelled to stomach
Initiated voluntarily in mouth &
continues as reflex process
(involuntary)
controlled by swallowing center
Skeletal/
in medulla
Deglutition process has 3 phases:
A. Oral phase (voluntary)
B. Pharyngeal phase (involuntary)
C. Esophageal phase
(involuntary)

Upper Esophageal
Sphincter (UES):
Made of skeletal m
Has resting tone (closed at rest)
Helps prevent air entry into esophagus
when breathing
Opens only in swallowing when ms relax
controlled only by swallowing center in
Medulla
Not influenced by hormones

Lower Esophageal
sphincter (LES):
Made of circular smooth ms
Has resting tone; cholinergic Vagal fibers keep them in
contracted state at rest
Prevents acidic gastric contents from entering
esophagus
Opening mediated by vagus n that secretes VIP &
NO as NT
Also relaxes in resp to primary peristalsis in esophagus
Relaxes before bolus (food) actually comes to that site
during swallowing

Funcal significance of UES & LES

Due to intra-thoracic location of esophagus, intra-esophageal pressure is equal to intrathoracic/intra-pleural pressure, which is lower than atmospheric pressure & abdominal pressure.
Intra-esophageal pressure increases during swallowing
lower intra-esophageal pressure creates 2 problems: keeping air out of esophagus at upper end, &
keeping acidic gastric contents out at lower end
upper esophageal sphincter prevents air from entering upper esophagus, &
lower esophageal sphincter prevents acidic gastric contents from entering lower esophagus
Both upper & lower esophageal sphincters are closed, except when foods passing from pharynx into
esophagus or from esophagus into stomach

Reflux Esophagitis (Gastro-esophageal

Reflux)
When contents of stomach reflux into esophagus & cause
inflammatory rxns
Occurs due to incontinence of lower esophageal sphincter (LES)
Acid injury leads to ulceration of distal esophagus mucosa
Heart burn sensation
Occurs when intra-abdominal pressure increases as seen in
pregnancy, obesity, weakness of diaphragm
GERD Barretss esophagus Ulceration & stricture (dysphagia
for solids) & Distal adenocarcinoma (MC cancer in esophagus)
MCC of nocturnal cough, Hoarseness w/sore throat, +chest pain

Phases of swallowing - Oral (Voluntary),

Pharyngeal & Esophageal (Involuntary)
A) Oral phase:
Initiated when tongue forces bolus back twds pharynx
Tongue contracts anteropostly pressing against hard palate

 B) Pharyngeal Phase: contact of food stimulates somatosensory receptors in pharyngeal

wall & initiates involuntary reflex; swallowing center coordinates all events below:
Soft palate pulled upwds preventing food entering to nasopharynx
Larynx moves upwds & fwds (epiglottis moves backwd) preventing food into larynx & air
UES relaxes, allowing food to pass to esophagus
Peristaltic wave of contraction of pharyngeal ms propel food into esophagus
Deglutition Apnea: breathing stops for moment during this phase for <1 sec b/c
Respiratory centre of Medulla directly inhibited by swallowing centre for very brief time it
takes to swallow
Soft palate prevents food
entry into nasopharynx
Tongue prevents
food entry back to
oral cavity

Only route food can take is:

entry into esophagus
b/c UES relaxes

Stoppage of breathing &

upward movement of larynx
prevents food entry into larynx

Pharyngeal phase-Summary of
events
1. Tongue pressed
against hard palate
2. Uvula elevated,
touches post pharyngeal
wall
3. Elevation of larynx
4. Epiglottis swings
backwds
5. Closure of airway

Food prevented from reentering mouth

Seals off nasal passage
Food prevented from reentering respiratory
passage

Bolus
Uvula

4
Epiglottis
Tongue

3
5

Laryngeal opening
Esophagus

Bolus
Uvula

4
Epiglottis
Tongue

3
5

Laryngeal opening
Esophagus

Phases of swallowing
C) Esophageal phase: when food
enters esophagus thru UES
sphincter; controlled by both
swallowing center & enteric NS
Once bolus pushed into esophagus,
UES closes
primary peristaltic wave: coordinated
by swallowing center, initiated just
below UES & travels down esophagus
propelling food along
By time food arrives at lower end of
esophagus, LES relaxes allowing
food to enter stomach
Gravity accelerates process if person
in erect posture
If primary peristalsis fails or not strong
enough to propel food, 2ndary
peristalsis is initiated at site of
distension & controlled by enteric NS,
which propels food into stomach

Bolus

Uvula

Epiglo
Tongue

Lary

Components
of Swallowing
reflex arc

(X CN)
(IX CN)

Afferent:
IX CN
X CN
Efferents:
V CN
X CN
XII CN

(V CN)

Pressure recordings
(in mm Hg)

Esophageal phase of deglutition

Time

Press
passe
leave
PATH
ACHA
RELA
ESOP

Beginning of the
esophageal phase

Note graph; x axis time VS. y axis pressure

LES relaxes & decreases pressure
Monitored by monometry: instrument to measure pressures in deglutitio

Pressures in Esophagus during

swallowing

Clinical correlate - Achalasia (Cardia)

MC motor disorder of esophagus.

LES fails to relax when food arrives due to
congenital absence of myenteric neural
cells (ganglia). (Ganglion cells normally
contain VIP which relaxes LES)
Absence of peristalsis
Dilatation of esophagus proximal to LES
Clinical feature:
Regurgitation of undigested food at night
Dysphagia (solids & liquids)
Radiograph following barium meal
showing narrow lower end w/
dilated proximal pt of esophagus
(bird beak appearance)

Gastric Motility
Stomach has 3 layers of smooth ms: outer longitudinal layer; Middle circular
layer; Inner oblique layer
Stomach can be divided into:
Orad region: fundus & proximal body; thinner, less contraction & stores
food
Caudad region: distal body & antrum; thicker, stronger contractions & for
mixing & propulsion
Innervation of stomach: via ANS
Parasymp via Vagus
Symp via Celiac ganglion (extrinsic) & ENS (intrinsic)

Major divisions of stomach

3 components of Gastric motility:

Receptive relaxation, Mixing movements & Gastric emptying
A) Receptive relaxation: orad region undergoes relaxation to receive food from esophagus to increase
volume of stomach to receive & store food for temporary period; completely relaxed stomach can
accommodate 1.5 L of food; mediated by Vagovagal reflex
) Mechanism of receptive relaxation: Vagovagal reflex
1. Stretching of fundus of stomach w/food
2. Stimulation of mechanoreceptors in stomach wall
3. Info goes to CNS via vagus n
4. Reaches Vagal center in medulla
5. Efferent thru vagus n inhibits smooth ms of fundus
6. Fundus relaxes
. NT at efferent: VIP - Produces relaxation of GI smooth m
. Vagotomy abolishes receptive relaxation
B) Mixing movements: occurs at caudal region waves of contraction begin in middle of body & move twds
pylorus, contractions becoming stronger near pylorus
. Contractions mix, churn food into small particles
. Retropulsion: if bigger particles, theyre moved back to body for further mixing
. Motilin: causes periodic gastric contractions that clears stomach of any residue from previous meal
C) Gastric emptying: particles less than 1 mm3 are allowed to enter thru pylorus to duodenum during every contraction
. Whereas particles >than 1 mm3 will be retropulsed to reduce their size
. *Complete gastric emptying takes about 3 hrs
. Liquid foods empty faster than solid
. Isotonic foods empty faster than hypotonic & hypertonic foods
. Carb rich foods empty faster than Protein > fatty foods

Advantages of slow, controlled gastric emptying:

permits adequate time for:
Neutralization of acid in duodenum
Pancreas to secrete enough bicarbonate (HCO3-) for neutralization of acid
Digestion & absorption of nutrients in small intestine
pt after gastrectomy is advised to eat small amt of food at time (multiple, small meals
per day) to avoid gastric dumping syndrome
Factors regulating Gastric emptying:
A) Factors that hasten emptying (decrease gastric emptying time):
Distension of stomach
Gastrin
B) Factors that delay emptying (increase gastric emptying time):
Fatty meal (thru CCK which slows gastric emptying)
Acid in duodenum (thru secretin & neural mechanism)
Distension of duodenum & hypertonic chyme (not neutralized yet) (via neural mechanism slows
gastric emptying)

Small intestinal motility

Slow waves in small intestine have diff frequency:
In duodenum:12/min; in ileum:9/min
Small intestinal contractions are of 2 types:
A) Segmentation contractions: segment of small intestine contracts, splitting chyme &
sending it in both orad & caudad directions; in next moment this segment relaxes, allowing split
chyme to mix together; back-&-forth movements serve to mix & churn chyme; purpose:
mixing chyme & exposing it to digestive enzymes & other secretions

B) Peristaltic contractions: ring of contraction occurs at point behind chyme in orad direction;
simultaneously segment in front of chyme, in caudad direction undergoes relaxation; Chyme
propelled in caudad direction; wave of peristaltic contractions moves from orad to caudad
direction, moving chyme w/it; Peristalsis is direction specific (law of gut) & its frequency is
very slow for sufficient digestion & absorption time; sequence of proximal contraction &
distal relaxation coordinated by Enteric NS
NT for contraction: Ach, Substance P
NT for relaxation: VIP (Vasoactive intestinal peptide) & NO
Peristalsis is abolished if Enteric NS is blocked

Both these movements coordinated by ENS (Enteric nervous system)

Segmentation
contractions

y
c

chy

chyme

me

Peristaltic contractions

chyme

chyme

chyme

Large Intestinal Motility

Movements of large intestine:
A) Segmentation
contractions
B) Mass movements
Feces: material not
absorbed in small intestine
enters large intestine &
become excreted; moves
from Cecum, Colon
(ascending, transverse,
descending & Sigmoid
colons), into rectum & anal
canal

Functional anatomy
of colon

A) Segmentation
contractions - in large
intestine
Segmental Contractions: in cecum
& proximal colon, for mixing contents
in Haustra (large sac-like segments
due to localized thickenings in
circular ms)
segment of large intestine contracts,
splitting chyme & sending it in both
orad & caudad directions
In next moment, segment relaxes,
allowing split chyme to mix together
back-&-forth movements serve to
mix & churn chyme
Purpose: mix chyme & expose it to
digestive enzymes & other secretions

B) Mass movements (Mass

Peristalsis) - in large intestine

Mass movements:
coordinated by Enteric NS,
help move contents over
long distances,
sometimes from transverse
colon to sigmoid colon;
differ from peristalsis b/c
contracted segment
remains contracted for
sometime
final mass movement
pushes fecal contents twds
rectum

Defecation-

act/process by which organisms eliminate solid or

semisolid waste material (Feces) from digestive tract via anus

1.
2.
3.
4.

Mass movements in large intestine

Fecal contents propelled into Rectum
SMs of rectum contract & internal anal sphincter relaxes
External anal sphincter under voluntary control is still tonically
contracted. Defecation will not occur yet
5. Rectum fills to 25% of its capacity, there is urge to defecate
6. When appropriate conditions, external anal sphincter relaxes,
rectal ms contract intra-rectal pressure which forces feces
out thru anal canal

Hirschsprungs Disease (Congenital

Megacolon)

due to congenital absence of

Myenteric neurons in certain pts
of colon results in failure of feces
to move fwd twds anus
produces funcal obstruction of
distal colon & dilatation of colon
proximal to obstruction
Infant fails to pass feces
(meconium); clinically manifests as
Funcal obstruction of distal colon &
chronic constipation &
dilatation of colon proximal to obstruction
abdominal distension
intestinal air radiographically in Hirschsprung
Most cases in newborns
HD should be considered in any
newborn who fails to pass
meconium w/in 24 - 48 hrs
Contrast enema useful in
establishing dx.
Rectal biopsy remains best dxic
test

Digestion & absorption in GI tract

Digestion: how ingested food is converted
to forms that can be absorbed by GIT Villi
Mechanical breakdown of food by
agitation movements
Chemal breakdown of food by
digestive enzymes
Absorption: how molecules are
transported from lumen of intestine
into blood; occurs by 2 paths:
a. Cellular path: substance must cross
intestinal epithelial cells into blood or
lymph
b. Paracellular path: substances move
thru intercellular space into blood or
lymph
Structure-Func relnship: mucosa of small
intestine is surface for digestion &
absorption; absorptive surface area
increased to many folds by:
a. Folding of mucosal surface
b. Finger like projections from above

Enterocytes

Structure of a
villus

Digestion & absorption of

carbohydrates:
Ingested food contains ~50% of CHO
Made up of: polysaccharide (starch),
disaccharides (sucrose, lactose), &
monosaccharides (glucose, fructose)
Only monosaccharaides are
absorbed in intestine
Hence, all ingested CHO must be
digested to monosaccharaides

Digestion of starch

By alpha amylase in saliva & pancreatic juice

Salivary amylase works at alkaline pH gets inactivated
when food enters stomach.
Chief source of amylase for starch digestion comes
from pancreas
Major site of starch digestion is duodenum & proximal
jejunum
Amylase from pancreas breaks starch
Amylase works at alkaline pH provided by bicarbonate
in duodenum
Starch split into 3 disaccharides: Dextrins, maltotriose
& maltose
These disaccharides are further broken into
monosaccharide (glucose) at brush border by separate
enzymes

Digestion at brush border

Each brush border enzyme is specific for substrate

End products of this digestion are all monosaccharides

- Dextrin
Maltose
Sucrose
Lactose
Maltotriose

Dextrinase
Maltase
Sucrase
Lactase
Sucrase

glucose
glucose
glucose + fructose
glucose + galactose
glucose

Intestinal lumen

Absorption of
monosaccharides:
Major sites: Jejunum, ileum
At apical memb. glucose &
galactose move by secondary
active transport using SGLT
Glucose & galactose move
into cell against [gradient]
From inside cell, move into
blood by facilitated diffusion
at basolateral memb
Absorption of fructose is
facilitated diffusion at both
sites

Intestinal epithelial cell

Interstitial
space

Lactose intolerance
Caused by deficiency of enzyme, lactase
may be congenital or acquired
Lactose (milk sugar) can not be digested
Indigestion occurs following ingestion of milk (dairy)
products
Undigested lactose holds water in intestine
Fermentation of lactose releases gases in gut
Clinical features: Osmotic diarrhea, bloating, abdominal
discomfort

Digestion & absorption of proteins:

~20% of ingested food contains proteins
Absorbable form of proteins: AAs, dipeptides & tripeptides
Digestion begins in stomach & completed in intestine
Digestion of proteins in stomach:
Enzyme responsible is pepsin: secreted in inactive form, pepsinogen
by chief cells pepsinogen activated to pepsin by HCl; optimum pH
for pepsin is 1-3;
Becomes inactive above pH 5
Its axn is terminated in duodenum
Pepsin

Proteins

amino acids + peptides

Digestion of proteins in small intestine:

Pancreatic & brush border enzymes essential for protein digestion
5 major pancreatic enzymes are:
Trypsinogen
Chymotrypsinogen
Proelastase
Procarboxypeptidase A
Procarboxypeptidase B
All enzymes in inactive form in pancreas activated in duodenum

Activation of pancreatic proteolytic enzymes

Enterokinase from intestinal secretion

Activation of other pancreatic proteolytic enzymes

Digestion of proteins in small intestine

Proteins

Dipeptides
Amino acids
Tripeptides
Dipeptides
Amino acids
Tripeptides

Absorption of amino acids

AAs transported by secondary active transport
coupled w/sodium in apical memb
There are separate Na+-AA transporter for diff
group of AAs
From cells, AAs are transported across
basolateral memb by separate facilitated
diffusion mechanisms
Summary of
digestion &
absorption
of proteins:
Follow steps 1 - 6

Digestion & absorption of lipids

Lipids make ~30% of ingested food

Dietary lipids include triglycerides, cholesterol &
phospholipids
Hydrophobic nature makes it difficult to digest &
absorb lipids
Hence theres a mechanism to make them soluble in
aqueous medium of intestinal fluid
End products of fat digestion:
Triglycerides converted to
Monoglyceride + 2 free fatty acids (FFA) (by pancreatic
lipase)
Cholesterol ester converted to
Cholesterol + FFA (by Pancreatic ester hydrolase)

Digestion of fat in stomach

Lingual lipase & gastric lipase split triglycerides; ~10% of fat
digestion
not essential for normal fat digestion
Digestion of fat in small intestine
Jejunum is major site for fat digestion where bile salts emulsify fat
Emulsification increases surface area of lipid droplets on which
enzymes act
Source of enzymes from pancreas/pancreatic lipolytic pancreatic
enzymes: Pancreatic lipase & colipase, Cholesterol ester
hydrolase, & Phospholipase A2
Absorption of end products of fat digestion
Since end products are hydrophobic, theyre made water soluble
by bile salts
Bile salts have both hydrophilic & hydrophobic surfaces on them so
make end products of fat digestion water soluble by formation of
mixed micelles
Mixed micelles: cylindrical structures w/inner core of end products
of fat digestion & outer core of bile salts; reach apical surface of
epithelial cells & release their contents (fat digestion end

Mixed micelle: made up of water insoluble

substances in core surrounded by
water soluble substances on surface
Bile salt

Bile salt
water soluble
pt of bile salt
faces out

Monoglyceride, Cholesterol,
Free fatty acids (water insoluble)

water soluble pt of
phospholipid faces out

Steps in absorption of fat

Intestinal lumen

Intestinal epithelial cell

Interstitial
space

Ferrying of end
products of fat
digestion by
mixed micelles

Mixed micelles

Mucosal cells

Role of bile acids in fat digestion & absorption

Bile acids emulsify fat- Large fat globule broken down into smaller
droplets by intestinal agitation & coated by bile acids so they dont
coalesce together; lipases act effectively on large surface area
Form micelles- Mixed micelles ferry end products of fat digestion &
fat soluble vits from lumen to absorption site
In biliary obstruction, theres decreased fat digestion & absorption,
resulting in Steatorrhea & deficiency of fat soluble vits (A,D, E, K)
Vit K deficiency can lead to deficiency of coagulation factors (II, VII,
IX, X)
In all conditions w/fat malabsorption, steatorrhea is common
presenting CF
Steatorrhea: excretion of excess fat in feces (Bulky, greasy,
fowl-smelling stools)
Estimation of fecal fat following fatty meal imp test for
malabsorption of fat

Substances absorbed in distal ileum:

Vitamin B12
Bile salts
Removal of ileum leads to macrocytic
anemia & malabsorption of fat

Intestinal fluid & electrolyte absorption:

GI tract absorbs vast quantities of fluid & electrolytes.
Small & large intestines absorb ~9 Ls of fluid daily.
Slightly >9 Ls of fluid enters GI lumen (Diet 2 Ls & 7 liters from
Saliva, gastric, pancreatic, biliary & intestinal secretions)
small volume thats not reabsorbed (100-200 ml) is excreted in feces
Disturbance in absorptive mechanisms leads to excessive fluid loss
from GI tract
SI & colon not only absorb large quantities of fluid &
electrolytes, but epithelial cells lining crypts of SI also secrete
fluid & electrolytes, which must be absorbed

Fluid ingested, secreted and absorbed in intestine

Ingested and
Secreted fluids
Small int (1 L)

Pancreati
juice &
bile (3 L)
Gastric
juice (2 L)
Saliva (1 L)
Diet (2 L)

Absorbed
fluids
Colon

Small
intestine
(>80%)

Excreted
in feces
(100-200 ml)

Intestinal absorption

Intestinal epithelial cells lining villi absorb large quantities of fluid 1st step
is absorption of solute, followed by absorption of water
fluid absorption is always isosmotic.
mechanism of isosmotic absorption similar to renal proximal tubules
solute absorption mechanisms vary among jejunum, ileum & colon.

Glucose or salts

Malabsorption:
Causes
1.Pancreatic Disease (Chronic Pancreatitis)
2.Small Intestine Disease : No absorptive surface
3.Bile salt deficiency: No emulsification & micelle formation
Malabsorption of ingested food common in many Small intestinal
diseases:
Celiac disease (gluten enteropathy): MCC of Malabsorption in US, in wheat
gluten sensitive ppl (antibodies develop against Gliadin Extract in gluten) Gluten
is in wheat, rye or barley; intestinal mucosa damaged due to immune resp &
shows blunting & atrophy of villi of duodenum (Iron deficiency) & jejunum (folate
deficiency); C/F failure to thrive w/abdominal distension in children, adults
have weight loss, diarrhea & malnutrition; Tx: Gluten free diet
Tropical sprue: intestinal mucosal damage by bacterial infection; C/F: diarrhea,
steatorrhoea, weight loss, anorexia, malaise & nutritional deficiencies (B12, folic acid,
A,D,E,K)
IBD (Inflammatory bowel disease): due to chronic inflammatory damage to intestinal
mucosa; consists of 2 disease entities:
Crohns disease (CD) most commonly afx Ileum; can result in B12, Calcium, Vit K & Iron deficiencies
Ulcerative colitis (UC) of large bowel
C/Fs: Fever, diarrhea, weight loss, & occasionally abdominal pain & bleeding

Diarrhea:

excessive & frequent

evacuation of watery feces
Causes of diarrhea:
1. Decreased surface area for absorption
2. Increased osmotic particles in intestine
that go unabsorbed
3. Secretory diarrhea

Osmotic diarrhea
Due to malabsorbed nutrients or poorly absorbed
electrolytes that retain water in lumen
Malabosorption occurs when ability to digest or
absorb particular nutrient is defective
Egs:
- Disaccharidase deficiency (Lactase deficiecy)
- Laxatives
- Pancreatic enzyme deficiency
- Bacterial overgrowth
- Pancreatic enzyme inactivation (ZE syndrome)

Lactose intolerance

signs & sx of lactose intolerance usually begin 30 mins to 2 hrs after eating
or drinking foods that contain lactose.
Common signs & sx include:
High volume diarrhea w/osmolarity less than that of plasma (OSMOTIC)
Nausea
Abdominal cramps
Bloating
Gas
Sx usually mild, but they may sometimes be severe.
-ve stool for fecal leukocytes
Tx: Avoid diets containing lactose (Milk & diary products), Lactase
containing tablets can be taken

Secretory diarrhea

Due to secretion of excess fluid by intestinal cells; occurs due to

Toxin producing Bacterial infections such as Vibrio cholera, Travellers diarrhea E.coli
Toxins produced by bacteria open Cl- channels in apical memb (adenyl cyclase
mediated) Increased cAMP lvls

Tumor secreting Vasoactive Intestinal Peptide (VIP) lvls elevated in these

pts. VIP increases cAMP lvls & causes chloride secretion.
GI luminal substance Bile acids (in excess)increase secretion of ClExcess secretion of chloride drags sodium & water into intestinal lumen
No mucosal inflammation (-ve for fecal Leukocytes)
loss of large volume of ECF

Acute Diarrhea
INFLAMMATORY
Fever & bloody
w/Leukocytes, volume
<1L/ 24 hr secondary to
colonic damage
Shigella, Salmonella,
Amebiasis, C.diff, E coli
0157:H7 toxin, Ischemia,
UC, Crohns, CMV

Non-INFLAMMATORY
Watery w/N/V, volume
>1L/ 24hr secondary to
small intestine disease
Norwalk & Rota virus,
enterotoxins as Giardia,
Staph aureus, Cholera, E
coli, Bile acid, Laxatives,
Malabsorption

Consequences of diarrhea

Loss of ECF volume

Decrease in intravascular fluid volume
Decrease in arterial blood pressure
Circulatory collapse
Loss of bicarbonate (metabolic acidosis)
Loss of potassium (hypokalemia)

GI CASES: Case 1
45-yr old man presents to the clinic with a 3-month history of gradually
worsening dysphagia. At 1st, he noticed the problem when eating solid food such
as steak, but now it happens even with drinking water. He has a sensation that
whatever he swallows becomes stuck in his chest & does not go into stomach.
He has chest discomfort and complains of regurgitation of food esp in night. A
Barium swallow x-ray reveals a decrease in peristalsis of the body of esophagus
along w/dilation esophagus proximal to LES. There is beaked appearance of
distal esophagus involving LES. There is very little passage of barium in to
stomach.
What is the mostlikely diagnosis?
What is the underlying pathophysiology?
Botulinum toxin can be used to treat this disorder. How does it help ameliorate
the sx?
What are the other treatment options?
Calcium channel blocker, Nitrates
Pneumatic dilation
Hellers myotomy

Case 2
A 32-year-old woman presents to her primary care
provider of a persistent burning sensation in her chest
and upper abdomen. The symptoms are worse at night
while she lying down and after meals. She is a smoker
and drinks alcohol mostly during weekends. She
complains of hoarseness and noturnal cough. She
notes a sour taste in her mouth on some mornings.
What is the likely diagnosis?
What is the pathogenesis of her GI disorder?
How may her lifestyle impact her symptoms?
What are some complications of this condition?
How would you like to treat this condition?

Case 3
A 74-year-old man with sever osteoarthritis presents to the
emergency department reporting two episodes of malena ( black
stools) without hematochezia or hemetemesis. He takes 600 mg of
ibuprofen 3 times a day to control his arthritis pain. He denis alcohol
use. On examination his BP is 150/70mmHg and his resting pulse is
96/min. His epigastrium is minimally tender on palpation. Rectal
examination reveals black tarry stool, and grossly positive for occult
blood. Endoscopy demonstrates a 3 cm gastric ulcer. H.pylori is
identified on biopsies of the ulcer site.
What is the likely diagnosis?
What are some of the proposed mechanisms for acid peptic disease?
How may this patients analgesic use predisposes him to acid peptic
disease?
What role does H.pylori infection play in pathogenesis of ulcer
disease?
Discuss the treatment?

Case 4
43 y/o woman presents to ER w/hx of worsening RUQ pain
started after she had pizza for dinner 2 days ago &
described as sharp pain under her R lower ribs. She also
felt ill, devd slight nausea & low grade fever. No vomitting
or diarrhea. PE w/obese women w/low grade fever &
tenderness to palpation of RUQ of abdomen (+ve murphys
sign). Abdominal US w/2 cm gallstone lodged in cystic duct
w/swelling of gallbladder & thickening of gallbladder wall.
What are the mechanisms involved in gall stone formation?
What factors in the pathogenesis of gall stones may be
responsible for the fact that is more common in
premenopausal women?
What local complications can ensue from gall stone
disease?

Case 5
36 y/o woman had 75% of her Ileum resected following a
perforation caused by severe Crohns (Chronic
inflammatory dis of intestine). Her post surgical
management included monthly injections of vit B12.
After surgery, she expd diarrhea & noted her stools
were floating in toilet bowl. Her physician prescribed
drug cholesteramine to control her diarrhea, but she
continues to have statorrhea.
What is the cause of diarrhea in this patient?
What is the cause of steatorrhea in this patient?
Why this patient is taking monthly injections of vitamin
B12?

Case 6
A 52-year-old man visits his physician complaining of
abdominal pain, nausea, loss of appetite, frequent
belching and diarrhea. He reports that his pain is
worse in the night and is sometimes relived by eating
food or taking antacids. Gastrointestinal endoscopy
reveals an ulcer in the duodenum. Stool samples are
positive for occult blood and fat. A CT scan reveals a
1.5 cm mass in the head of the pancreas
What is likely diagnosis?
What else would you do to confirm your diagnosis?
What is the mechanism for malabsoption in this
patient?
Discusss the treatment

Endocrinology:

Endocrine (ductless) glands: glands that

secrete their product directly into blood stream
rather than thru duct

Hormone:( means I Excite / arouse):

Hormones: chemal msngrs released from endocrine glands
directly into blood stream & enter target organs
Hormone Specificity: hormones afx only cells that possess
receptors specific to that particular hormone
Eg: ACTH & LH both increase secretion of steroid hormones,
but, ACTH does this in Adrenal cortex & LH in gonadal tissue
ACTH stimulates adrenal cortex to release cortisol & androgens
LH stimulates testes to release androgens (ie. Testosterone)

669

Stimulus
Hormone release directly
into blood stream
Hormone + Receptor
Enzyme Activation
Morphological, Biochemal &
Funcal changes in target tissues
670

Major Endocrine Organs in our body

Hypothalamus makes GnRH, CRH,

TRH, GHRH, PIF
Ant makes FSH, LH, ACTH, TSH
& prolactin & GH
Post pituitary releases ADH &
Oxytocin (produced by
Hypothalamus)
Thyroid gland produces T3, T4,
calcitonin
Parathyroid gland produces
parathormone
Adrenal cortex produces
Aldosterone, cortisol & androgens
Adrenal medulla produces E (80%) &
NE (20%)
Pancreas produces insulin,
glucagon, somatostatin
Ovaries produces estrogen
(testosterone originally & converted)
& progesterone
Testes produces testosterone

671

Some Non- Endocrine Organs producing

hormones are:
Organ

Hormone

ANP (Atrial natriuretic peptide) when too much

blood volume, lowers it
CCK,SECRETIN & VIP (vasoactive intestinal
peptide), GIP (gastric inhibitory peptide),
Gastrin
EPO (Erythropoetin stimulates bone marrow
to produce RBCs, whenever have hypoxia
(reduced oxygen carrying capacity/delivery of
blood to tissue(s)) to restore O2 carrying
MELATONIN
(sleep
hormone
regulates circadian rhythm
capacity
of blood;
1,25Dihydroxycholecalciferol,
7-dehydrocholesterol
(vit D) from skin

.
2.
3.

Heart
GIT
KIDNEY

.
5.

PINEAL GLAND
SKIN

6.

LIVER

gets converted to cholecalciferol on

exposure to sunlight (UV-rays)
IGF-1 & II (INSULIN-LIKE GROWTH FACTORS)
stimulated by growth hormone from ant
pituitary
1: causes growth of body

Types of Secretions:
A) Endocrine Secretion:

ENDOCRINE CELL

TARGET CELL

Releases

Reaches

HORMONE

enters

BLOOD

HORMONE

Eg: Thyroid follicular cells release Thyroid hormone into blood

stream. These hormones reach target organs via blood
673

B) Neuroendocrine Secretion:

Released
NEURON
Synthesizes
Hormone
in Cell body

(NEUROENDOCRINE)

Reaches
Nerve
terminal

Hormone

Carried by neural tract (axons)

Ex: Hypothalamic neurons synthesize ADH & Oxytocin

thats carried to Post Pituitary via Hypophyseal tract.
This later gets released to act on target organs
674

CLASSIFICATION OF HORMONES:

I) Based on chemical Structure:

A) STEROID HORMONES: all derived from cholesterol! Egs: Sex hormones (estrogen,
progresterone & testosterone), adrenocortical hormones (aldosterone, cortisol & androgens),
Active Vit D (1,25 DHCC)
B) PROTEINS & POLYPEPTIDE HORMONES: Egs: Ant & post pituitary hormones, Hypothalamic
hormones, Parathyroid hormones, Calcitonin, Insulin, Glucagon
C) AA DERIVATIVES: Egs: Catecholamines - E, NE (produced from adrenal medulla & symp
postganglionic neurons; adrenergic), T3 (Triodothyronine) & T4 (Thyroxine)
II) Based on localization of receptors & hormone receptor interaxn:
D) Hormones acting on IC receptors: receptors either in cytoplasm/nucleus; lipid soluble, synthesized
when needed & not stored* except for thyroid hormones made & stored in endocrine glands (b/c
attached covalently to protein in thyroid gland), life is longer (in hrs/days) & is proportional to
their affinity for protein carrier; greater affinity = longer life; slow acting b/c 1 st must be made
(not stored), longer -life & must get proteins made (not modified)
A) Egs: Steroid hormones (receptor in cytoplasm) & Thyroid hormones (receptor in nucleus)
B) Plasma proteins carry lipid soluble hormones in blood circulation ie. Globulins (specific),
prealbumins & few by albumins
C) These hormones diffuse across cell memb of target cells & bind to nuclear receptor causing
conformational change in receptor
D) Initiates transcription production of new mRNA Translation in cytoplasm production of
specific proteins which brings about physiologic axns; so produce brand new proteins!
E) Hormones acting on cell memb receptors: water soluble, stored in vesicles, have shorter half life &
-life is proportional to their MW; greater MW = longer -life; act via production of 2 nd msngrs like
cAMP; fast acting!
A) Egs: Peptide hormones & hormones derived from AAs (except Thyroid hormones)

B) Hormones acting on cell memb receptors act via

production of 2nd msngrs:
Mechanism of hormone axnvia interaction w/cell memb receptors

Mainly takes place via formation of 2nd msngrs that carry info from cell surface to interior of cell
2nd msngrs involved: cAMP, IP3 (Inositol triphosphate), Tyrosine Kinase & Ca2+-Calmodulin complex

G-protein is GTP (Guanosine triphosphate) binding protein that helps in coupling hormone receptor to
effector molecules

associated w/GTPase, Gs, Gi & Gq, plus has binding site for GTP (when active) or GDP (when not active); associated w/ & associated w/

Exs are:
a) 2nd messenger cAMP:

CRH

ACTH, TSH

FSH, LH

MSH

ADH

CALCITONIN, PTH

CATECHOLAMINES (most actions)

HCG

Glucagon increases blood [glucose] via gluconeogenesis & glycogenolysis

Vasopressin (ADH) via V2 receptors on epithelial cells; increases water reabsorption by activating cAMP to recruit
aquaporins (water channels)
nd
b ) 2 msngr cGMP:

*ANP, Nitric Oxide or EDRF (endothelial derived relaxing factor; made by endothelial cells using arginine, go to smooth
m cells for their relaxation)
nd
c) 2 msngr Calcium\Phosphatidyl Inositol Triphosphate (IP3): to release Ca2+ for smooth m contraction

TRH, GnRH, VASOPRESSIN via V1 receptors (presses/contracts/constricts blood vessels), GHRH

OXYTOCIN (contracts smooth ms)

CATECHOLAMINES (some axns ie. NE)

nd
d) 2 msngr: Tyrosine Kinase/ Phosphatase*:

676 activity)
GH, PROLACTIN, INSULIN* (binds w/receptor in target tissue to stimulate tyrosine kinase

a) cAMP / Adenylate cyclase Mechanism

HORMONE RECEPTOR COMPLEX on cell memb
subunit of G-protein dissociates & binds to GTP

subunit-GTP complex activates Adenylyl cyclase

ATP converted to cAMP

cAMP activates PKA (Protein Kinase A)

PKA phosphorylates specific proteins that brings about specific
677
physiologic axns

cAMP/Adenylate
Cyclase mechanism
1 receptors in <3; 2nd msngr is cAMP; increases cAMP in SA node, AV node (conduction velocity) &
ventricles increasing APs to conduct impulses from atrium to ventricle conduction velocity
increases! FOC & <3 rate increases! Amt of Ca2+ released increases! Aka symp stimulation

678

Cellular Response

cAMP/Adenylate
Cyclase mechanism
679

PHOSPHOLIPASE C MECHANISM
Gq signaling

Effector molecule

PIP2- Phosphatidyl Inositol

diphosphate
IP3- Inositol 1,4,5
triphosphate, mobilizes
Ca2+ from storage sites
IP3 goes to ER release of Ca2+ this w/DAG activates PKC physiologic axns
680

A) Axn via IC receptors.ie. Lipid soluble steroid

hormones binding to receptors in cytosol!

Transcription

Translation

681

Steps of (A) Hormone Axn via IC receptors.

1) Steroid hormone diffuses across cell memb & enters its target cell
2) Binds to specific receptor protein (Step 2) in either cytosol or nucleus

Steroid hormone receptors are monomeric phosphoproteins; each receptor has 6 domains
steroid hormone binds in E domain near C-terminus; central C domain has 2 zinc fingers, & is
responsible for DNA-binding
W/hormone bound, receptor undergoes conformational change & activated hormone-receptor complex
enters nucleus of target cell

3) hormone-receptor complex dimerizes & binds (at its C domain) to specific DNA
sequences SREs (steroid-responsive elements) in 5 region of target genes
4) hormone-receptor complex has now become transcription factor that regulates
rate of transcription of that gene
5) New mRNA is transcribed
6) Leaves nucleus
7) & is translated to new proteins
8) that have specific physiologic axns
Ex. Steroid hormone Aldosterone regulates total body sodium, by increasing
sodium [ECF]; produces epithelium Na+ channels, increases Na+ reabsorption
back into ECF; does this by producing brand new proteins
682

Hormone Synthesis & Reg:

Peptide hormone synthesis: ie. Insulin
1. in nucleus, gene for hormone transcribed to mRNA
2. mRNA transferred to cytoplasm & translated on ribosomes of ER to
protein (preprohormone)
3. Pre-pro-hormone (precursor of peptide hormone in rER) converted to
Prohormone & transported to golgi
4. In Golgi, prohormone packaged in secretory vesicle in which it gets
converted to final hormone & then stored in secretory vesicles
. Steroid hormones - derivatives of Cholesterol
. Amine Hormones (THs (except calcitonin), E & NE +DA?) - derivatives
of Tyrosine
Reg of hormone secretion:
. Mainly controlled by Hypothalamo-pituitary axis
. 2 types of Reg: Positive feedback & Negative feedback

683

-ve feedback:

Thyroid Hormone ve Feedback Loop

MC feedback mechanism
increase in [ ] of particular
hormone or their effect
directly/indirectly inhibits
further secretion of that
hormone
For ex:
-cells of Pancreas
secrete Insulin

Decreases
ood glucose by increasing glucose
uptake by cells

Decreased blood glucose inhibits

further Insulin secretion

684

Positive feedback

RARE; hormone has biologic axns that directly/indirectly causes more

secretion of that hormone
Ex: Leutinizing hormone (LH) from Ant pituitary gland stimulates secretion of
Estrogen from ovaries. This estrogen causes more secretion of LH as +ve
feedback mechanism.
Estrogen lvls at highest peak at midcycle b4 ovulation; rmr whole thing is 28 day
cycle, ovulation at 14 days, 2 days b4 menses, estrogen lvls drop
High estrogen lvls in blood has +ve feedback on ant pituitary stimulates
gonadotrophs to produce huge LH & FSH surge = OVULATION
Thus need high lvls of estrogen for OVULATION
Low lvls have ve feedback (b4 & after high lvls)

685

Regulation of Hormone receptors (Down or Up):

A)

Down Reg of receptors aka tissue resistance: chronic high circulating

lvls of hormone decrease # of its receptors on target cell
A) Exs: i) insulin resistance: chronically elevated plasma Insulin
decreases # of Insulin receptors in Type II NIDDM (Non-insulin
dependent DM)
B) ii) In uterus, progesterone down regulates its own receptors &
receptors for estrogen
C) Exception to Down reg: hormones secreted in pulsatile manner (every
few hrs/mins; thus prevents down-reg of receptors in Ant Pituitary).
Egs: GnRH, GH, ACTH, Cortisol do not have down-reg of receptors
b/c of their pulsatile release
B) Up Reg of receptors: increase in # of receptors on surface of target cells,
making cells/tissues more sensitive to that hormone
A) Ex: In ovary, estrogen up regulates its own receptors & receptors for
LH, increasing sensitivity to LH as estrogen increases in 1st of cycle
B) increase in uterine Oxytocin receptors in 3rd trimester of pregnancy,
promoting uterine contraction

Transport of hormones
Hormones transported in 2 forms: (always in equilibrium)
A) Free form: Peptide & protein hormones, Catecholamines; its free hormone
thats available to tissues & free unbound form determines plasma activity,
ie. Less than <1% of T3 & T4 in free form available to tissues for their
physioal axns (thus normally low)
B) Bound form: steroid & thyroid hormones; bound to binding proteins made by
liver
Liver makes binding proteins that bind to these lipid-soluble hormones. Exs:
CBG (Cortisol Binding Globulin), TBG (Thyroid Binding Globulin) to T3 & T4
(99%), Estrogen/Testosterone Binding Globulin

Binding proteins

Binding proteins are synthesized in Liver

Estrogen causes release of more binding proteins by liver = free form of estrogen
decreases initially, but then returns to normal; total lipid soluble hormone lvls increase
[bound form + free form] = but no physioal effect b/c its only bound form that
increases in #
Liver dysfunc & androgens decrease circulating lvls of plasma/binding
proteins
687

During Pregnancy.
Though there is an increase in Estrogen levels,
pregnant females do not show any signs of
Estrogen hyperfunction. Why???
During pregnancy, Estrogen levels are elevated.
Estrogen causes release of more binding
proteins. THUS plasma lvls of bound hormone
elevated but Free hormone at normal lvl. Since
Free hormones are active form, no signs of
Estrogen hyperfunc (excess) are seen.
688

To Summarize.

Differences between Endocrine & Neural control

Classification of hormones:
A) Based on chemical structure
Steroid hormones - Sex hormones, Vit. D3, Adrenocortical hormones
Amino acid derivatives - E, NE, T3, T4
Proteins & Polypeptides - other hormones
B) Based on localization of receptors - Hormones acting on Intracellular receptors - Steroid & Thyroid
hormones
Hormones acting on cell membrane receptors
Mechanisms of hormone actions: Cell membrane receptors
- Role of G-proteins
- A) cAMP/Adenylate cyclase mechanism:
H+R
(+) G-protein
(+) Adenylate cyclase
Conversion of ATP to cAMP - Stimulates Protein Kinase A Phosphorylation of enzymes & brings about physiological efx
B) Phospholipase C Mechanism
Nuclear receptors: Steroid & Thyroid hormones
Hormone Synthesis
Regulation of hormone actions - Positive & Negative feedback mechanisms. Give examples
Upregulation & Downregulation of receptors with examples
689
Role of binding proteins - What happens during pregnancy????

Hypothalamus:

690

Action of hypothalamic hormones:

HYPOTHALAMIC
HORMONES:

TARGET PITUITARY
HORMONE:

TARGET OF
PITUITARY HORMONE:
ADRENAL CORTEX to produce
cortisol (zona fasciculata) &
androgens (zona reticularis)

CRH (PVN) acts on

corticotrophs of ant pit

ACTH goes to

TRH (PVN) (Thyrotropin

releasing hormone)

TSH (thyroid stimulating

hormone)

GnRH (PO) (Gonadotropin

releasing hormone)

acts on Gonadotrophs to secrete

FSH, LH

GHRH (AN)

GH (somatotrophs)

GENERALISED

SOMATOSTATIN

inhibits GH

GENERALISED

(GHIH) (PVN)

PRIH (DA; prolactin

inhibitory hormone)
(AN)

PROLACTIN
(produced by
lactotrophs of AP)

THYROID

GONADS (FSH & LH required for

estrogen production; LH for ovulation
& progesterone, testosterone)

BREASTS

INHIBITS RELEASE OF THE PITUITARY691

HORMONE

Hypothalamus as seat of control for other

endocrine glands

692

HYPOTHALAMUS
Secretes Releasing hormones
These hormones diffuse into Hypothalamic capillaries

Join to form Hypothalamo-hypophyseal

Portal venous system
Releasing hormones are carried to
Anterior Pituitary by portal vs
Stimulate release of Ant pituitary Hormones

Hypothalamo Hypophyseal Portal

System

694

Relnship of Hypothalamus to Post Pituitary.

Hypothalamic neurons Supraoptic & Paraventricular
neurons/nuclei secrete ADH & Oxytocin packaged in secretory
granules & transported by HypothalamoHypophyseal tract
(axons collection) to Post Pituitary.
In Post Pituitary, theyre stored, to be released when required

695

696

Classification of Hormonal disorders:

Based on site of hormone defect (either increase or decreased secretion),
Endocrine disorders classified as:
A) Primary Disease: If defect in target gland from which hormone has
originated; exs:
A) Primary Thyroid def (hypothyroidism): due to decreased secretion of TH
from thyroid itself
B) Primary hypocortisolism: problem in adrenal gland, decreased cortisol
lvls, increased
B) Secondary Disease: If defect in Ant Pituitary; exs:
A) Secondary Thyroid def (hypothyroidism): due to def of Ant pituitary
hormone that stimulates production of TH from Thyroid; low lvls of TSH,
T3, T4 & high lvls of TRH
B) Secondary hypocortisolism: due to def Ant pituitary hormone, CRH lvls
in blood increase
C) Tertiary Disease: If defect in Hypothalamus; exs:
A) Tertiary Thyroid def: def Hypothalamic hormone (due to hypothalamic
damage)
B) Tertiary hypocortisolism: due to def hypothalamic hormone CRH lvls
decrease
697

What happens if there is a damage to the

Pituitary stalk?
Pituitary stalk: connection btwn Hypothalamus & Pituitary
In a lesion involving Pituitary stalk, theres neurovascular
damage. Secretion of all pituitary hormones decrease
EXCEPT Prolactin (PRL). Why???
PRL inhibition by PRL inhibiting factor secreted by
hypothalamus is absent
Note: GH decreases even though GH inhibiting hormone is
absent b/c its GHRH which is main regulator of GH
secretion

698

Give Physiological basis for.

Hypothyroidism with Galactorrhea? Excessive/inappropriate
milk production (in nonlactating women)
Dwarfism with Galactorrhea? Infantile body proportions, gross
retardations of mental & physical devt, decreased TRH &
GHRH leading to decreased TSH & GH
In both above cases, defect is in Hypothalamus
Thus DA cannot inhibit PRL secretion from Ant Pituitary
resulting in Galactorrhea
Since TRH & GHRH not secreted from Hypothalamus, TSH &
GH secreted from Ant Pituitary decreased, resulting in
Hypothyroidism & Dwarfism

699

High yield facts

Releasing Hormones of Hypothalamus
CRH

ACTH

Adrenal
Cortex

TRH

TSH

GnRH

GHRH

FSH,
LH

GH

Thyroid Gonads
Gland

Generalized
700

High yield facts.

Hypothalamic neurons - SON, PVN
ADH & Oxytocin
Stored in
Posterior
Pituitary
Primary & Secondary Endocrine disorders
Consequences of damage to the Pituitary stalk / Hypothalamus
701

Pituitary Gland ( Hypophysis; Master Gland!):

702

703

Anterior Pituitary Gland

704

Ant pituitary secrete 6 Trophic

hormones:
1.
2.
3.
4.
5.

TSH (Thyroid stimulating hormone) / Thyrotropin

ACTH (Adrenocorticotropic hormone) / Corticotropin
GH (Growth hormone) / Somatotropin / STH
FSH (Follicle stimulating hormone)
LH (Leutinizing hormone) / ICSH (Interstitial cell stimulating
hormone)
6. PRL (Prolactin) / Luteotropic hormone (LTH)
/Luteotropin/Lactogenic hormone/ Mammotropin
Hormones stored in Post Pituitary: ADH (Vasopressin) & Oxytocin

705

Pituitary Gland:
Has 2 lobes- (1) Ant lobe/pituitary/Adenohypophysis & (2) Post
lobe/pituitary/neural lobe/neurohypophysis
5 types of active chromophilic secretory cells in Ant pituitary.
(Chromophilic means cells which can be stained); can be
acidophilic or Basophilic
Acidophilic cells secrete GH, PRL
Basophilic cells secrete: FSH, LH, ACTH, TSH (B- FLAT)
Following cells in Ant Pituitary:
1) Somatotropes - secrete Growth hormone
2) Lactotropes (Mammotropes) - secrete Prolactin
3) Corticotropes - secrete ACTH
4) Thyrotropes - secrete TSH
5) Gonadotropes secrete FSH & LH

706

Intermediate lobe of Pituitary:

rudimentary in humans
In lower animals, secrete & MSH (Melanocyte stimulating
hormone) / Melanotropin which is responsible for pigmentation
In humans ACTH has MSH like activity
ACTH binds to Melanotropin-1 receptors & causes Melanin
production giving rise to pigmentation
thus, increased ACTH secretion as seen in Addisons Disease
causes Hyper pigmentation

707

Pro opiomelanocortin (POMC):

POMC found in Ant & Intermediate lobes of Pituitary
POMC is precursor for ACTH & MSH

POMC

ACTH

-MSH

(primary stimulator of melanocytes)

708

Reg of GH (Somatotropin/STH) secretion

Growth hormone (GH): single chain polypeptide w/species specificity;
released in pulsatile manner; structural resemblance to PRL & Human
Placental Lactogen (HPL); mechanism of axn: acts via cell memb receptors
A) Role of Hypothalamus: Hypothalamus regulates GH secretion via GHRH
(GH releasing hormone) & GH inhibiting hormone (GHIH/ Somatostatins);
(GHRH stimulates synthesis & secretion of GH; GHIH inhibits GH secretion
by blocking resp of ant Pituitary to GHRH)
B) -ve feedback control by Somatomedins (SM) (aka Insulin-like growth
factors (IGF)) made mainly by LIVER
) When GH binds to its receptors on liver, Somatomedins (IGF) made by liver
) When GH lvls start increasing, theres increased secretion of SMs by liver.
This in turn inhibits GH secretion by stimulating secretion of Somatostatin
from Hypothalamus
) Increased GH lvls also inhibit their own secretion by (+) secretion of
Somatostatin from Hypothalamus

709

GHIH

Inhibits growth production

somatotrophs

C
Primary target tissue: liver, binds w/its GH receptors & increases somatomedins (IGF-1)

710

Factors Affecting GH Secretion:

Stimulatory Factors:
Decreased [glucose]/hypoglycemia
b/c GH raises blood [glucose]
Decreased free [FA]
Arginine admin
Fasting or starvation
Hormones of puberty (estrogen,
testosterone)
Exercise
Stress
Stage III & IV sleep
-Adrenergic agonists

Inhibitory Factors:
Increased [glucose]
Increased [FFA]
Obesity
Senescence (aging)
Somatostatin
Somatomedins (-ve)
Growth hormone (-ve)
-Adrenergic agonists
Pregnancy

Control of GH secretion
GH secretion is pulsatile
Pulses more likely to occur at night in stage III & IV (non-REM) of sleep vs day
GH secretion requires normal lvls of thyroid hormone. Ie. GH secretion markedly
reduced in hypothyroid inds
During 6th Decade of life & later, GH secretion diminishes considerably in both sexes
GH is stress hormone (other stress hormones are Glucagon, cortisol & E) can occur
711
via hypoglycemic stress

GH HAS 2 TYPES OF AXNS:

DIRECT CATABOLIC axns & INDIRECT ANABOLIC axns

Most anabolic (indirect) afx of GH - on growth, cartilage & protein metabolism are
indirect & mediated by Somatomedins/IGF; has -life of 20 mins
Somatomedin: polypeptide made mainly in liver (also by kidneys, cartilage & skeletal ms)

Somatomedin-C: in humans, most imp; aka IGF-I (Insulin-like growth factor)

Circulate in blood binding to protein (1/2-life very long 20 hrs), blood IGF lvl reflect 24hr GH secretion as GH secreted in pulses w/shorter -life & more elevated during
sleep

IGFs increase lean body mass; decreases w/age. Thus, in old age, decrease in lean
body mass due to decreased IGF-1 & also decreased in catobolic states, esp PEM
(protein energy malnutrition)
1) Stimulates growth of bones, cartilage & CT: (GHs main axn) mediated by IGF-1
(Somatomedin C)
a)
On Bones & cartilage (b4 epiphyseal closure aka fusion of epiphyseal plate):
)
GH causes liver to secrete IGF-1 (SM) causes proliferation of Chondrocytes
(cartilaginous tissue aka Chondrogenesis) in epiphyseal plates of long bones
increases length of long bones
)
GH promotes formation of Osteoblasts
)
also stimulates DNA & RNA synthesis & collagen formation in cartilage
Net result: increased thickness of epiphyseal cartilaginous end plate - increased linear
skeletal growth; max during puberty due to increased GH secretion resulting in
Pubertal Growth Spurt
b) After Epiphyseal closure (Fusion): no increase in bone length
) Increase in bone thickness thru periosteal growth
) Increased protein synthesis in most organs causing hyperplasia, hypertrophy
increase tissue mass & organ size
712

2) Axns of GH on Metabolism:
a)

On Carb Metabolism: direct axn; doesnt need IGF as GH is

Diabetogenic hormone ie; blood sugar & causes
hyperglycemia by increasing hepatic glucose output by 2 ways:
(1) promoting gluconeogenesis by liver
(2) decreases peripheral utilization of glucose (Anti-Insulin
Effect) by skeletal m & adipose tissues
b) On Fat metabolism: GH has direct Catabolic Effect as ketogenic
hormone - mobilizes fat from adipose tissues by increasing
lipolysis w/help of hormone sensitive lipase; doesnt need IGF
for this
FFAs further used for Gluconeogenesis/energy (& glycerol
into glucose)
Ketogenic: produces FFA that undergo hepatic oxidation &
form ketone bodies
c)
On Protein metabolism: as protein anabolic hormone via indirect axn
b/c needs IGF;

uptake of AAs & stimulates synthesis of DNA, RNA & Proteins

protein synthesis in m & increases lean body mass

Also protein synthesis in organs & increases organ size

Other axns of GH
) milk production b/c GH has structural similarity to PRL
713
) (+) erythropoiesis (production of RBCs)

Growth Changes:
During puberty, if T4 is normal, increase in androgens drive
increased GH secretion, which drives increased IGF-1.
In males androgen arise from testes & females from adrenals
Near end of puberty, ***androgens promote mineralization
(fusion or closure) of epiphyseal plates of long bones. QUES*
not only cause growth during puberty but also mineralization of
bones twds end of puberty

714

Clinical correlates of Anterior Pituitary

DWARFISM: occurs due to GH deficiency
Results in Short stature/Stunted growth
Endocrine causes for dwarfism are:
Panhypopituitarism is lack of all Ant Pituitary
hormones
Decreased GHRH / IGF-1
Hypophysectomy (removal of pituitary gland)
Hypothyroidism

715

Clinical features of GH deficiency

- Pituitary Dwarfism
GH deficiency results in Short stature due to Growth
retardation. Inds referred to as Dwarfs
Other associated features in GH deficiency are:
Decreased hair growth due to decreased protein
synthesis, fasting hypoglycemia (cortisol deficiency),
Immature genital organs leading to sexual immaturity
KNOW HYPOGLYCEMIA W/GH DEFICIENCY

716

Other forms of Dwarfism..

A) Laron Dwarfism / GH insensitivity: plasma GH
lvls elevated, but GH receptors defective
Investigations reveal, Increased GH & increased
GHRH lvls & markedly reduced IGF-1 (as
production of IGF-1 dependent on interaxn of
GH w/its receptors)

717

DIFFERENCES BETWEEN :
PITUITARY DWARF:
Caused due to : GH ,GHRH

HYPOTHYROID DWARF
(CRETINISM):
due to deficient TH

Clinical features:
Plumpiness, Immature face,
Small genitalia
Body proportion according to
chronological age
Delayed skeletal & dental
devt
circulating lvls of GH

GR & MR
Infantile body proportion
(head to body ratio)
Other features of
hypothyroidism

718

INFANTILE BODY
PROPORTION

BODY PROPORTION
ACCORDING TO
CHRONOLOGICAL AGE

6Months 1year 3years 6 years 13years 21years

(SHORT
Large head
LEGS) (Puberty) (Adult)
& trunk

RATE OF GROWTH AFTER BIRTH IN BOYS & GIRLS(A):

GROWTH IN HEIGHT(B)

719

Case..
Parents of a 4year old child come to you with
complains that their child is short for his age
Hormonal assays in child reveal decreased GH lvls
On giving GHRH infusions, if GH levels start
increasing, where is the site of defect?
Hypothalamus or pituitary stalk

On giving GHRH if GH does NOT increase where is

the site of defect?
Ant pituitary
720

Classification of pituitary adenomas:

Tumor type Sec. product (s) R. Frequency
Prolactinoma
PRL
50%
Somato.adeno. GH/PRL
10%
Cortoco. adeno. ACTH
5%
Thyro. adeno
TSH
1%
Non-sec. adeno
34%
aka chromophobe tumors can develop into
macroadenomas (> 1 cm) (other tumors above can
also develop into this)
In females, usually get microadenoma (b/c may present
earlier vs males)
- Pts can present w/intracranial pressure & visual field
dfx (due to pressing on optic chiasm)

Growth Hormone excess Before Puberty

GIGANTISM (GIANTISM): due to

overproduction of GH in adolescence, b4
puberty (b4 epiphyseal closure) results
in excessive growth of long bonesHeight (8 ft)
Clinical features:
Tall stature (upto 8 ft / 2.5 mts)
Large hands & feet
Other associated features Bilateral
Gynaecomastia (enlargement of breasts
due to structural similarity of GH to
Prolactin)
Coarse facial features due to increased
tissue proliferation

722

GH excess after Puberty

ACROMEGALY: due to excessive secretion of GH during adulthood (after epiphyseal closure); 2 Causes:
1. Acidophilic tumor of ant pituitary
2. Hypothalamic GHRH secreting tumors (associated w/ PRL efx)
Clinical features of Acromegaly: mainly due to growth of cartilaginous (peripheral) areas
. Prognathism - elongation & widening of mandible
. Prominent brow
. Bulbous nose
. Facial changes as ACROMEGALIC FACIES thickening of skin & coarse facial features - proliferation of CT
resulting in Facial edema
. Increased Blood glucose lvls (as GH is diabetogenic)
Other features of Acromegaly:
.
Kyphosis - periosteal growth of vertebrae
.
Enlarged hands & feet (Acral pts) - periosteal growth of metatarsals & metacarpals; increased glove size/ring size
.
Hypertrophy of soft tissues
.
Hyperglycemia develop insulin resistance
- Heart (Cardiomegaly)
- Liver (Hepatomegaly)
- Kidney (Renomegaly)
- Spleen (Splenomegaly)
- Tongue & ms - Macroglossia during sleep can result in absent breathing apnea (tongue obstructs
airway)
.
In 4% cases-Gynaecomastia (breast enlargement in males w/ or w/out lactation- b/c of structural similarity of GH
to PRL; GH efx on breast tissues)
.
Visual field dfx if pituitary tumor compresses Optic Chiasma
Tx of GH excess: w/Somatostatin analogues (Ex: Octreotide, Lanreotide) that inhibits GH secretion
Unless pt presents w/macroadenoma or visual field dfx then do
. DA agonists: Bromocriptine & Cabergoline; reduce tumor size! Can also be used for prolactinomas
. Last option: tumor removal aka trans-sphenoidal surgery; complication: destroys 30% of pts pituitary
panhypopituitarism

Progressive coarsening Progressive

of facial features
with of
coarsening
advancing age - Acromegalic
facialfacies
features w/advancing
age - Acromegalic facies

724

725

Case

25 yr old lady who just delivered a baby, has severe Post partum
hemorrhage. Couple of months later she presents to Physician
w/amenorrhea, loss of hair, failure to lactate & signs of Hypothyroidism.
Hormonal assays reveal decreased TSH, FSH, LH & ACTH lvls.
What could be the probable diagnosis in this case?
Blood volume decreases, thus BP decreases, thus if not txd, blood vessels
of pituitary can go into vasospasm blood supply to pituitary decreases
if not brought back to normal, pituitary can exp ischemia necrosis
destroying pituitary gland & its cells Ant pituitary hormones wont be
produced decreased TSH (b/c thyrotrophs destroyed), FSH & LH
(gonadotrophs & so thyrotrophs as well), ACTH (corticotrophs);
somatotrophs & lactotrophs

Gonadotrophs & thyrotrophs destroy earliest***

Depends on severity of bleeding & duration

Pts can present w/absence of lactation due to this; symptoms can present
even yrs later
726

Causes for Pituitary Insufficiency:

Sheehans Syndrome

Panhypopituitarism: decreased secretion of all ant pituitary hormones

Ant Pituitary insufficiency commonly occurs in females w/post-partum
hemorrhage resulting in Sheehans Syndrome
Sheehans Syndrome: post partum pituitary necrosis can occur b/c ant
pituitary which is highly vascular, gets enlarged during pregnancy so during
childbirth, if mother suffers post-partum hemorrhage, leading to pituitary
infarction & necrosis giving rise to decreased lvls of all ant pituitary
hormones resulting in panhypopituitarism
Post pituitary hormones not affected as ADH & oxytocin made by
hypothalamic neurons
OTHER PITUITARY HORMONES:
FSH, LH Reproductive funcs
TSH - regulation of thyroid secretion
ACTH: Stimulates release of Adrenocortical hormones

727

PRL (Lactogenic/Mammotropic/Galactopoietic hormone):

Prolactin (PRL): single chain polypeptide, structurally similar to GH,
increases during pregnancy & lactation
Receptors resemble GH receptors
Physiological axns of PRL
PRL: major hormone responsible for Lactogenesis
Stimulates milk production in breasts by formation of Casein & Lactalbumin
Stimulates breast devt along w/estrogen
F: Inhibits ovulation by decreasing synthesis & release of Gonadotropin
Releasing Hormone (GnRH) from Hypothalamus so LH & FSH decreases
decreasing ovary func amenorrhea & galactorrhea infertile
M: Inhibits spermatogenesis by decreasing GnRH loss of libido/desire for
sex infertile/impotence; rarely see gynocomastia
Ques???? A lactating mother gives history of absence of menstrual cycles
What is the physiological basis for Lactational Amenorrhea in this lady?
PRL inhibits GnRH release from Hypothalamus, which decreases FSH, LH
secretion by Ant Pituitary, thereby preventing ovulation. Thus absence of
Menstrual cycle (Amenorrhea) during lactation

Regulation of prolactin secretion:

1) Hypothalamic control:
Via DA (PIF) & Thyrotropin releasing
hormone (TRH)
PRL secretion tonically inhibited by DA
(Prolactin inhibiting factor PIF)
secreted by Hypothalamus
TRH from Hypothalamus increases PRL
secretion
2) Negative Feedback Control:
PRL (-) its own secretion by stimulating
Hypothalamic release of DA
729

Factors affecting PRL secretion:

Factors increasing PRL secretion
Estrogen (during Pregnancy
stimulates lactotropes to secrete
PRL)
Breast feeding (nipple stimulation)
TRH
DA antagonists (ie. Schizos can
have hyperprolactenemia due to
taking this drug for tx)

Factors decreasing PRL secretion

Dopamine
Bromocryptine (DA agonist) (act like
DA)
Somatostatin
PRL (by ve feedback)

NOTE: Estrogen inhibits mRNA production & synthesis of milk

proteins. THUS increases PRL secretion but INHIBITS axns of

PRL

Give physiological basis for..

Lesions of Hypothalamic pituitary stalk gives rise to
sustained lactation (Galactorrhea)?
- thats b/c PIF (DA) from Hypothalamus cannot inhibit PRL & theres
a sustained increase in PRL lvls which leads to Galactorrhea
730

Galactogogues:
Galactogogues: substances which increase milk secretion
Exs: TRH analogues
Dopamine (PIF) antagonists
Used in txing lactational deficiencies seen in Ant pituitary
lesions which can result in failure to lactate in nursing mothers

731

Clinical aspects
HyperProlactinemia: PRL excess resulting from:
Hypothalamic lesions b/c lose inhibitory control of PIF (DA) on
PRL secretion
Prolactinomas PRL secreting tumors of Ant Pituitary; most
common pituitary tumors
Clinical Features:
Galactorrhea
Amenorrhea (Lack of Menstrual cycles) seen b/c PRL inhibits
GnRH release from Hypothalamus causing decreased FSH &
LH & failure to ovulate
In females Infertility & Amenorrhea
In males Gynaecomastia & Impotence
Tx: DA agonists like Bromocryptine/Cabergoline which decreases
PRL secretion

732
Gynaecomastia
in male

MEN1 (Multiple endocrine neoplasia type 1/

Wermer syndrome):
AD familial tumor syndrome
Ppl develop tumors of parathyroid glands, enteropancreatic
neuroendocrine system, ant pituitary gland, & skin.
MC endocrine tumors are parathyroid tumors that cause
hyperparathyroidism & hypercalcemia
Other tumors include gastrinomas, insulinomas,
prolactinomas & carcinoid tumors

733

Post Pituitary Gland:

Post Pituitary hormones are:
a) ADH (Antidiuretic hormone) aka Vasopressin
b) Oxytocin
These hormones are made by Hypothalamic nuclei
Travel down n axons & get stored in Post Pituitary to
be secreted by it as & when required

734

735

Antidiuretic Hormone (ADH) / Vasopressin:

aka Vasopressin b/c of its vasoconstrictor axns via V1 receptors (IP3 & DAG) at high lvls
Originates in Supraoptic nucleus (SON) of Hypothalamus, transported by its carrier protein
Neurophysin II
ADH exerts Antidiuretic effect via V2 receptors by stimulating Adenylyl cyclase activity
(cAMP) in renal tubules
Major factors regulating ADH secretion are:
Changes in plasma Osmolarity (Osmotic stimuli); MAJOR REGULATORY FACTOR
PLASMA (ECF) Volume changes

Factors that influence ADH secretion

ADH secretion is stimulated by:
Increased plasma/ECF
osmolarity (even 1%!) VERY
IMP*
Means decreased plasma/ECF
volume
Angiotensin II (aka in attempt
to restore low blood volume/
low BP from renin!)
Pain/stress

ADH secretion is inhibited by:

Decreased plasma/ECF osmolarity
Increased plasma/ECF volume
ANP (when excess blood volume
due to too much body fluid volume)
Alcohol*** (complain of thirst)
Weightlessness (no gravity ie.
Space, lack of distended vs, blood
comes back twds <3 increased
BP ADH decreases)
736

Osmoreceptors & ADH secreting neurons

located very close to each other in
hypothalamus
ADH made most in SupraOptic
Hypothalamus: Paraventricular

Nucleus of hypothalamus & stored in

and Supraoptic nuclei
post pituitary
Osmoreceptors
Osmoreceptors stimulated by increase
in osmolarity of ECF/plasma
Osmoreceptors (ORs) in turn activate
ADH neurons in hypothalamus.
ORs also stimulate consumption of
Posterior
pituitary
water thru hypothalamic centers
regulate thirst
SO & PVN receive info from arterial
baroreceptors
Secretion of ADH most sensitive to
plasma osmolarity;
BUT if BV decreases or cardiac output
fails, high ADH lvls are secreted even
if it causes low plasma osmolarity
737

Reg of ADH by Osmolarity & blood volume:

Know effect of Alcohol here

738

Cellular mechanism of axn of ADH in principal cells of DT & CD

Know what drugs affect here

Tubular fluid

Tubular
lumen

P cells of DCT & CD

V2 receptors

Adenylyl cyclase
enzyme
Second messenger
AQP2: aquaporin 2 are protein
water channels that increase
water permeability of DT & CD

Clinical aspects - Diabetes Insipidus (DI):

Diabetes Insipidus (DI): syndrome that results when theres Vasopressin deficiency or
when kidneys fail to respond to ADH
A) Central/Neurogenic DI: complete or partial failure of ADH secretion (diseases of
hypothalamus / post pituitary); causes:
Idiopathic - 30%
Malignant or benign tumors of brain or pituitary - 25% (Eg; Craniopharyngioma
in children)
Cranial surgery - 20%
Head trauma 16%
B) NEPHROGENIC DI: complete/partial failure of kidneys to respond to ADH due to defect in V2
Receptors / Aquaporins (Water channels in collecting ducts); causes:
1. Lithium carbonate used to treat Bipolar disorders; impairs ADH stimulatory effect on
adenylate cyclase, resulting in less cAMP
Decreased Aquaporin 2 expression (decreased AQP 2 mRNA, lvls) this results in
resistance to axns of ADH leading to Nephrogenic DI
2. HYPERCALCEMIA (>11mg/dl)
3. Other Drugs: Amphotericin B, Demeclocycline, ofloxacin
4. Heriditary (mutation in AVP receptor gene)
. To differentiate btwn the 2 forms, give exogenous ADH
- If theres resp (Urine Osmolarity increases) its Neurogenic DI
- If theres no resp (Urine osmolarity fails to increase) - It is Nephrogenic DI
740

Clinical features of DI:

Polyuria - loss of large volumes of urine (3-20 Ltrs/day) due to decreased renal water
reabsorption by collecting ducts due to deficiency of ADH
Dilute urine w/low osmolarity (< 300mOsm/L)
Low specific gravity (1.010)
Polydipsia: increased thirst; loss of water stimulates thirst center & causes polydipsia
How is DI diff from DM ???? Differentiating features are:
Blood sugar lvls normal in DI
Urine osmolarity decreased in DI, but urine Osmolarity greater in DM due to presence
of glucose in urine
Diagnosis:
a) Fluid deprivation - In presence of ADH, on fluid deprivation, urine osmolarity
increases. In absence of ADH, urine osmolarity fails to increase.
b) Injection of ADH: In Neurogenic DI, urine osmolarity increases only after admin of
Desmopressin (synthetic form of ADH)
In Nephrogenic DI, urine osmolarity fails to increase even after giving injection ADH
Tx: Vasopressin analogue - Desmopressin has marked antidiuretic activity w/little
pressor activity

741

Syndrome of inappropriate ADH (SIADH):

abnormally excessive ADH lvls secreted either from post
pituitary or from ectopic sites like tumor cells of lungs
ADH secretion is autonomous & not in resp to plasma
osmolarity or volume changes
High plasma ADH lvls (seen in nephrogenic DI & SIADH)
To differentiate:
hypertonic urine = SIADH
hypotonic urine = DI
excessive H2O reabsorption in LDT & CD leading to increased
water retension, HYPONATREMIA
High plasma/ECF volume & low plasma osmolarity
Hypertonic & low volume urine excretion
Tx: fluid restriction but not salt restriction & demococycline
(blocks ADH receptors on renal tubules) (know drugs reld
to this!)
742

Exs of ADH secretion in certain physioal & pathological conditions:

: Increase or High;

: Decrease or Low
743

Oxytocin:
Originates in (PVN) of Hypothalamus
Transported by its carrier protein Neurophysin I
Factors (+) Oxytocin release:
Suckling
Sight / smell / sound of babys cry
Dilating cervix (Parturition); goes to CNS to post pituitary to make oxytocin for contractions
Orgasm
Factors (-) Oxytocin release:
stress, fright
Drugs: Opiods, Alcohol
Axns of Oxytocin:
Stimulates Myoepithelial cells contraction in Mammary glands causes Milk Ejection Reflex in
lactating breasts
stimulates release of PRL from Ant pituitary
stimulates contraction of smooth ms of uterus (myometrium) - crucial role in labor - causes
Parturition Reflex
used in induction of labor & reduce postpartum bleeding
Milk Ejection Reflex: Via Stimulus - Suckling by baby
Afferent fibers from spinal cord reach PVN of Hypothalamus
Efferent fibers carry Oxytocin to post pituitary
Oxytocin released causes simultaneous increase in PRL secretion from Ant pituitary that
maintains constant milk production
Oxytocin causes contraction of Myoepithelial (smooth m) cells of breasts that results in milk
expulsion from mammary alveoli into mammary ducts to infant
744

Milk ejection reflex

(Milk-Let-Down):

745

Suckling reflex

746

Process of birth: Parturition reflex

During pregnancy
increased # of
Oxytocin receptors in
uterus
Stimulus fetal head
stretches cervix &
stimulates its stretch
receptors
Afferents carried by
spinal pathways to PVN
of Hypothalamus causes
release of Oxytocin
upreg of Oxytocin
receptors in uterus
Efferent fibers carry
Oxytocin to uterus
This increases contractions of myometrium (Uterine smooth m) - Fetus pushed down
- further stretch of cervix
This cycle continues till baby & placenta finally expelled out
Childbirth usually occurs in 3 stages:
1st stage: time of onset of true labor until cervix is completely dilated to 10 cm.
2nd stage: period after cervix is dilated to 10 cm until baby is delivered.
747
3rd stage: delivery of placenta

Craniopharyngioma:

Craniopharyngioma: slow-growing, extra-axial, epithelial-squamous, calcified cystic

tumor arising from remnants of craniopharyngeal duct &/or Rathke cleft
Both Rathke pouch & infundibulum develop during 4th week of gestation & together
form hypophysis. This tumor is in pituitary stalk & projects into Hypothalamus; can
compress both Ant & Post pituitary
Bimodal age distribution, w/peak incidence in kids 5-14 yrs & elderly aged 65-74 yrs
MC presenting symptoms: headache, endocrine dysfunc & visual disturbances
(bitemporal hemianopsia). Headache is slowly progressive, dull, continuous &
becomes severe in most when endocrine symptoms become obvious
On presentation, pts may have symptoms of hypothyroidism due to decreased TSH
(e.g., weight gain, fatigue, cold intolerance, constipation), have associated signs &
symptoms of adrenal failure due to decreased ACTH (eg: hypotension,
hypoglycemia, hyperkalemia, cardiac arrhythmias & may have DI (eg, excessive fluid
intake & urination).
Decreased sex hormones due to decreased FSH, LH may cause impotence in men &
amenorrhea in women
Most young pts present w/growth failure & delayed puberty
Optic pathway dysfunc on presentation noted in 40-70% of pts
748

Correct Answer749
: D

Thyroid Gland:

750

751

Thyroid Gland

TH made in follicular epithelial cells of TG

follicular epithelial cells arranged in circular
follicles 200-300 micrometer in dm
cells have basal memb facing blood & apical
memb facing follicular lumen
Colloid material in lumen of follicle
Colloid is made of newly synthesized THs
attached to Thyroglobulin
Synthesize & Release THs: Thyroxine (T4),
Triiodothyronine (T3) major thyroid
hormones
Thyroid gland also makes Calcitonin
Steps involved in biosynthesis are:
Thyroglobulin synthesis
Iodide (I-)Trap mechanism
Oxidation of Iodide (I-) to Iodine (I2)
Organification of Iodine
Coupling of MIT & DIT

Synthesis of THs:
Synthesis of Thyroglobulin (TG): glycoprotein w/large quantities of tyrosine; made on RER &
GA of thyroid follicular cells; then incorporated into secretory vesicles & extruded across apical
memb into follicular lumen

Later tyrosine residues of TG iodinated to form thyroid hormones

1. Iodide Trap mechanism (Na+ - I- cotransport): Iodide pump in thyroid follicular epithelial cells actively
transports I- from blood into thyroid follicular cells; pump activity regd by I- lvls in body. Eg; Low lvls of Istimulate pump;
When dietary deficiency of I-, pump increases its activity, to compensate for deficiency. (If severe Ideficiency pump cannot compensate leading decreased TH synthesis)
2. Oxidation of Iodide to Iodine: once inside cell, Iodide traverses cell to apical memb where its oxidized to
Iodine (I2), catalyzed by thyroid Peroxidase in follicular cell memb
Peroxidase enzyme inhibited by Thioamides (Eg: Propyl Thiouracil, Methimazole & Carbimazole; Note:
Propyl Thiouracil FDA warning b/c can cause liver toxicity, but can be safely used in 1 st trimester of
pregnancy. Used to treat Thyroid storm (severe form of hyperthyroidism, as it prevents peripheral
conversion of T4 to T3); these drugs used in hyperthyroidism
3. Organification (Iodination): at apical memb, just inside lumen of follicle, I2 combines w/tyrosine moieties of
TG catalyzed by thyroid peroxidase producing MIT (Moniodotyrosine) & DIT (Diiodotyrosine);
*(Wolff-Chaikoff) effect: high lvls of I- inhibit organification & synthesis of THs
4. Coupling of MIT & DIT: w/MIT & DIT being attached to Thyroglobulin, 2 coupling rxns occur
DIT + DIT = T4 (Thyroxine)
DIT + MIT = T3 (Triiodothyronine)
A portion of MIT and DIT does not couple

10 X more T4 produced than T3

Iodinated Thyroglobulin (containing T4,T3, left over MIT & DIT is stored in follicular lumen till Thyroid
gland is stimulated by TSH to secrete THs)

Role of Potassium iodide (KI) in nuclear disasters:

Thyroid cancers very common in areas of nuclear
disasters
KI tablets given b4/immediately after exposure to
nuclear emissions that contain radioactive iodine which
can cause thyroid cancers.
KI saturates thyroid gland inhibiting further uptake of
radioactive iodine

754

Endocytosis of Thyroglobulin
When TGland is stimulated by TSH, iodinated TGlobulin (w/it attached T4,T3,
MIT & DIT) is endocytosed by follicular epithelial cells

Hydrolysis of T4 & T3
T globulin molecules fuse w/lysosomes
Lysosomal proteases hydrolyse peptide bonds to release T4, T3, MIT & DIT
from thyroglobulin
T4 & T3 transported across basal memb into nearby capillaries to be
delivered to systemic circulation
MIT & DIT deiodinated by thyroid deiodinase & Iodine used to make new T
hormones

755

Perchlorates & Thiocyanates

Propyl Thiouracil and
Methima

Thyroid deiodinase enzyme

deficiency may mimic Iodine
deficiency Hypothyroidism
756

Binding of T3 & T4:

In circulation, T3 & T4 bind to TBG (Thyroxine Binding Globulin; made in liver)
In hepatic failure - TBG lvls decrease
In pregnancy - TBG lvls increase. Thus, pregnant lady is Euthyroid (normal),
even though total TH lvls increased as most of it in inactive bound form
Thyroid Hormones (T3 vs. T4):
T4 lvls synthesized greater (50X more) than T3
~70% of circulating TH bound to TBG, w/remainder to thyroxine binding
prealbumin (transthyretin) & albumin
T4 has greater affinity for TBG binds more tightly & T4 (6 days) has greater
-life than T3 (1 day)
In target tissues, T3 binds more strongly to nuclear receptor & has
greater affinity for its receptor than T4
Thus T3 more active form of TH

757

T4 activation in Target tissues:

5- monodeiodinase in target tissues converts T4 to T3 by
removing 1 I2 atom; & 5-monodeiodinase also converts T4 to
reverse T3 (rT3)
In starvation target tissue 5monodeiodinase plays interesting
role
Starvation (other states like fasting, medical & surgical stress,
catabolic states & increased cortisol) inhibits 5deiodinase in
tissues such as skeletal m, thus lowering O2 consumption &
BMR to conserve energy sources

758

Radioactive Iodine Uptake:

Iodine uptake = index of thyroid func,

measured by using tracer doses of radioactive
isotopes of Iodine, admind orally, w/out any
adverse efx on Thyroid gland; aka amt of RA
Iodine taken up by Thyroid gland in given
period of time. 123I commonly used
Radioactive Iodine uptake used to differentiate
btwn Hyper- & Hypothyroidism
In Hyperthyroidism, due to increased synthesis
of THs by Thyroid gland, Radioactive Iodine
uptake by Thyroid gland increases
Egs;
In exogenously admind THs, mostly given as
weight loss supplement, blood TH lvls high,
synthesis of TH by gland decreases due to
ve feedback. Radioactive Iodine uptake
decreased
In Hypothyroidism, due to defect in synthesis
of THs, Radioactive Iodine uptake by Thyroid
gland decreases

759

What is the Physiological basis for ?

Using Thiocyanate & Perchlorate in Hyperthyroidism?
Block sodium-iodide co-transporter

What is the role of Propyl Thiouracil in

Hyperthyroidism?
Inhibit synthesis of T3 & T4 by blocking thyroid peroxidase
(synthesis, organification, & coupling rxns)

What is Wolff - Chaikoff effect?

Ppl who have higher lvls of Iodine in blood circulation
synthesis of T3 & T4 reduced; & iodine uptake from
transporter decreased

760

Factors affecting TH
secretions

Or antibodies (seen in Graves disease)

761

Reg of TH secretion:
Hypothalamic - Pituitary Control: By TRH & TSH
TSH stimulates synthesis & secretion of THs by follicular cells via cAMP
mechanism; has slowly induced (Trophic) efx
causes proliferation/increased hypertrophy of Thyroid cells leads to
increased gland size
increases blood flow to Thyroid gland (Bruit; terminal blood flow = bruit
= Laminar flow transformed into turbulent flow)
Thus chronic elevation of TSH causes Hypertrophy of Thyroid gland
TRH - secreted by Hypothalamus; stimulates TSH secretion by Ant Pituitary
Increased T3, T4 lvls down regulates TRH receptors in ant pituitary & inhibits
TSH secretion
Why does decrease in TH lvls cause enlargement of Thyroid gland (Goiter) ?
Decreased T3 & T4 - leads to increased TSH b/c of loss of ve feedback
TSH causes Thyroid proliferation & hypertrophy of Thyroid gland, causing
Goiter

762

REGULATION

Primary
Hypothyroidism:
Decreased T3, T4
Increased TSH,
Increased TRH
Secondary
Hypothyroidism:
Decreased TSH &
Decreased T3, T4
Increased TRH
Tertiary
Hypothyroidism:
Decreased TRH,
Decreased TSH &
Decreased T3, T4

Primary
Hyperthyroidism
Increased T3, T4,
Decreased TSH,
Decreased TRH
Secondary
Hyperthyroidism
Increased TSH &
Increased T3, T4,
Decreased TRH
Tertiary
Hyperthyroidism
Increased TRH,
Increased TSH &
Increased T3, T4
763

6 Physioal axns of THs: INCREASES BASAL METABOLIC

RATE* (via Na+K+ ATPase pump) except in CNS (brain***)
1)

On growth: Thyroid hormones act synergistically w/GH &

Somatomedins to promote bone formation
) Thyroid hormones stimulate bone maturation as result of
ossification & fusion of growth plates
) Thus, in TH deficiency, bone age is less than chronological
age & child has infantile body proportions
2) On CNS: during perinatal period, maturation of CNS absolutely
depends on THs b/c causes formation of synapses, myelination
of n fibers
) TH deficiency in child less than 1 yr, leads to defective
myelination causing irreversible MR

764

Screening for Neonatal hypothyroidism is mandatory.

Why?????

During brief perinatal period, TH replacement is helpful & prevents MR

Once child crosses that period, it can lead to irreversible MR (cannot be
cured)

In adults..
Efx on CNS seen in disorders
In Hypothyroidism - causes decreased mental capacity, slowed speech,
impaired memory
In Hyperthyroidism - causes hyperexcitability & irritability, anxiety

765

Axns of Thyroid hormones.

3) On ANS: up-regulate 1-adrenergic receptors in <3 & has axns similar to symp NS
Thus palpitations in Hyperthyroidism b/c increase <3 rate (atrial fibrillation)
Propranalol: -adrenergic blocking drug used in Hyperthyroidism to treat palpitations
4) Calorigenic axn (Basal metabolic rate -BMR): increases O2 consumption by increasing
synthesis of Na+-K+ ATPase, thus increased Na+-K+ pump activity & BMR in all tissues
except brain, gonads & spleen; also increases heat production in body
5) Axns on CVS & Respiratory system: increases <3 rate & stroke volume, thus
increasing Cardiac output & ventilation rate combined efx ensure adequate O2 supply
to tissues
6) Metabolic efx: overall metabolism increased to keep up w/increased O2 consumption
(increases Sodium-Potassium pump activity)
Increases glucose absorption from GIT, increases glycogenolysis & gluconeogenesis
Increases blood glucose lvls
Increases Lipolysis
Overall effect on protein metabolism is Catabolic
Decreases circulating Cholesterol lvls as increases formation of LDL receptors in liver
(increasing hepatic removal of cholesterol from circulation)
THs convert - Carotenes to Vit-A
766

Role of Thyroid stimulating Immunoglobulins:

These are IgG immunoglobulins that bind to TSH
receptors & like TSH, stimulate secretion of T3 & T4 by
Thyroid gland
In Graves Disease, theres high circulating lvls of
Thyroid stimulating immunoglobulins, that leads to
increased T3, T4 & decreased TSH lvls

767

Pathophysiology of Thyroid gland:

A) Hyperthyroidism:
Causes include:
Thyroid neoplasia,
Graves disease (antibodies to TSH receptors),
TSH secreting Pituitary tumors, Exogenous T4 adminis
Toxic multinodular Goiter
Sx: Increased metabolic rate - polyphagia
heat production - causes sweating, heat intolerance
Cardiac output (Palpitations), increased BP
Tremor (-adrenergic activity)
Weight loss, weakness (Protein catabolism)
Exophthalmos, Goiter, irritability, excitability
TSH lvls in Primary Hyperthyroidism, b/c high THs cause ve feedback inhibition
on Ant Pituitary
TSH lvls in Secondary hyperthyroidism where ant pituitary produces excessive
TSH (-ve feedback not working)
Tx: Propylthiouracil/Methimazole- Blocks Peroxidase enzyme & inhibits TH synthesis
Thyroidectomy - Removal of Thyroid gland
Iodine(I131) - destroys Thyroid gland
-blockers like Propranalol used to treat symptoms of adrenergic overactivity
768

Thyrotoxicosis:

Exopthalmos!
Associated
w/inflammatio
ns &/or
accumulated
GAGs

Thyroid enlargement w/toxic

features like Exophthalmos
Seen in Graves disease:
autoimmune disorder where
antibodies bind to TSH receptors
Pt has features of Hyperthyroidism
w/Exophthalmos (protrusion of
eyeballs)
Presence of peri-orbital & retroorbital edema b/c of Cytokine
release (inflammatory mediator)
Symp over-activity causes lid
retraction, giving rise to Staring Look

Graves Disease

770

Pretibial Myxedema
(Dermopathy)

771

Hypothyroidism:
Causes:
Hashimotos Thyroiditis
Subacute thyroiditis (de Quervain/painful thyroiditis) w/viral infection
Thyroidectomy (can also present w/parathyroid issues since theyre behind)
Pituitary adenoma (esp nonsecretory adenomas aka chromophobe cells, deficient
TSH)
Tumors impinging on Hypothalamus (decreased TRH)
Sheehans syndrome (necrosis of post pituitary post partum hemorrhage)
Iodine deficiency (Not in USA)
Drug induced (Amiodarone, Lithium)
Radioactive Iodine 131- (Tx for graves disase )
Thyroiditis (Hashimotos Thyroiditis/Autoimmune Thyroiditis) MC cause of hypothyroidism
Antibodies made that destroy Thyroglobulins & Thyroid peroxidase (TPO). Results in
inflammation leading to structural damage of Thyroid gland
Decreased Thyroid Peroxidase (TPO) in Hashimotos Thyroiditis
can be Primary (defect in Thyroid itself; decreased T3,T4, ^^TSH & TRH) or
Secondary (defect in Ant pituitary/ Hypothalamus; decreased TSH, T3 & T4)
**On TSH admin, if T3, T4 ^^: Secondary Hypothyroidism
**On TSH admin, if T3, T4 DOES NOT ^: Primary Hypothyroidism b/c TG itself not
funcing!

Hypothyroidism in Adults (Myxedema)

Clinical features:

metabolic rate & O2 consumption, & heat production (cold intolerance)

Dry & cold skin

appetite, Weight gain,

Cardiac output, hypoventilation (b/c no reg of beta-receptors)

Lethargy, mental slowness, Psychosis (Myxedema Madness) IF SEVERE aka not pitting edema b/c
accumulated GAGs/mucopolysacharrides in interstitium of tissues w/water retaining gel edema in brain,
skin (face), larynx (hoarse voice) & pericardial/pleural space (Accumulated mucopolysaccharides (hyaluronic
acid) myxedema (Non-Pitting edema)

Ptosis (drooping of eyelids due to m weakness), peri-orbital edema

Goiter b/c of increased TSH in Primary Hypothyroidism

Constipation

Hoarseness in speech

Deep tendon reflexes w/slow/delayed relaxation phase; takes longer to relax

Anemia

Myxedema coma is end stage of untxd hypothyroidism; major features: hypoventilation, fluid & electrolyte
imbalances & hypothermia; ultimately shock & death

Beta-Carotenemia: yellowish discoloration of skin due to accumulated - Carotenes. (Normally Thyroid

hormones convert - Carotenes to Vit-A)

To differentiate from Jaundice - look for yellowish discoloration of mucus memb absent in Beta-Carotenemia

Husky slow voice due to laryngeal edema

plasma cholesterol (b/c TH helps expressing its receptors) atherosclerosis/MI risk

Menstrual irregularities ranging from absent or infrequent to very frequent & heavy

Amenorrhea - In Primary & Secondary Hypothyroidism, T 3, T4 lvls , TRH PRL inhibits GnRH that in
turn inhibits FSH, LH leading to Amenorrhea

TSH lvls in Primary Hypothyroidism (defect in Thyroid) b/c THs leads to feedback inhibition of Ant
Pituitary

TSH lvls in Secondary Hypothyroidism (Defect in Hypothalamus/Ant Pituitary)

Tx: TH replacement OR Levothyroxine; monitor TSH lvls

Myxedema

Before

After Treatment
774

Cretinism:

Untxd postnatal hypothyroidism results in cretinism (form of dwarfism w/MR)

often appear normal following delivery but may have respiratory difficulty, jaundice,
feeding problems & hypotonia
Abnormalities rapidly develop w/CNS maturation & result in MR
MR (Infantile brain) due to defective myelination in axons of cortical neurons
epiphyses marked by multiple ossification centers that severely deform long bone &
give it stippled appearance & thickened shaft
Crucial up to 1 yr. Thus early diagnosis very imp Large tongue; macroglossia
Pubertal growth, including bone ossification is retarded in absence of THs (stippled
epiphysis sign of hypothyroidism)
CRETINS - have MR, motor rigidity & deafness. WHY??? b/c TH deficiency afx
funcs of cerebral cortex, Basal ganglia & Cochlea (inner ear, neurons generating AP
to signal hearing to brain)
mainstay in tx of congenital hypothyroidism is early diagnosis & TH replacement
Optimal care includes diagnosis b4 age 10-13 days & normalization of TH blood lvls
by age 3 weeks

Infantile Body Proportions

(aka Dwarfism) in Cretinism
775

Goiter (ENLARGED THYROID GLAND):

CAUSES: Endemic Iodine deficiency (endemic colloid Goiter) - decreases

TH synthesis resulting in Primary Hypothyroidism causes increased
TSH causing hypertrophic thyroid gland
Goiter also in Secondary Hyperthyroidism due to TSH, Primary
Hyperthyroidism due to Thyroid tumors
Goiter absent in Secondary Hypothyroidism as TSH is low
Toxic nodular goiter? Some pts of thyroid gland overactive produce more
T3 & T4 hyperthyroidism; multiple nodules possible in whove suffered
iodine deficiency

776

777

Calcium Metabolism: PTH, CALCITONIN, VIT D

Calcium homeostasis:
Free ionized Ca 2+ is biologically & physioally active; can diffuse across capillaries &
this is precisely regd form!
Plasma Ca+2 : 9-11 mg%/deciL (4.3-5.3 mEq/L or 2.2-2.7 mmol/L); >11 =
hypercalcemia; <9 = hypocalcemia
Serum [Ca2+] depends on:
Intestinal absorption (major mechanism of absorbing calcium into blood)
Renal excretion
Bone remodeling (Bone resorption & formation)
Plasma (serum) calcium represents 45% ionized free (biologically active),
40% bound to proteins (cannot get across capillary), 15% w/anions ie.
phosphate & citrate
Bound form in equilibrium w/free form
Alkalosis (Hyperventilation) decreases & acidosis increases free calcium by
varying amt bound to protein
3 Hormonal controls of Calcium:
1,25 DHCC (1,25 Dihydroxycholecaciferol) - Active Vit D - increases Ca2+ absorption
from intestine
PTH: mobilizes Ca +2 from bones; raises calcium lvls in blood by activating
osteoclasts, stimulates bone resorption/breakdown, release from kidneys & gut
Calcitonin secreted by Para follicular cells of Thyroid; Ca +2 lowering hormone778
inhibits bone resorption

779

Relnship btwn Ca 2+ & Phosphate:

Bone contains special form of CT w/collagen framework (organic)
Has Hydroxyapatites (Ca+2 & Phosphate (PO4) salts deposited on
inorganic matrix bone mineralization)
[Ca+2] x [PO4 ] = a constant (Solubility product)
[Ca+2] x [PO4 ] > Solubility product = Bone deposition/mineralization
[Ca+2] x [PO4 ] < Solubility product = Bone resorption
(demineralization)/breakdown as PTH lowers phosphate lvls in blood, dumps
phosphate into urine)

5 Roles of calcium in physioal processes:

1. Vital 2nd msngr
2. Blood coagulation (Hemostasis)
3. M contraction (release calcium from SR in skeletal m, & smooth m has 3
ways voltage gated Ca2+ channels, NT ligand gated channels or
IP3/DAG pathway)
4. N excitability (voltage gated calcium channels)
5. Hormone & NT release by exocytosis
780

Parathyroid hormone (PTH):

PTH: synthesized & secreted by chief cells of Parathyroid glands when low serum/ECF/plasma
calcium lvls
major hormone that regulates serum Calcium
Acts via cAMP
PTH secretion controlled by serum Ca 2+
Decreased serum Ca 2+ increases PTH secretion
Axns of PTH produces increase in serum [Ca 2+ ] & decrease in serum Phosphate

3 MAJOR SITES OF PTH AXNS: BONES, KIDNEY & GIT

A) On Bones: DIRECTLY causes bone resorption (osteolytic activity) - increases serum Ca2+

PTH binds to PTH receptors on Osteoblasts causing Cytokines (IL-6,RANK-L) release from Osteoblasts
Osteoclasts do not have PTH receptors*; these receptors are on osteoblasts & osteocytes;
stimulates osteocytes to release osteoclastic activating factors (cytokines) to activate
osteoclasts

Cytokines released act on osteoclasts to cause bone resorption

Thus, effect of PTH on bone resorption is Indirect

B) On Kidneys: DIRECTLY inhibits renal Phosphate reabsorption in proximal tubule, thereby increasing PO 4
excretion Phosphaturia (PIC)

PTH increases renal Ca2+ reabsorption in distal tubule increases serum[Ca+2]

Normally phosphate reabsorbed in blood, but PTH inhibits reabsorption of phosphate & phosphate gets
excreted in urine

C) On GIT: INDIRECTLY PTH stimulates 1- Hydroxylase in kidneys & increases formation of 1,25 DHCC (active
vit D) that in turn increases intestinal Ca2+ & Phosphate absorption. Thus PTH indirectly increases intestinal
Ca 2+ absorption
782

To summarize PTH axns:

Net efx: Hypercalcemia, Hypophosphatemia & Hyperphosphaturia (loss of phosphate in urine, so also called
PTH- Phosphate trashing hormone)

Increased bone resorption

Stimulates 1- Hydroxylase in kidneys to increase formation of 1,25 DHCC that in turn increases intestinal
Ca2+ absorption

1.

2.

Along w/phosphate absorption

3.

In Distal Tubules!

783

Pathophysiology of PTH Hyperparathyroidism:

A)

B)

Primary Hyperparathyroidism: caused by Parathyroid (single benign

tumor) Adenoma & results in ^PTH secretion; CFs:
serum [Ca 2+] Hypercalcemia
serum Phosphate Hypophosphatemia
urinary Phosphate excretion Hyperphosphaturia (inhibited
reabsorption in proximal tubules)
bone resorption due to osteoclasts (osteitis fibrosa cystica; cystic
lesions in bone as brown tumors)
serum Calcium predisposes to Nephrocalcinosis (clear calcium
deposition in renal tissues, not in urinary tract)
- Eventually, Nephrocalcinosis may cause Renal tubular damage
causing Polyuria
- Renal stones (Nephrolithiasis renal stones in pelvis, ureter or
bladder aka somewhere in urinary tract) (STONES, BONES &
GROANS)
- ~85% cases, caused by single adenoma. In 15%, multiple glands
involved (ie, either multiple adenomas or hyperplasia) or rarely, caused
by parathyroid carcinoma/cancer
Secondary Hyperparathyroidism: N parathyroids but low serum
calcium stimulates ^PTH secretion; causes:
Vit D def (lack sun exposure, b/c UV rays convert, Bile salt def,
intestinal epithelium damaged so lack absorption) &
CRF. (1,25-hydroxylase def) calcium, phosphate, PTH
demand for calcium in pregnancy (& lactation)
PTH elevated in both conditions

Secondary Hyperparathyroidism & Vit D deficiency (nonrenal failure):

Causes: Inadequate sun exposure, Vit D malabsorption, enzyme deficiencies in activating Vit D
Characd by increased PTH, decreased plasma calcium & decreased phosphate
Even though elevated PTH increases phosphate resorption from bone, PTH inhibits phosphate
reabsorption in kidneys thereby decreases phosphate
Bone mass lost to maintain plasma calcium
Diagnostic would be low plasma vit D

VS> Secondary Hyperparathyroidism & Renal failure:

If ind devd kidney failure & went onto dialysis, following sequence of events might occur.
1. Fall in blood lvls of calcium = 1st major change. As kidneys dont convert vit D into active form,
calcium doesnt get into body from food
2. Tx is to replace active vit D
3. Phosphate lvls in blood rise, b/c kidneys not excreting excess phosphate into urine high lvls
of phosphate can cause itching
4. Tx is to reduce phosphate lvls by diet, dialysis & medication
. In chronic renal failure, there is Secondary Hyperparathyroidism. Why?

.
.
.

YES. b/c due to renal failure, causes hypocalcemia due to vit D deficiency b/c cannot activate 1,25 hydroxy vit D
(normally becomes 1,25 (OH3) vit D via 1,alpha-hydroxylase)

Diseased renal tissue leads to decreased activity of 1- Hydroxylase enzyme resulting in

decreased synthesis of 1,25 DHCC (active Vit D) & decreased serum [Ca 2+]
Decreased serum [Ca 2+] in turn causes increased secretion of PTH from Parathyroid gland,
resulting in Secondary Hyperparathyroidism
This results in increased bone resorption
785

Tertiary Hyperparathyroidsm
seen in pts w/long-term secondary
hyperparathyroidism which eventually leads to
hyperplasia of parathyroid glands & a loss of resp to
serum calcium lvls
most often in pts w/chronic renal failure & is an
autonomous activity
Chronic overactivity of parathyroid gland due to low
calcium lvls for prolonged period of time; leading to
hyperplasia of PTG; so it starts producing PTH on its
own irrespective of Ca2+ lvls in blood
786

Humoral hypercalcemia of malignancy:

Malignant tumors of lung, Renal cell carcinoma & breast - secrete PTH
reld peptide (PTH- rp) structurally similar to PTH & has all its physioal axns
Blood investigations reveal low PTH lvls even though pt has sx of PTH
excess due to hypercalcemia caused by PTH rp, which suppresses
actual PTH secretion from parathyroid gland
Clinical features: Blood profile very similar to primary hyperparathyroidism but
low PTH
Hypercalcemia
Hypophosphatemia
Hyperphosphaturia
Confused mental func decreased coma reduced neuronal activity
decreased AP decreased m contractions, lethargic
Tx for hypercalcemia in this condition:
FUROSEMIDE (inhibits Ca2+ reabsorption): Loop diuretics that act on
thickness of Loop of Henle to inhibit calcium reabsorption, want to give
after rehydrating w/some fluids
ETIDRONATE (Inhibits bone resorption): bisphophonate that inhibit
787
osteoclast activity

Hypoparathyroidism:
Causes:
Most commonly seen as consequence of Thyroid surgery
(Thyriodectomy) due to removal of Parathyroids (for tx of
thyroid cancer or Graves Disease) or parathyroid surgery (for
Hyperparathyroidism)
Other causes of Hypoparathyroidism are:
Auto immune or Congenital are rare
Pseudohypoparathyroidism
Clinical features:
serum [Ca 2+] - Hypocalcemia & Tetany
Hyperphosphatemia & urinary Phosphate excretion
cAMP lvls

788

Tetany:
Hypoparathyroidism leads to Hypocalcemia & gives rise to
Tetany (uncontrolled muscular contractions) due to increased
excitability of motor neurons
Clinical features of Tetany:
Neuromuscular hyperexcitability - decreased threshold for
excitability of n fibers as theres less of calcium to stop activity
of Sodium channels
Laryngeal spasm - life threatening complication of Tetany
Carpopedal spasm - Flexion of thumb & wrist w/hyperextension
of metacarpophalangeal & interphalangeal jts
2 imp clinical signs elicited in Tetany are:
TROUSSEAUS SIGN : Wrap BP cuff around arm & raise
pressure; hand of pt will go in for carpopedal spasm due to
increased neuromuscular excitability
CHVOSTEKS SIGN: Tap facial n over cheek to see puckering
of mouth & angle of mouth deviates to that side
789

Carpopedal spasm:
Trousseaus sign in a 50-year-old woman
with total thyroidectomy and hypocalcemia

790

CHVOSTEKS SIGN:

791

Hypoparathyroidism: Pseudohypoparathyroidism Type

1a aka Albrights hereditary Osteodystrophy
Pseudohypoparathyroidism
Type 1a aka Albrights hereditary

Osteodystrophy: inherited AD disorder

w/defective Gs protein for PTH in
kidney & bone. So when PTH binds to
its receptors in these tissues, it doesnt
activate Adenylyl cyclase causing
resistance to PTH axns in target organs
Plasma PTH lvls but PTH cannot act;
cAMP lvls; cannot be corrected by
PTH admin
Features: Hypocalcemia,
hyperphosphatemia, short stature, short
neck, obesity, subcutaneous
calcification & shortened or absent 4th
Note round face, wide forehead, lowOR 5th Metacarpals/metatarsal bones
set ears, deep set eyes, down-slanted
palpebral fissures, thin upper lip
vermilion, V-shaped nasal tip

HYPERVENTILATION CAUSES TETANY- WHY???

Hyperventilation increases plasma pH due to

Respiratory alkalosis
At this alkaline pH, plasma proteins are more
ionized, these protein anions bind w/Calcium
This in turn leads to decreased Serum ionic
Calcium lvls causing Tetany

Vit D
Provides Calcium & Phosphate to ECF for bone mineralization
Vit D metabolism:
Active Vit D form is 1,25-Dihydroxycholecalciferol (1,25 DHCC) aka Calcitriol
Production of 1,25 DHCC in kidney (Proximal Tubule cells) catalyzed by 1
hydroxylase that increases its activity in resp to decreased serum [Ca 2+]

794

3 AREAS of 1,25 DHCC (Active Vit D) AXN:

A) On GIT: Main axn; synthesis of Calbindin D (Ca2+ binding protein)
on intestinal epithelial cells, thus ing intestinal Ca2+ absorption;
also intestinal PO4 absorption; thus maintaining low lvls
B) On Kidneys: increases renal *re-absorption of Calcium (distal
tubules) & PO4 (proximal tubules)
C) On Bones: stimulates osteoblasts & enhance bone formation; can
also cause osteoclasts proliferation, ing bone resorption &
provides Ca2+ & PO4 for mineralization of new bone; thus aids in
bone remodeling
Clinical aspects:
) Vit D deficiency:
Causes: occurs due to inadequate dietary intake, inadequate exposure to
sunlight, Renal & Liver diseases
) Leads to: Rickets in children
) Osteomalacia in adults - defective bone mineralization easy susceptibility
to fractures; leads to Ca2+ lvls
) In osteomalacia, ratio of mineral to matrix decreased (too much
matrix relative to bone amt)

Clinical features of Rickets:

Deformed bones
Bow Legs (Knock Knees) due to bowing of weight
bearing areas
Thickening of wrists & ankles
Retarded growth & dentition
Widening of epiphyseal
cartilaginous plates
Frontal bossing
*Rickety Rosary (beaded
prominence of costochondral
junc btwn ribs & cartilage)

796

797

Bow legs
(Genu Varum)

Knock Knees
(Genu Valgum)

798

Beforetreatment
treatmentand
and22years
yearsafter
aftertreatment
treatment
withcalcium
calcium
799with
Before

Calcitonin (CT):

Synthesized & secreted by Parafollicular cells of Thyroid

Increased Serum [Ca 2+] stimulates Calcitonin secretion

lowers circulating serum Ca2+ & PO4 lvls

inhibits bone resorption by inhibiting osteoclastic activity

Increases Ca2+ excretion
Clinical aspects
Calcitonin (CT) lvls increase in pregnancy. Why?
protects mother from excessive Ca2+ loss from bones during
pregnancy
Increased CT lvls also during growing periods b/c help in
skeletal devt
CT used to treat Pagets Disease occurring due to increased
osteoclastic activity in bones & abnormal bone formation
CT also used to treat Hypercalcemia
800

Osteoporosis:

X-ray of
Spine in
Pt w/
Osteoporosis

Excessive osteoclastic funcs w/breakdown of bone

matrix, leads to Osteoporosis (characd by decrease
in bone mass & bone mineral density which can lead
to increased risk of fracture)
Bone formation cannot keep pace w/bone resorption
Characd by weakened bones
Female sex hormone estrogen is protective to bones
as it promotes osteoblastic funcs & inhibits release of
cytokines (IL-1,6, RANK- L & TNF ) which stimulate
osteoclasts. Estrogen also stimulates TGF release
to increase apoptosis of osteoclasts
Thus, females after Menopause more prone to
osteoporosis
NOTE: In ppl immobilized for prolonged periods (during
space flight, prolonged bed rest), bone resorption
exceeds bone formation. Plasma Calcium elevated
& Urinary Calcium & Phosphate excretion increases.
PTH & Vit D lvls decreased (so phosphate lvls
increase b/c decreased PTH)
801

802

Similar to hyperparathyroidism, but not low PTH

803

To Summarize the overall effect

804

ADRENAL/SUPRARENAL GLANDS:
Has 2 layers
1. Outer Adrenal cortex (80% of
gland): secretes steroid hormones
2. Inner Adrenal medulla- secretes
catecholamines (Adrenal Medulla
is Emergency Gland which
prepares ind for Fight / Flight);
made of chromaffin cells
In Fetus - During 3rd-4th month of intrauterine life, Adrenals larger than
kidneys
. Func of fetal Adrenals is secretion
of DHEA (Dehydroepiandrosterone) thats converted
in placenta to sex hormones
androgen & estrogen

805

ADRENAL GLANDS:
3 Zones of Adrenal Cortex
(outer to inner):
i) Zona glomerulosa: secretes
mineralocorticoids (Aldosterone &
Deoxycorticosterone) play role in
mineral metabolism (need for
survival; Na+ & K+ regulators); regd
by angiotensin II
ii) Zona fasciculata: secretes
Glucocorticoids (Cortisol/Hydrocortisone) play role in
carb & protein metabolism
iii) Zona reticularis: secretes sex
steroids (Androgens DHEA &
Androstenedione); minor effect on
reproductive funcs b/c gonads
secrete most of sex hormones
) CORTICOSTEROIDS:
Mineralocorticoids & Glucocorticoids
) ZF & ZR regd by ACTH
806

Need ACTH to make cortisols & androgens

Cholesterol desmolase is rate limiting step in
synthesis of adrenocortical hormones aka
steroid hormones* 17-Ketosteroids (DHEA & Androstenedione)

Need angiotensin II in final pathway to

produce aldosterone (+hyperkalemia)
807

REGULATION OF CORTISOL
SECRETION

Pro-Opiomelanocortin

ACTH

ACTH has MSH

MSH

- Lipotropin

Endorphin
s
Modulate perception
of pain

^both stimulate melanocytes; but if produced

in excess can hyperpigmentation
808

Reg of secretion of Adrenocortical hormones:

1) Glucocorticoid (GC) secretion: (Cortisol) production oscillates w/ACTH-dependent 24-hr
periodicity aka Circadian rhythm
) This diurnal variation due to Biological clock in Suprachiasmatic nucleus of hypothalamus
) Cortisol & ACTH lvls highest in morning (8 AM), & lowest in late evening (12 midnight)
) Rhythm reversed in night workers

PEAK: EARLY
MORNING
LOW: LATE
EVERING
809

Reg of GC secretion:
A)

Hypothalamic control: Via CRH (Corticotropin-releasing hormone) released by PVN of

Hypothalamus into Hypothalamo-hypophyseal portal blood & carried to Ant Pituitary
) In ant pituitary, CRH stimulates synthesis of POMC (ACTH precursor) leading to forming ACTH
B) Pituitary Control:
) ACTH increases steroid hormone synthesis in Adrenal cortex by stimulating cholesterol
desmolase to increase conversion of Cholesterol to Pregnenolone
) ACTH has lesser effect on ZG that secrete Mineralocorticoids as its mainly controlled by ReninAngiotensin Aldosterone system
) Chronically elevated ACTH causes persistent stimulation of Adrenal cortex resulting in
hypertrophy/hyperplasia of Adrenal glands
C) ve feedback control by elevated Cortisol: this inhibits CRH secretion from Hypothalamus &
ACTH from Ant pituitary

Factors affecting ACTH secretion:

810

+low sodium

2) Reg of Aldosterone secretion:

Regd mainly by Renin - Angiotensin system
Aldosterone secretion stimulated by serum Sodium &
Potassium lvls
Also controlled by ACTH to lesser extent as ACTH has no sig
effect on Zona Glomerulosa
A) Renin-Angiotensin system: kicks in when decreased blood
volume/pressure (decreased renal blood flow) renin AGI
AG-II which acts on ZG of Adrenal cortex, stimulates
Aldosterone Synthase to form increased Aldosterone
Aldosterone increases Na+ & H2O reabsorption restoring ECF
volume
Thus regulates BP!
B) Hyperkalemia increases Aldosterone secretion that brings
about increased renal K+ excretion

811

Reg of Aldosterone secretion:

RB
F

Decreased pressure in
renal afferent
arteriole

Increased
Na+ RA and
H20

3 factors macula densa, B1 receptors in JG & hypotension/hypovolemia 812

Pathway by which
increased potassium
intake induces
greater
potassium excretion
mediated by
Aldosterone
Hyperkalemia increases ZG to release aldosterone
to reabsorb sodium & excrete potassium (all in
ECF)

813

10 Physiological axns of Glucocorticoids

1) Stress (states such as trauma, exposure to cold, iIlness, starvation & Exercise)

capacity to w/stand stress dependent on adequate GCs secretion

Stress hormones: mobilize energy store; counter-regulatory hormones/insulin-opposing) are:

GH ( glucose, mobilizes fats by Lipolysis)
Glucagon (mobilizes glucose by glycogenolysis & gluconeogenesis)
Deficiency in stress hormone causes Hypoglycemic
Cortisol mobilizes fat, protein & carb
Episodes
E (in some form stress as Exercise) mobilizes glucose via glycogenolysis & FA by lipolysis in
skeletal m!
2) Metabolic axns of cortisol: blood sugar lvls (Hyperglycemia) by 2 mechanisms:
1. glucose uptake in m, adipose & lymphoid, thus - Anti Insulin axn
2. Gluconeogenesis by liver by:
Enhances Glucagons effect for glycogenolysis (permissive axn) thus w/out cortisol fasting
hypoglycemia rapidly develops
Protein catabolism in ms, protein synthesis, gets more AAs to liver for Gluconeogenesis
Lipolysis (stimulating hormone sensitive lipase), & delivery of FAs & Glycerol. Glycerol used for
Gluconeogenesis, favors Ketone bodies formation
. These afx can worsen DM (anti-insulin efx + hyperglycemia)
3) Cortisols Permissive axns: enhances capacity of glucagon & catecholamines (permissive effect)
. Glucagon promotes gluconeogensis & glycogenolysis thus maintaining blood glucose
. Catecholamines: E & NE released from adrenal medulla; binds to a1 & b2 receptors; alpha 1 on blood vessel
promotes vasoconstriction (to maintain blood vessels vascular tone & BP (Cortisol deficiency BP
decreases)
. Promote lipolysis
. Promote Bronchodilation
4) GCs Anti-inflammatory axns: (In pharmacological doses)
. Phospholipase A2: liberates Arachidonate from memb Phospholipids Arachidonate (precursor for
inflammatory mediators like Prostaglandins & Leukotrienes (produced by COX & LOX, respectively from
arachidonic acid (from PIP clipped by phospholipase A2))
. GC induces synthesis of Lipocortin (Phospholipase A2 inhibitor), thus inhibiting Arachidonate formation

4) Anti-inflammatory axns: (In pharmacological

doses)
Ie. Hydrocortisone
Prednisone
Prednisolone
Dexamathazone
Betamethazone

HEAT

REDNESS

SWELLING

PAIN815

LOSS OF
FUNCTION

Membrane phospholipids
(-)

GC

Phosholipase A2

Arachidonate

Prostaglandins & Leukotrienes

Inflammation

816

5) GC inhibits release of Histamine & Serotonin from mast cells & platelets (used to tx
allergies)
6) Inhibits collagen synthesis, thereby prevents tissue adhesions to prevent intestinal
obstruction. Thus given therapeutically after abdominal surgeries
7) GCs used in prevention / reduction of Immune resp in organ transplant recipients
In pharmacological doses, GC suppress immune resp by inhibiting production of IL-2
& T-lymphocytes crucial for cellular immunity
Destruction of lymphoid tissues
Prevents rejection of transplanted organs
8) Maintenance of vascular responsiveness to Catecholamines b/c GC up regulates
1receptors on arterioles, increasing vasoconstrictor effect of NE. Thus BP
increases w/Cortisol excess & BP decreases w/Cortisol deficiency
9) On bones: GC in excess increases bone resorption by increasing osteoclastic
activity & decreases bone formation.
Also causes increased protein catabolism lead to breakdown of bone matrix &
Osteoporosis; used in autoimmune diseases
10) GC are contraindicated in Epilepsy. Why???
GC in excess, increase electrical activity in brain
Thus contraindicated in Epilepsy as this is disorder w/already increased brain activity

817

10 Axns of Glucocorticoids:
Increase gluconeogensis
Decreased glucose utilizaiton
Decrease insulin sensitivity
Increased lipolysis
Increased proteolysis
Inhibit inflammatory response
Suppress immune response
Enhance vascular responsiveness to catecholamines
Increase GFR
Decreased REM sleep

818

Axns of Mineralocorticoids - MC
(Aldosterone)
1)
)
)
)
)
)
)
)
)
)
)

Reabsorption of Sodium & water, excretion of Potassium & Secretion of H +:

MC act on Principal cells of late distal tubule & collecting ducts
renal Na+ reabsorption by increasing epithelial Na+ channels in Principal cells
of late distal tubule & collecting ducts of nephron, also stimulates Na+- K+ ATPase
pump
renal K+ secretion into tubular lumen
renal H+ secretion into tubular lumen. For every H+ secreted into lumen, HCO3gets reabsorbed into blood
2 cell types lining late distal tubule & collecting ducts principal cells & aintercalated cells
Principal cells reabsorb sodium & secrete potassium
Alpha-intercalated cells secrete H+ & reabsorb bicarbonate
Aldosterone does 3 things reabsorbs sodium, secretes K+ & H+
ADH acts on principal cells in late distal tubules & collecting duct
Excess aldosterone causes metabolic alkolosis (not respiratory
hyperventilation)

819

Adrenocortical excess Cushings Syndrome

Cushings Syndrome/Hypercortisolism: result of chronic excess of GCs
(Cortisol): causes:
1. MC due to high pharmacological GCs doses (used to treat Asthma, SLE
(systemic lupus), Rheumatoid Arthritis, Organ transplant)
2. Pituitary adenoma secreting ACTH (CUSHINGS DISEASE), leading to high
cortisol & Androgens
3. Bilateral hyperplasia of Adrenal glands (GC & Androgens)
4. Adrenal adenoma (ZR&ZF; GC & Androgens)
5. Adrenal carcinoma (GC & Androgens)
6. Ectopic ACTH secretion by oat cell or small cell carcinoma (not produced
from normal site = ectopic, from lung tumor)

VS> Cushings Disease:

Glucorticoid excess (Hypercortisolism) due to increased secretion
of ACTH from Ant pituitary (Secondary cause)
Ectopic ACTH secretion seen in tumors of other organs like tumors
of lungs
To differentiate btwn Primary & Secondary cause, do DMT
820
suppression test

Dexamethasone (DMT) Suppression Test:

To diagnose & differentiate btwn Primary/Secondary cause for Cushings disorder

Dexamethasone (DMT) = synthetic Glucocorticoid
On admin of low dose DMT, (Exogenous steroid), normally, ACTH would decrease
due to ve feedback, that in turn decreases Cortisol
In ACTH secreting tumors (SECONDARY DISEASE/ CUSHINGS DISEASE), low
dose DMT doesnt suppress ACTH & Cortisol secretion, as tumor cells secreting
ACTH are less responsive to ve feedback by Cortisol
Low-dose overnight -- get 1 mg of dexamethasone at 11 p.m., & draw blood at 8
a.m. for a cortisol measurement.
High-dose overnight -- measure cortisol on morning of test. Then receive 8 mg of
dexamethasone at 11 p.m. Blood drawn at 8 a.m. for cortisol measurement.
high dose of DMT
suppress both ACTH & Cortisol in Cushings disease (pituitary adenoma secreting
ACTH)
In Ectopic ACTH, adrenal tumor cortisol not suppressed
In Ectopic ACTH secreting tumors as in Carcinoma of lungs- Low or high dose DMT
fail to decrease both ACTH & Cortisol as ectopic ACTH not under Hypothalamo Pituitary control
Cortisol lvls decrease in pt w/secondary hypercortisolism vs. primary (remain high)

Cushings Syndrome:

Cortisol & Androgen lvls

ACTH if Secondary (Cushings disease), ACTH in
Primary Adrenocortical excess

Clinical features:

Hyperglycemia, FFAs via lypolysis, b/c of Cortisol

protein catabolism m wasting
Redistribution of fat - Central obesity w/Pendular
abdomen, Moon-face having narrow slit-like eyes & fishlike mouth, Buffalo-hump, giving pt (back of neck &
supraclavicular area) Lemon-on-stick appearance
Purplish abdominal striae due to abdominal skin
stretching
Poor wound healing & susceptibility to infections due
to immunosupression & blood sugar
Adrenal Androgens causes Virilization (hypertrophy of
clitoris +hirsutism +deep male voice) of women
Hirsutism (excess hairiness on women on abnormal pts
ie. Beard, chest hair), Amenorrhea, Impotence, deep
male-like voice
Hypertension (DUE TO GC + MC axns)

Common
Compressed
Hip & spine fractures

MC = mineralocorticoid axns retaining sodium, increasing ECF volume

= hypertension

Osteoporosis (Cortisol lvls bone resorption &

cause excessive protein catabolism) so pt on
glucocorticoids over many yrs will have bone density
Tx: Ketoconazole (antifungal), inhibitor of steroid hormone
synthesis

822

Purplish abdominal striae due to abdominal skin

stretching

Abdominal Striae

823

Aldosterone is essential for life- Why???

Removal of Adrenal cortex causes Na+ & water loss

Decreased ECF Volume causing Hypotension, dehydration,
circulatory collapse death
K+ retention Hyperkalemia, dehydration & circulatory collapse

824

Pathophysiology of Adrenal cortex:

A) Adrenocortical insufficiency (deficiency): 2 types
1. Primary Adrenocortical insufficiency aka Addisons Disease: most commonly
due to autoimmune destruction of Adrenal cortex leading to adrenal crisis
) GC, MC & Androgen secretion
) ACTH b/c low Cortisol lvls stimulate ACTH secretion
) Since ACTH has MSH-like activity, disease characd by Hyperpigmentation
pigmentation of skin, mucous memb, gums, pressure points, folds & creases
Other associated clinical features of Addisons disease:
) Hypoglycemia b/c of Cortisol deficiency (b/w meals)
) Deficient Adrenal Androgens leads to decreased pubic & axillary hair in women
) Aldosterone deficiency causes decreased ECF volume, weakness, hypotension &
hyperkalemia/hyponatremia (due to aldosterone deficiency), metabolic acidosis

825

Addisons disease: B4
tx & after tx. Note
change in
pigmentation

826

Secondary Adrenocortical insufficiency:

Caused by deficiency of ACTH Adrenocortical hormones
No hyperpigmentation as ACTH is decreased
ACTH doesnt affect Aldosterone secretion. Thus no signs of Aldosterone
insufficiency
Other symptoms similar to Addisons disease
ACTH stimulation test: administer ACTH to pt
If Cortisol on giving ACTH = defect in Ant pituitary (Secondary Adrenal
disease)
If no improvement = defect in adrenal itself (Primary Adrenal disease)

Hyperaldosteronism (Conns Syndrome):

Caused by Aldosterone secreting tumor
Clinical features:
Hypertension - due to Na+ & H2O retention ECF & BV
This ECF volume & BP in turn decreases Renin secretion
Hypokalemia - due to K+ excretion by Aldosterone
Metabolic Alkalosis - occurs b/c Aldosterone causes H+ excretion in
exchange for HCO3- reabsorption
Question???
In Hyperaldosteronism, no Edema inspite of Na+ & H2O retention. Why?
Release ANP to lower blood volume
This isWhat is Aldosterone escape?
Aldosterone - causes Na+ & H2O retention - ECF volume - venous
return - stretches Atria - releases ANP (Atrial Natriuretic peptide) - causes
Natriuresis thus no edema
This phenomenon is known as Aldosterone Escape
828

Clinical correlates: Congenital Virilizing Adrenal

Hyperplasia / Adrenogenital Syndrome:

Congenital deficiency of enzymes 21 & 11 Hydroxylase leads to deficient

Cortisol secretion leading to CAH (congenital adrenal hyperplasia)
MC cause of CAH is 21 -hydroxylase deficiency (>90% of cases)
Due to absence of ve feedback inhibition, ACTH lvls elevated causing CAH
(Congenital Hyperplasia (enlargement) of Adrenals)
Precursor steroids are increased, which get converted to Androgens
leads to Congenital Virilizing Adrenal Hyperplasia / Adrenogenital
Syndrome - characd by devt of male secondary sexual characs in female

829

Congenital Adrenal Hyperplasias

MC cause due to 21-beta-hydroxylase

V2 receptors

AG-II

(Aldosterone synthase)

ALDOSTERONE
Mineralocorticoids
Glucocorticoids

830

Congenital Adrenal Hyperplasias

MC cause due to 21-beta-hydroxylase
BUT HERE 2nd MC cause is 11-betahydroxylase

AG-II

(Aldosterone synthase)

ALDOSTERONE
Mineralocorticoids
Glucocorticoids

831

CONGENITAL VIRILIZING
ADRENAL HYPERPLASIA (21 &
11- hydroxylase deficiency) - leads to
excessive secretion of Androgens,
deficiency of Aldosterone &
Glucocorticoids

Clinical features: In females:

Baldness, Hirsuitism, small breasts,
amenorrhea, heavy arms & legs, male
pattern of hair growth (adrenal virilism)

In prepubertal boys - leads to

Precocious Pseudopuberty
Other features may be: hypotension,
Hypoglycemia, (due to decreased
Cortisol) Hyperkalemia (due to
Aldosterone deficiency in 21-hydroxylase
deficiency)

Tx: Glucocorticoid admin - inhibits ACTH

832
& suppresses Androgen production

CAH
Clinical presentation
in males:

CAH
Clinical presentation in females:

Females w/severe CAH due to

deficiencies of 21--hydroxylase, 11-hydroxylase, or 3--hydroxysteroid DH

have ambiguous genitalia at birth (classic virilizing

adrenal hyperplasia); genital anomalies range from
complete fusion of labioscrotal folds & clitoromegaly,
partial fusion of labioscrotal folds, or both

Females w/mild 21--hydroxylase deficiency

identified later in childhood b/c of precocious pubic hair,
clitoromegaly, or both, often accompanied by accelerated
growth & skeletal maturation (simple virilizing adrenal
hyperplasia)
Females w/still

hydroxylase activity may present in adolescence or

Females w/17-hydroxylase deficiency appear

phenotypically female at birth but do not develop
breasts or menstruate in adolescence; may present
w/hypertension

normal genitalia
If defect is severe & results in salt wasting, as neonates at
age 1-4 weeks w/failure to thrive, recurrent vomiting,
dehydration, hypotension, hyponatremia, hyperkalemia, &
shock (classic salt-wasting adrenal hyperplasia)
Males w/less

severe deficiencies of 21-hydroxylase present later in childhood w/early devt

of pubic hair, enlargement of penis, or both,
accompanied by accelerated linear growth &
advancement of skeletal maturation (simple virilizing
adrenal hyperplasia)

Adrenogenital syndrome during childhood, but NO SALT

WASTING in mild 21--hydroxylase deficiency*

milder deficiencies of 21--

adulthood w/oligomenorrhea, hirsutism, &/or infertility

(nonclassic adrenal hyperplasia)

Males w/21--hydroxylase deficiency have

Males w/17--hydroxylase deficiency have

ambiguous genitalia or female genitalia; may be raised
as girls & seek medical attention later in life b/c of
hypertension or lack of breast devt

833

Deficiency of 17 -Hydroxylase:
Deficiency of 17 -Hydroxylase:
Androgens & Glucocorticoids
Mineralocorticoid lvls
Lack of pubic & axillary hair (Adrenal Androgen func) in women
Hypoglycemia (b/c Glucocorticoids)
Metabolic alkalosis, Hypokalemia, Hypertension b/c Aldosterone
Cortisol increases ACTH
Males w/17-hydroxylase deficiency have ambiguous genitalia or
female genitalia; they may be raised as girls & seek medical attention later
in life b/c of hypertension or lack of breast devt
Need this enzyme to produce testosterone in males, thus low testosterone in male fetus
no male genetalia instead see blind vaginal pouch; wont be able to identify sex

Females w/17-hydroxylase deficiency appear phenotypically

female at birth but dont develop breasts or menstruate in adolescence;
may see hypertension
need this enzyme to produce estrogen (b/c made from testosterone), thus low estrogen in
female but only during puberty* (b/c required during fertile life), cannot go on to menarche
(amenorrhea)

Adrenal Medulla:

Secretes Catecholamines (CA) E, NE & DA

Consist of Chromaffin cells (PHEOCHROMOCYTES)- 8090% of cells which secrete E/ Adrenaline

10-20% of these cells secrete NE/Nor-adrenaline. NE

also secreted by Symp ganglia & Hypothalamus
Cholinergic fibers
1.
All Preganglionic fibers in both Symp &
parasymp ns
2.
All parasymp postganglionic
3.
Few symp postganglionic fibers (ie. Sweat
glands)
. Adrenergic fibers
1.
Most of postganglionic symp fibers
Main Receptors in ANS:
Based on type of NT theres 2 types of
receptors:
2. Cholinergic receptors (where ACh acts)

Muscarinic. M1 ,M2 M3 M4 M5 All Gprotein coupled

Nicotinic NM & NN .Ion channel

mediated
3. Adrenergic receptors
(Where E/NE/DA acts)1 (blood vessels for
vasoconstriction), 2 & 1 (<3), 2
(bronchioles for bronchodilation & in uterus
for relaxation), 3.All G-protein coupled

835

Consequences of Receptors activation in diff

organs:
Cholinergic
Heart 1: reduces HR,
Adrenergic
FOC, CO
Increases HR, FOC, CO
Blood vessel 1:
Vasodilatation, low BP Vasoconstriction, BP
Smooth m 2:
Contraction..bronchosp
Relaxation:
asm Diarrhea,
Bronchodilation,
Urination
constipation, Urinary
Sphincters: Relaxation
retention
Pupil: miosis
Contraction
Glands: more
Mydriasis (in eye
Salivation, sweating,
w/symp stimulation)
gastric acid

M1

Neurons

CNS effects

M2

Heart

Reduces heart ratebradycardia

M3

Smooth
muscle
and
glands

Contraction (except in blood vessels)

diarrhea, bronchoconstriction,
urination, Secretions .salivation,
stomach acid, sweating, lacrimation

M3

Pupil and
ciliary
muscle

Contracts .Miosis, increased flow of

aqueous humor

Nm

Skeletal
muscle
end plate

Contraction of skeletal muscle

Blood
vessels
Pupil (Iris)
smooth
muscle

presynaptic Reduces release of NEbradycardia,

neurons
hypotension

Heart
JGA

Contraction, Increased heart rate,

renin release

Smooth
muscles

Fat tissue

Relaxation so bronchodilation, urinary

retention, constipation, uterus
relaxation
Lipolysis

Vasoconstriction , Mydriasis (dilator

pupillae)
sphincter contractionso Constipation
and Urinary retention

Nicotinic receptor activation

10 Axns of Catecholamines via & Receptors:

1)

Adrenergic receptors: mostly excitatory, except (-) to GIT motility; in smooth m cells
adrenergic receptors: mostly inhibitory, except excitatory to myocardium
1 Cardiac m Excitatory HR, contractility (increased FOC due accumulated Ca 2+)
2 Relaxation of smooth m GIT, bronchioles, blood vessels (vasodilation); also in skeletal m
On CVS: HR & BP, FOC; tachycardia & fibrillation in high doses. Thus not given intravenously
1)

CO = HR * SV

2) On metabolism: BMR, Glycogenolysis, Gluconeogenesis, peripheral utilization net effect

Hyperglycemia; lipolytic, increases FFA & leads to formation of Ketone bodies (Ketogenic)
3) Bronchial ms - causes Bronchodilatation. Thus used in tx of Asthma (2 agonists Ie. Albutoril,
terbutaline, E/adrenaline miniscule dose subcutaneously if pts dont resp to 2 agonists)
4) Selective secretion: secretion of CAs during emergencies & stress due to activated SympathoAdrenal Medullary system gives rise to Flight/Fight Resp keeping ind in Alert & Arousal state - due
to activation of RAS (Reticular activation system)
5) Protective changes: dilates pupil by contracting dilator pupillae, causing more light to enter eyes;
HR, Cardiac output, Venous return - causing better perfusion of vital organs
6) Cutaneous vasoconstriction - minimizes bleeding by binding to 1 receptors
7) Piloerection of hair (Horripilation) due to pilomotor contraction
8) Sweating (Adrenergic sweating)
9) DA causes renal vasodilatation & peripheral vasoconstriction in resp to low BV/BP (hypovolemia)*
10) DA used in tx of shock

840

Flight / Fight
response

841

Pheochromocytoma:
tumor of Chromaffin tissues of Adrenal Medulla
Results in hypersecretion of Catecholamines in
EPISODIC fashion
Clinical features: Hypertension, headache, sweating,
palpitations, anxiety, moist skin, blurring of vision b/c
of pupillary dilatation
body temp BMR, Hyperglycemia leading to
Glycosuria
urinary excretion of CA in form of VMA (Vanillyl
Mandelic acid)
1 receptors (vasoconstriction & cardiac output so
BP increases), 1 & 2

Case.

A 40 year old male who is a known Asthmatic had severe exacerbation of

Asthmatic attacks for which his Physician prescribed him high dose of
Prednisolone (a synthetic steroid)
A few days later he felt better. His doctor advised him to taper the steroid
dose and gradually stop the drug.
Can present w/sx of adrenal crisis b/c adrenal func in pts on glucocorticoids over long
period of time

What is the basis for stopping the steroid therapy by slowly decreasing
steroid dose over a long period of time?
Prolonged tx w/anti-inflammatory doses of GCs ACTH synthesis due to
ve feedback of GC on ACTH secretion
Adrenals become atrophic & unresponsive after such tx
Ant pituitary unable to secrete normal amts of ACTH for as long as month.
Thereafter ACTH slowly - stimulates Adrenals- GCs
If steroids suddenly w/drawn, theres no sufficient endogenous Cortisol
secretion by adrenal cortex

843

Can you tell the sex of this newborn??!!

Sex is usually determined by external features

But it is NOT always True

Determination of sex
A true male or female is determined if ind fulfils ALL 3 diff sexes
Three types of sex:
A) Genetic sex
B) Gonadal sex
C) Genital sex

844

One should satisfy all three Gs to consider as true male or female

A) Genetic Sex
Genetic sex is based on sex chromosomes
Genetically male:
46 XY (44 autosomes + 2 sex chromosomes)
Genetically female:
46 XX (44 autosomes + 2 sex chromosomes)
Genetic sex is determined by Karyotype analysis

845

B) Gonadal sex

Gonads: reproductive organs that produce gametes &

secrete sex hormones
Male gamete Spermatozoa; Female gamete - Ovum
Male gonad Testis; Female gonad - Ovary
Testis: produces spermatozoa & secretes testosterone
Ovaries: produce ova & secrete estrogen &
progesterone
Genetic sex normally determines gonadal sex
Determination of gonadal sex requires histological
exam of gonads

Testis

Ovary

846

Basis of Gonadal sex:

Until 6 weeks of
embryonic life, primitive
gonad is called bipotential
gonad or undifferentiated
gonad has potency to
develop into testes or
ovaries; has both cortex &
medulla
Sex determining region, Y
(SRY) in Y chr of genetic
male fetus is responsible
for devt of bipotential
gonad into testes
Absence of SRY gene in
genetic female fetus
results in devt of
bipotential gonad into
ovaries
Absence of SRY gene
even in genetic male fetus
will result in devt of
ovaries (~6-7 weeks of
life)
When medulla develops
into testes; cortex
regresses
When cortex develops into
ovaries; medulla
regresses

Genetic
Male fetus
(46 XY)

SRY gene

Testis

Bipotential
gonad
(6 week)

Genetic
Female fetus
(46 XX)

No SRY gene

6-8 weeks of
embryonic life

Ovary

847

C) Genital sex aka Phenotypic Sex:

determined by type of genitalia (both internal & external
genitalia)
Male type internal genitalia include: epididymis, vas deferens,
seminal vesicles
Male type external genitalia are: prostate, penis & scrotum
Female type internal genitalia include: fallopian tubes, uterus &
upper third (1/3) of vagina
Female type external genitalia are: Labia majora, labia minora,
clitoris & lower two thirds (2/3) of vagina

848

Basis of Genital sex:

A. Devt of internal genitalia:

Fetus at 7 weeks has both Wolffian & Mullerian ducts
Wolffian duct develops into male internal genitalia
Mullerian duct develops into female internal genitalia (W for
male; M for female)
In male fetus, hormones of fetal testes essential for devt of
male internal genitalia
Devt of Wolffian duct requires hormone, *Testosterone,
secreted by Leydig cells of fetal testes +regression of
Mullerian
Regression of Mullerian duct requires hormone, *Anti-Mullerian
hormone (AMH) / Mullerian inhibiting substance (MIS),
secreted by Sertoli cells of fetal testes
Thus need 2 hormones for Wolffian duct devt into male internal
849
genetalia: Testosterone & AMH/MIS

A. Development of male internal genitalia:

Wolffian duct develops
into male internal
genitalia only when
TESTOSTERONE is
secreted by fetal testes

At 7 week
Mullerian duct regresses
In male fetus only when
ANTI-MULLERIAN HORMONE
is secreted by fetal testes

At 9 week
850

A. Development of female internal genitalia:

Mullerian duct develops
into female internal
genitalia w/out any
hormones

At 7 week
In absence of AMH,
Mullerian duct develops
into female internal
genitalia in genetic &
gonadal male fetus
At 9 week
NO HORMONAL INPUT IS REQUIRED FOR DEVT FEMALE INTERNAL STRUCTURES!
851

Sexual differentiation in males & females:

SRY

No SRY gene

852

Comment on devt of internal genitalia if genetically

male fetal testes secretes:

Anti-Mullerian hormone (AMH) alone

(responsible for regression of mullerian duct thus inhibition of

female internal structures) w/no male internal structures if no
testosterone

Testosterone alone

(responsible for devt of male internal genetalia); for male

internal organs + female internal if no AMH

Neither AMH nor testosterone?

No male internal structures, ONLY female internal structures

Solutions:

No internal genitalia of either type

Devt of internal genitalia of both male & female types

Devt of internal genitalia of female type (uterus & fallopian tubes)

853

Basis of Genital sex

B. Devt of external genitalia
External genitalia develops from undifferentiated, bipotential
external genitalia at 9-12 weeks
Devt of male external genitalia needs hormone,
Dihydrotestosterone (DHT)
Testosterone

5-alpha reductase

Dihydrotestosterone

This enzyme is in bipotential genitalia of fetus

Devt of female type of external genitalia doesnt require any
hormone
If no DHT male will have FEMALE EXTERNAL STRUCTURES
854

B. Development of external genitalia.

Bipotential, undifferentiated fetal external genitalia (7 week)

No DHT

Female type external genitalia

(12 week)

DHT

Absence of DHT
in male fetus
leads to female
type external
genitalia!!

Male type external genitalia

(12 week)
855

Aberrant sexual differentiation:

Refers to abnormal sexual devt during fetal stage; can be due
to 2 reasons:
A. Genetic (chral) abnormalities
B. Hormonal abnormalities
A) Genetic (chral) abnormalities: Basis:
i) Abnormal separation of chrs during meiosis in
gametogenesis leads to abnormal gametes. Fertilization of
abnormal gametes result in defective zygotes & abnormal
sexual devt in fetus
ii) Faulty mitosis in early zygote can also lead to same dfx

856

A. Aberrant sexual differentiation due to genetic

(chral) dfx:
Defective
Oocyte
22
O

46
XX
Normal
Oogonia
(diploid cell)

Normal
Spermatozoa
+

23
X

Defective
Zygote
45
XO

Gonadal dysgenesis of females

(Turners syndrome)
AKA OVARIAN FAILURE (b4 or after

Abnormal
Meiosis

24
XX

23
Y

Gametes:
Female & Male
(haploid cells)

47
XXY

Seminiferous tubule
Dysgenesis of male gonads
(Klinefelters syndrome)
ABNORMALITY OF
SPERMATOGENESIS

Turners syndrome (Gonadal dysgenesis):

Chr pattern: 45 XO
Rudimentary or absent gonads
Born w/female internal & external genitalia
Short stature
Lack of sexual maturity at puberty & become infertile (ovarian failure)
Amenorrhea (primary or secondary)
Charac webbed neck
May be associated w/other congenital birth dfx ie. congenital <3 diseases,
coarctation of aorta (hyperplasia of ventricles), horse-shoe kidney & short 4th
metacarpals (also in pseudohypoparathyroidism)
MR is uncommon

85
8

Klinefelters syndrome (Seminiferous tubule dysgenesis) 47XXY:

Chr pattern: 47 XXY

Gonads: Testes w/poorly devd seminiferous
tubules
Born w/male internal & external genitalia since fetal
testes secretes testosterone & AMH
Poorly devd male secondary sex characs at puberty
due to small testes (high LH)
Low plasma testosterone & high plasma estradiol &
Gonadotropins
Not able to produce sperms leading to male infertility
in adults
Has feminine features & Gynaecomastia due to high
Estradiol/testosterone ratio
Commonly associated w/MR
859

Klinefelters
syndrome
OR
Seminiferous
tubule
dysgenesis

860

B. Aberrant sexual differentiation due to

hormonal abnormalities:
Abnormal sexual devt as result of hormonal abnormalities due to:
i) Abnormal secretion (increase/decrease) of hormones during fetal
stage
ii) Insensitivity of target organs to hormones in fetus
Examples:
1) Female pseudohermaphroditism (phenotypically male,
genitically & gonadal female)
2) Male pseudohermaphroditism due to :
A) Hormonal dfx
B) 5-alpha reductase deficiency syndrome
C) Testicular feminization / Androgen Insensitivity Syndrome
(AIS)
861

True hermaphroditism
Ind is born w/both testes & ovaries
Chral pattern: 46XX/46XY due to
faulty mitosis in early zygote
Genitalia may vary from male to
female depending on dominance of
fetal testes
May have ambiguous genitalia
Gynecomastia in low testosterone,
high estrogen secretors

862

863

Pseudohermaphroditism
Ind born w/genetic & gonadal sex of
1 type & genital sex of other type
Types:
Male pseudohermaphroditism
Female pseudohermaphroditism

+
Prefix, male/female indicates type of genetic
& gonadal sex in each of these variants
864

1) Female Pseudohermaphroditism:
Ind has female genetic & gonadal sex but born w/male type
external genitalia
Inds have 46 XX; & Ovaries as gonads
Hypertrophied clitoris appears as penis
They all have female internal genitalia
This can occur in:
i) female fetus exposed to high [androgens] (similar to
testosterone) during early pregnancy
ii) female w/Congenital Virilizing adrenal hyperplasia

865

2) Male Pseudohermaphroditism:
has male genetic & gonadal sex but born w/female
external genitalia THUS NO MALE EXTERNAL*
GENETALIA
Inds have 46 XY; & Testes as gonads
They may or may not have female internal genitalia
They may or may not have male internal genitalia
Dfx due to: failure of fetal testes to secrete testosterone
or both Testosterone & AMH
If both hormones are deficient: Ind will be born
w/female external genitalia & female internal genitalia
If testosterone alone is deficient: Ind will be born
w/female external genitalia & absent internal genitalia
of either type

866

3) 5-alpha reductase deficiency syndrome:

variant of Male pseudohermaphroditism
undifferentiated external genitalia lacks 5-alpha reductase
Testosterone not converted to DHT so failure to develop male
external genitalia
born w/female external genitalia (blind vaginal pouch)
46 XY & funcing testes (intra-abdominal) (cryptorchidism =
undescended testes in abdominal cavities)
Has male internal genitalia
Vagina ends as blind pouch b/c no female internal genitalia,
absent uterus & cervix
brought up as girl till puberty; w/Amenorrhea
At puberty rising lvls of testosterone produces masculine
features & enlargement of clitoris that appears as penis (Penis
at 12 syndrome)
Prostrate also wont develop well; need DHT for this
867

4) Testicular Feminization/ Androgen

Insensitivity Syndrome (AIS):

variant of Male pseudohermaphroditism

defect in androgen receptors at target site resp to DHT (more active;
stronger binding) & Testosterone
Person is genetically male, has Testes as gonads that secrete Testosterone,
but cant act effectively on tissues
Most cases identified in newborn period by presence of inguinal masses
(cryptoorchidism), later identified as testes during surgery
**Testosterone receptors defective at target site

So MALE internal & external genitalia cannot be formed

Since AMH present, Mullerian duct also regresses & Female internal
genitalia also cannot be formed

normal testes w/normal production of testosterone & normal

conversion to DHT (differentiates this from 5-a reductase def)
868

Cont.
Individual has female external genitalia. Vagina ends as
a blind pouch as female internal genitalia is absent
At puberty, more of testosterone gets converted to
Estradiol (by Aromatase in Adipose tissue) & the
individual develops breasts
Individual is raised as a woman & seeks medical advice
when there is failure to develop menstrual cycles

869

Functional anatomy of male reproductive organs

Male gonad: Testis
Male gamete: Spermatozoan (sperm)

Vas deferens

Male internal genitalia

(blue labels)
Seminal vesicle
Prostate

Male external genitalia

(red labels)

Penis
Epidydimis

Ejaculatory duct

Scrotum
870

Structure of testis

Thus need FSH & LH

for spermatogenesis!

Seminiferous
tubules

Precursor cells
of spermatozoa

Interstitial cells
(Leydig cells):
Secrete Testosterone

Sertoli cells in here

responsible for
spermatogenesis;
acted on by FSH

Regd by LH
Testosterone
essential for
spermatogenesis

872

Structure of Testis
Structure of Testes: Testes made up of loops of
convoluted seminiferous tubules that open to epididymis.
interstitial space of testes have Leydig cells that secrete
testosterone
Seminiferous tubules have (germ) Sertoli cells.
Germinal cells are spermatogonia & various stages of
devt of spermatozoa occur
Blood Testes Barrier: tight juncs btwn 2 adj Sertoli cells
that make barrier btwn interstitial space & interior of
seminiferous tubules called blood-testis barrier; prevents
movement of large molecules, toxins, drugs, immune
cells & microorganisms into lumen of seminiferous
tubules

873

in g
p
o
l
deve
f
o
es
g
a
zoa
t
s
o
t
s
a
m
ou
Vari
sper

Principal cells in testis = SERTOLI CELLS MAKE BM T

Immature
spermatozoa

Spermatogonia

BM

Blood-testis barrier
Leydig cells

874

Functions of Testis
FUNCTIONS OF TESTIS:
A) Gametogenic function:
Spermatogenesis
B) Endocrine function:
Testosterone secretion

875

Spermatogenesis
Occurs in stages:
Spermatogonia (diploid cells, 46 XY)
Mitosis
Primary spermatocytes (diploid cells, 46 XY)
First meiotic division
Secondary spermatocytes (haploid cells, 23X or
23Y)
Second meiotic division
Spermatids
(haploid cells)
Spermiogenesis

Spermatozoa (haploid cells)

All stages take place in deep folds of cytoplasm of
Sertoli cells which nourishes developing cells
Total duration: ~10 weeks
Normal functioning of Sertoli cells is very
876
essential for normal spermatogenesis

Spermiogenesis: imp deval stage during Spermatogenesis. (spermatids

spermatozoa)
Spermatids undergo condensation, shrinkage of cytoplasm, formation of
Acrosome (IMP FOR PENETRATION) & devt of tail.
Avg sperm count varies from 50-100 mil sperms /ml of semen
Sperm count >20 mil sperms /ml is considered normal
877

Factors that influence spermatogenesis:

A. Hormones:
i) Pituitary gonadotropins: LH & FSH
LH Stimulates Leydig cells to secrete testosterone (provides ve
feedback for LH in blood to pituitary)
FSH Stimulates Sertoli cells to secrete Inhibin (-ve feedback to
ant pituitary; regulates FSH)
ii) Hormone from testis: Testosterone diffuses into seminiferous
tubule & reinforces axns of FSH
B. Androgen binding protein (ABP): secreted from Sertoli cells
in testis; binds & helps concentrate testosterone in tubules
(>CONCENTRATED in testes)
C. Low temp in testes (relative to core body temp)

878

Effect of temperature on spermatogenesis

Spermatogenesis requires
temp of 35-36 C
Cooling mechanisms in testes
maintain this temp by:
i) Counter current heat
exchange btwn as & vs in
spermatic cord
ii) Cremasteric & dartos ms
(Contraction low temp &
relaxation high temp)
Testes in abdominal cavity
will not be able to maintain
this temp
Testis
879

Descent of Testes

Clinical focus: Cryptorchidism

Testis develop in abdomen & descend into scrotum during fetal
life (28th week)
Testis fail to descend in scrotum b4 or shortly after birth is
known as Cryptorchidism / Undescended Testes
Cryptorchidism must be corrected for proper fertile gonads
otherwise leads to infertility
Sertoli cells & Leydig cell maturation is adversely affected in
Cryptorchidism.
In adults w/bilaterally undescended testis:
Inhibin secreted by Sertoli cells normally inhibit FSH. FSH
secretion elevated due to Inhibin production by Sertoli cells
LOW Testosterone secretion by Leydig cells resulting in
elevated lvls of LH

881

Synthesis of Testosterone in Leydig cells:

Testosterone is a steroid derived from cholesterol
Cholesterol
Cholesterol desmolase* LH regulates this in
Leydig cells (in Adrenal glands is ACTH); increased cAMP
formation
Pregnenolone
17- alpha hydroxylase (absent no menses or
testes)
17- Hydroxypregnenolone
17,20 Lyase
Dehydroepiandrosterone (DHEA)
3 beta-hydroxysteroid DH
Androstenedione
17 beta-hydroxysteroid DH**
Testosterone estrogen (for females)
* Cholesterol desmolase enzyme is stimulated by LH
882
** 17 beta-hydroxysteroid DH only in Leydig cells of

Mechanism of axn of testosterone:

Physiological efx

DHT

Androgens
increase
protein
synthesis;
THUS
ANABOLIC

Testosterone acts via IC receptors

5-reductase in male accessory sex organs (Prostate), converts
Testosterone into active form DHT
Target tissues requiring DHT are: fetal external genitalia
Male body, scalp & facial hairs, Sebaceous gland, Prostate

Physiological axns of Testosterone:

Devt & maintenance of male secondary sex characs at puberty

Inhibition of LH from ant pituitary
Protein anabolic effect on ms, bone marrow & liver
Due to Protein anabolic efx, exogenous androgens (Anabolic steroids) taken
in attempt to increase m mass
Promotion of skeletal growth & closure of epiphysis
Role in fetal stage - prenatal differentiation into Wolffian ducts
(Testosterone) & external genitalia (DHT)

Finasteride (5-reductase
inhibitor) is used to treat Benign
Prostatic hypertrophy. Why
B/c it blocks activation of
Testosterone into DHT in
prostate & decreases
prostatic volume & also
decreases cellular
proliferation
Note: Normally DHT increases
Prostatic size & volume

884

Clinical focus: Use & Abuse of Steroids

Some athletes use anabolic steroids to increase strength & m
mass
Such a practice is illegal & it may cause:
Suppression of Hypothalamo -pituitary axis by ve feedback
This leads to LH, FSH & *intratesticular testosterone (b/c
elevated exogenous testosterone in blood but decreased
endogenous testosterone in testes) HYPOGONADISM
This results in gonadal atrophy, impaired spermatogenesis
peripheral metabolism of anabolic androgens to estrogens
(via aromatase) results in feminizing efx as Gynaecomastia in
males
Irreversible Virilization in women (hirsutism + hypertrophy
of clitoris)

885

Control of Testicular Funcs:

Control is by Hypothalamo- hypophysio-gonadal axis

Hypothalamus secretes Gonadotropin releasing hormone (GnRH) that
stimulates ant pituitary to secrete FSH & LH
FSH stimulates Sertoli cells in seminiferous tubules & thus helps in
maintenance of spermatogenesis; also stimulates secretion of Inhibin from
Sertoli cells
Inhibin inturn inhibits secretion of FSH from ant pituitary
LH acts on Leydig cells & stimulates secretion of Testosterone
Testosterone in turn causes feed back inhibition of LH & acts
intratesticularly to reinforce spermatogenic efx of FSH in Sertoli cells
Hypothalamic lesion damaging GnRH secreting neurons would produce
decreased secretion of LH & FSH & thus cause hypogonadism (tertiary)
Castration (removal of testes) leads to elevated lvls of FSH & LH. (Primary)

886

Control of testicular functions

By negative feedback
mechanism

Testis

887

Variations in FSH & LH lvls over lifespan in

males
In fetal stage- Testosterone higher as its
required for sexual differentiation
In childhood - hormone lvls are lowest
At puberty & during reproductive yrs - hormone
lvls increase, Testosterone > LH
In aging adult, testosterone decreases & due to
loss of testosterone feedback, LH increases

Plasma concentration

Plasma levels of Testosterone & LH

Testosterone
LH

1. Fetal 2. Childhood
life

3. Puberty

4. Adult

889

5. Aging
adult

Abnormalities of male Reproductive funcs:

A) Male hypogonadism

B) Male infertility

C) Effects of castration (removal of testes)

890

A) Male Hypogonadism
characd by reduced testicular funcs (both gametogenic &
endocrine)
Clinical picture depends on age of onset: b4 puberty or after
puberty (adult)
It can be primary (in Testis) or secondary (Ant pituitary)
hypogonadism
Plasma hormonal assay is used to differentiate:
Condition

Testosterone

LH

FSH

Primary
hypogonadism
Secondary

hypogonadism

= increase; = decrease
891

Hormonal Changes in specific Altered

States
Intratesticular
Testosterone

LH

FSH

In old age

1*

Anabolic Steroid therapy

(exogenous testosterone
increases in blood)

Inhibin Infusion

only*

GnRH Infusion, constant

(decrease everything b/c
downreg of receptors)

GnRH Infusion, pulsatile

(prevents downreg)

Male hypogonadism before puberty:

Delayed puberty
Failure to develop male secondary sex characs
Decreased muscle m
High pitched voice
Decreased body hair
Underdevd genitalia & testes
Excessive arm & leg length in reln to trunk (continued
growth b/c lack of testosterone no fusion of
epiphyseal plate)
Tall stature
Gynaecomastia
893

Male hypogonadism (after puberty) in

adults:

Erectile dysfunc (impotence)

Low sperm count (infertility)
Decrease in beard & body hair
Decrease in muscle m
Increase in body fat
Decrease in size of testes
Gynecomastia
Loss of bone mass (osteoporosis overactive
osteoclasts)
Decreased libido
Fatigue & anemia (lack of EPO production; low
RBC count, normally 4.5-5.5 mil/mm 3 ;
hemotocrit also decreases)
Emotional instability

B) Male infertility

Persistent inability of couple to have child due to certain problems in male

partner
Physioal basis:
a. Defective spermatozoa
b. Defective spermatogenesis
Exs:
Cryptorchidism (Undescended testes)
Deficiency of androgen binding protein (ABP)
Failure of testicular cooling mechanisms (as in Varicocele)
Tx w/anabolic steroids
Defective sperm motility, Deficient acrosomal enzyme that aids in fertilization

C) Efx of castration (Orchiectomy)

Castration means removal of testes
Clinical picture is same as that of hypogonadism b4 or after puberty
Enuchoidism= clinical picture that occurs due to castration b4 puberty
Low testosterone, high FSH & LH
895

Structure of ovary:

~2 mil follicles at birth

At puberty 400,000 follicles remain
Of these only ~400 undergo maturation thru out reproductive life of woman
In all these follicles, oocytes have started 1st meiotic division which is arrested
in Prophase stage

Synthesis of Estrogen & Progesterone:

In Theca cells of ovaries, LH binds
to its receptors & stimulates
conversion of Cholesterol to
Pregnenolone
Pregnenolone gets converted to
Progesterone
Theca cells of ovaries secrete
Testosterone
Aromatase: in Granulosa cells,
converts Testosterone to 17Estradiol; also in adipose tissue

17-alpha-hydroxylase; females
deficient of this cannot produce
estrogen

Clinical Focus:
Timing of puberty in females influenced by lvl of body
fat
Lean girls tend to enter puberty later.
Female athletes w/low body fat lvls often have
amenorrhea (menstruation absence). Why?
This is b/c adipose tissue is site of aromatization of
androgens to estrogens due to presence of
aromatase enzyme

Menstrual Cycle:
Regular, cyclical changes that occur in reproductive system of
female
Menstruation: means periodic bleeding thru vagina
Duration of a cycle: 28 days (range: 24-32 days)
Phases of menstrual cycle:
Day 1 to 14: Follicular/Proliferative phase
Day 14 to 28: Luteal/Secretory phase
Bleeding
phase

Day 01

Midcycle:
Ovulation

Day 14
High estrogen
^LH
Follicular phase

High progesterone
Luteal phase

Day 28

Duration of the phases of a cycle

duration of luteal phase is fixed at 14 days
duration of follicular phase varies depending
on length of cycle
Follicular phase

Luteal phase
Day 14

Day 01

Follicular phase
Day 01

Luteal phase

Day 10

Follicular phase
Day 01

Day 28

Day 24
Luteal phase

Day 18

Day 32

Time of ovulation is calculated by deducting 14 days

from the last day of the cycle

Changes in ovaries during menstrual cycle (Ovarian cycle):

Primordial follicles contain primary oocyte surrounded by single layer of Granulosa cells.
These primary oocytes derived from oogonia during fetal life. Once they enter 1 st meiosis, become primary
oocytes. Primary oocytes remain in prophase of their 1st meiotic division till that follicle selected for
maturation during menstrual cycle

During follicular phase: (day 01 to day 14):

Day 1-6: many primordial follicles start growing & develop to primary follicles & to secondary follicles under
stimulation of FSH & LH (due to estr & progr dropping)
Day 6-14: 1 of secondary follicles in 1 ovary starts growing rapidly & becomes dominant Graafian follicle

Graafian follicle secretes large amt of Estrogen; other follicles regress & disappear
On day 14: (Ovulation): process of rupture of Graafian follicle & extrusion of oocyte into abdominal cavity

Very high plasma LH lvls (LH Surge) essential for ovulation

After ovulation, 1st meiotic division completed & daughter cell is called Secondary oocyte.

Secondary oocyte begins 2nd meiotic division which is completed only if spermatozoon penetrates it

During Luteal phase: (day 14 to day 28):

Once Graafian follicle ruptures, its devoid of oocyte, becomes filled w/blood as Corpus hemorrhagicum
Cells proliferate rapidly to form Corpus luteum. Theca & Granulosa cells get converted into Luteal cells.
This followed by in Aromatase activity & drop in estrogen production
Corpus luteum secretes both Progesterone & Estrogen (progesterone >than estrogen)
Progesterone increases vascularity & secretory activity of endometrium - prepares to receive fertilized ovum
Corpus luteum has life span of 12 days
On 26th day, corpus luteum starts degenerating, stops secreting hormones & becomes scar tissue
Estrogen & Progesterone decrease abruptly

Primordial
follicle (Day 01)
Primary
follicle

Primary oocyte
Antrum filled with fluid
Granulosa cells
Theca cells

Secondary
follicle

Maturation of
follicle during
follicular phase

Graafian
follicle
(Day 14)

Maturation of Follicle & Oocyte:

ESTROGEN

PROGESTERONE
/egg released

Primary follicle

Ovarian cycle
Primordial
follicle

Secondary follicle
Graafian follicle
Matured graafian
follicle

After releas
Corpus
hemorrhagicum

Corpus
albicans
Regressing
corpus luteum

Oocyte

Mature
corpus luteum

Young corpus luteum (YELLOW)

Changes in uterine endometrium during menstrual cycle (Uterine cycle)

Proliferative phase (Day 1-14): at start of MC endometrium thin, glands

sparse & straight w/narrow lumen
Deep layer (functionalis) layer starts growing under Estrogen (proliferation
of endometrium)
Growth of endometrial glands, stroma & blood vessels increase thickness
Secretory phase (Day 14-28): glands show Secretory changes due to
Progesterone from corpus luteum
Stroma becomes edematous; blood vessels dilate
Endometrial changes suitable for implantation of embryo (5-7 days after
ovulation) if fertilization takes place
changes continue till plasma lvls of progesterone & estrogen are high (then
drop after 7 days of this phase)

Changes in uterine endometrium

during menstrual cycle (Uterine
cycle)
Proliferative phase
Thin secretions

Secretary phase
Thick secretions

Bleeding phase

Hormone of proliferative
phase : Estrogen

Major hormone of secretory

phase : Progesterone

Endometrial changes.

Bleeding phase (day 01 to 05):

When corpus luteum stops secreting hormones on 26th day,

plasma Progesterone & Estrogen fall sigly by 27th/28th day
Mechanism of bleeding:
endometrial blood vessels undergo spasm

Necrosis of endometrium

Sloughing of endometrium

Menstrual flow (bleeding)

Since bleeding due to w/drawal of hormonal influence on
endometrium, menstrual bleeding called Withdrawal bleeding
(passive effect on endometrium)

Endometrial changes due to Estrogen during follicular phase:

microscopic appearance of normal proliferative endometrium in menstrual cycle.

Endometrial changes due to Progesterone

during Secretory phase:

Early secretory endometrium w/presence of sub-nuclear vacuoles.

Menses

Hormonal control of Menstrual Cycle:

Control is by Hypothalamo-pituitary-ovarian axis
Both ve & +ve feedback work at diff periods of cycle
During follicular phase: FSH & LH stimulate growth of follicle; secretion of estrogen
from follicle inhibits FSH & LH
At midcycle: High plasma Estrogen stimulates further secretion of LH & FSH by +ve
feedback that leads to LH surge
During Luteal phase: High plasma progesterone inhibits FSH & LH (-ve feedback)

In ovary
Follicular phase

Luteal phase

Basal body temperature

0.5-1.0 F increase;
Woman feels hot
Plasma progesterone

Plasma estrogen

Plasma gonadotropins
FSH

LH

Female sex hormones: A) Estrogen & B) Progesterone:

A) Estrogen:
Major estrogen secreted by ovaries: Estradiol (17-beta estradiol)
Major estrogen secreted by placenta: Estriol
Major estrogen secreted by adipose tissue: Estrone; axns of Estrogen
) Growth of uterus, fallopian tubes, cervix & vagina (accessory sex organs)
) Devt of female secondary sex characs
) On breast: for enlargement of breast, growth of ducts of glands (risk of ductal carcinoma reld
to estrogen), adipose tissue
) Proliferation of granulosa cells & growth of follicle
) Proliferation of endometrium during proliferative phase
) Secretion of watery, elastic mucus from uterine cervix
) -ve & +ve feedback on FSH & LH
) Maintenance of pregnancy & blocking PRL on breast in pregnancy (preventing milk production)
) Lowers myometrial threshold to contractile stimuli at term
) Salt & water retention, cholesterol lowering efx (^^in post-menopausal women)
B) Progesterone: secreted by corpus luteum & placenta; axns secretory changes in uterine
endometrium, devt of lobules & alveoli in breast increasing breast size
) -ve feedback effect on LH & FSH
) Responsible for thick, less elastic mucus secretion by uterine cervix
) Maintenance of pregnancy: decreases excitability of myometrium & prevents contractions
during pregnancy by decreasing uterine resp to Oxytocin
) Thermogenic effect: responsible for rise in basal body temp in Luteal phase; also stimulates
appetite

Cervical Mucus changes during Menstrual cycle:

During follicular phase, Estrogen

stimulates production of copious quantity
of thin, watery, alkaline stringy (elastic)
mucus
Spinnbarkeit Effect when dropped on
slide, touched & elevated mucus forms
long string. This facilitates sperm
movement.
When mucus allowed to dry on slide, fern
like (ferning) pattern formed due to high
electrolyte contents of mucus
During Secretory phase, Progesterone
causes cervical mucus to become scanty,
thick, sealing off uterus from further entry
of sperm or bacteria

Indicators/ Tests of Ovulation:

BBT (Basal body temp) by 0.5-1.0F due to
thermogenic efx of Progesterone
Nature of cervical mucus - absence of ferning pattern
& thick cervical mucus indicates ovulation has
occurred
Endometrial biopsy to study nature of endometrium
Ultrasound scan

Abnormalities of menstrual cycle:

Dysmenorrhea (Painful menstruation), Amenorrhea (absence of
menstruation) & Menorrhagia (increased menstrual bleeding)
Primary amenorrhea: failure to have menstrual cycle
Secondary amenorrhea: cessation of cycles in woman
w/previously normal periods
MC physioal causes for 2ndary amenorrhea: pregnancy &
lactation (PRL lvls hyperprolactenemia, inhibits GnRH
inhibits FSH & LH no menstrual cycle)
Pathological causes for amenorrhea: hypothalamic diseases,
pituitary diseases, ovarian diseases, systemic diseases (ie.
Hypothyroidism b/c high PRL inhibits GnRH), emoal stimuli
Anovulatory cycle: menstrual cycle in which no ovulation
occurs; normal in most girls, anovulatory cycles in 1 st 1-2 yrs
after menarche; no corpus luteum formed & progesterone efx
on endometrium absent; estrogens continue to cause growth &
proliferate endometrium that becomes thick enough to break
down & slough; menstrual flow is generally scanty

Dysmenorrhea aka Painful Menstruation:

Current evidence suggests pathogenesis of primary
dysmenorrhea due to Prostaglandin F2 (PGF2): potent
myometrial stimulant & vasoconstrictor, in secretory
endometrium
increase in prostaglandins in endometrium after fall in
progesterone in late Luteal phase results in excessive uterine
contraction
NSAIDs given to inhibit COX (arachidonic acid
prostaglandins) reducing PG lvls preventing
dysmenorrhea

Menopause:
Menopause: permanent cessation of menstruation in
elderly woman
In post menopausal woman, theres decreased
Estrogen secretion that this in turn increases FSH &
LH lvls

PHYSIOLOGY OF PREGNANCY
Fertilization & implantation:
Fertilization should occur w/in 24
hrs after ovulation since oocyte
survives for day
Enzymes in head of spermatozoa
such as Hyaluronidase & Acrosin
help to adhere to oocyte
Acrosomal rxn releases sperm
nucleus into cytoplasm of oocyte
Fertilization occurs in ampulla of
fallopian tube
Zygote rapidly divides & moves
twds uterus
Implantation takes place on day 5-7
after fertilization
Trophoblasts cells around zygote
responsible for invading
endometrium & implantation of
blastocyst

Sperm Cell Movement

Sperms reaching Ovum..

Acrosomal reaction!!!

ysozomal Enzymes
n Acrosomal cap help in
enetration of sperm
nto female ova.
ence called
crosomal Rxn

Sperm not having Acrosomal enzymes fails to

fertilize ovum & results in infertility

Zygote Devt: Cell Division & Implantation

Implantation
Occur 5-7 days
after fertilization

Ovulation

Sperms reaching the Ovum

Sperm reaching the Ovum

One successful sperm penetrates the

ovum

B-hCG binds to LH receptors on luteal cells of corpus luteum to save it by causing release of
estrogen & progesterone thus endometrium lining survives

Blastocyst undergoes implantation in uterine wall:

Fetus formation

Fetus formation..

Mature Fetus

The final stage - A Newborn Infant

God! It was
better
inside

Hormonal support to early Pregnancy:

Trophoblast = outer rim of cells in blastocyst; invades maternal endometrium & develops into
Placenta
Syncytiotrophoblast cells begin to secrete hormone HCG (human Chorionic
Gonadotropin), ~8 days after ovulation
Placental HCG has -subunit similar to LHs so has LH activity stimulates corpus luteum to
continue to secrete progesterone & estrogen. Corpus luteum continues to func as corpus
luteum of pregnancy b/c of HCG for 1st few weeks of pregnancy
Placenta takes over func of corpus luteum by ~6-8 weeks of pregnancy
Why???
Ovariectomy (removal of ovaries) before 6th week of gestation leads to
abortion. Why?
Ovariectomy before 6th week of gestation will remove corpus luteum that
nourishes fetus till placenta takes over this func by ~6-8 weeks. This results in
spontaneous abortion due to w/drawal of hormonal support
But ovariectomy thereafter has no effect on pregnancy
--------------------------------------------------------------------------------------------------------- Secretion of HCG increases sigly & gets excreted in urine of pregnant woman during 1st
trimester. Detection of HCG in urine is basis for pregnancy test
5 Maternal Hormones of Pregnancy are:
Human Chorionic Gonadotropin (HCG)
Human Chorionic Somatomammotropin (HCS) or Human placental Lactogen, (HPL)
Estrogen
Progesterone
Prolactin

Changes in Hormones During Pregnancy:

Plasma lvls of imp h

pregnancy:

Human Chorionic Gonadotropin (HCG)

HCG secreted by Syncytiotrophoblast cells
HCG appears in plasma 8-10 days after
ovulation
Peaks at 8-10 weeks of pregnancy
HCG Beta subunit appears in urine
Useful for diagnosis of pregnancy
Supports early pregnancy

Acts like LH

Human Chorionic Somatomammotropin or

Human Placental Lactogen (HCS or HPL)
Resembles human growth hormone
& is secreted in proportion to size of
placenta
Plasma lvl of HPL is index of
placental well-being
Can be detected in serum by 3 weeks &
rise thru out remainder of pregnancy

HPL increases maternal lipolysis, ketogenesis & decreases

maternal glucose utilization, thus making maternal energy stores
more available for fetus
Its antagonistic axn to insulin is major basis for diabetogenicity of
pregnancy (gestational diabetes normal woman
w/hyperglycemia due to pregnancy & HPL)
HPL attributed to be factor responsible for causing
Gestational Diabetes

Fetoplacental unit:
Pregnenolone: precursor for
estrogen made from placenta &
diffuses into fetal circulation
In fetal adrenal gland, this
Pregnenolone is converted to
DHEA (dehydroepiandrosterone)
DHEA converted into 16-Hydroxy
DHEA in fetal liver & diffuses to
placenta & is converted to estriol
Major placental Estrogen is
Estriol
Thus, for placenta to secrete
Estriol, it should get precursor
from fetus
Plasma estriol estimation in
mother is good index of fetal
well being. In cases of
intrauterine fetal death, estriol
lvl in plasma reduces sigly

Fetoplacental u

Plasma estriol in
mother is index of
fetal well-being

Estriol in
maternal
circulation

Lactation: LGE!
Lactation includes: Lactogenesis, Galactopoiesis & Milk ejection
Lactogenesis: initiation of milk production by breast via Prolactin; note:
during pregnancy, this axn is inhibited by estrogen
Galactopoiesis: maintenance of milk production in lactating woman
Suckling by baby stimulates secretion of Prolactin by neuroendocrine reflex
Regular breast feeding increases PRL secretion
PRL inhibits GnRH & causes Lactational Amenorrhea following child birth
Why???? Women who do not wish to breastfeed their babies are prescribed
w/large doses of Estrogen to stop milk production; How does this work?
Mechanism:
large dose of estrogen inhibits lactation (as it does during pregnancy) by its
direct inhibitory axn on enzymes involved in milk synthesis in mammary
gland; just know this*

Physiological efx of hormones on breast:

1) Estrogen:
Growth of
duct system
Deposition of
adipose tissue

Duct system
Interlobular ducts

Adipose tissue

2) Progesterone:
Devt of lobules

3) Prolactin:
Milk secretion

Openings of ducts
Lactiferous duct

4) Oxytocin:
Milk ejection

Lobule

Tubuloalveolar unit

Fertile period of MC
ovum remains viable after ovulation for ~24 hrs.
Thus sperm must be available soon after ovulation
for fertilization
few sperm can remain fertile in female reproductive
tract up to 5 days.
Thus for fertilization intercourse must occur btwn 4 &
5 days b4 ovulation up to few hrs after ovulation
Thus period of female fertility during each MC is of 45 days

Rhythm Method of Contraception:

1 of practiced method of contraception is to
avoid intercourse near time of ovulation
If MC is regular (28 days) ovulation occurs
w/in 1 day of 14th day of MC
Thus avoiding these days a couple can plan
the family.
On other hand its good for female in need of
fertilization & pregnancy.

Hormonal Suppression of Ovulation- Pill:

Admin of low dose estrogen or progesterone in

appropriate quantity in 1st half of MC inhibits ovulation
due to prevention of preovulatory surge of LH
secretion (essential for ovulation)
Appropriate combos of estrogen & progesterone as
pills suppress ovulation & used as contraception
method
Progesterone can also be used alone, but not
estrogen Avoid using estrogen alone as
contraceptive b/c causes risk of cancer

Introduction to Physiology
Homeostasis: maintenance of steady state of internal env of body
Internal env of body is ECF
All organ systems of human body
func to achieve homeostasis
Homeostasis depends on funcing of
# of biological control systems
Control system: group of organs
that works together
to keep variable at its normal value in
ECF
Exs:
Temp control system
BP control system
Blood glucose control system
Blood pH control system
ECF volume control system
Theres control systems to
regulate practically every

Internal
environment

Human Body

Basic components of typical biological control system

Sensor: detects difference btwn physioal variable & its

set point value
Afferent pathway: pathway that carries info to center
Integrating center: receives info, decides how to deal
w/situation & directs effectors
Efferent pathway: pathway that carries info from
center to effector organs
Effectors: func to bring variable back to set point
value

Components of temp control system as ex IN COLD ENV!

Normal body temperature: 37 C / 98.6F (set point value)

Stimulus: exposure to cold
Danger: Body temp starts falling
Sensor: Thermoreceptors in skin (Cold receptors)
Afferent pathway: somatic ns in skin
Integrating center: Hypothalamus
Efferent pathway: ns to skeletal ms & blood vessels
Effectors: skeletal ms & blood vessels in skin
Response:
Shivering (generates heat)
Vasoconstriction of skin vessels (reduces heat loss)
What is achieved: body temp is maintained at set point value

Temp control system RESP when exposed to HOT

ENV

Normal body temperature: 37 C / 98.6F (set point value)

Stimulus: Exposure to hot temperature
Danger: Body starts gaining temperature
Sensor: Thermoreceptors in skin (warmth receptors)
Afferent pathway: Somatic nerves in the skin
Integrating center: Hypothalamus
Efferent pathway: ns supplying sweat glands & blood vessels
Effectors: Sweat glands & Blood vessels in skin
Response:
Sweating (helps heat loss)
Vasodilatation of skin vessels (brings hot blood to body surface & helps
heat loss to atmosphere)
What is achieved: body temp is maintained at set point value

Functional morphology of a CELL

Terms associated with cell-to-cell

communication
6 different ways of cell-to-cell comm:
Gap junction communication
Paracrine communication
Autocrine communication
Endocrine communication
Neuronal communication
Juxtacrine communication

6 types of cell-to-cell comm.

Cell 1

1) Gap junctions communication:

allow molecules to move btwn cells via
Connexons
Substances (molecular weight <1000
Cell 2
daltons) can pass thru these gap juncs
propagate electrical signals
in neuron, cardiac & smooth ms

2) Paracrine communication: molecules

Target
cell

from 1 cell act on another cell close by eg:

Enterochromaffine-like cells (ECL) of
stomach secretes a substance called
Histamine that acts on neighboring
parietal cell & causes it to secrete HCl

Terms associated with cell-to-cell

communication.
3) Autocrine communication: molecules
act on same cell that secreted it

4) Endocrine comm: hormones secreted into blood

stream & act on distant target cells

Blood
stream

6 types of cell-to-cell comm.

5) Neuronal comm: seen at Neuromuscular junc
Neurotransmitter

Neuron

Neuron, m or
gland

6) Juxtacrine communication:
Cell A

Cell B

mechanism of growth control & intercellular

comm involving specific cell-to-cell contacts;
established by interaxn of memb-bound forms
of growth factors, & cytokines normally
secreted, w/receptors on adj cell.
Eg: Immune cells in body (WBCs)

Structure of cell membrane

Membrane is lipid bilayer w/proteins at places
Hydrophilic heads
(lipophobic part)

Hydrophobic tails
(lipophilic part)

Peripheral protein

Integral protein

Cell memb model referred to as Fluid

mosaic model
Extracellular fluid

Lipid
bilayer

Peripheral protein

Integral proteins
Intracellular fluid

Lipid soluble substances dissolve in hydrophobic lipid bilayer & thus can cross cell memb (Exs: O2, CO2,
steroid hormones)

Water soluble substances cannot dissolve in lipid bilayer but can cross cell memb thru water-filled
channels or pores, or may be transported by carrier proteins (Egs: Na+, Cl -, Glucose, H2O)
B) Proteins:

2 types - Integral & Peripheral proteins

Funcs of memb proteins: act as Transporters, channels, receptors, enzymes, antigens

i)
Integral /Intrinsic /Transmemb proteins: Eg: Ion channels, Transport proteins; span entire cell memb or
are embedded in memb
ii) Peripheral/Extrinsic Proteins: Exs: Ankyrin, anchors cytoskeleton of RBCs to integral memb protein, Cl- HCO3 exchanger; these are not embedded & are located on 1 side of cell memb, either IC or EC side

Integral Proteins

Transport across cell memb:

Substances may be transported across cell membs in

these 3 ways:
A) Passive transport (downhill transport): Transport of
substance occurs along electrical, chemical or
pressure gradient; requires no energy (ATP)

2 types/exs: Simple diffusion, Facilitated diffusion

B) Active Transport (uphill transport): transport occurs
against gradient; requires energy as ATP

2 types/exs: Primary & Secondary active transport

C) Carrier- mediated transport: requires carrier protein
Exs: - Facilitated diffusion,
- Primary & Secondary active transport

Carrier - mediated transport

Include Facilitated diffusion, Primary & Secondary active transport
All forms of carrier-mediated transport have 3 common features:
a) Chemical specificity; b) Competition; c) Saturation
a) Stereospecificity (Chemical specificity): binding sites for solute on
transport proteins are stereospecific
) Ex: transporter for glucose in renal proximal tubule is specific for Dglucose & cannot transport its isomer L- glucose
b) Competition: Although binding sites for transport solutes are quite specific,
they may recognize, bind & even transport chemally reld solutes. THUS,
structurally & chemally similar solutes compete for binding sites on
carrier molecules
) Ex: D-glucose transporter recognizes & transport closely reld sugar Dgalactose (Galactose is competitive inhibitor of Glucose transport in small
intestine)
C) Saturation: carrier proteins have lmtd # of binding sites for solute
) At [low solute]s, many binding sites are available & rate of transport
increases rapidly w/increasing concentrations
) After sometime, binding sites become limited & at [high solute]s, rate of
transport reaches plateau, as all binding sites are saturated (occupied)
) This point of saturation is called Transport Maximum (T ) = plateau phase

Transport Maximum (Tm): max rate

at which substance can be
reabsorbed
plateau

Transport maximum (Tm)

Clinical application of concept of Transport max (Tm)

Normally, all filtered glucose is reabsorbed by glucose transporters in proximal

tubule, w/none remaining in lumen to be passed on to loop of Henle. Thus
glucose is absent in urine normally
Any increase in filtered load above Tm, that represents pathological situation
(ie. Diabetes Mellitus where blood glucose is elevated due to absent Insulin),
results in glucose being passed on to loop of Henle & spilling out in urine
(Glycosuria)

If filtered load of glucose abnormally high, upper limit for reabsorption,

tubular max (Tm) for glucose is reached. It is 350 mg/dL
Insulin admin in DM, increases utilization of Glucose, decreasing blood glucose
lvls & thereby reducing filtered load of glucose much lower than Tm. All
glucose gets absorbed & glucose is absent in urine

Clinical application of the concept of

Transport maximum (Tm)

A patient comes to the Physician with history of

polyuria (excessive urination), polydipsia
(excessive thirst) & polyphagia (excessive
hunger)
Blood investigations revealed elevated blood
glucose lvls, Dipstick test revealed presence of
Glucose in urine
The Physician diagnosed this clinical condition
as Diabetes Mellitus & prescribed Insulin
On Insulin administration urine glucose
disappeared
a) Why is there normally absence of Glucose in
urine?
b) What is the basis of Glycosuria in this patient?
c) Why on administration of Insulin urine glucose
disappeared?

Types of Membrane transports

Simple diffusion
Facilitated diffusion
Primary active transport
Secondary active transport
Vesicular transports
Osmosis

I) Simple diffusion

process of movement of substance (molecule) along (downhill) gradient)

Diffusion continues till concentration becomes equal on both sides
Rate of diffusion depends on:
- Concentration gradient
- Permeability of memb
- Surface area
Permeability of memb is:
Directly proportional to lipid solubility
Inversely proportional to size of molecule (MW)
Inversely proportional to memb thickness

Simple diffusion

In simple diffusion, rate of diffusion directly

proportional to concentration difference

Example for Simple diffusion

Lipid soluble substances, such as blood gases
or steroids, can diffuse directly thru lipid bilayer

Simple diffusion - red particles are

moving from area of [high]
to areas of [lower] till []s are equal on
both sides

II) Facilitated Diffusion:

Transport substance
along gradient w/help
of carrier protein in
memb
type of passive
transport
Rate of diffusion is
faster at [lower] due to
carrier protein
(facilitated by carrier
protein)
Rate of diffusion
reaches saturation at
[higher]s
follows all general
charac features of
carrier mediated
transport

Comparison btwn simple diffusion &

facilitated diffusion

Facilitated diffusion

Simple diffusion

Exs for facilitated diffusion

Intestinal epithelial cell

Intestinal lumen

Transport of Glucose
from intestinal
epithelial cells/ renal
tubules into blood
Transport of glucose into
skeletal m & adipose cells
by GLUT-4 transporter
Transport of fructose in
gut all way from lumen
Into blood

Blood

FD

FD

FD

FD

III) Primary active transport

Solutes transported from [lower to higher] (against/uphill gradient)

active process uses energy (ATP) directly to pump solutes
Carrier also has ATP splitting (ATPase) activity
follows all features of carrier mediated transport: saturation,
specificity, competition
Exs:
Sodium-potassium ATPase (Na+-K+ pump) in all cells create
[gradient] of Na+ & K+ thus maintaining low Na+ inside cell &
high K+ in cell to keep ve charge, cell volume & contribute to
ve RMP
Exs of inhibiting this pump: whenever lack ATP, like MI (arrythmias MCCOD
immediately after MI), hypoxia, ischemic stroke (reducing blood supply),
brain edema/swelling (Na+ attracting water)

Other exs of Primary active transport are..

b) Ca2+ ATPase ( Ca2+ Pump) present in cell memb, SR & ER
transports Calcium against electrochemal gradient
c) H+-K+ ATPase (Proton pump) in gastric parietal cells transports
H+ into lumen of stomach against its electrochemal gradient.
Acidifies gastric contents; inhibited by PPIs (Omeprazole blocks
Primary active transport)

dium-potassium ATPase (Na+-K+ pump)

electrogenic pump
blocked by cardiac glycoside,
digitalis
If Na+ - K+ ATPase blocker,
digitalis, is given, there
is depolarization inside cell
a) Na+-K+ ATPase (Na+-K+ pump) in cell memb transports Na+ from IC to ECF & K+ from EC to ICF against their
electrochemal gradients, thereby maintains low IC [Na+] & high IC [K+]
) pumps 3 Na+ ions out & 2 K+ ions in cell. More +ve charges pumped out than pumped in more vity inside cell
& >+vity outside & hence creates electrical potential difference across memb. Therefore termed Electrogenic pump
) In all cells of body!
) Cardiac Glycoside drugs Digitalis, Digoxin & Ouabain are specific inhibitors of Na+-K+ ATPase

Primary active transporter:

sodium-potassium pump (Na+-K+
ATPase) is ex of counter-transport in
which 2 kinds of particles are transported
at same time in opp directions by same
mechanism

IV) Secondary active transport

When solutes coupled w/sodium gets transported
against gradient
active, carrier mediated process
Sodium moves downhill gradient but provides
energy for moving solutes uphill
Energy used indirectly; not directly by carrier
Driving force for carrier is sodium [gradient],
created by primary active transport
If no sodium gradient, transport stops
Inhibiting Na+-K+ pump, stops this transport
carrier may transport 1 or + solutes
Ie. SGLT

Ex #1 for secondary active transport:

1. Glucose transport in gut:
Sodium-Glucose cotransport (SGLT):

Symport

Glucose movement into cell stops if

Na+-K+ pump is blocked

Ex #2 for secondary active transport:

2. Calcium transport out of heart m:
Sodium-calcium exchange:

Antipor
t

What happens if you administer Digitalis???

Hint: Digitalis is used to improve Myocardial contractility

General terms for type of transport using carrier

proteins

1. Uniport: Transport of single substance

2. Symport (cotransport): Transport of >1 substance in same
direction
3. Antiport (countertransport/exchange): transport of >1
substance in opp directions
These terms are applicable to all carrier mediated transports

Symporter /Cotransport
Symporter involves
more than 1 type of
particle being
transported by in
same direction at
same time by same
mechanism
Exs: i) Na+ -glucose
cotransport in small
intestine using carrier
SGLT-1
ii) Na+ AAs
cotransport

Secondary active transport

b) Counter transport/ Antiport/Exchange :
If solutes move in opp directions across
cell memb
Exs: Na+ - Ca2+ exchange & Na+ - H+
exchange

V) Vesicular transport

transport of macromolecules in & out of cell in form of

vesicles that fuse to memb
2 types:

Endocytosis: Movement into cell

Exocytosis: Movement out of cell

A) Endocytosis: movement of macromolecules (solids/ liquid)
from outside to inside of cell by active invagination of
plasma memb

for solids (bacteria/ dead tissue) is called Phagocytosis (cell

eating)

Another ex is Receptor mediated endocytosis by forming

Clathrin coated vesicles thru which viruses, toxins,
hormones & Growth factors enter cells

Endocytosis is energy dependent, active process

4 Steps of Endocytosis:
Outside of the cell

Inside of cell (cytoplasm)

Step 1. Cell memb invaginates making pocket
containing macromolecules

Step 2. Pocket begins to pinch off

Step 3. Memb closes around material to form

vesicle

Step 4. Vesicle separates from cell memb,

carrying material into cell cytoplasm

B) Exocytosis
Exocytosis: macromolecules are packed in secretory vesicles &
then extruded from cell; requires calcium & energy
Ex: release of water-soluble hormones packed in secretory vesicles by
exocytosis
Inside of the cell
Outside of the cell
Step 1. Vesicle moves twds cell memb

Step 2. Fuses w/memb

Step 3. Memb ruptures at fusion point

Step 4. Release of contents;

Vesicle memb becomes pt of cell memb

Steps of
Exocytosis

VI) Osmosis:

Osmosis: movement of water across cell memb from region of [higher water] to region of [lower water] OR
selectively permeable memb due to [difference] of solutes

[water] of soln is determined by [solute]

[difference] of impermeable solutes creates osmotic pressure making water able to move

Water continues to move until [solutes] become equal on both sides

Exs:

water movement from intestinal lumen to blood when solutes move in same direction;

water movement from tubular fluid of kidney to blood when solutes move in same direction
Osmotic pressure of soln depends on:
1. [impermeable solutes] in ECF
2. memb permeability to solutes

Greater concentration of solutes = greater osmotic pressure

Ex: Greater albumin in plasma = greater osmotic pressure at capillary aka Colloid Oncotic pressure

If solute is less permeable, greater will be osmotic pressure exerted by that solute
Exs: (1) ***Sodium exerts greater osmotic pressure across cell memb;
(2) urea exerts no osmotic pressure at all as its a rapidly penetrating solute;
(3) Glycerol is slowly penetrating/permeable solute, takes longer to get into ECF compartment; initially can
increase osmotic pressure, later on when [ ] on both sides become equal, contributes no osmotic pressure
(4) Hypernitremia: high sodium (>145 mEq/L), water from ICF to ECF (thus this, ISF & plasma volume goes up),
cell shrinks; when taking too much sodium
(5) Hyponitremia: low sodium, water from ECF to ICF, cell swells
(5) Type 2 DM: leading to hyperosmolarity , hyperglycemia, pt can slip into coma
(6) Type 1 DM: diabetic ketoacidosis

Osmolarity of a solution

Osmolarity: [ ] of osmotically active solutes in soln in milliosmoles/L

(mOsm/L); determines movement of water across cell memb, esp that of
Na+
mOsm (miliosmolar) or mOsm/L = [index] of particle per L of soln or per
kg H2O
Mm (millimolar) or mM/L = [index] of molecules dissolved per L of soln;
calculated as:
Osmolarity (mOsm/L) = C x g

Where, C = Concentration of solute in mM/L;

g = # of particles of solute in soln
g for sodium chloride in soln is 2 (NaCl)
g for glucose in solution is 1
g for calcium chloride in solution is 3 (CaCl 2)

Isotonic solns = 300 mOsm = 150 mM Nacl (1 Nacl molecule yields 2

particles in soln) (normally 135-145 mEq/L in ECF outside cell)
300 mOsm = 300 mM glucose OR 150 mm Glucose = 150 mOsm of
glucose b/c it doesnt split into particles
300 mOsm/L is rounded off from true value of 280-295 mOsm/L

1 mm NaCl = 2 mOsm of NaCl

Comparison of Osmolarity of solns

Isosmotic soln: 2 solns have same calculated
osmolarity
Ex: 300 mOsm/L each of glucose & sodium chloride are
isosmotic solns
Hyperosmotic soln: soln w/higher osmolarity than
that of other soln compared
Hyposmotic soln: soln w/lower osmolarity than that
of other soln compared
Exs:
300 mOsm/L solution of NaCl is hyperosmotic to 200
mOsm/L of glucose soln
Glucose soln is hyposmotic to NaCl
Normal osmolarity of both ICF & ECF is ~300 mOsm/L

Problem
Are 15 mmol/L solution of sodium chloride and 10
mmol/L solution of calcium chloride isosmotic
with each other?
Consider g for sodium chloride=2 mOsm/mmol
and
g for calcium chloride =3 mOsm/mmol.
Solution:
Osmolarity of a solution = C x g (mOsm/L)
Osmolarity of sodium chloride solution = 15 x 2 =
30 mOsm/L
Osmolarity of calcium chloride solution = 10 x 3
= 30 mOsm/L
Since calculated osmolarity of both solutions are
same, they are Isosmotic

Can u tell.
What happens if u suspend RBCs in
Isotonic saline, Hypotonic saline &
Hypertonic saline?
In Isotonic saline, No osmosis occurs, no
change in size & shape of RBCs
In Hypotonic saline, water enters RBCs
known as (enter=end) Endosmosis. RBCs
get bulged & swollen & may rupture
In Hypertonic saline, water leaves RBCs
known as (Exit=ex) Exosmosis. RBCs
shrink & get crenated

Application of osmosis in clinical practice:

Isotonic NaCl soln (isotonic
saline) is used for intravenous
rehydration or for admin of
meds.
Its given to pts b/c it doesnt
cause any changes in cell
volume

RBCs are suspended in hypotonic saline

are bulged

thing can occur for all cells in body if a

motic solution is infused intravenously
F)

Hypertonic saline RBCs are crenated

Normal biconcave RBC

RBC in Hypotonic; loses

biconcave

RBC crenated in
hypertonic soln

What happens if RBC is suspended in a beaker

containing :

1) 200 mOsm NaCl =

2) 200 mOsm of Nacl & 200 mOsm of Urea
3) 200 mOsm of NaCl & 200 mOsm of
Glycerol
Answers:
1) Cell will swell
2) Cell will swell b/c urea doesnt
contribute to osmotic pressure
3) Initially cell will shrink, as initial
effective osmolarity of solution is 400
mOsm, then as Glycerol reaches

High yield facts

Biological control systems- Response to Cold & Hot temperatures

Cell membrane - Integral & Peripheral proteins, Fluid Mosaic model of cell membrane
Terms associated with Cell-to-cell communication
- Gap junction communication
- Paracrine communication
- Autocrine communication
- Endocrine communication
- Neuronal communication
- Juxtacrine communication
Carrier - mediated transport - characteristics
( Stereospecificity, competition, saturation- concept of Transport maximum Tm - Eg: Glucose)
Simple Diffusion - Characteristics
- Factors affecting
- Examples for simple diffusion
Facilitated Diffusion - characteristics & examples
Primary active transport - characteristics & examples
Secondary active transport - characteristics & examples
- Cotransport (Symport)
- Countertransport (Antiport / Exchange)
Vesicular transport - Endocytosis & Exocytosis
Osmosis
Osmolarity
Behavior of RBCs when suspended in Isotonic, Hypotonic & Hypertonic saline

Water content of human body

Water is largest single
component of body
makes 60% of body weight
A man weighing 70 Kg will
have 42 Liters of water
This is called total body
water (TBW)

991

Distribution of Body Fluids:

TBW is present in 2 major body fluid

compartments:
Intracellular fluid (ICF)
Extracellular fluid (ECF)
ICF makes 2/3rds of TBW (40%)
ECF makes 1/3rds of TBW (20%)
ICF & ECF separated by cell memb
Estimation of Fluid volumes &
osmolarity
In normally Hydrated subject,
above rules can be used to
estimate fluid volume &
distribution. If weight is expressed
in kgs, then:
TBW in Liters = 0.6 x weight (If wt
= 70 kg, then TBW = 42 L)
ICF = 0.4 X wt (70 Kg) = 32 L
ECF = 0.2 X wt (70 kg)= 16 L

2/
3

1/
3
992

Composition of ICF:
ICF is cytoplasm of cell
Major cations: Potassium,
Magnesium
Major anions: proteins,
Phosphates

993

ECF has subcompartments:

ECF consists of 2 major subdivisions:
1. Plasma: fluid portion of blood; ~1/4 of ECF
volume
2. Interstitial fluid: ~3/4 of ECF volume
. Fluid in spaces btwn cells in tissues/organs
. Plasma & interstitial fluid separated by
capillary endothelium

994

Composition of ECF
EC fluids have high
concentrations of
*Sodium, Chloride &
Bicarbonate ions
Plasma has large amt of
proteins compared to
ISF as theyre
impermeable thru
capillary memb

995

Summary of body water

distribution

60-40-20 Rule:
60% of body weight is water
40% of body weight is ICF
20% of body weight is ECF

Values are for

adult man of
70 Kg

(42 Liters)

(28 L)

(14 L)

(10.5 L)

(3.5 L)996

Blood volume Vs Plasma Volume

Blood volume = plasma volume + volume of RBCs
(~50/50)
Hematocrit (Hct) = fractional concentration of RBCs
Calculation of blood volume:
Blood volume= plasma volume
1-Hct
Example: Hct=50% (0.50)
Plasma volume= 3L
Blood volume= 3Lts = 6 Lts
1-0.50
997

Measuring volume of body fluid compartments:

volumes of body fluid compartments measured by Dilution method in following steps:
1. ID of appropriate marker substance
a. Marker for TBW substances (lipid soluble) distributed wherever water is found. Eg: Isotopic
water (D20) or Titrated water & antipyrine**** get into plasma then ISF then ICF
b. Markers for ECF substances that distribute thru out ECF but dont cross cell membs. Eg:
Mannitol & Inulin; thus only get into ISF & plasma
c. Markers for Plasma (aka only vascular compartment): substances that distribute in plasma but
not in ISF. Eg: Radioactive albumin & evans blue
2. known amt of marker injected into blood (in mg, mmol or millicuries (mCi))
3. Equilibriation & measurement of plasma concentration.
- marker allowed to distribute (equilibrate) in body fluids,
- correction made for any urinary losses during equilibration period
- concentration of marker is measured in plasma (& urine if present)
4. Calculation of volume of body fluid compartment
Use formula:

Amount of marker Amount of marker

injected (mg)
- 998excreted (mg)
Volume of compartment =
(mL)
Concentration of the marker (mg/mL)

Problem:
A 20-year-old college student volunteered for plasma volume
estimation (ie. Radioactive albumin or Evans blue). He was
injected 150 mg of a marker which remained in only plasma. The
concentration of the marker after equilibration was found to be
0.05 mg/mL. Find out plasma volume of the student.

Soln:
Amount of the marker injected amount Excreted

Plasma volume =
Concentration of marker at equilibration

= 150/0.05 = 3000 mL
999

Directly measured fluid volumes

Total Body Water:
Marker: D2O (duterium
oxide) or tritiated water,
anti-pyrine
ECF volume:
Marker: Inulin, Mannitol
Plasma volume:
Marker: Radioactive
albumin, Evans blue
above markers get
distributed only in above
respective compartments
1000

Indirectly measured fluid volumes:

Since theres no markers that exclusively get distributed in
these compartments, their volumes cannot be measured
directly
Their volumes are calculated from measurements of directly
measured fluid volumes
fluid volumes indirectly measured are:
a. Intracellular fluid volume (ICF) thus any markers of ECF &
TBW will be indirectly used to measure ICF
b. Interstitial fluid volume (ISF) thus any markers of ECF &
Plasma will be indirectly used to measure ISF
ICF volume is calculated by 1st measuring TBW & ECF
volumes, and by using relationship:
ICF = TBW ECF
ISF volume is calculated by 1st measuring ECF & plasma
volumes, & by using relnship:
ISF volume = ECF Plasma volume
1001

Tonicity of solutions:
Tonicity of solns: measure of ability of soln to cause change in
cell shape by promoting osmotic flow
Isotonic soln soln does not change volume of body cells
Hypertonic soln soln causes body cells to shrink
Hypotonic soln soln causes body cells to swell
It is comparison of osmolarity of soln w/that of body fluids
Osmolarity of all body fluids is same in steady state &
close to 300 mOsm/L***

1002

Osmolarity
Osmolarity: concentration of osmotically active particles,
expressed as mOsm/L; in practice, same as osmolality
(mOsm/kgH20)
Plasma osmolarity rflx osmolarity of ECF as well as ICF
Sodium chloride being major constituent of plasma, represents
impermeable particles of ECF & contributes max to plasma
osmolarity
[Na+] represents most of effective osmolarity of this
compartment
Twice the Na+ concentration in ECF is good index of plasma
osmolarity (Na = 135-145 mEq/L)
Posmolarity = 2 x plasma sodium concentration + 10
= 2 x 145 = 290 mOsm/L + 10 = 300 mOsm/L of ECF
1003

Accurate estimation of plasma osmolarity (POsm):

Apart from Na+, concentration of glucose & blood urea nitrogen
(BUN) are to be considered
P osm = 2([Na+] in ECF) + ([glucose in mg/dl] in ECF / 18) +
((BUN in mg/dl) / 2.8)
divisors for glucose & urea are conversions from mg/dl to
mOsm/L
This estimation of plasma osmolarity esp useful in pts
w/plasma glucose or BUN increased sigly
Ex: Pt w/uncontrolled diabetes mellitus have high blood glucose
Ex: Pt w/chronic renal failure have high BUN (body cant
excrete urea)

1004

Steady state:
In steady state, ICF osmolarity is equal to ECF osmolarity
(osmolarity is same thru out body fluids)
To maintain this equality, water shifts freely across cell memb
If any disturbance causes change to ECF osmolarity, water
will shift across cell membs to make ICF osmolarity equal to
new ECF osmolarity
After shift of water, new steady state will be achieved

***Disturbances in body fluid volumes

Body fluids may change in 2 major ways:

A. Volume expansion increase in ECF volume
B. Volume contraction decrease in ECF volume

In both conditions body fluid volumes alter only in ECF or in

both ECF & ICF

Volume changes also depend on osmolarity changes in ECF

Osmolarity (mOsm/L)

Normal & disturbances of body fluid volumes may be interpreted by

Darrow-Yannet diagrams:

ICF

ECF

Volume (Liters)

Darrow Yannet diagram

3 principles of volume & osmolarity

changes:
1.
Any changes in volume will 1st
affect ECF volume which may or
may not alter ICF volume
2.
change in ICF volume occurs only
by changes in ECF osmolarity!*
3.
At equilibrium (steady state), ICF &
ECF osmolarity will be same

Disturbances of body fluids:

A. Volume expansion: 3 ways
in which volume of ECF increases:
. A1. Isosmotic volume expansion
(same amt of sodium & water)
. A2. Hyperosmotic volume
expansion (more sodium in ECF
&/or less TBW)
. A3. Hyposmotic volume
expansion (less TB Na+ &/or

A1. Isosmotic volume expansion

addition of isosmotic fluid into ECF
Exs: Infusion of isotonic NaCl
soln/saline, gain of isotonic fluid
increase in ECF volume ONLY w/out
any change in volume of ICF b/c no
change in osmolarity of ECF & ICF
No shift of water btwn ECF & ICF
At new steady state: increase in
volume of ECF w/no change in
volume of ICF; no change in
osmolarity of both
Darrow-Yannet diagram
Continuous line: Before
Dotted line: After adding fluid

1007

A2. Hyperosmotic volume expansion

rise in ECF osmolarity initiated
disturbance
Exs: administering hypertonic fluids
ingesting dry NaCl (Eating lots of
chips), infusion of hypertonic fluids,
excess aldosterone (increases
absorption of sodium into ECF more
than water, along w/excreting
potassium in kidneys; produced in
adrenal cortex (zona glomerulosa
tumor aka Conns syndrome))
Conns syndrome:
hyperaldosteronism, pdf pg.13
physiology block I
Increase in ECF osmolarity causes shift
of water from ICF to ECF
At new steady state: ICF volume &
increased ECF volume; in osmolarity
of both

Osmolarity

H2O

Darrow-Yannet diagram
Continuous line: Before
Dotted line: After adding
fluid
1008

fall in ECF osmolarity initiated

disturbance
Via infusion of hypotonic fluids, exs:
High ADH (aka SIADH where you see
Hyponatremia Na+ reabsorption
inhibited by ANP), half normal saline,
Polydipsia, small oat cell carcinoma,
congestive <3 failure, liver cirrhosis &
nephrotic syndrome decreased
blood volume & pitting edema in
all these conditions
Decreased ECF osmolarity causes shift
of water from ECF to ICF
By increasing # of aquaporins on
luminal memb
Baroreceptors detect this & signal
aldosterone secretion
At new steady state: increased
volumes of both ECF & ICF; decreased
osmolarity of both

Osmolarity

A3. Hyposmotic volume expansion:

H2O

Darrow-Yannet diagram
Continuous line: Before
Dotted line: After adding
fluid
1009

Disturbances of body fluids:

. Volume contraction:

volume of ECF decreases

3 ways it can happen:
1. Isosmotic volume contraction
2. Hyperosmotic volume contraction
3. Hyposmotic volume contraction

1010

B1. Isosmotic volume contraction:

(loss of ECF volume)
loss of isosmotic fluid from ECF
Exs: Diarrhea, Burns, hemorrhage,
severe vomiting (loss of isotonic
fluid)
decrease in ECF volume w/out
any change in ICF volume
no change in osmolarity of ECF &
ICF
No shift of water btwn ECF & ICF
At new steady state: decreased
ECF volume ONLY w/no change in
volume of ICF; no change in
osmolarity of both

Darrow-Yannet diagram
Continuous line: Before
Dotted line: After loss
of fluid
1011

 rise in ECF osmolarity initiated

disturbance
loss of hypotonic fluid, exs:
water deprivation, excessive
sweating, fever, diabetes
insipidus due to lack of ADH,
drinking alcohol, increase in
ECF osmolarity causes shift of
water from ICF to ECF
[Sodium] or TBW (losing
hypotonic fluid)
At new steady state:
volumes of both ECF & ICF;
osmolarity of both

Osmolarity

B2. Hyperosmotic volume

contraction: (loss of hypotonic fluid)

1.

2.

H2O

Darrow-Yannet diagram
Continuous line: Before
Dotted line: After loss
of fluid

 fall in ECF osmolarity initiated

disturbance
Loss of hypertonic fluid
Exs: Diuretics (MCC), Addisons
disease (antibodies produced
against all 3 layers of adrenal
cortex, low BP, low sodium,
hypernitremia), Aldosterone
deficiency
ECF osmolarity causes shift of
water from ECF to ICF
At new steady state: ICF volume
& ECF volume; osmolarity of
both

Osmolarity

B3. Hyposmotic volume contraction

(Hypertonic fluid loss)

H2O

Darrow-Yannet diagram
Continuous line: Before
Dotted line: After loss
of fluid

1013

Summary of changes in Volume & body Osmolarity

following changes in body hydration

1014

Case
Donald Finn is a 65 y/o man
was dxd w/Oat cell carcinoma
of lung.

osmotic volume expansion

tx: demacocyline

How will you approach this case???

Investigations
Lab findings
What type of fluid disturbance based on Darrow
Yannet diagram will you see in this patient?
Water intoxication?
1015

Excitable tissues via 4

potentials:

Diffusion potential:
Resting membrane potential: cell at
resting state; not excited
Equilibrium potential: no net ionic
movement regardless of open channels
Axn potential: depolarization,
repolarization & RMP of cell; impulse
generated to convey signal thru neurons
& ms
VG Na+ K+ channels involved in1016
axn

Ion Channels

Ion channels: integral proteins that permit passage of certain ions in memb; selective (allows
only ions w/specific characs to move thru them)
Selectivity based on both size of channel & charges lining it
3 types:
A. Ungated channels: b/c have no gates always open for specific ion, ex: Ungated Potassium
channels (all cells possess); always efflux of K+ thru these channels unless K+ at equilibrium
B. VG channels: channels sensitive to memb voltage; gates open & /or close in resp to memb
voltage change; exs:
1. Voltage gated sodium channels: in excitable cells; closed under resting conditions, but
memb depolarization (aka change in memb potential) cause them to quickly open & quickly
close
2. Voltage gated potassium channels: efflux of K+ until memb reaches equilibrium
3. Voltage gated calcium channels: depolarization signal (aka axn potential) causes them
to open
C. Ligand gated channels: includes receptor to specific substrate or ligand (Hormones, NTs);
channels open & close when ligand binds to them
. Ex: Nm receptor (Nicotinic Ach receptor) protein on motor end plate, which opens when ACh
binds to receptor; ACh gated channel in post synaptic memb @NMJ; axn potential or end plate
potential
. When open, channel is permeable to Na+ & K+ ions (K+ ICF ECF hence efflux)

Ligand - gated Channel

1018

Membrane conductance
Memb conductance: # channels open in memb;
similar to memb permeability
Ex:
Na+ conductance is proportional to # of open channels
thatll allow Na+ to pass thru memb
Doesnt indicate if therell be net diffusion of ions thru
channels
If conductance is increasing/higher, channels are
opening
If conductance is decreasing/lower, channels are closing
rate at which ions move across memb depends on # of
channels open & net force
When ions flow thru channels (carrying charges), cells memb
potential (MP) changes. However, too few ions flow to produce
sig efx on ions [ ] difference ( aka [ ] gradient) 1019
across cell

Diffusion potential
: potential generated when charged ions diffuse along
[gradient]

10

10

2 requirements:
1. Concentration gradient
2. Selective permeability of
membrane

1020

Sign of diffusion potential

depends on
charge on ion that diffuses

When memb is permeable only to chloride,

interior of cell becomes +ve
More ve cell = hyperpolarization
More +ve cell = depolarization

1021

Net Force = [ ] force +/- electrical force:

net force on ion across memb is sum of 2 independent forces:
1. Concentration force: determined by [ ] difference across memb; greater [ ]
difference = greater [ ] force
2. Electrical force: determined by electrical difference across memb (in mV)
in vivo (inside body) magnitude determined by MP (Em), (value measured or
given)
direction of force based on like charges repel & unlike charges attract. Ex: If MP
is -70 mV = force of 70 mV that attracts all +ve ions & repel all ve ions
Ie. Na+ direction out to in at RMP (-ve)
. 2 forces (concentration force & electrical force) represented by vectors (direction &
magnitude)
. If 2 vectors act in same direction, net force = sum of ind forces; ie. Na+ electrical
force out to in & chemal force out to in; means overall greater force of out to in
. If 2 vectors act in opp directions, net force = difference btwn 2 forces (but directed
along larger force)
. If 2 forces are equal & opp = no net force acting on ion (ion in state of equilibrium)
thus at equilibrium, 2 forces always equal & opp in direction
. Equilibrium Potential: diffusion potential of ion across memb at equilibrium (at
steady state); at equilibrium, electrical & chemal forces acting on ion are equal &
opp, net movement of ion = ZERO
ie;
Chemical force
= Electrical force
(concentration difference)
(Charge difference)
.

potential at this point calculated by Nernst equation & expressed as Eion

Nernst Equation:
??

used to calculate equilibrium potential for ion

at given [ ] difference across memb

E = Equilibrium potential
2.3RT = Constant (60mV at 37 C)
zF
Z = Charge of ion (+1 for Na+; +2 for
Ca2+ ; -1 for cl- )
Ci = IC concentration
Co = EC concentration
1023

Examples of equilibrium potentials:

Sodium equilibrium potential (ENa+)
ECF
ICF

Na+
(14 mEq/L)

+
+
+
+
+
+
+
+
+
+
+

Na+
(140 mEq/L)
Chemical Force
Electrical Force

ENa+ = + 65 mV
Cell inside positive
1024

Why???

Examples of equilibrium potentials:

Potassium equilibrium potential (EK+)
ECF
ICF

K+
(120 mEq/L) -

+
+
+
+
+
+
+
+
+
+
+

Chemical Force
Electrical Force
K+
(4 mEq/L)

EK+ = - 85 mV
Cell inside negative

1025

Problem:
What would be the sign of equilibrium
potential for chloride?
What are the directions of chemical and
electrical forces?
Given: Cl- in ECF = 105 mEq/L
Cl- in ICF = 10 mEq/L
Answer: ECl- is negative interior
Chemical force: inward directed
Electrical force: outward directed
1026

Magnitude of Equilibrium potential depends on ions [gradient]

When you open channels for any given ion, memb potential will
move in direction of that ions equilibrium potential!
Consider following exs of potassium: RMP closer to -85 mV of K+
as cell always more permeable to K+ vs any other ion
ECF

- +
- +
- + Chemical Force(C)
K+ + Electrical Force(E)
(120 mEq/L)
- +
- +
K+
- + (4 mEq/L)
- +
- +
ICF

EK+ = - 85 mV
Chemical gradient
= 120 - 4 = 116

ECF

- +

K+

- +

(120 mEq/L)
-

C
E

- + K+

(40 mEq/L)

ICF

- +

EK+ = - 8.5 mV
Chemical gradient
= 120 - 40 = 80
1027

RMP (Resting Membrane Potential):

RMP: potential difference that exists across cell memb at rest in

millivolts (mV); in all cells when not excited; imp for excitable cells
such as n & ms
Value in excitable cells : -70 to -90 mV
RMP of -70 mV means 70 mV, cell interior ve
+++++++++++++++++++
___________________
ICF

Polarity of excitable cells is:

interior negative
exterior positive

___________________
+++++++++++++++++++
ECF

3 factors contribute to genesis of RMP (1st 2 factors most imp):

1. High permeability for potassium ions at rest
2. [difference] of potassium btwn ECF & ICF
3. Sodium-potassium pump maintains [gradient] for K+ across cell memb
. potassium diffusion potential responsible for major pt of RMP
. RMP very close to equilibrium potential for potassium ions
. [Potassium] inside is 140 mEq/L & outside in 3.5-5 mEq/L (thus high inside, low
outside)

At RMP.
ECF
ICF

Na+
(14 mEq/L)

Na+
(140 mEq/L)
Chemical Force
Electrical Force

- 70 mV

Electrical gradient is directed inwards as

RMP is ve & it attracts +ve Na+ ions
1029

At RMP.
ECF
ICF

K+
(120 mEq/L)
- 70 mV

Chemical Force
Electrical Force
K+
(4 mEq/L)

Electrical gradient is directed

inwards as ve RMP attracts
+ve K+ ions

Comment on Cl- & Ca2+

1030

Resting Membrane Potential

1031

Efx of changes in ECF Potassium on

RMP
Hyperkalemia (increase in ECF K ): chemal gradient & RMP
+

magnitude decrease
RMP becomes less ve or more +ve aka depolarization
When K+ ECF/plasma >5.5
Ie. In kidney failure (cannot absorb K +; other K+ will remain inside
cell cells RMP will depolarize AP can die of arrythmia, even
b4 developing seizures)
Can result in m weakness & m paralysis
Hypokalemia (decrease in ECF K+): chemical gradient & RMP
magnitude increase
RMP becomes more ve or less +ve aka hyperpolarization (cells
get inhibited)
When K+ ECF/plasma <3.5
Both dangerous b/c such membs cannot generate AP (excitation)
Ie. When ms dont receive AP cannot contract m paralysis!
Both can cause this !!!

1032

Problem 1:
If potassium concentration of the fluid bathing the axon is
decreased at arrow, which labeled line best represents the
membrane potential?

Potassium is most
imp ion for RMP;
changing ECF potassium
alters RMP
-70 mV
Anything below RMP =
hyperpolarization; hypokalemia

Answer: E
1033

Problem 2:
The resting membrane potential of an alpha motor neuron
axon is measured. At the arrow, a Na+ channel blocker is
injected into axon.
Which of the labeled lines best represents the result?

-70 mV

Answer: D

Sodium does not

contribute to RMP
1034

Axn Potential (AP) or Impulse:

AP: phenomenon of rapid depolarization followed by
repolarization of memb potential; unique feature of
excitable cells
Excitation = production of AP
basic mechanism of transmission of info (comm) in NS
essential for contraction of skeletal & cardiac ms
To generate AP, memb potential must be taken to
threshold potential

1035

Phases of a nerve AP!

Due to opening of Na+ channels

b. Depolarization
phase (upstroke)
+35

Membrane potential (mV)

Overshoot potential
Due to opening of K+ channels

c. Repolarization phase
Na+

K+
Due to opening of ligand-gated Na+ channels

d. Hyperpolarizing (downstroke)
afterpotential (undershoot)
- 70

a. RMP

Time (msec)

1036

3 phases in ionic basis of AP:

A) Depolarization phase (Upstroke) of AP:
due to flow of +ve charges into cell (influx)
Rapid opening of voltage gated Na+
channels (only 1-2 ms)
Memb permeability high for Na+, even more
than for K+ at rest
Inward Na+ current due to electrochemal
gradient in inward direction
Memb potential goes twds ENa+ but not
equal to it
Net result = reversal of polarity of cell (+ve
inside & -ve outside)
B) Repolarization phase of AP: due to 2
events:
1. Closure of voltage gated Na+ channels &
hence stoppage of inward Na+ current
2. Opening voltage gated K+ channels &
increasing permeability of K+, even more
than at rest
. K+ moves out of cell (efflux)
. Outward K+ current is again along
electrochemal gradient
. Voltage gated K+ channels open at +ve

Most Na+ channels

open around late
depolarization
More Na+ coming in

1037

C) Hyperpolarizing afterpotential (Undershoot): for brief period after

repolarization, K+ conductance higher than at rest; memb potential driven
closer to K+ E potential ie; -85mV (Hyperpolarizing Afterpotential)
This occurs b/c voltage gated K+ channels close slower than voltage gated Na+
channels
Eventually, K+ conductance returns to resting lvls & potential comes back to
RMP
Memb now ready to generate another AP
Charac features of voltage gated Na+ channels
Voltage gated Na+ channels have activation/outer gate & inactivation/inner
gate
When memb interior is ve (at rest): outer gate closed; inner gate open
When memb interior is +ve (depolarization): outer gate open; inner gate
closed (w/delay)
activation gate

ECF

ICF

--

--

++

++

inactivation gate
1038

Voltage gated
Sodium channels

During
REPOLARIZATION

At REST

During
DEPOLARIZATION
1039

Ionic basis of Action Potential.

1040

Graph showing time course of voltage & conductance

hanges during n AP
+65 mV

Membrane voltage/Conductance

Action potential

Inward sodium current

(Sodium conductance)
Outward potassium current
(Potassium conductance)
RMP

Time (msec)

1041

Properties of AP:
All-or-none Resp: weak stimulus WONT produce AP
since memb potential WONT reach threshold (None)
Once threshold reached, AP produced is always of
same size, irrespective of strength of stimulus (All)

No
action
potential

Weak
stimulus

action
potential

Threshold
stimulus

action
potential

Stronger
stimulus

action
potential

Strongest
stimulus
1042

Refractory Period
Refractory Period: during which 2nd AP cannot be
elicited w/threshold stimulus
2 pts of Refractory period:
i) ARP (Absolute Refractory Period): time when another
AP cannot be elicited, no matter how strong stimulus
is; b/c closure/inactivation (inner) gates of Na+
channel
ii) RRP (Relative Refractory Period): begins at end of
Absolute Refractory period & continues until memb
potential returns to resting lvls; time when 2nd AP can
be elicited by stimulus stronger than threshold; due to
stronger inward Na+ current required to reach
threshold from hyperpolarized state of RMP

Propagation of AP in myelinated axon:

Myelin sheath insulates axons. No ions can move in/out
thru it.
Ions can move only at nodes of Ranvier
Saltatory conduction: makes conduction faster; AP
occurs only at nodes & jumps from 1 node to another

1044

Velocity of conduction in N fiber:

Conduction velocity (CV): speed of propagation of AP;
depends on 2 factors
1. Diameter of n fiber: faster conduction if fiber dm is
large
2. Myelination of n fiber: faster conduction if myelinated
fiber
Clinical aspect..
. MS (Multiple sclerosis): demyelinating disease of CNS
due to loss of myelin sheath around n fibers, impaired
conduction of AP interferes w/local current flow &
spread of depolarization no generation of APs &
defective transmission of impulses
. Clinical features: severe m weakness (cannot control
bladder), blurring of vision, diplopia, Nystagmus, optic
neuritis etc
1045

Consequence of damaged myelin in multiple sclerosis

1046

1047

How generation of AP can be

stopped/affected?

AP can be inhibited by 2 ways:

A) By blocking voltage-sensitive Na+ channels:
Lidocaine: blocks voltage-sensitive Na+ channels & prevent
occurrence of n APs; thus abolishes pain, as blocks transmission of
pain impulses; widely used as local anesthetic
TTX (Tetrodotoxin): (toxin from Japanese puffer fish) blocks these
voltage-sensitive Na+ channels & abolishes APs Net Force
B) By persistent depolarization of memb:
If memb potential at depolarized state for long period, inner gates of voltage
gated Na+ channels remain in close state
Ex: Occurs when plasma K+ is elevated (Hyperkalemia)
Efx of Serum K+ levels
Both Hyperkalemia & Hypokalemia result in m weakness & paralysis
Why?
Hyperkalemia causes persistent depolarization & inner gates of voltage
gated Na+ channels remain in close pos. No AP possible (neurons could
get seizures but pt usually dies of arrythmia b4 that)
Hypokalemia causes hyperpolarization & thus RMP becomes more ve.
Such memb becomes less excitable/unexcitable
Failure to produce AP in n &/or m leads to m weakness1048
or paralysis!

High yield facts..

Ion Channels - Voltage & Ligand gated, Examples for each

Diffusion Potential - Definition, factors affecting

Equilibrium Potential - Definition

Resting Membrane Potential - Definition, Ionic basis

Action Potential (AP) - Definition
Ionic basis of Action potential:
A) Depolarization
B) Repolarization
C) Hyperpolarizing afterpotential (Undershoot)
Characteristics of AP All or None Response
Refractory period - Absolute & Relative defns & physioal basis for them
Velocity of conduction, Multiple Sclerosis
Efx of Hyperkalemia & Hypokalemia on AP, Sodium-channel blockers
1049

Terms associated with chemical synapse

Presynaptic neuron

Postsynaptic neuron

Simplified representation of a synapse:

Chemical Synapses
Chemical synapses: specialized juncs thru which neurons
signal to each other & to non-neuronal cells such as those in
ms or glands; provide means thru which NS connects to &
controls other systems of body. Eg: Neuromuscular Junc (NMJ)
Ultrastructure of
chemical synapse
Presynaptic
terminal

Receptor site
Neurotransmitter

Postsynaptic
membrane
Synaptic
vesicles

Synaptic
cleft

4 steps of synaptic transmission:

Synaptic vesicle

1. Arrival of AP at presynaptic
terminal & depolarization
2. Calcium influx thru voltage gated
Ca+2 channels in presynaptic
neurons
3. NT release by exocytosis
4. Binding of NT w/specific receptors
on postsynaptic memb &
increasing permeability to certain
ions producing postsynaptic
potential (depolarizing or
hyperpolarization type)

Postsynaptic potential:
Excitatory postsynaptic potential (EPSP)

+ + +

+
Na+

Na+

EPSP: depolarizing potential w/Na+

influx thru Na+ ion channels in
postsynaptic memb
Memb potential driven to +ve potential
(depolarization)
If its able to reach threshold, AP is
produced in postsynaptic neuron
Such synapses are called Excitatory
synapses
Excitatory NTs: ACh, NE
(postganglionic neurons of symp
system), Aspartate, & Glutamate

Postsynaptic potential:
Inhibitory postsynaptic potential (IPSP)

- - -

Cl-

Cl-

IPSP: hyperpolarizing potential w/Clinflux thru Cl- ion channels in

postsynaptic memb
Memb potential driven to more ve than
at RMP (hyperpolarization)
Memb potential goes away from
threshold & postsynaptic neuron not
able to produce AP; such synapses are
called Inhibitory synapses
Inhibitory NTs: Glycine, GABA

5 Classifications of NTs:

1.
2.
3.
4.
5.

ACh (Acetylcholine): excitatory NT produced by motor neurons

(cholinergic) which synapse w/skeletal m
AAs: excitatory (Glutamate, Aspartate) & inhibitory (GABA, Glycine)
Biogenic amines: derivatives of AAs (ie. Tyrosine ): E, NE, DA, 5-HT
(made from tryptophan) & Histamine (from histidine)
Neuropeptides: AA chains ie. endorphins, Enkephalins, Oxytocin,
Vasopressin
Gas NT: Nitric Oxide (aka EDRF - Endothelial Derived Relaxing Factor)

Clinical Importance of Neurotransmission:

. Deficiency or excess of NTs lead to clinical disorders; Exs:
Alzheimers disease (Senile dementia): degeneration of ACh-neurons in
brain; w/loss of memory followed by loss of cognitive & other funcs
Parkinsons disease: degeneration of DA-neurons in basal ganglia; w/tremors
& rigidity; abnormal gait (walking)
Schizophrenia: hyperactivity of DA secreting neurons in brain; form of
psychosis characd by personality disorder

Neuromuscular transmission
NMJ (neuromuscular junc): synapse btwn axon terminal of motor neuron &
skeletal m fiber
() Motor neurons are ns that innervate m fibers; arise from spinal cord &
brainstem innervate skeletal ms by releasing ACh & thus are cholinergic
Motor unit = single motor neuron & m fibers it innervates
Skeletal ms dont have gap juncs, so every m fiber must be innervated by
motor n
Neuromuscular junction

Motor nerve

Motor unit
Motoneuron
pool
Muscle fiber

Motor Units
Small motor units: for fine motor activities. Eg; Facial
expressions
Large motor units: for gross muscular activities Eg;
Quadriceps used for running
Large Motor units

Small Motor units

Ultrastructure of NMJ:
Axon of motor neuron
Synaptic vesicles containing ACh
Presynaptic terminal
Postsynaptic m memb
containing nicotinic ACh
receptors

Motor end plate

Junctional folds: used
to increase SA;
increases # of ACh
receptors

Synaptic cleft

7 steps of Neuromuscular transmission:

1)
2)
3)

4)
5)

6)
7)

AP travels down motor neuron to presynaptic terminal

Depolarization of presynaptic terminal opens Ca2+ channels, & Ca2+ flows into terminal; ~150250 release their content into cleft
Ach released from their vesicles into synapse by Exocytosis
1) Note: Ach formed from Acetyl CoA & Choline by CAT (Choline acetyl transferase); ACh
stored in vesicles w/ATP
2) On stimulation, entire content of synaptic vesicle released into synaptic cleft & reaches
postsynaptic memb
ACh binds to its receptor (Nicotinic receptors) on motor end plate ;
1) Motor end plate: specialized region on postsynaptic memb w/Nicotinic receptors
Channels for Na+ & K+ opened in motor end plate. *Both Na+ & K+ try to drive motor end plate
twds its Equilibrium potential. But net force on Na+ is greater & Na+ influx dominates. Finally
depolarization seen at Motor End plate
1) This potential due to depolarization of Motor end plate called EPP (End Plate Potential)
2) single synaptic vesicle produces MEPP (small change in memb potential of motor end
plate (0.4mV)
3) MEPP (Miniature End Plate Potential); this summates & give rise to EPP
4) EPP: End plate potential; depolarization of motor end plate
EPP (motor end plate depolarization) causes depolarization of adj m fibers & this reaches
threshold & causes APs in adj m tissue leading to m contraction
EPP at motor end plate is terminated when, ACh degraded to choline & acetate by AChE on
Motor end plate; choline taken back into presynaptic terminal on Na+-choline cotransporter

Synthesis & degradation of ACh:

Sequence of events in Neuromuscular

transmission

Agents that alter Neuromuscular func:

Several agents block neuromuscular transmission by blocking steps involved in

neuromuscular transmission
A) Botulinum toxin: blocks release of ACh from presynaptic terminals, causing total
blockade of neuromuscular transmission, skeletal m paralysis & eventually death
resulting from respiratory paralysis; GP anaerobic baccili often in canned & not properly
cooked food; gets to presynaptic memb of neuromuscular junc & prevents release of
ACh from presynaptic memb thus cant develop EPP no AP m weakness &
paralysis death via diaphragm (major respiratory SM)

Agents which block release of ACh from vesicles

ACh

BOTULINUM TOXIN

Therapeutic uses of Botulinum

In treating Blepharospasm (pt b4 injection w/Botox is
unable to open her eyes due to abnormal m contractions)

Botulinum toxin type A promoted for use as wrinkle remedy.

Apparently, some practitioners injecting substance to ease
wrinkles by weakening face ms.

Agents that alter Neuromuscular func:

B) Curare: competes w/Ach for Nicotinic receptors on motor end plate, thereby decreasing
EPP size. Large doses cause paralysis & death due to respiratory paralysis (pancuronium,
atracurium)
used by inhabitants of SA as arrow poison
D-Tubocurarine: curare therapeutic anesthetic, causes skeletal m relaxation
- Bungarotoxin: neurotoxin in kraits venom, binds irreversibly to ACh receptors
Rocuronium used for endotracheal intubation as alternative to SCh
AChE inhibitors also given to keep ACh working; when using curare clinically
These bind reversibly/irreversibly w/nicotinic receptors & prevent ACh binding

ACh

Exs:
a. D- Tubocurarine
b. Bungarotoxin

Clinical aspects:

25 y/o lady presents to Physician w/ptosis (drooping eyelids), easy

fatigability even for simple day to day tasks, progressive m weakness
Physician orders for blood investigations which reveal ^Abs to ACh
receptors
N stimulation studies w/decreased responsiveness of skeletal m upon
repeated stimulation of motor neurons
Physician prescribes Pyridostigmine & pt improves drastically after some
days
What is your dx for above clinical disorder?
Myasthenia Gravis often in reproductive aged females based on ACh receptors
due to lack of ACh choline resp; auto Abs bind ACh receptors causing their
endocytosis & less ACh used

Physioal basis for ptosis & progressive m weakness?

Cant produce EPP no AP m weakness & paralysis

Physioal basis for prescribing Pyridostigmine to this pt?

AChE Is prevent ACh breakdown ^m contraction

I) Myasthenia gravis

Myasthenia gravis: autoimmune dis where Abs formed to ACh receptors

on motor end plates of skeletal m w/severe m weakness esp of arms, legs &
eyes, ptosis (or diplopia), difficulty chewing & swallowing (dysphagia b/c
upper 1 3rd esophagus formed by skeletal m);
N ACh amts, but Abs prevent binding Ach to its receptor on motor end plate
Due to this, EPP & AP cant be generated muscular weakness

ACh receptors decrease in post

synaptic memb

Involves facial ms predominantly:

Clinical features:
Drooping eye lids (Ptosis)
Double vision (Diplopia)
Decreased facial expressions
Dysphagia (difficulty in swallowing)
Dysarthria (difficulty in speech)
Daily routines are tiring

Ptosis

Myasthenia gravis
What do you
observe in
this patient????

Physioal basis of tx of Myasthenia gravis:

Use anticholinesterase agents ie. Neostigmine &
Pyridostigmine; to inhibit enzyme, AChE (Acetyl cholinesterase)
ACh remains in synaptic cleft for longer period & in larger amts,
prolonging time available for ACh to activate its receptor
Enables larger amplitude of EPP whichll be able to generate m
AP
Better m contractions

Lambert-Eaton syndrome

condition resembling myasthenia gravis w/skeletal m weakness

may be associated w/small cell carcinoma of lungs (also seen w/SIADH) or
any other autoimmune disorder
Pathogenesis:
Antibodies destroy voltage gated calcium channels in presynaptic n terminal

Decreased calcium influx w/every n excitation

Decreased quantum of ACh released during each n AP

Failure of neuromuscular transmission & m weakness

Types of muscle fibers

I)

Skeletal m: striated m fibers due to regularly arranged Actin

& Myosin filaments, exs: Biceps, Quadriceps
II)
Smooth ms: lacks visible cross striations as Actin & myosin
filaments irregularly arranged, not arranged in sarcomeres
)
poorly devd SR, Lack T- tubules, absent troponin
)
involuntary & innervated by ANS
)
2 Types of smooth muscles
A. Multiunit type: each m cell behaves as separate cell, no gap
juncs
Dilator pupillae
Ex: Ms of iris

Constrictor pupillae
Contraction of
dilator pupillae
produces dilatation
(innervated by symp)

Contraction of
constrictor pupillae
produces constriction
(innervated by parasymp)

Types of smooth muscles.

B. Single-unit type (Unitary type):
Cells connected w/each other by gap junctions
Whole m mass contract as single unit
Gap junctions

Exs: Muscles of GIT, Uterus, Urinary bladder Smooth Muscle

1073

Types of muscle fibers.

III) Cardiac muscle: striated & have gap juncs (low
resistance bridges for spread of excitation from 1 fiber
to another)
Thereby cardiac m funcs as Syncytium
Cardiac Muscle

1074

Skeletal muscle
Each skeletal m fiber behaves as single unit
Each m fiber contains Myofibrils surrounded by SR &
invaginated by Transverse (T) tubules (has ECF)
Each Myofibril contains thick & thin filaments arranged regularly
in Sarcomeres which causes unique banding pattern/striations

Skeletal Muscle striations

1075

Structure of a Skeletal m:
Muscle belly

Muscle fascicle

Muscle fiber
Myofibril

Myofibrils: bundles of contractile

filaments w/in cytoplasm of m fiber
Myofilaments aka actin & myosin

1076

Structure of skeletal m fiber:

Skeletal m fiber: long, cylindrical, multinucleated
cell
Striatiations

M fibers arranged parallel btwn 2 ends

Myofibrils w/m
fiber (each
innervated by
alpha-motor
neuron)

Sarcoplasm

Sarcolemma (m fiber memb

1077

Arrangement of myofilaments in myofibrils

Thick
filaments

Thin
filaments

TRIAD = T
tubule (yellow
line) w/SR on
both sides of it;
SR T SR

SR =
terminal
cisternae +
longitudinal
tubules

T tubules have voltage gated

sodium
& potassium channels
1078

Thick & thin filaments in skeletal m:

A) Thick filaments: have large MW protein Myosin
Myosin has 1 pair of heavy chains that coil around each other to form tail of Myosin
& 4 light chains
Light chains w/terminal portions of heavy chains form 2 globular heads of Myosin

Light chains

Heavy chains

Head
Has ATPase that breaks ATP into ADP & Pi

Tail

Head

Myosin head has 2 imp features:

1. ability to hydrolyze ATP (ATPase activity)
2. high affinity for binding w/actin (when ATP split into ADP & Pi)

Thick & thin filaments in skeletal m.

B) Thin filaments: made of 3 proteins; Actin, Tropomyosin & Troponin
1. F-Actin: 2 strands of Actin; actin has Myosin-binding sites covered by Tropomyosin
when m at rest (when no Ca2+s released from SR), thus preventing actin-myosin
interaxn
2. Tropomyosin: filamentous & runs along groove of twisted actin filament. For
contraction to occur, must move out of way & expose myosin-binding sites on Actin
3. Troponin: calcium binding protein; complex of 3 globular proteins Troponin C (C for Ca2+) binds to Ca2+ producing conformational change moving
Tropomyosin away, exposing Myosin-binding sites on Actin
Troponin T (T for Tropomyosin) attaches Troponin complex to Tropomyosin
Troponin I (I for inhibition) inhibits actin-myosin interaxn along w/Tropomyosin by
covering Myosin-binding sites on (F-)Actin, at rest

Thin Filament has 3 diff proteins

Actin

2 strands of Tropomyosin

3 Troponin proteins (I, C, T)

1080

Interaction of Actin & Myosin

1081

Arrangement of thick & thin filaments:

Sarcomere: basic contractile unit of m; each has A band in
centre w/thick (Myosin) filaments. Thus appear dark. Thick &
thin filaments may overlap at this region during cross bridge
formation
I bands: on either sides of A band; only has thin filaments,
mainly actin, also troponin & tropomyosin. THUS, appear light
Z disks: darkly staining & run in middle of each I band; give attachment
to thin filaments

Bare zone (H band): in centre of each Sarcomere; has no thin

filaments & w/no overlap of thick & thin filaments at this zone
M line in Bare zone connects central portions of thick filaments together

Each Sarcomere extends from 1 Z-line to another; has 1 full Aband & 2 half I-bands
Normal, fully stretched resting length of Sarcomere is ~2-2.2
m

Arrangement of myofilaments (Thick & thin filaments) in

Sarcomere of skeletal m:

Z line

Z line

M line
H zone
A band

I band

Sarcomere
1083

 Transverse (T) tubules: invaginations of m cell (Sarcolemmal)

memb; carry depolarization during APs from m cell surface to interior
make contact w/terminal cisternae of SR
have voltage-sensitive protein Dihydropyridine receptor (undergo conformational
change at AP, connected to ryanodine receptor, Ca2+!)

Sarcotubular system
Consists of :
a. Transverse tubules (T tubules)
b. Sarcoplasmic reticulum

Terminal
cisternae

Longitudinal
SR

T tubule

ECF

Triad

ICF

Role of Sarcotubular system in m contraction:

Dihydropyridine
Receptor (DHP)

Ryanodine Receptor opens & release

Ca2+ to myofibrils during AP

Ca+2
Ca+2 storage
Ca+2 site
Ca+2

Muscle
AP

Ca+2 Ca+2
Ca+2

Ca+2 released into sarcoplasm initiates contraction

SR (Sarcoplasmic reticulum): site of storage & release of Ca2+ for
excitation-contraction coupling; has Ca2+-releasing Ryanodine receptor
channel
Ca2+- ATPase pumps Ca2+ from ICF of m fiber into SR. W/in SR, Ca2+ is
bound to Ca2+ binding protein Calsequestrin
Thus large quantities of Ca2+ stored in bound form w/in SR

Excitation - Contraction Coupling in Skeletal m (EC coupling):

EC coupling: sequence of events that translate m AP into m contraction; 6 steps:
1) APs in m cell memb propagated along T-tubules carry depolarization from cell surface to interior
of m fiber
2) Depolarizing T-tubules causes conformational change in voltage-sensitive Dihydropyridine
receptor, that opens up Ca2+- releasing channel in SR (Ryanodine receptor)
3) Opening of Ca2+- releasing channel causes Ca2+ release from its storage site (SR) into ICF of m
fiber Ca2+ binds to Troponin C on thin filaments resulting in conformational change in
Troponin
4) This causes Tropomyosin to move away & expose Myosin-binding sites on Actin
5) Myosin heads can bind to Actin & form Cross-bridges that needs energy by ATP hydrolysis
6) Cross-bridge cycling:
At beginning, no ATP bound to Myosin & Myosin tightly attached to Actin (Rigor pos) (brief state
in actively contracting ms)
ATP binding to Myosin head, causes conformational change in Myosin, decreasing its affinity for
Actin & releases it from its binding site on Actin
ATP gets hydrolyzed to ADP & Pi ADP remains attached to Myosin head Myosin attaches
to new site on Actin forming cross bridge btwn Actin & Myosin
It undergoes further conformational change causing Myosin head to tilt twds its body (center of
sarcomere) = power-stroke movement (aka cycling of cross bridge)
ADP gets released. Another ATP gets bound to break cross bridge btwn Actin & Myosin (Myosin
returned to its original state)
This cross-bridging cycle continues w/Myosin walking twds 1 end of Actin, generating force
Therefore called as Power-stroke
This cycle continues as long as Ca2+ is bound to Troponin C
1086

Steps of Excitation-Contraction coupling in skeletal m:

1. Spread of m APs thru T tubules
2. Release of Ca2+ from terminal cisternae into sarcoplasm
3. Binding of calcium w/Troponin-C of troponin complex
4. Exposure of myosin binding sites of actin filaments
5. Binding & movement of myosin head (power stroke) & crossbridge cycling w/help of ATP
6. Sliding of thin filaments on thick filaments & shortening of
sarcomere
Muscle contraction !
1087

Actin
myosin head

Detachment

Movement
Attachment

Cross-bridge
cycling during
contraction:
Myosin head
binding w/actin
called crossbridge formation
Myosin head
undergoes 4
chemal rxns

Actin Myosin cross-bridging

1089

Relaxation of Skeletal m:
Relaxation occurs when Ca2+ returns to its storage site in SR by
Ca2+-ATPase, decreasing IC Ca2+
Decreased ICF Ca2+ Ca2+ release from Troponin C,
Tropomyosin returns to its resting pos, where it blocks Myosinbinding sites on Actin & further cross-bridge cycling cant occur
This leads to relaxation of m
Role of ATP:
a) provides energy for m contraction
b) Breakdown of cross-bridges
c) pumping back Ca2+ from Sarcoplasm into SR after contraction
over

Summary Steps of Excitation-Contraction

coupling in skeletal m:
As long as calcium high in sarcoplasm & ATPs available, m contraction
continues
M relaxation occurs when calcium pumped back to its storage site by Ca2+
ATPase pump
Both contraction & relaxation need ATP & are energy dependent processes
Changes in band pattern during contraction:
Sarcomere length decreases (shortens)
I band & H zone decrease & may disappear
A band remains unchanged in size

1091

Sarcomere length decreases during contraction

Thin filament

Thick filament

Relaxed
state
H zone
A band
I band
(half)

I band &
H zone
decrease;
A band
remains
unchanged

Contracted
state

1092

Single stimulation of m fiber produces single contraction:

Electrical VS. mechanical event

Voltage

Electrical event: m AP; faster & shorter than

mechanical event
ATP

Mechanical event: m contraction & relaxation; slower & longer

Tension

Time (MS)
Contraction
period

time

Relaxation period

1093

What is Rigor Mortis????

Rigor mortis: state of sustained muscular
contraction, seen after death of person due to
lack of ATP
ATP required to separate Myosin from its binding
site on Actin (breaking of cross-bridges)
Thus lack of ATP, leads to sustained state of m
contraction known as Rigor mortis

1094

2 Types of muscle contractions:

Isometric & Isotonic
A) Isometric contraction: force of m contraction
w/out change in m length; force of contraction
equal to load against which it contracts. Hence
NO work done; since no shortening of m, no
movement around jt & no movement of object,
Exs: pushing against wall & standing
B) Isotonic contraction: force of contraction
against constant load, where m length
decreases; force of m contraction greater than
load against which it contracts. Hence work is
done; since shortening of m, movement occurs
around jt & object is moved; Exs: all activities
w/movements (walking, swimming, lifting
weight)

Multiple stimuli w/quick succession:

TETANUS: If m stimulated w/high frequency in way IT CANT
relax, contractions fuse to give rise to sustained contraction of m
M tension increases many folds since IC Ca2+ very high
Clinical implication of Tetanus: neurologic
disorder caused by toxin made by bacterium Cl.
tetani found in soil blocks release of inhibitory
NT GABA & Glycine ^repetitive stimulation of
motor neurons causing ^IC calcium
continuous binding of Ca2+ to Troponin C &
continues cross-bridge cycling, resulting in
state of sustained contraction Tetanus
CFs: stiff facial ms & jaw (Lock Jaw), that
progresses down neck, shoulder, back & limbs,
generalized spasms may lead to respiratory
distress & death
Each arrow in graph
indicates a stimulus
1096

Lock-jaw / Trismus

:
ntitoxin admin that neutralizes circulating toxin
ny wound should be explored & cleaned properly
nti-tetanus injection should be taken immediately
ollowing injury
ntibiotics - Metornidazole, Penicillin-G
Ophisthotonus (arching of
back, due to spasm of ms
Around spine)

Length-Tension relnship:
Muscle tension = force generated in m; 3 types during contraction:
A. Passive tension: force generated in m when its stretched (w/out
contraction) by load at rest (Preload); proportional to degree of stretching;
m elasticity resists stretching by load & develops passive tension
B. Active tension: force generated in m when it contracts (myofilaments
sliding); proportional to # of cross-bridges active aka cycling at time # of
active cross-bridges proportional to amt of intra-sarcoplasmic calcium lvl
(aka Ca2+ amt released from ER)
A. maximal when maximal overlap of thick & thin filaments & max # of
cross bridges (at Resting length of skeletal m fiber (aka optimal
length, Lo);
B. when m stretched, # cross bridges reduce & active tension reduces
C. similarly, when m length reduced, thin filaments collide w/each other
at Sarcomeres center, reducing # cross-bridges & active tension
C. Total tension = passive tension + Active tension

Active tension directly proportional to # of cross-bridges at that moment

Overlapping of
myofilaments at
diff points at rest

MAX

Too less & too great overlaps of

myofilaments reduce crossbridges & hence reduce active
tension

Active muscle tension

Overlap optimum at optimum m

length
D

Muscle length

1099

tal tension = passive tension + Active tension

Total
tension

Muscle tension

Active
tension

Passive tension

Resting length

Muscle length

In our body:
Max tension devd at
resting length
Hence called
optimum length

Velocity of contraction: aka speed of

contraction & speed of cross-bridge cycling
Contraction VELOCITY depends on 3 things:
A) Speed of myosin ATPase activity: if ATP splitting faster = greater velocity
of contraction; based on this, ms classified into fast & slow
B) Afterload on m: ^in afterload decreases velocity; max velocity at 0 afterload
C) Motor unit recruitment: if more motor units contracting = more force
generated in unit time & hence velocity increases

1101

White & Red ms:

White muscle: Egs:

Leg
ms
of a
sprinter

Ocular
muscles

Red muscles: Egs:

Postural muscles

White muscle (Fast):

Red muscle (Slow):

Large, powerful m utilized for short

term
High ATPase activity (fast m)
Larger # m fibers in each motor unit
High capacity for anaerobic
glycolysis
Low Myoglobin

Small, less powerful m utilized long

term (endurance m)
Lower ATPase activity (slow m)
Smaller # of m fibers in each motor
unit
1102
High capacity for aerobic
metabolism (glycolysis)
Red color due to high Myoglobin

Load (Force) - Velocity relationship

Max velocity at 0 afterload (Vmax)
Velocity of contraction

Force velocity relnship:

Afterload = force against
which m contracts
Force-velocity relnship
describes velocity of
shortening of m fiber
when afterload is varied
max velocity of
shortening when
afterload on m is 0 (Vmax)
As afterload increases,
velocity decreases b/c
lesser cross-bridges
formed due to greater
resistance & velocity
approaches 0

0 velocity: beyond this

load, m is not able to
lift load (V=0)

Afterload

Velocity of contraction depends on

myosin ATPase activity

Velocity of contraction

Fast muscle
Slow muscle

0
Afterload
1104

Force-Velocity of skeletal m changes w/recruitment of motor units!

Max velocity at zero afterload

Velocity of contraction

Muscle contracting w/less motor units

Muscle contracting w/more motor units

0
Afterload
1105

Smooth muscle: lacks T-tubules & Troponin, has poorly devd SR

& has Ca2+ regulate Myosin activity
3 Mechanisms that increase IC calcium in smooth ms: Major
source of Calcium in smooth ms is ECF Calcium

C. IP3-gated Ca2+ channels in SR

A. VG Ca2+ channels in
SM memb, that
open in resp to APs

B. LG Ca+2 channels in
SM memb, that open
in resp to NTs &
hormones

7 Steps for CONTRACTION in Smooth ms:

1. Increased [calcium] in cytoplasm

2. Calcium binds w/calmodulin in cytoplasm

3. Activated MLCK (myosin-light-chain kinase) in cytoplasm

4. Phosphorylation of myosin head *

5. Binding of phosphorylated myosin head to actin

6. Cross-bridge cycling by using ATP

7. M contraction continues as long as myosin head

phosphorylated (step #4)
1107

4 Steps for RELAXATION in smooth ms:

1.Decreased [calcium] in cytoplasm by moving into SR or to ECF

2. Activated MLCP (myosin-light-chain phosphatase)

3. Dephosphorylation of myosin head

4. Decreased affinity of myosin head to actin

5. Relaxation of m
Tension devd is proportional to IC [calcium]
1108

High yield facts in M Physiology:

Skeletal, Smooth & Cardiac m fibers - Compare & contrast, exs
for each
Structural org of skeletal m fibers - Actin & Myosin filaments
T-tubules & SR - Role in Ca2+ homeostasis
EC-coupling defn, sequence of events in Skeletal m
Skeletal m relaxation
Rigor Mortis physioal basis
Isotonic & Isometric contractions w/exs
Tetanus
Length-tension relationship - Preload
Force-Velocity relationship - Afterload, Vmax
Excitation- contraction coupling & relaxation in Smooth muscle

1109

Case 1
A 48-year -old women with insulin dependent diabetes mellitus
reports to her physician that she is experiencing severe muscle
weakness. She is being treated for hypertension with propranolol, a
beta adrenergic blocking agent. Her physician orders blood studies,
which reveal a serum K+ of 6.5 mEq/L and elevated BUN. The
physician tapers of the dosage of proranolol, w/eventual
discontinuation of the drug. He adjusts her insulin dosage. Within
few days the patients serum decreased to 4.7mEq/L, and she
reports that her muscle strength has returned normal?
Q. What is mostlikely diagnosis?
Q. How does propranolol, Low insulin and Renal failure lead to this
condition?

1110

Case 2
A 35-year-old woman presents to the clinic with a chief complaint of double vision.
She reports intermittent and progressively worsening double vision for
approximately 2 months, rarely at first but now every day. She works as a computer
programmer, and the symptoms increase the longer she stares at the computer
screen. She has also noted a drooping of her eyelids, which seems to worsen with
prolonged working at the screen. Both symptoms subside with rest. She is generally
fatigued but has noted no other weakness or neurologic symptoms. Her medical
history is unremarkable. Physical examination is notable only for the neurologic
findings. Cranial nerve examination discloses impaired lateral movement of the right
eye and bilateral ptosis, which worsen with repetitive eye movements. Motor,
sensory, and reflex examinations are otherwise unremarkable .
Questions
A. What is the likely diagnosis? What is the pathogenesis of this disease?
B. What other neurologic manifestations might one expect to see?
C. What is the mechanism by which this patient's ocular muscle weakness increases with
prolonged activity?
D. What associated conditions should be investigated in this patient?
E. What treatments should be considered?
1111