Module Name: Introduction to

Medicine
Pharmacology course

Abraham N (PhD)
Assist. Prof of Pharmacology
Pharmacology contents to be
covered
 Introduction to pharmacology
 Drug Body Interactions
Pharmacokinetics
Pharmacodynamics

 Drug interaction

 Adverse drug reaction

 Drug discovery and development

2
Pharmacology contents to be
covered…
 Introduction to autonomic nervous system pharmacology
 Overview of Chemotherapeutic agents
Definitions
Classification antimicrobial agents
MOA of antimicrobial agents
Principle of antimicrobial therapy
Mechanism of resistance of antimicrobial agents
Antineoplastic agents
 General principle of drug toxicity and poisoning
 Common Ethiopian traditional medicine practices
3
I. Introduction to pharmacology
A. Definitions
 Pharmacology:
• Blend of two Greek words, “Pharmakon” to mean
drug or medicine, & “Logos” to mean study.
• The study of substances/chemicals that interact
with living biological systems through chemical
processes (particularly by binding to regulatory
molecules) & alter (activate or inhibit) biologic
function or response
• These substances may be chemicals (drugs) that are
administered to a pt (humans) in order to achieve a beneficial
therapeutic effect or for their toxic effects on regulatory
processes in parasites infecting the patient.

5
Definitions …

 Toxicology:

Is the branch of pharmacology that deals with the

undesirable effects of chemicals on living systems,
from individual cells to humans to complex
ecosystems
 Xenobiotic: (xenos “stranger”)

 Any substance/chemical that is foreign to the

human body (not synthesized in the body)
6
Definitions …

 Prodrug:

Is an ‘inactive’ form of a drug that requires

metabolic activation inside the body
(bioactivation) in order to release the ‘active’
form of the drug. Once released in vivo, the
active form of the drug will then exert its
pharmacological effect

7
Definitions …

 Receptor:
The component of a cell or organism that
interacts with a drug & initiates the chain of
biochemical events leading to the drug’s
observed effects.
 Pharmacodynamics (PD):
Refers to the actions of the drug on the human
body (what the drug does to the body)
• Play the major role in deciding whether that
class of drugs is effective therapy for a
particular disease or symptom
8
Definitions …

 Pharmacokinetics (PK):

Refers to the actions of the human body on the

drug (what the body does to the drug)
It is the study of ADME properties of the drug with
respect to time
• Great significance in the selection &
1
Fig. Major areas of study in pharmacology
administration of a particular drug for a
particular pt
9
Definitions …

 Pharmacogenomics (or Pharmacogenetics):

The study of the genetic variations among

humans that cause differences in PD/PK & lead
to individual differences in drug response

10
 Reading assignment

The history of pharmacology

Basic & Clinical Pharmacology, 16th edition, Page 2
B. The nature of drugs

a) The nature of drugs

In the most general sense, a drug may be
defined as any substance that brings about a
change in biologic function through its chemical
actions

In most cases, the drug molecule interacts as

an agonist (activator) or antagonist
(inhibitor) with a specific molecule in the
biologic system that plays a regulatory role

12
The nature of drugs…

 In a very small number of cases, drugs known as

chemical antagonists may interact directly with
other drugs, whereas a few drugs (osmotic agents)
interact almost exclusively with water molecules

 Drugs may be synthesized within the body (eg,

hormones ) or may be chemicals not synthesized in
the body (ie, xenobiotics, from the Greek xenos ,
meaning “stranger”)

13
The nature of drugs…

 Poisons are drugs that have almost exclusively

harmful effects
However, Paracelsus (1493–1541) famously
stated that “the dose makes the poison,”
meaning that any substance can be harmful if
taken in the wrong dosage

 Toxins are usually defined as poisons of biologic

origin
i.e, synthesized by plants or animals

14
The nature of drugs…

 To interact chemically with its receptor, a drug

molecule must have the appropriate:
Size
Electrical charge
Shape, &
Atomic composition

15
The nature of drugs…

 A drug is often administered at a location distant

from its intended site of action, eg, a pill given
orally to relieve a headache
Therefore, a useful drug must have the
necessary properties to be transported from its
site of administration to its site of action

 A practical drug should be inactivated or excreted

from the body at a reasonable rate so that its
actions will be of appropriate duration

16
The nature of drugs…

i. The physical nature of drugs

Drugs may be solid at room temp (eg, aspirin,
atropine), liquid (eg, ethanol), or gaseous (eg,
nitrous oxide)
These factors often determine the best route of
administration
The various classes of organic compounds—
carbohydrates, proteins, lipids, & their
constituents—are all represented in
pharmacology

17
The nature of drugs…

 The physical nature of drugs…

A number of useful or dangerous drugs are
inorganic elements, eg, lithium, iron, & heavy
metals

Many organic drugs are weak acids or bases

• This fact has important implications for the way they
are handled by the body
• B/c pH differences in the various compartments of
the body may alter the degree of ionization of such
drugs

18
The nature of drugs …

ii. Drug size

The molecular size of drugs varies from very
small (lithium ion, MW 7) to very large (eg,
alteplase [t-PA], a protein of MW 59,050)

However, most drugs have molecular wt b/n 100

& 1000

19
The nature of drugs…

 Drug size…
The lower limit of this narrow range is probably
set by the requirements for specificity of
action
• To have a good “fit” to only one type of receptor,
a drug molecule must be sufficiently unique in
shape, charge, & other properties, to prevent its
binding to other receptors
• To achieve such selective binding, it appears that
a molecule should in most cases be at least 100
MW units in size

20
The nature of drugs…

 Drug size…
 The upper limit in mol. wt is determined 10 by the
requirement that drugs must be able to move within
the body (eg, from the site of administration to the
site of action)
• Drugs much larger than MW 1000 do not
diffuse readily b/n compartments of the body
• Therefore, very large drugs (usually proteins)
must often be administered directly into the
compartment where they have their effect

21
The nature of drugs…

iii. Drug reactivity & drug-receptor bonds

Drugs interact with rps by means of chemical
forces or bonds
These are of 3 major types:

• Covalent

• Electrostatic, &

• Hydrophobic

22
The nature of drugs…

 Drug reactivity & drug-receptor bonds…

Covalent bonds are very strong & in many cases
not reversible under biologic conditions
• Example: The covalent bond formed b/n the acetyl
group of ASA (aspirin) & cyclooxygenase, its
enzyme target in platelets, is not readily broken
• The platelet aggregation–blocking effect of
aspirin lasts long after free ASA has
disappeared from the bloodstream (about 15
min) & is reversed only by the synthesis of new
enzyme in new platelets, a process that takes
several days
23
The nature of drugs…

 Drug reactivity & drug-receptor bonds…

Electrostatic bonding
• It is much more common than covalent
bonding in drug-rp interactions

• Electrostatic bonds vary from relatively strong

linkages b/n permanently charged ionic
molecules to weaker hydrogen bonds & very
weak induced dipole interactions such as van
der Waals forces & similar phenomena

24
The nature of drugs…

 Drug reactivity & drug-receptor bonds…

Electrostatic bonds are weaker than covalent
bonds

Hydrophobic bonds are usually quite weak &

are probably important in the interactions of
highly lipid-soluble drugs with the lipids of cell
membranes & perhaps in the interaction of drugs
with the internal walls of receptor “pockets”

25
The nature of drugs…

 Drug reactivity & drug-receptor bonds…

The specific nature of a particular drug-rp bond is
of less practical importance than the fact that
drugs that bind through weak bonds to their
receptors are generally more selective than
drugs that bind by means of very strong bonds

• This is b/c weak bonds require a very precise

fit of the drug to its receptor if an interaction is
to occur

26
The nature of drugs…

iv. Drug Shape

The shape of a drug molecule must be such as
to permit binding to its rp site via the bonds
• Optimally, the drug’s shape is complementary
to that of the rp site in the same way that a
key is complementary to a lock
The phenomenon of chirality
(stereoisomerism) is so common in biology that
>half of all useful drugs are chiral molecules; that
is, they can exist as enantiomeric pairs

27
The nature of drugs…

 Drug Shape…
Drugs with 1 asymmetric centers have
enantiomers, eg, Carvedolol, a α and β blocker
drug
In most cases, one of these enantiomers is much
more potent than its mirror image enantiomer,
reflecting a better fit to the receptor molecule
The more active enantiomer at one type of
receptor site may not be more active at another
receptor type, eg, a type that may be responsible
for some other effect
28
The nature of drugs…

 Drug Shape…
B/c enzymes are usually stereoselective, one
drug enantiomer is often more susceptible than
the other to drug metabolizing enzymes
• As a result, the duration of action of one
enantiomer may be quite different from that
of the other

Similarly, drug transporters may be

stereoselective

29
Basic principles of
pharmacology…
II. Drug Body Interactions
Drug-body interactions

 The interactions b/n a drug and the body are

conveniently divided into 2 classes
Pharmacodynamic processes :
• The actions of the drug on the body
• These properties determine the group in which
the drug is classified, and they play the major
role in deciding whether that group is
appropriate therapy for a particular symptom or
disease

31
Drug-body interactions…

 Pharmacokinetic (PK) processes :

The actions of the body on the drug

PK processes govern the absorption, distribution,

& elimination of drugs and are of great practical
importance in the choice & administration of a
particular drug for a particular pt
• Eg, a patient with impaired renal function

32
Introductory case study-1

 A 40-yr-old woman presents to the emergency dept of

her local hospital somewhat disoriented, complaining of
midsternal chest pain, abdominal pain, shaking, &
vomiting for 2 days. She admits to having taken a
“handful” of Lorcet (hydrocodone/acetaminophen, an
opioid/nonopioid analgesic combination), Soma
(carisoprodol, a centrally acting muscle relaxant), &
Cymbalta (duloxetine HCl, an
antidepressant/antifibromyalgia agent) 2 days earlier. On
physical examination, the sclera of her eyes shows
yellow discoloration.

33
Introductory case study-1…
 Laboratory analyses of blood drawn within an hour of her
admission reveal abnormal liver function as indicated by the
↑ed indices: ALP 302 (41–133),* ALT 351 (7–56),* aspartate
aminotransferase (AST) 1045 (0–35),* bilirubin 3.33 mg/dL
(0.1–1.2),* & PT of 19.8 seconds (11–15).* In addition,
plasma bicarbonate is reduced, & she has ∼45% reduced
GFR from the normal value at her age, elevated serum Cr &
BUN, markedly reduced blood glucose of 35 mg/dL, and a
plasma acetaminophen conc of 75 mcg/mL (10–20).* Her
serum titer is significantly positive for HCV. Given these
data, how would you proceed with the management of this
case? *Normal values are in parentheses.

34
Introductory case study-2

 A 78-year-old woman is brought to the hospital

because of suspected aspirin overdose. She has
taken aspirin for joint pain for many years without
incident, but during the past year, she has
exhibited signs of cognitive decline. Her caregiver
finds her confused, hyperventilating, and vomiting.
The caregiver finds an empty bottle of aspirin
tablets and calls an ambulance.

35
Introductory case study-2

 In the emergency dept, samples of venous &

arterial blood are obtained while the airway,
breathing, & circulation are evaluated. An IV drip is
started, & GI decontamination is begun. After blood
gas results are reported, Na bicarbonate is
administered via the IV. What is the purpose of the
Na bicarbonate?

36
A. PK processes : Absorption

 Absorption: the process by which unchanged drug

proceeds from the site of administration to the
site of measurement within the body
 Drugs can be absorbed from GIT(oral, sublingual
or rectally), mucous membranes, skin, lungs,
muscle or SC tissues
 In order for a drug to be absorbed, it must pass
through cell membranes
PK processes : Absorption

 Transport across cell membranes

Every PK parameters involve the penetration of drug

across cell membrane
Transport MZM across cell- membrane are:

• Passive transport: through aqueous channels or lipid

cell membranes Passive Transport

 Passage through lipid cell Mn by dissolution in Mn

 Rate dependent on conc gradient & lipid: water
partition coefficient of drug
 Rate markedly higher for unionized form of weak

• Active transport or facilitated diffusion: specialized

electrolyte b/c of its higher lipophilicity than the
ionized form
 Obeys first-order kinetics (rate of transport is
proportional to conc gradient at transport site
 Filtration through aqueous channels within Mns &
b/n cells

carriers
Endocytosis & exocytosis 38
Figure: Mechanisms of drug permeation.
Drugs may diffuse passively through aqueous channels in the intercellular junctions (eg, tight junctions, A), or
through lipid cell membranes [transcellular] (B).
Drugs with the appropriate characteristics may be transported by carriers into or out of cells (C).
Very impermeant drugs may also bind to cell surface receptors (dark binding sites), be engulfed by the cell
membrane (endocytosis), and then be released inside the cell or expelled via the membrane D) or expelled
via the membrane ­limited vesicles out of the cell into the extracellular space (exocytosis, D)
39
 PK processes: Absorption…

 Transport of drugs across cell membrane depend on:-

 Size, degree of ionization, shape, lipid solubility

 Since most drugs are weak acid or weak base their conc of
ionized & unionized state depend on: PH of media & PKa of
the drug
 The Henderson-­Hasselbalch equation relates the ratio of protonated to
unprotonated weak acid or weak base to the
molecule’s pKa and the pH of the medium as follows:

40
PK processes: Absorption…

 The equation applies to both acidic & basic drugs

 Inspection confirms that the lower the pH relative to the pKa,
the greater will be the fraction of
drug in the protonated form
B/c the uncharged form is the more lipid­soluble, more of a
weak acid will be in the lipid­soluble form at acid pH,
whereas more of a basic drug will be in the lipid­soluble
form at alkaline pH
 GI absorption of acidic & basic drugs???
 Application of this principle is made in the manipulation of
drug excretion by the kidney (Ion-trapping)

41
Fig. Trapping of a weak base (methamphetamine) in the urine when the
urine is more acidic than the blood.
In the hypothetical case illustrated, the diffusible uncharged form of the
drug has equilibrated across the membrane, but the total conc (charged
plus uncharged) in the urine (more than 10 mg) is 25 times higher than 42 in
the blood (0.4 mg).
PK processes: Absorption…

 Factors affecting drug absorption

 Route of administration
 Dosage forms
 Physicochemical properties of the drug
 Circulation at the site of absorption
 Conc of the drug
 Surface area of absorption site
 Contact time at site of absorption
PK principles: Absorption…

 Bioavailability
It is defined as the fraction of unchanged drug
reaching the systemic circulation following
administration by any route
For an IV dose of the drug, bioavailability is
assumed to be equal to unity
For a drug administered orally, bioavailability may
be <100% for two main reasons:
• Incomplete extent of absorption across the gut
wall
• First-pass elimination by the liver
44
PK principles: Absorption…

 Bioavailability…
After oral administration, a drug may be incompletely
absorbed,
• Eg, only 70% of a dose of digoxin reaches the
systemic circulation
• Mainly due to lack of absorption from the gut

Other drugs are either too hydrophilic (eg,

atenolol) or too lipophilic (eg, acyclovir) to be
absorbed easily, & their low bioavailability is also
due to incomplete absorption
45
PK principles: Absorption…

 Bioavailability…
Drugs may not be absorbed b/c of a reverse
transporter associated with P-glycoprotein
• This process actively pumps drug out of gut
wall cells back into the gut lumen

• Inhibition of P-glycoprotein & gut wall

metabolism, eg, by grapefruit juice, may be
associated with substantially ↑ed drug
absorption

46
 PK principles: Absorption…
 Bioavailability…
Factors that influence bioavailability:
• The extent of absorption may be reduced b/c
• A drug is incompletely released from its DF
• Undergoes destruction at its site of administration
• Physicochemical properties such as insolubility
• Prevent complete absorption from its site of
administration
• First-pass" effect

First-pass" effect

 When a drug is administered orally, it must traverse

the intestinal epithelium, the portal venous system,
& the liver prior to entering the systemic circulation
Once a drug enters the enterocyte
• It may undergo metabolism, be transported into
the portal vein, or undergo excretion back into
the intestinal lumen
• Both excretion into the intestinal lumen &
metabolism ↓ systemic bioavailability

47
B. PK processes : Distribution

 It is the process of reversible transfer of a drug to &

from the site of measurement, usually the blood or
plasma
 The pathway for return of drug need not be the
same as that leaving the circulation
Eg. A drug may be excreted in the bile, stored in
gallbladder, transit into the small intestine & be
reabsorbed in to the circulation
• By doing so, the drug completes a cycle, the
enterohepatic cycle
• A component of distribution
48
PK processes : Distribution …

 Following absorption or systemic administration into

the bloodstream, a drug distributes into interstitial
& intracellular fluids
 This process reflects a number of physiological
factors & the particular physicochemical
properties of the individual drug
Factors that determine the rate of delivery &
potential amount of drug distributed into tissues
• CO, regional blood flow, capillary
permeability, & tissue volume

49
 PK processes : Distribution …
 With exceptions such as the brain, diffusion of drug into the
interstitial fluid occurs rapidly
B/c of the highly permeable nature of the capillary
endothelial Mn
Thus, tissue distribution is determined by:
• The partitioning of drug b/n blood & the particular
tissue
• Lipid solubility & transmembrane pH gradients
are important determinants of such uptake for
drugs that are either weak acids or bases
• However, in general, ion trapping associated with
transmembrane pH gradients is not large b/c the pH
difference b/n tissue & blood (~7.0 vs. 7.4) is small
50
PK processes : Distribution …

 The more important determinant of blood-tissue

partitioning:
The relative binding of drug to plasma proteins &
tissue macromolecules that limits the conc of free
drug

51
PK processes : Distribution…

I. Plasma protein binding

Drug in systemic circulation exist as bound &
unbound form
Drug ordinarily bind with plasma protein in
reversible fashion & in dynamic equilibrium
D + P →[DP] → D + P

As free drugs leave the systemic circulation the

bound drug dissociate

52
PK processes : Distribution…

 Plasma protein binding…

The fraction of total drug in plasma that is

bound is determined by:
• The drug concentration

• The affinity of binding sites for the drug

• The number of binding sites

53
 PK processes : Distribution…

 Plasma protein binding…

The extent of this binding will influence the
drug’s distribution & rate of elimination b/c
only the unbound drug can:
• Diffuse through capillary beds & cell Mn
1
• Produce therapeutic or toxic effect
• Be metabolized or excreted

The major binding macromolecules are: Albumin,

α1 –acid glycoprotein, Globulin, etc

54
PK processes : Distribution…

Plasma protein binding…

a) Albumin:
Some factor affect the binding of drugs with albumin:
Age
Pregnancy
Disease state: Hyperalbuminemia, Hypoalbuminemia,
Liver disease, etc
b) α1 –acid glycoprotein
 Serum plasma level ↑ in situation such as:
 Stress, injury, trauma, rheumatoid arthritis, surgery

55
PK processes : Distribution…

II. Tissue uptake:

 Drugs will not always be uniformly distributed to &
retained by body tissues; some drug will be either
considerably higher or considerably lower in
particular tissues: due to tissue different affinity
 E.g. Adipose tissue
 Fat as a reservoir: drugs with extreme lipid
solubility
 ↓ therapeutic activity ( eg thiopental),
prolonged activity & toxicity ( eg-DDT)

56
PK processes : Distribution…

 Bone:
The TTC antibiotics (& other divalent metal-ion
chelating agents) & heavy metals may
accumulate in bone by adsorption onto the bone
crystal surface & eventual incorporation into the
crystal lattice
Bone can become a reservoir for the slow
release of toxic agents such as lead or radium
into the blood
• Their effects thus can persist long after
exposure has ceased
57
PK processes: Distribution…

III. Specialized physiological barrier:

a) Blood brain barrier (BBB)
• Transfer of drug to brain is regulated by BBB
• Inflammation such as due to meningitis or
encephalitis ↑ the permeability of BBB so
permeating the passage of ionized, lipid soluble
drugs
• Eg:- penicillin G – not cross BBB but
inflammation–can pass BBB --used for antibiotic
effect centrally

58
PK processes: Distribution…

• Specialized physiological barrier…

b) Placental blood barrier
• Blood vessel of mother & fetus separated by
PBB
• Highly polar & ionized drugs do not cross
placenta readily
• Drugs which cross PBB may cause fetal
abnormalities called teratogenic effects

59
PK processes : Distribution…

IV. Tissue perfusion:

Different tissue have d/t rate & amt of blood flow

• Highly perfused tissue:- heart, lung, brain, liver,

kidney
• Intermediate perfused tissue:- skeletal muscle

• Poorly perfused tissue:- skin, bone, nail, fat

tissue

60
PK processes : Distribution…

Volume of distribution (Vd):

It is the measure of the apparent space in the
body available to contain the drug
Relates drug conc in the plasma to total drug
in the body
Gives rough estimation of overall distribution of a
drug in the body
Vd = Amount of drug in body
Amount of drug in blood

61
PK processes : Distribution…

Volume of Distribution…

Is apparent/ideal

Its value can be >TBW

As a result of drug sequestration in d/f tissues

Having high Vd – high distribution

Vd have inverse relationship with PPB

↑PPB ----- ↓VD (mainly found in plasma)

62
PK processes : Distribution…

Vd can indicate where the drug is

Strongly plasma protein-bound molecules & very
large molecules: plasma (0.04 L/kg); E.g Heparin
Larger water-soluble molecules: Extracellular water
(0.2 L/kg); E.g. Gentamicin
Small water-soluble molecules—TBW (0.6 L/kg);
E.g. ethanol
Highly lipid-soluble molecules: Fat (0.2-0.35 L/kg) Eg
thiopental, DDT
Certain ions: Bone (0.07 L/kg); eg, lead, fluoride

63
C. PK processes: Metabolism/
Biotransformation (BT)
What is BT?
A chemical change (transformation) of drugs by
body enzyme
Why BT?
To facilitate excretion of drugs by changing to more
water soluble form
Lipophilic → → hydrophilic

 NB: Elimination is the irreversible loss of drug from the site

of measurement
Elimination occur by 2 process: excretion &
metabolism
64
PK processes: Metabolism/
Biotransformation…
Where BT?
Metabolism of drug occur in all body parts
Liver, GI, Lung, kidney, blood, etc….

But mainly take place in liver; b/c it contain large

amount of metabolizing enzyme

How BT?
Metabolism in liver involve 2 steps
Phase I
Phase II
65
PK processes: Metabolism/
Biotransformation…

• Phase I reactions
 Phase I reactions generally make the drug
molecule more polar & water soluble so that it
is prone to elimination by the kidney

 Phase I modifications include oxidation,

Microsomal mixedfunctionoxidasesystem&

hydrolysis, & reduction

PhaseI Reactions
• Microsomal drug oxidations require P450, P450 reductase, NADPH, & molecular oxygen
• Steps
• Step 1: oxidized (Fe+3) P450 combines with a drug substrate to form a binary complex
• Step-2: NADPH donates an electron to the flavoprotein P450 reductase, which in turn
reduces the oxidized P450-drug complex
• Step 3: a second electron is introduced from NADPH via the same P450 reductase (or
even microsomal cytochrome b5), which serves to reduce molecular oxygen & to form
an “activated oxygen”–P450–substrate complex
• Step 4: This complex in turn transfers activated oxygen to the drug substrate to form
the oxidized product

 Mainly Involve cytochrome P-450 enzyme

66
PK processes: Metabolism/
Biotransformation…
 Type of phase II rxn:

• Phase II reactions involve conjugation to form

glucuronides, acetates, or sulfates
• In general, conjugates are polar molecules that are readily
excreted & often inactive
• Phase II reactions are relatively faster than P450­catalyzed
rxns, thus effectively accelerating drug biotransformation

Important points
• Drug conjugations were once believed to represent terminal
inactivation events and as such have been viewed as “true
detoxification” reactions.
• However, this concept must be modified, b/c it is now known that
certain conjugation rxns (acyl glucuronidation of NSAIDs, Osulfation
of Nhydroxyacetylaminofluorene, & Nacetylation of isoniazid) may
lead to the formation of reactive species responsible for the toxicity
of the drugs
• Furthermore, sulfation is known to activate the orally active prodrug
minoxidil into a very efficacious vasodilator, & morphine-6-
glucuronide is more potent than morphine itself.

67
PK processes: Metabolism/
Biotransformation…

Consequence of BT… 1
Fig. Biotransformation (Metabolism)

Inactivation of parent drug

Conversion of drug to its toxic metabolite
Conversion of pro-drug to active drug
Maintenance of activity

68
PK process: Metabolism/ Biotransformation…
Table. Sources of Variation in Intrinsic Clearance
Genetic factors
Genetic differences within population
Racial differences among different populations
Environmental factors & drug interactions
Enzyme induction
Enzyme inhibition
Physiologic conditions
Age
Gender
Diet/nutrition
Pathophysiology
Drug dosage regimen
Route of drug administration
Dose dependent (nonlinear) pharmacokinetics
PK process: Metabolism/ Biotransformation…
Table. Examples of Drug Interactions Affecting CYP450 Enzymes
Inhibitors of Drug
Metabolism Example Result
Acetaminophen Ethanol ↑ed hepatotoxicity in chronic alcoholics
Cimetidine Warfarin Prolongation of PT
Erythromycin Carbamazepine ↓ed carbazepine clearance
Fluoxetine Imipramine (IMI) ↓ed clearance of IMA
Fluoxetine Desipramine (DMI) ↓ed clearance of DMI
Inducers of Drug
Metabolism Example Result
Carbamazepine Acetaminophen ↑ed acetaminophen metabolism
Rifampin Methadone ↑ed methadone metabolism, may
precipitate opiate withdrawal
Phenobarbital Dexamethasone ↓ed dexamethasone elimination half-life
Rifampin Prednisolone ↑ed elimination of prednisolone
70
D. PK process : excretion

71
PK process: Excretion …

 Drugs are eliminated from the body either unchanged

by the process of excretion or converted to
metabolites

 Excretory organs, the lung excluded, eliminate polar

compounds more efficiently than substances with high
lipid solubility

 Lipid-soluble drugs thus are not readily eliminated until

they are metabolized to more polar compounds

72
PK process: Excretion …

 Excretion is a process of drug transfer from

the internal to the external environment

 Where…?

Kidney, biliary system, sweat, saliva, milk,

lung

73
PK process: Excretion …

 Substances excreted in the Urine :

The kidney is most important organ for

excreting drugs & their metabolites
 Substances excreted in the feces:

They are principally unabsorbed orally ingested

drugs or drug metabolites excreted either in the
bile or secreted directly into the intestinal tract &
not reabsorbed
74
PK process: Excretion …

 Excretion of drugs in breast milk:

Important not b/c of the amounts eliminated, but b/c

the excreted drugs are potential sources of unwanted
pharmacological effects in the nursing infant
 Excretion from the lung:

Important mainly for the elimination of anesthetic

gases

75
PK process: Excretion …

a) Renal Excretion
Excretion of drugs & metabolites in the urine
involves 3 distinct processes: glomerular
filtration, active tubular secretion, & passive
tubular reabsorption
Changes in overall renal function generally
affect all 3 processes to a similar extent

76
PK process: Excretion …

 The amount of drug entering the tubular lumen by filtration

depends on:
The GFR & the extent of plasma binding of the drug

 In the proximal renal tubule, active, carrier-mediated

tubular secretion also may add drug to the tubular fluid
Transporters such as P-gp & the MRP2, localized in the
apical brush-border membrane
• They are responsible for the secretion of amphipathic
anions & conjugated metabolites respectively
77
PK process: Excretion …

 Solute carrier transporters that are more selective

for organic cationic drugs are involved in the
secretion of organic bases

 Membrane transporters, mainly located in the distal

renal tubule, also are responsible for any active
reabsorption of drug from the tubular lumen back
into the systemic circulation
However, most such reabsorption occurs by
non-ionic diffusion

78
PK process: Excretion …

 In the proximal & distal tubules, the non-ionized

forms of weak acids & bases undergo net passive
re-absorption
 The conc gradient for back-diffusion is created by
the reabsorption of water with Na+ & other inorganic
ions
 Since the tubular cells are less permeable to the
ionized forms of weak electrolytes, passive
reabsorption of these substances depends on the
PH

79
PK process: Excretion …

 Excretion of weak Acids

When the tubular urine is made more alkaline
• Weak acids are largely ionized & thus are
excreted more rapidly & to a greater extent
When the tubular urine is made more acidic
• The fraction of drug ionized is reduced, &
excretion is likewise reduced
 Excretion of weak bases
Alkalinization & acidification of the urine have
the opposite effects

80
PK process: Excretion …

 In the Tx of drug poisoning, the excretion of some

drugs can be hastened by appropriate alkalinization
or acidification of the urine
Whether alteration of urine pH results in a
significant change in drug elimination depends on:

• The extent & persistence of the pH change

• The contribution of pH-dependent passive

reabsorption to total drug elimination

81
PK process: Excretion …

 The effect is greatest for weak acids & bases with

pKa values in the range of urinary pH (5-8)

However, alkalinization of urine can produce a

4-6-fold ↑ in excretion of a relatively strong acid
such as salicylate when urinary pH is changed
from 6.4 to 8.0 & the fraction of non-ionized
drug is reduced from 1% to 0.04%

82
PK process: Excretion …

 Generally the rate of urinary drug excretion will

depend on
 Drug Vd
 Degree of protein binding
 GFR
 Tubular fluid PH
 Extent of back-diffusion of unionized form
 Extent of active tubular secretion of cpd
 Possibly, extent of active tubular reabsorption

83
PK process: excretion…

b) Biliary & Fecal Excretion

Transporters are also present in the canalicular
membrane of the hepatocyte, & these actively
secrete drugs & metabolites into bile
Ultimately, drugs & metabolites present in bile
are released into the GIT during the digestive
process
B/c secretory transporters also are expressed on
the apical membrane of enterocytes, direct
secretion of drugs & metabolites may occur from
the systemic circulation into the intestinal lumen

84
PK process: excretion…

 Subsequently, drugs & metabolites can be

reabsorbed back into the body from the intestine,
which, in the case of conjugated metabolites such
as glucuronides, may require their enzymatic
hydrolysis by the intestinal microflora
 Such enterohepatic recycling, if extensive, may
prolong significantly the presence of a drug (or
toxin) & its effects within the body prior to
elimination by other pathways
 For this reason, drugs may be given orally to
bind substances excreted in the bile

85
PK process: excretion…

 Excretion by other routes

Excretion of drugs into sweat, saliva, & tears is
quantitatively unimportant
Elimination by these routes depends mainly on:
Diffusion of the non-ionized lipid-soluble form of
drugs through the epithelial cells of the glands &
The pH

86
PK process: excretion…

Drugs excreted in the saliva enter the mouth,

where they are usually swallowed
The conc of some drugs in saliva parallels that in
plasma
Saliva therefore may be a useful biological fluid in
which to determine drug conc when it is difficult or
inconvenient to obtain blood

87
PK process: excretion…

The same principles apply to excretion of drugs in breast

milk
Since milk is more acidic than plasma, basic compounds
may be slightly concentrated in this fluid; conversely, the
conc of acidic compounds in the milk is lower than in
plasma
Non-electrolytes, such as ethanol & urea, readily enter
breast milk & reach the same conc as in plasma,
independent of the pH of the milk
Thus, the administration of drugs to breast-feeding women
carries the general caution that the suckling infant will be
exposed to some extent to the medication and/or its
metabolites Answer case 1
Answer case 2
• Acetaminophen (APAP) is a relatively safe drug, provided it is taken at the
recommended therapeutic doses.
• At normally ingested dosages, 95% of APAP is converted by phase II enzymes into
much less toxic and more water-soluble APAP-glucuronide and APAP-sulfate, both
of which are eliminated in the urine
• Five percent of parent APAP is converted by phase I P450 enzymes into a reactive
toxic product that is conjugated by GSH, excreted in the urine, and thus
detoxified.
• However, APAP’s safety may be greatly compromised in mixed drug overdoses,
eg, when ingested with other drugs such as hydrocodone, duloxetine, and
carisoprodol, which compete with APAP for phase II-dependent elimination or for
cellular cofactors (GSH, UDPGA, PAPS[3′ phosphoadenosine 5′phosphosulfate]
involved in these processes.
• Aspirin overdose commonly causes a mixed respiratory alkalosis and • Accordingly, more APAP is diverted into its hepatotoxic reactive metabolite
metabolic acidosis.

88
pathway, resulting in liver cell damage.

• Because aspirin is a weak acid, serum acidosis favors entry of the drug into
tissues (increasing toxicity), & urinary acidosis favors reabsorption of
excreted drug back into the blood (prolonging the effects of the overdose)
• Sodium bicarbonate, a weak base, is an important component of the
management of aspirin overdose.
• It causes alkalosis, reducing entry into tissues, and increases the pH of the
urine, enhancing renal clearance of the drug.
PD Process
Introductory case study

 A 51-year-old man presents to the emergency

department due to acute difficulty breathing. The pt
is afebrile & normotensive, but anxious,
tachycardic, & markedly tachypneic. Auscultation of
the chest reveals diffuse wheezes. The clinician
provisionally makes the dx of bronchial asthma &
administers epinephrine by IM injection, improving
the pt’s breathing over several minutes.
90
Introductory case study...

 A normal chest X-ray & ECG is subsequently obtained,

and the medical history is remarkable only for mild HTN
that is being treated with propranolol. The clinician
instructs the pt to discontinue use of propranolol, &
changes the pt’s antihypertensive medication to verapamil.
Why is the physician correct to discontinue propranolol?
Why is verapamil is likely to be a more suitable choice for
managing HTN in this pt? Are there alternative
pharmacotherapies that the clinician should also consider?
91
1. PD processes

A. Introduction
There are 4 principle protein targets with which
drugs can interact:
• Enzymes (e.g. neostigmine & acetyl
cholinesterase)
• Membrane carriers (e.g. TCAs &
catecholamine uptake-1)
• Ion channels (e.g. nefidipine & voltage-gated
Ca2+ channels)
• Receptors

92
PD processes : Introduction…

 Receptors

Most drugs exert their effects, both beneficial &

harmful, by interacting with receptors—i.e,
specialized target macromolecules—present on the
cell surface or intracellularly
Receptors bind drugs & initiate events leading to
alterations in biochemical &/or biophysical activity
of a cell, & consequently, the function of an organ
93
PD processes : Introduction…

 Most receptors are named to indicate the type of

drug/chemical that interacts best with it
E.g., the receptor for histamine is called a
histamine receptor

 Cells may have tens of thousands of receptors for

certain ligands (drugs)

94
PD processes : Introduction…

 Cells may also have different types of receptors,

each of which is specific for a particular ligand
On the heart, for example, there are β
receptors for NE, & muscarinic receptors for
ACH

• These receptors dynamically interact to control

vital functions of the heart

 Most drugs must bind to a receptor to bring about

an effect
95
PD processes : Introduction…

 However, at the cellular level, drug binding is only the

first in a sequence of possible steps:
Drug (D) + receptor-effector (R) → drug-receptor-
effector cpx → effect
D + R → drug-receptor cpx → effector molecule →
effect
D + R → D-R cpx → activation of coupling molecule
→ effector molecule → effect
Inhibition of metabolism of endogenous activator →
↑ed activator action on an effector molecule → ↑ed
effect
96
PD processes : Introduction…
 Types of Drug-Receptor Interactions

97
PD processes : Introduction…

 Agonists that Inhibit their binding molecules

Some drugs mimic agonist drugs by inhibiting the
molecules responsible for terminating the action of an
endogenous agonist

B/c they amplify the effects of physiologically released

endogenous agonist ligands, their effects are
sometimes more selective & less toxic than those of
exogenous agonists

98
 PD processes : Introduction…
 Agonists, partial agonists, & inverse agonists
 Full agonists: have a much higher affinity for the Ra
conformation & stabilize it
 Partial agonists: have an intermediate affinity for both Ri & Ra
forms
• Have low intrinsic efficacy
 Inverse agonists: have a much higher affinity for the Ri form
• Reduce constitutive activity and may produce a contrasting
physiologic result

 Antagonist: have equal affinity for both receptor forms & maintain
the same level of constitutive activity

99
Fig. A model of D-Rp interaction. The hypothetical Rp is able to assume 2
conformations. In the Ri conformation, it is inactive & produces no effect,
even when combined with a drug molecule. In the Ra conformation, the Rp can
activate downstream MZMs that produce a small observable effect, even in the
absence of drug (constitutive activity)
100
 PD processes …

B. Major receptor families

They are proteins that are responsible for transducing
extracellular signals into intracellular responses
These receptors may be divided into four families:
1. Intracellular receptors
2. Ligand-regulated transmembrane enzymes including receptor
Tyrosine Kinases
3. Cytokine Receptors (A, C, substrates; B, D,
products; R, receptor; G,
G protein; E, effector
[enzyme or ion channel];
Y, tyrosine; P, phosphate.)

1 : A lipid-soluble chemical signal crosses the plasma membrane & acts on an

intracellular receptor (which may be an enzyme or a regulator of gene

4. Ligand-gated ion channels

transcription); 2 : the signal binds to the extracellular domain of a transmembrane
protein, there by activating an enzymatic activity of its cytoplasmic domain; 3 : the
signal binds to the extracellular domain of a transmembrane receptor bound to a
separate protein tyrosine kinase, which it activates; 4 : the signal binds to & directly
regulates the opening of an ion channel; 5 : the signal binds to a cell-surface
receptor linked to an effector enzyme by a G protein
1

5. G protein–coupled receptors
The type of receptor a ligand will interact with depends on the
nature of the ligand
101
PD processes : Major receptor
families…

a) Ligand-gated ion channels

A ligand-gated transmembrane ion channel is
induced to open or close by the binding of a
ligand
Response to these receptors is very rapid,
having durations of a few milliseconds

102
PD processes : Major receptor
families…
• Ligand-gated ion channels…
The nicotinic receptor & the GABA receptor are
important examples of ligand-gated receptors, the
functions of which are modified by numerous drugs
• Stimulation of the nicotinic receptor by ACH
results in Na influx, generation of an AP, &
activation of contraction in skeletal muscle
Fig. The nicotinic acetylcholine (ACh) receptor

• Benzodiazepines, on the other hand, enhance

the stimulation of the GABA receptor by GABA,
Fig. A model of the GABAA receptor–chloride ion channel
macromolecular complex

resulting in ↑ed Cl influx & hyperpolarization of

the respective cell
103
PD processes : Major receptor
families…

b) G protein–coupled receptors
These receptors are comprised of a single
peptide that has 7 membrane-spanning regions, &
these receptors are linked to a G protein having 3
subunits, an α subunit that binds GDP or GTP & a
βγ subunit
Fig. The guanine
nucleotide-dependent
activation-inactivation cycle
of G proteins
Fig.

104
PD processes : Major receptor
families…
• G protein–coupled receptors…
Binding of the appropriate ligand to the extracellular
region of the receptor activates the G protein so that
GTP replaces GDP on the α subunit
Dissociation of the G protein occurs, & both the α-
GTP subunit & the βγ subunit subsequently interact
with other cellular effectors, usually an enzyme or ion
channel
• These effectors then change the conc of 2 nd
messengers that are responsible for further actions
within the cell

105
PD processes : Major receptor
families…
• G protein–coupled receptors…
Second messengers:
• These are essential in conducting & amplifying
signals coming from G protein–coupled
receptors
• A common pathway turned on by Gs, & other
types of G proteins, is the activation of adenylyl
cyclase by α-GTP subunits, which results in the
production of cAMP—a 2nd messenger that
regulates protein phosphorylation

106
PD processes : Major receptor
families…

• G protein–coupled receptors…
Second messengers…

• G proteins also activate phospholipase C, which is

responsible for the generation of 2 other 2nd
messengers, namely IP3 & DAG

• These effectors are responsible for the

intracellular free calcium concentrations, & of
other proteins as well regulation of
107
PD processes : Major receptor
families…
• G protein–coupled receptors…
This family of receptors transduces signals derived
from odors, light, & numerous NTs, including NE,
dopamine, serotonin, & ACH

GPCRs also activate Guanylyl cyclase (GC), which

converts (GTP) to cGMP that stimulates PKG
• cGMP signaling is important in only a few cells, for
example, intestinal mucosa & vascular smooth
muscle, where it causes relaxation of vascular
smooth muscle cells
108
PD processes : Major receptor
families…
c) Ligand-regulated transmembrane enzymes
including receptor Tyrosine Kinases
Such receptors have cytosolic enzyme activity as an
integral component of their structure or function
Binding of a ligand to an extracellular domain
activates or inhibits this cytosolic enzyme activity
Duration of responses to stimulation of these
receptors is on the order of minutes to hours
E.g.: epidermal growth factor, platelet-derived growth
factor, atrial natriuretic peptide, insulin, & others

109
 PD processes : Major receptor
families…
• Receptor Tyrosine Kinases…
Typically, upon binding of the ligand to receptor
subunits, the receptor undergoes conformational
changes, converting from its inactive form to an
active kinase form
The activated receptor autophosphorylates, &
phosphorylates tyrosine residues on specific
proteins
The addition of a phosphate group can substantially
modify the 3-dimensional structure of the target
protein, thereby acting as a molecular switch
Fig. Mechanism of activation of the epidermal growth factor (EGF) receptor.
The receptor polypeptide has extracellular & cytoplasmic domains, depicted above
& below the plasma membrane. Upon binding of EGF (circle), the receptor
converts from its inactive monomeric state ( left) to an active dimeric state (right), in
which two receptor polypeptides bind non-covalently. The cytoplasmic domains
become phosphorylated (P) on specific tyrosine residues (Y), & their enzymatic
activities are activated, catalyzing phosphorylation of substrate proteins (S)

110
PD processes : Major receptor
families…
d) Intracellular receptors
The receptor is entirely intracellular &, therefore,
the ligand must diffuse into the cell to interact
with the receptor
This places constraints on the physical &
chemical properties of the ligand in that it must
have sufficient lipid solubility to be able to move
across the target cell membrane

111
PD processes : Major receptor
families…
• Intracellular receptors…
B/c these receptor ligands are lipid soluble, they are transported
in the body attached to plasma proteins, such as albumin
• E.g., steroid hormones exert their action on target cells via
this receptor mechanism
 The mechanism used by hormones that act by regulating gene expression has
two therapeutically important consequences:
 All of these hormones produce their effects after a characteristic lag period of
30 minutes to several hrs—the time required for the synthesis of new proteins
 The effects of these agents can persist for hrs or days after the agonist conc
has been reduced to zero

112
PD processes : Major receptor
families…
• Intracellular receptors…
Binding of the ligand with its receptor follows a
general pattern in which the receptor becomes
activated b/c of the dissociation of a small
repressor peptide
The activated ligand–receptor complex migrates
to the nucleus, where it binds to specific DNA
sequences, resulting in the regulation of gene
expression
Fig. Mechanism of glucocorticoid action

The glucocorticoid receptor polypeptide is

schematically depicted as a protein with three
distinct domains.
A heat-shock protein, hsp90, binds to the
receptor in the absence of hormone &
prevents folding into the active conformation of
the receptor.
Binding of a hormone ligand (steroid) causes
dissociation of the hsp90 stabilizer & permits
conversion to the active configuration.

113
 PD processes : Major receptor
families…
e. Cytokine Receptors
Respond to a heterogeneous group of peptide
ligands, which include growth hormone,
erythropoietin, several kinds of interferon, & other
regulators of growth & differentiation
Closely resembling that of receptor tyrosine
kinases, except that in this case, the protein
tyrosine kinase activity is not intrinsic to the
receptor molecule
like receptor tyrosine kinases, have extracellular &
intracellular domains and form dimers.

However, after activation by an appropriate ligand,

separate mobile protein tyrosine kinase molecules the
Janus-kinase (JAK) are activated, resulting in
phosphorylation of signal transducers &
activation of transcription (STAT) molecules.
STAT dimers then travel to the nucleus, where they
regulate transcription.

Fig. Cytokine receptors

114
PD processes …

D. Relation b/n drug dose & clinical response

The degree of effect produced by a drug is
generally a function of the amt of drug in the site
of action (receptor)
• Response ~ conc of drug at receptor site
• Conc of drug at receptor site ~ conc of drug in
plasma
• Conc of drug in plasma ~ drug administered
> So, response ~ drug administered
• Expressed in dose—response curves

115
 PD processes: Relation b/n drug dose
& clinical response
a) Dose & response in patients
i. Graded dose–response relations
Graded response : the response continuously ↑
as the administered dose continuously ↑
The response is a graded effect, meaning that
the response is continuous & gradual
More common than quantal dose response,
since involve single pt/animal
Graph is done by giving d/f doses of a drug to
single individual & recording response
PD principle: Relation b/n drug dose &
clinical response

 Two important properties of drugs can be

determined by graded dose–response curves
Potency
Efficacy (intrinsic activity)
i. Potency:
It is a measure of the amount of drug necessary
to produce an effect of a given magnitude
The conc producing an effect that is fifty percent
of the maximum is used to determine potency
• It commonly designated as the EC50
This im age c annot c urrently be dis played.

116
 PD processes: Relation b/n drug dose &
clinical response…

ii. Quantal dose-response curves

Show the effect of d/t dose on response among
all ( many) individuals taking the drug
Show individual variation in response for a given
dose
Follow none or all for dose administered
For example, after the administration of a
hypnotic drug, a patient is either asleep or not
Usually done on animals than humans
Fig. B. Quantal dose-response curves

117
PD processes: Relation b/n drug dose &
clinical response…
b) Variation in drug responsiveness
There is a great deal of variability in the
responsiveness to a drug among individuals
• NB: Variation in drug responsiveness has also
been shown in a single individual at different
times during the course of Tx by the same drug
Numerous factors affect drug responsiveness
including age, sex, body size, disease state, genetic
factors, & simultaneous administration of other drugs

118
PD processes: Relation b/n drug dose &
clinical response…

 4 major mechanisms are known to contribute to

variation in drug responsiveness:

i. Alteration in drug conc at the receptor site:

• Due to PK differences (in drug ADME) among pts,
which leads to variability in the clinical response

119
PD processes: Relation b/n drug dose &
clinical response…

ii. Variation in conc of an endogenous receptor ligand:

This particular MZM leads to a great deal of

variability in responses to drug antagonists &
partial agonists
E.g. the levels of endogenous catecholamines
affect the clinical response to the β-adrenoceptor
antagonist propranolol

120
PD processes: Relation b/n drug dose &
clinical response…

iii. Alterations in the number or function of

receptors:
An ↑ or ↓in the number of receptor sites or
alterations in the efficiency of the occupancy-
response coupling can cause variability in drug
responsiveness
Alteration in the number of receptor sites is
sometimes caused by other hormones
• E.g. thyroid hormones ↑ both the number of
β-adrenoceptors & cardiac sensitivity to
catecholamines
121
PD processes: Relation b/n drug dose &
clinical response…
iv. Changes in components of response distal to
the receptor:
Drug response in a pt depends not only on the
drug’s ability to bind to the receptor, but also on:
• The functional integrity & efficiency of the
biochemical processes in the cell
(occupancy-response coupling) &
• The physiologic regulation by interacting
organ systems

122
PD processes: Relation b/n drug dose &
clinical response…
 Changes in components of response distal to
the receptor…
Changes in these postreceptor events
represent the most important MZM that causes
variation in responsiveness to drug therapy

Factors that influence these events include age

& general health of the pt &, most importantly,
the severity & pathophysiologic MZM of the
disease that is being treated

123
PD processes: Relation b/n drug dose &
clinical response…
 Changes in components of response distal to
the receptor…
An unsatisfactory therapeutic response is
sometimes attributed to the physiologic
compensatory MZMs that respond to &
oppose the effects of a drug (e.g., compensatory
vasoconstriction & fluid retention by the kidney
can cause tolerance to the antihypertensive
effects of a vasodilator drug)
In such cases, additional drugs may be required
to treat the patient

124
PD processes: Relation b/n drug dose &
clinical response…

c) Clinical Selectivity: Beneficial (therapeutic) vs.

Toxic effects of drugs
Clinical selectivity of a drug is determined by
separating drug effects into 2 categories:
• Beneficial/therapeutic effects vs toxic effects
3 major mechanisms for mediating the beneficial &
toxic effects of drugs are known:

125
 PD processes: Relation b/n drug dose &
clinical response…

i. Therapeutic & toxic effects mediated by the same

receptor-effector MZM
Much of the serious drug toxicity encountered
clinically is the result of a direct pharmacologic
extension of the therapeutic actions of the drug
E.g., Hypotension caused by GTN therapy

• Hypoglycemia caused by insulin therapy

Therapeutic&toxiceffectsmediatedbythesame
receptor-effectorMZM
• Toxicity may be avoided by:
• Judicious management of the dose of drug administered
• Guided by careful monitoring of effect and
• Aided by ancillary measures
• Not administering the drug at all, if the therapeutic indication is weak or if
other therapy is available.

126
 PD processes: Relation b/n drug dose &
clinical response…

ii. Therapeutic & toxic effects mediated by

identical receptors in different tissues (or via
different effector pathways)
Many drugs exert both their therapeutic & toxic
• Three therapeutic strategies are used to avoid or mitigate this sort of toxicity
• First, the drug should always be administered at the lowest dose that
produces acceptable benefit.

• Second, adjunctive drugs that act through different receptor mechanisms &
produce different toxicities may allow lowering the dose of the first drug, thus
limiting its toxicity
• E.g., use of other immunosuppressive agents added to glucocorticoids in

effects by acting on a single receptor type in

treating inflammatory disorders

• Third, selectivity of the drug’s actions may be ↑edby manipulating the conc
of drug available to receptors in different parts of the body
• E.g., by aerosol administration of a glucocorticoid to the bronchi in asthma

different tissues
E.g., Digitalis glycosides, Methotrexate

iii. Therapeutic & toxic effects mediated by

different types of receptors
Case study-1 answer

 Propranolol, a nonselective β-adrenoceptor blocker, is a useful

antihypertensive agent b/c it reduces CO & probably vascular
resistance as well
 However, it also prevents β 2 -receptor-induced bronchodilation
and may precipitate bronchoconstriction in susceptible
individuals
 CCBs such as verapamil also reduce BP but do not cause
bronchoconstriction or prevent bronchodilation
 An alternative approach in this pt would be to use a more highly PK & PD: Rational dosing & the time
selective adrenoceptor antagonist drug (e.g. metoprolol) that
binds preferentially to the β1 subtype, which is a major β course of drug action
adrenoceptor in the heart, & has a lower affinity (ie, higher Kd)
for binding the β2 subtype that mediates bronchodilation
 Selection of the most appropriate drug or drug group for one
condition requires awareness of the other conditions a pt may
have & the receptor selectivity of the drug groups available

127