NOTRE DAME OF DADIANGAS UNIVERSTY (NDDU)

College of Pharmacy
COURSE TITLE PHARMACOLOGY I COURSE CODE Pharm26
CREDIT UNITS 3 units COURSE Human Physiology and
REQUISITES Pathophysiology
CONTACT HOURS 3 hours/week Contact 6hours/ Week 1 (Online)
54 hours/sem Hours/Date for
this topic ______________
COURSE 2nd Year, Summer SME: Melba M. Roma, RPh, MSPh
PLACEMENT
MODULE 1: Basic Principles of Pharmacology
Content Standards Demonstrate understanding on the basic concepts of Pharmacology
Objectives o Define pharmacology and discuss basic concepts of pharmacokinetics and
pharmacodynamics
o Describe receptor concepts, its interactions, signaling mechanism and drug
action

Flipped vidwatch-

PK- https://www.youtube.com/watch?v=NKV5iaUVBUI&ab_channel=SpeedPharmacology
PD- https://www.youtube.com/watch?v=tobx537kFaI&ab_channel=SpeedPharmacologySpeedPharmacologyVerified
https://www.youtube.com/watch?v=PGzT3cTPah8&ab_channel=ProfessorDaveExplainsProfessorDaveExplainsVerified
https://www.youtube.com/watch?v=t0OEm-cJs40&ab_channel=PharmapediaPharmapedia

PHARMACOLOGY
 The study or science of drugs
 The study of the biochemical and physiologic aspects of drug effects, including (
absorption, distribution, metabolism, excretion, toxicity, and specific mechanism of
drug action (LADMERT)

Two major areas of pharmacology:

1. Pharmacokinetics- refers to the way the body handles absorption, distribution,
metabolism (biotransformation), and excretion of drugs.
2. Pharmacodynamics- refers to the molecular, biochemical, and physiological effects
of drugs, including drug mechanism of action.
Originating in the 19th century, the discipline makes drug development
possible. Pharmacology is one of the cornerstones of the drug discovery process. The
medicinal chemist may create the candidate compound, but the pharmacologist is the one
who tests it for physiologic activity.

Drug  Any chemical that affects the processes of a living organism

- Any substance or product that is used for diagnosis, prevention, treatment/cure of a
disease or is intended to be used to modify or explore physiological systems or
pathological states for the benefit of the patient.

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Drug Nomenclature:
 Chemical name – from the drug’s chemical composition and molecular structure
 Generic name (nonproprietary name) - Name given by the United States Adopted Name
Council
 Trade name (proprietary name) - The drug has a registered trademark; use of the name
restricted by the drug’s owner (usually the manufacturer)

Ex. Chemical name : 2-(p-isobutylphenyl) propionic acid Comment [a1]: Ex. S-CMC, APAP, ASA,

Generic name: ibuprofen

Trade name : Motrin

Pharmaceutics - The study of how various drug forms influence pharmacokinetic and
pharmacodynamic activities

Pharmacokinetics -The study of what the body does to the drug: ADME (from LADMERT)

 Absorption
 Distribution
 Metabolism
 Excretion
Pharmacodynamics -The study of what the drug does to the body: The mechanism of drug
actions in living tissues

Pharmacotherapeutics -The use of drugs and the clinical indications for drugs to prevent and Comment [a2]: Clinical pharmacy

treat diseases

Pharmacognosy -The study of natural (plant, mineral and animal) drug sources

PHARMACOKINETICS

A. General Principles
1. Drug Transport. The movement of drug molecules in the body affects absorption,
distribution, and excretion. Drugs can cross cellular membranes by simple diffusion,
carrier-mediated diffusion, filtration, active transport, or endocytosis. The cell
membrane, being a bimolecular lipid layer, can also act as a barrier to some drugs.
a. Passive diffusion. Most foreign compounds penetrate cells by diffusing as
the un-ionized moiety through the lipid membrane. Factors affecting the
passage of the molecule through a membrane are the molecule’s size and
charge, the lipid-water partition coefficient, and the concentration gradient.

The two types of passive drug transport are simple diffusion and filtration.
1. Simple diffusion
a) Simple diffusion is based on Fick’s Law.

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 dQ/dt = (-D) (A) (dc/dx)

i. The greater the concentration gradient, the greater the

rate of absorption
ii. The larger the absorbing surface, the greater the drug
flux
iii. The diffusion constant, D, is directly proportional to the
temperature and is inversely related to the molecular
size.
iv. The greater the lipid-water partition coefficient, the
greater the drug flux.

b) In simple diffusion, molecules cross the lipid membrane in an

uncharged form. The distribution of the uncharged form is a
function of the pKa of the compound and the pH of the
medium and is expressed by the Henderson-Hasselbalch
equation:
i. If the drug is a weak acid:

pKa = pH + log concentration of unionized acid

concentration of ionized acid

ii. If the drug is a weak base:

pKa = pH + log concentration of ionized base
concentration of unionized base

c) The pH of the medium, therefore, affects the absorption and

excretion of passively diffused drug.
i. Aspirin and other weak acids are best absorbed in the
stomach because of its acidic environment
ii. Alkalinic drugs are best absorbed in small intestine,
which has a higher pH.
iii. Since pH of urine is acidic, a weakly acidic drug can be
extensively reabsorbed into the body from the urine. If
the pH of urine is increased, excretion of the drug can be
increased.

2. Filtration
a) Water, ions, and some polar and nonpolar molecules of low
molecular weight can diffuse through membranes, suggesting
that pores or channels may exist.

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 b) The capillaries of some vacular beds (e.g. in the kidney) have
large pores, which permit the passage of molecules as large as
proteins.

b. Carrier-mediated facilitated diffusion

1) In this type of transport, movement across the membrane is facilitated by

a macromolecule.
2) The properties of carrier-mediated diffusion are as follows:
a) It is a saturable process; that is, external concentrations can be
achieved in which increasing the external/internal concentration
gradient will not increse the rate of influx.
b) It is selective for the chemical structure of a drug; that is, the carrier
mechanism transports only those drugs having a specific molecular
configuration.
c) It requires no energy.
d) It cannot move against a concentration gradient, and, therefore, is
still a diffusion process.

c. Active transport

1) Active transport is similar to carrier-mediated diffusion in several ways:

a) Movement across the membrane is mediated by the macromolecule.
b) It is a saturable process.
c) It is selective for chemical structure.
2) Several important features, however, distinguish active transport from
diffusion processes:
a) It requires metabolic energy; this is often generated by the enzyme
known as Na+-K+-ATPase.
b) It transports molecules against a concentration gradient.
d. Endocytosis is a minor method by which some drugs are transported into cells
1) A vacuolar apparatus in some cells is responsible for the process.

2. BIOAVAILABILITY is the relative rate and extent to which an administered drug

reaches the general circulation; this is especially important when a drug is administered
orally. Factors that influence bioavailability are:

a. Solubility of the drug in the contents of the stomach

b. Dietary patterns
c. Tablet size

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 d. Quality control in manufacturing and formulation

B. Absorption -The rate at which a drug leaves its site of administration and the extent to
which absorption occurs.

 Bioavailability
 Bioequivalent
Bioequivalence. Two related drug preparations are bioequivalent if they show
 Comparable bioavailability
 Similar times to achieve peak blood concentrations.
Therapeutic equivalence. Two similar drug products are therapeutically equal if they
are pharmaceutically equivalent with similar clinical and safety profiles

1. Route of administration is an important determinant of the rate and efficiency of

absorption.

Factors That Affect Absorption:

1. Administration route of the drug

2. Food or fluids administered with the drug
3. Dosage formulation
4. Status of the absorptive surface
5. Rate of blood flow to the small intestine
6. Acidity of the stomach
7. Status of GI motility
Routes -A drug’s route of administration affects the rate and extent of absorption of that
drug.
I. Enteral route (alimentary) - Drug is absorbed into the systemic circulation
through the oral or gastric mucosa, the small intestine, or rectum.
 Oral
 SL
 Buccal
 Rectal
o Advantages:
o Disadvantages:

Drug Absorption of Various Oral Preparations

 Liquids, elixirs, syrups Fastest

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  Suspension solutions ↓
 Powders ↓
 Capsules ↓
 Tablets ↓
 Coated tablets ↓
 Enteric-coated tablets Slowest

Extensive hepatic metabolism may occur before the drug reaches the site of action.
This is known as First-Pass Effect.
o The metabolism of a drug and its passage from the liver into the circulation.
o A drug given via the oral route may be extensively metabolized by the liver before
reaching the systemic circulation (high first-pass effect).
o The same drug—given IV—bypasses the liver, preventing the first-pass effect from
taking place, and more drug reaches the circulation.

Routes that bypass the liver: Sublingual, Transdermal, Buccal, Vaginal, Rectal*,
Intramuscular, Intravenous, Subcutaneous ,Intranasal Inhalation
*Rectal route undergoes a higher degree of first-pass effects than the other routes
listed.

II. Parenteral route- bypass the alimentary tract

 Intravenous - Fastest delivery into the blood circulation
 Intramuscular
 Subcutaneous
 Intradermal
 Intrathecal
 Intraarticular
o Advantages:
o Disadvantages:

III. Miscellaneous route

 Topical - Skin (including transdermal patches), Eyes , Ears , Nose
 Inhalation-lungs
 Vagina

2. Factors affecting drug absorption

a. Solubility of the drug affects absorption
b. Dosage affects the drug’s concentration at its site of action and, thus,
greatly influences the biologic response to the drug. The larger the dose,

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 the greater the effect, until a maximum effect is achieved. This is called
the dose-response relationship.
c. Route of administration affects the area of absorbing surface available
to the drug. Drugs are absorbed more quickly from large surface areas.
1) After any route of administration except intravenous
administration, the absorption of most drugs follows first-order
(exponential) kinetics; thus a constant fraction of drug is
absorbed
2) After IV administration, the absorption of drug follows zero-
order kinetics; thus, a constant amount (i.e.) 100% of drug is
absorbed.

C. Distribution. After absorption or injection, drugs may be distributed into interstitial or

cellular fluids.

1. Once in the circulatory system, some drugs can bind nonspecifically and reversibly
to various plasma proteins; that is to albumins or globulins.
a. In this case, the bound and free drug reach an equilibrium
b. Only the free drug exerts biologic effect; the bound drug stays in the vascular
space, and is not metabolized or eliminated.
2. Some areas of the body (e.g. the brain) are not readily accessible to drug due to
anatomic barriers. The placenta also provides a barrier to some drugs.
3. Some drugs may be sequestered in storage depots; for ex., lipid-soluble drugs in
fatty tissue and in equilibrium with free circulating drug.
4. Eventually, the drug achieves a free state and is excreted either directly or after it
has been metabolized.
5. Factors modifying the distribution of a drug to a particular region of the body:
a. Physical and chemical characteristics of the drug (lipid to water partition
coefficient)
b. Cardiac output
c. Capillary permeability in various tissues
d. Lipid content of the tissue
e. Binding to plasma proteins and tissues

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D. Drug Metabolism (also known as Biotransformation)
It is the biologic transformation of a drug into an inactive metabolite, a more soluble
compound, or a more potent metabolite.
1. Principles:
a. The liver is the major site of metabolism for many drugs or other xenobiotocs,
but other organs, such as the lungs, kidneys, and adrenal glands, can also
metabolize drugs.
b. Many lipid-soluble, weak organic acids or bases are not readily eliminated
from the body and must be conjugated or metabolized to compounds that are
more polar and less lipid-soluble before being excreted.
c. Metabolism often, but not always, results in inactivation of the compound.
d. Some drugs are activated by metabolism. These substances are called
prodrugs.

2. Biochemical reactions involved in drug metabolism occur in two phases.

Phase I Reactions (Non synthetic) alter chemical reactivity and increase
aqueous solubility. Ex. Oxidation, reduction, hydrolysis
Phase II Reactions (synthetic) further increase the solubility, promoting
elimination. Ex. Conjugation
a. Oxidation, (removal of H+) the most common metabolic reaction, involves
the addition of oxygen or the removal of hydrogen from the drug.
1) Microsomal Oxidation
a) The smooth endoplasmic reticulum of cells in many organs,
especially the liver, contains membrane-associated enzymes,
which are responsible for drug oxidation. This enzyme system has
been termed a mixed-function oxygenase. The subcellular
components of the endoplasmic reticulum, called microsomes, can
be isolated by centrifugation of organ homogenates.
b) The primary components of this enzyme system are cytochrome
P-450.
c) Types of microsomal oxidation reactions are:
i. Carbon oxidation-hydroxylation of aliphatic or aromatic
groups (e.g. pentobarbital and phenytoin)
ii. N- or O-dealkylation (e.g. diazepam and codeine)
iii. N-oxidation or N-hydroxylation (e.g. 2-acetylaminofluorene)
iv. Sulfoxide formulation (e.g.chlorpromazine)
v. Deamination (e.g. amphetamine)
vi. Desulfuration (e.g. thiobarbital)

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 2) Nonmicrosomal oxidation
a) Soluble enzymes found in the cytosol or mitochondria of cells are
responsible for the metabolism of relatively few compounds. These
enzyme activities are, however, important.
i. Alcohol dehydrogenase and aldehyde dehydrogenase,
which oxidize ethanol to acetaldehyde and acetate,
respectively, in reactions requiring oxidized nicotinamode
adenine dinucleotide (NAD+)
ii. Xanthine oxidase, which converts hypoxanthine to xanthine
and xanthine to uric acid
iii. Tyrosine hydroxykase, which is important to the metabolism
of catecholamines and serotonin
b. Reduction (addition of H+) occurs in both the microsomal and
nonmicrosomal metabolizing systems, it is less common than oxidation.
i. Ex. Of microsomal reduction include nitro (chloramphenicol)
and azo (prontosil)
ii. Ex. Of nonmicrosomal reduction include aldehyde (chloral
hydrate), ketone (naloxone), and quinone (menadione)
c. Hydrolysis
1) Nonmicrosomal hydrolases exist in a variety of body systems,
including the plasma. Examples.
a) Nonspecific esterases for drugs, such as acetylcholine,
succinylcholine, and procaine
b) Peptidases (e.g. proinsulin)
c) Amidases for drugs, such as procainamide and indomethacin
d. Conjugation involves coupling of a drug or its metabolite with an
endogenous substrate, usually inorganic sulfate, a methyl group, acetic acid,
an amino acid, or a carbohydrate. Usually, a conjugate is a readily excreted
polar substance.
1) Glucuronide conjugation is the most common conjugation reaction
which occurs frequently with phenols, alcohols, and carboxylic acids.
Glucuronides ae generally inactive and are rapidly excreted in urine or
bile by anionic transport systems.
2) Other conjugation reactions. All conjugatins except glucuronide
formation are catalyzed by nonmicrosomal enzymes. These include
a) Sulfate formation, in which phenols, alcohols, and aromatic
amines are converted to sulfates and sulfanilates, (e.g. steroids)
b) O-, S-, and N-methylation (e.g. norepinephrine)
c) N-acetylation (e.g. isoniazid)

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 d) Lycine and glutamine conjugation with acids (e.g. salicylic acid)
e) Glutathione conjugation (e.g. ethacrynic acid)

3. Factors affecting drug metabolism

a. Genetics. The most important factor is genetically determined
polymorphisms.(water-soluble)ex. Acetylation of INH and hydrolysis of
succinylcholine are genetically controlled.
b. Chemical properties of the drug. Certain drugs may stimulate or inhibit
the metabolism of other drugs (e.g. phenobarbital stimulates the
metabolism of diphenylhydantoin)
c. Route of administration. The oral route , for example, can result in
extensive hepatic metabolism of some drugs (the first-pass effect).
d. Diet . Starvation can deplete glycine stores and alter glycine conjugation
e. Dosage. Toxic doses can deplete enzymes needed for detoxification
reactions.
f. Age. The liver cannot detoxify drugs, such as chloramphenicol, as well in
neonates as it can in adults.
g. Gender. Young males are more prone to sedation from barbiturates than
in females.
h. Disease. Liver disease decreases the ability to metabolize drugs, while
kidney disease hampers the excretion of drugs.
i. Species difference. Experimental findings in animals do not necessarily
translate to humans.
j. Circadian rhythm. The rate of hepatic metabolism of some drugs follows
a diurnal rhythm.

Factors that decrease metabolism:

 Cardiovascular dysfunction
 Renal insufficiency
 Starvation
 Obstructive jaundice
 Slow acetylator
 Erythromycin or ketoconazole drug therapy

Factors that increase metabolism:

 Fast acetylator
 Barbiturates
 Rifampin therapy

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 Delayed drug metabolism results in:
 Accumulation of drugs
 Prolonged action of the effects of the drugs
Stimulating drug metabolism causes:
 Diminished pharmacologic effects

E. Drug Excretion – The elimination of drugs or metabolite from the body

1. Rate of elimination
a. For most drugs, elimination from the blood (liquid soluble) follows
exponential (first-order) kinetics. The fractional change in the amount of
drug in the plasma or blood per unit of time is expressed by the half-life
(t ½ )- or by the elimination rate constant (k), which is equal to
0.693/ t ½
2. Routes of elimination
a. The kidney is the most important organ for excretion of drugs and their
metabolites which involves the three processes:
i. Glomerular filtration
ii. Passive tubular reabsorption
iii. Active tubular secretion
b. The biliary tract and the feces are important routes of excretion for
some drugs that are metabolized in the liver.
c. Other routes. Drugs and their metabolites can also be eliminated in
expired air, sweat, saliva, tears, and breast milk. And they tend to be lipid-
soluble and nonionized.

Half-Life

 The time it takes for one half of the original amount of a drug in the body to be
removed.
 A measure of the rate at which drugs are removed from the body. Comment [a3]: Ex.250mg/hr

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 F. Effect of repeated doses

A drug accumulates in the body if the time interval between doses is less than four of its
half-lives, in which case the total body stores if the drug increases exponentially to a
plateau and is known as steady-state concentration.

PHARMACODYNAMICS
Action of drugs in the body; the cellular processes involved in the drug and cell
interaction

A. Mechanism of drug action

1. Most drugs interact with macromolecular components, called receptors, of a cell or
an organism to begin biochemical and physiologic changes that produce the drug’s
observed effects or response.
a. Receptors bind ligands and transduce signals.
b. Drug receptors are identified primarily by the effect or lack of effect of
antagonists and the relative strength of agonists.

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 1) A drug is called an agonist if it produces some of the effects of
endogenous compounds when it interacts with the receptor. The
agonist, acetylcholine, has intrinsic activity.
2) An antagonist is a drug that has no intrinsic activity yet can reduce
or abolish the effect of an agonist.
a) Examples of pure antagonists are atropine and curare, which
inhibit the effect of acetylcholine.
b) Atropine and curare occupy cholinergic receptor sites,
preventing the further binding of acetylcholine to these
receptors
3) Some drugs (e.g. nalorphine) are partial agonists; that is, they
possess some intrinsic activity.
2. Other drugs may not cause a response by interacting with receptors. These drugs may
combine with small molecules or ions found in the body (e.g., chelating agent).

B. RECEPTORS Comment [a4]: A receptor are protein that

binds to an extracellular ligand , and then
undergoes a conformational or biochemical shift
The term receptor is used in pharmacology to denote a class of cellular macromolecules that in such a way that it initiates a chain of
intracellular events by which the cell reacts to
are concerned specifically and directly with chemical signaling between and within cells. Thru the extracellular signal .
the MOA: Comment [a5]: mostly proteins

• Affinity: The capability of a drug to form the complex (Drug Receptor Complex)
with its receptor.
• Intrinsic activity: The ability of a drug to trigger the pharmacological response
after making the drug-receptor complex.
D + R  DR
Where
 D: Drug or endogenous ligand
 R: Receptor
 DR: Drug-Receptor Complex

Chemistry of Drug-Receptor Interactions: Most drug-receptor interactions

 are reversible
 weak chemical bonds

Irreversible drug-receptor interactions Comment [a6]: gives undesirable effects

 not common
 strong chemical bonds (covalent)
 e.g. aspirin, anti-tumor drugs
 usually undesirable
o reversal of effects/toxicity
o mutagenicity/carcinogenicity

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 Agonist: These are the drugs which have both high affinity as well as high intrinsic
activity.
Antagonist: – These are the drugs which have only the affinity but no intrinsic activity. Comment [a7]: in their mechanism to receptors
Vidwatch https://www.youtube.com/watch?v=nqmLitfBrz4&t=832s

Types of receptors
1. Ligand-gated ion channels
2. G protein coupled receptors
3. Enzyme-linked receptors
4. Intracellular receptors

Ligand-gated ion channels Comment [a8]: in chem, a ligand is an ion or

molecule (functional group) that binds to a
 The first receptor family comprises ligand-gated central metal atom to form a coordination
ion channels that are responsible for regulation complex.
of the flow of ions across cell membranes
 The activity of these channels is regulated by
the binding of a ligand to the channel.
 Response to these receptors is very rapid, having durations of a few
milliseconds.
 The nicotinic receptor and the gamma-aminobutyric acid (GABA)
receptor are important examples of ligand-gated receptors, the functions of
which are modified by numerous drugs
 Agonist opens the channel.
 Antagonists prevents agonist from opening the channel
 Inverse agonist closes an open channel

G protein coupled receptors

 A second family of receptors consists of
G protein coupled receptors.
 These receptors are comprised of a
single peptide that has seven
membrane-spanning regions, and these
receptors are linked to a G protein (Gs
and others) having three subunits.
 Binding of the appropriate ligand to the
extracellular region of the receptor
activates the G protein so that GTP
replaces guanosine diphosphate (GDP)
on the subunit.
 Stimulation of these receptors results in
responses that last several seconds to minutes.

Enzyme-linked receptors

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  A third major family of receptors
consists of those having 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.
 The most common enzyme-linked
receptors (epidermal growth factor,
platelet-derived growth factor, atrial
natriuretic peptide, insulin, and
others) are those that have a tyrosine
kinase activity as part of their structure Comment [a9]: tyrosine kinase is an enzyme
that can transfer a phosphate group from ATP to
 Typically, upon binding of the ligand to receptor subunits, the receptor undergoes the tyrosine residues of specific proteins inside a
conformational changes, converting from its inactive form to an active kinase cell. It functions as an "on" or "off" switch in many
cellular functions.

Intracellular receptors
 The fourth family of receptors differs considerably
from the other three in that the receptor is entirely
intracellular and, therefore, the ligand must
diffuse into the cell to interact with the receptor.
 This places constraints on the physical and
chemical properties of the ligand in that it must
have sufficient lipid solubility to be able to move
across the target cell membrane.
 Because these receptor ligands are lipid soluble,
they are transported in the body attached to plasma
proteins, such as albumin.
 For example, steroid hormones exert their action on
target cells via this receptor mechanism.

Receptor Regulation

Overview

 Intrinsic Regulation • receptors initiate regulation of a variety of events and are themselves
subject to regulatory and homeostatic controls.
 Disease States • disease states can alter the number, function, and/or activity of receptors.

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 Comment [a10]: a group of substances that bind
 Drugs • drugs can act as agonist, antagonists and allosteric modulators all of which can alter to a receptor to change that receptor's response to
receptor function and number. stimulus.
Allostery-capable to change or being changed

Intrinsic Regulation • receptors are subject to regulation and

homeostatic control. Left unregulated, receptors may be over
stimulated, which may lead to pathological changes, including
apoptosis. Therefore, regulation helps protect cells. There are
times when an increased response is needed and others when a
decreased response is preferred.

Cellular mechanisms of Increased Response

 Super/Hyper Sensitivity
 Synergism
 Upregulation Comment [a11]: Sensitive response

Super/Hypersensitivity • Super or hypersensitivity refers to an

enhanced response to an agonist. Hypersensitivity may occur as
a result of unmasking of receptors or accentuation of signal
amplification.

 Unmasking of Receptors • some receptors have a masking protein covering the intracellular
portion of a receptor, like the GPCR seen below for example. This masking protein prevents
signal transduction and leads to decreased activity. When a masking protein in removed,
activity increases.

 Accentuation of Signal Amplification • this may occur with an increase in receptor

phosphorylation or increased enzymatic activity. As was discussed earlier, phosphorylation Comment [a12]: A biochemical process that
involves the addition of phosphate to an organic
can lead to the activation of a chain of second messengers and signal amplification. Therefore, compound. Examples include the addition of
as phosphorylation increases, so does signal transduction and amplification. Likewise, there phosphate to glucose to produce glucose
are enzymes that catalyze components in a signal transduction pathway leading to increased monophosphate and the addition of phosphate to
adenosine diphosphate (ADP) to form adenosine
signal transduction and amplification as well. triphosphate (ATP).
It regulates protein function and cell signaling by
causing conformationl changes in the phosphate
Synergism • when two receptors produce a combined effect that is greater than the sum of group.
their individual effect.

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 Upregulation • Upregulation refers to an increase in the number of receptors due to prolonged
deprivation of receptors of interacting with their physiological neurotransmitter (e.g. by
denervation of chronic use of a receptor antagonist). By expressing more receptors, there is a
greater probability that a hormone will bump into and stimulate its receptor.

Cellular mechanisms of Decreased Response

 Desensitization
 Downregulation Comment [a13]: Lead to tolerance
 Tachyphylaxis
 Tolerance

Desensitization • Desensitization refers to a reduced response to an agonist drug due to over

activation of a receptor (high doses, prolonged exposure to agonist). There is a number of
mechanisms of desensitization including: loss of receptor function through a decrease in
receptor-coupled signaling components (e.g., G-proteins). Receptor desensitization may occur
in the absence of significant changes in the number of receptors.

This example here demonstrates loss of receptor function; one of several types of
desensitization. As you can see on the far right, the agonist is bound to
the receptor, however, this does not result in the channel opening.

Downregulation • Downregulation specifically refers to a reduction in

the total number of receptors available to be stimulated due to
prolonged receptor activation (e.g. by chronic treatment with a
pharmacological agonist drug or prolonged inhibition of metabolism of a
neurotransmitter). This reduction in receptors in turn will decrease the
cell’s sensitivity to an agonist or drug. Downregulation occurs through
endocytosis. Internalized receptors may either be degraded in the
lysosomes or recycled back to the membrane surface later.

As the image shows, endocytosis involved the internalization of a

receptor preventing it from carrying out signal transduction. A receptor
may either go to the endosome then lysosome to be degraded or
recycled back to the membrane surface to once again carry out signal
transduction.

Tachyphylaxis • Tachyphylaxis is a rapid decrease in response to an agonist drug following

repeated administration within a brief period; an acute form of desensitization. This can occur
without a change in the number of receptors or the ability of a receptor to affect the

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downstream signaling molecules. Increasing the dose of the drug will not improve the
response.

Tolerance • Tolerance refers to a gradual decreased response to a drug, requiring a higher

dose of drug to achieve the same initial response. Tolerance is different from tachyphylaxis
because it develops over a long period of time, whereas, tachyphylaxis is an acute event. In
addition, tolerance can be overcome by increasing the dose, unlike tachyphylaxis.

Changes in receptor response by disease states

Disease states may alter the number of available receptors, which can alter the sensitivity
and response of a given cell or tissue. Disease states may therefore alter the actual function
or activity of those receptors; either through loss or gain of function.
Example • Loss of Receptors

Myasthenia Gravis is an autoimmune disorder in which antibodies destroy nicotinic

acetylcholine receptors [nAChR] located in skeletal muscle. nAChRs help communicate
signals resulting in muscle contraction. Thus, Myasthenia Gravis causes muscle weakness,
droopy eyes and even difficulty in swallowing.

Myasthenia Gravis is treated with immunosuppressants to decrease the production of

antibodies that destroy nAChRs as well as with acetylcholine esterase inhibitors [AChEIs] that
prevent the breakdown of acetylcholine, a nAChR agonist, to increase its level in the synapse.

Example • Loss of Function • Androgen Receptors [AR]

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Androgen receptors have variants caused by genetic mutations. These variants have varied
levels of function, ranging from partial to complete loss of function. Individuals who have
complete AR insensitivity exhibit Complete Androgen Insensitivity Syndrome [CAIS], and
those who have partial AR insensitivity suffer from Partial Androgen Insensitivity
Syndrome [PAIS]. Both syndromes cause a loss of receptor function.

Treatment for these syndromes includes hormone therapy; testosterone and/or

dihydrotestosterone [DHT]. One great advantage of DHT over testosterone is that cannot be
aromatized to estrogen, eliminating possible side effects associated with estrogen exposure.

Example • Gain-of-Function •A number of endocrine diseases are caused by gain-of-function

mutations of GPCRs.

Type 2 Diabetes Mellitus [DM2] • DM2 can be associated with a gain-of-function mutation,
resulting in increased expression of the α2 (A-adrenergic receptor 2); a GPCR that
prevents or suppresses the secretion of insulin. As you can imagine, a patient with this gain-of-
function mutation will have elevated blood glucose, potentially leading to type II diabetes
mellitus.

Familial Hypocalcemia Hypocalciuria • This disease involves a gain-of-function mutation of

the calcium-sensing receptor [CaSR]; a GPCR that allows the body to monitor and regulate
the amount of calcium in the blood. This gain-of-function leads to increased sensitivity to
calcium. Because CaSR maintains calcium homeostasis, its exaggerated response to calcium
tells the body to excrete more calcium. This leads to decreased calcium levels in the blood
(hypocalcemia) by suppressing the secretion of parathyroid hormone and increased renal
excretion of calcium (hypercalciuria).

The synapse

How neurons communicate with each other at synapses. Chemical vs. electrical synapses.
A single neuron, or nerve cell, can do a lot! It can maintain a resting potential—voltage
across the membrane. It can fire nerve impulses, or action potentials. And it can carry out the
metabolic processes required to stay alive.
A neuron’s signaling, however, is much more exciting when we consider its interactions with
other neurons. Individual neurons make connections to target neurons and stimulate or inhibit
their activity, forming circuits that can process incoming information and carry out a response.

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How do neurons "talk" to one another? The action happens at the synapse, the point of
communication between two neurons or between a neuron and a target cell, like a muscle or a
gland. At the synapse, the firing of an
action potential in one neuron—
the presynaptic, or sending, neuron—
causes the transmission of a signal to
another neuron—the postsynaptic, or
receiving, neuron—making the
postsynaptic neuron either more or less
likely to fire its own action potential.

Chemical transmission involves release of chemical messengers known

as neurotransmitters. Neurotransmitters carry information from the pre-synaptic—sending—
neuron to the post-synaptic—receiving—cell.
As you may remember from the article on neuron structure and function, synapses are usually
formed between nerve terminals—axon terminals—on the sending neuron and the cell body or
dendrites of the receiving neuron.

A single axon can have multiple branches, allowing it to make synapses on various
postsynaptic cells. Similarly, a single neuron can receive thousands of synaptic inputs from
many different presynaptic—sending—neurons.
Inside the axon terminal of a sending cell are many synaptic vesicles. These are membrane-
bound spheres filled with neurotransmitter molecules. There is a small gap between the axon
terminal of the presynaptic neuron and the membrane of the postsynaptic cell, and this gap is
called the synaptic cleft.

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When an action potential, or nerve impulse, arrives at the axon terminal, it activates voltage -
gated calcium channels in the cell membrane. Ca2+, which is present at a much higher
concentration outside the neuron than inside, rushes into the cell. The Ca2+ allows synaptic
vesicles to fuse with the axon terminal membrane, releasing neurotransmitter into the synaptic
cleft.

The molecules of neurotransmitter diffuse across the synaptic cleft and bind to receptor
proteins on the postsynaptic cell. Activation of postsynaptic receptors leads to the opening or
closing of ion channels in the cell membrane. This may be depolarizing—make the inside of
the cell more positive—or hyperpolarizing—make the inside of the cell more negative—
depending on the ions involved.
References:
https://www.slideshare.net/rajud521/pharmacological-principles
https://www.slideshare.net/harshit172/receptor-pharmacology-115226744
https://open.lib.umn.edu/pharmacology/chapter/receptor-regulation/
https://www.khanacademy.org/science/biology/human-biology/neuron-nervous-system/a/the-synapse
Refer to the video https://www.neuroscientificallychallenged.com/glossary/g-protein-coupled-receptor

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