Download Pharmacology introduction Lecture three Dr. nahlah 21-10

Pharmacology introduction
Lecture three
Dr. nahlah
21-10-2015
Pharmacodynamic Phase
•Describes the biochemical and physiologic action and effects of drugs in the
body.
•This phase occurs when the medication reaches the target cell, tissue, organ and
a therapeutic effect occurs.
•It is the study of the biological and therapeutic effects of drugs and their
mechanisms of action i.e. effect of drug on the body.
Mechanism of drug action:
Physical action, alter of the environment of the cell through physical
e.g., mannitol induces osmotic diuretics and kaolin adsorbs toxins in diarrhea.
Chemical action, alter of the environment of the cell through chemical
processes that usually do not affect cell function. e.g,. NaHCO3 in hyperacidity
and dimercaprol (BAL) to chelate mercury.
Cytotoxic action (stop cell division), e.g., anticancer drugs.
Interfere with selective passage of ions as Ca +2 and Na+ entry
e.g. local anaesthetics and antiarrhythmic drugs.
Interference with normal metabolic pathway, e.g.,
sulphonamides competes with PABA which is essential for bacterial
growth.
Action on enzyme either stimulation or inhibition. Enzyme
inhibition could be:
1. Reversible which is usually short lasting as allopurinol
(xanthine oxidase inhibitor), neostigmine (cholinesterase
inhibitor, ....)
2. Irreversible which is usually long-lasting for new enzyme
synthesis, e.g., irreversible anticholinesterases.
Action on specific receptors (Drug Receptor Interactions):
receptors are macromolecular protein structures present on cell
membrane or within the cell (cytoplasmic or nuclear) that react
specifically with a ligand (drug, hormone or neurotransmitter) to
produce a biological response. Receptors transduce (translate) the
signal from the ligand to several subcellular elements e.g. enzymes,
second messengers or ion channels to produce intracellular
biochemical response.
Drugs can be categorized into:

Agonists are drugs, which stimulate receptors, i.e., initiate
changes in cell function producing effects of various types. They have
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affinity, efficacy and rapid dissociation rate. Agonist potency
depends on affinity (i.e. tendency to bind receptors) and efficacy (i.e
ability to initiate changes which lead to effect).

Antagonists are drugs which block receptors, i.e. they bind to
receptors without initiating change in receptors. They have affinity,
no efficacy and slow dissociation rate. They have no effect in absence
of agonist, but prevent action of agonist. Antagonist may be
competitive or non-competitive.
A. Reversible competitive antagonist where antagonist competes
for the same receptor and can be displaced by an excess agonist. A
reversible competitive antagonism causes a parallel shift of the log
dose response curve to the right. So slope and maximum effect are
not changed.
B. Irreversible non competitive antagonist where the
antagonist cannot be overcome by excess agonist. A non-competitive
antagonist decreases efficacy of the agonist, so it shifts the log dose
response curve to the right and changes the slope of the curve e.g.
phenoxybenzamine.
Competitive antagonism
Maximum response (Emax) is the same
ED50 is shifted to right
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Non competitive antagonism
Emax is decreased
ED50 is constant

Partial agonists are drugs which stimulate and block receptors,
so they have affinity, efficacy (less than full agonist) and moderate
dissociation rate.

Inverse agonists: produce effects opposite to that of agonist e.g.
benzodiazepines (Bz) are agonists of Bz receptors _ sedation, muscle
relaxation and anxiolytic action, while carbolines are inverse agonists
of the same receptors_convulsions and anxiety.
Affinity Efficacy Dissociation rate Examples
Agonist
Antagonist
Partial agonist
Inverse agonist
+
+
+
+
+++
-+
+++
Rapid
Slow
Moderate
Rapid
Diazepam
Flumazenil
Buprenorphine
Carbolines
Types of Antagonists
1- Pharmacological Antagonists


Competitive Antagonist
o They compete for the binding site.
o Reversible & Surmountable
o The effect of a reversible antagonist can be overcome by more drug
(agonist). A small dose of the antagonist (inhibitor) will compete
with a fraction of the receptors thus, the higher the concentration of
antagonist used, the more drug you need to get the same effect.
Non-competitive Antagonist
o Bind elsewhere in the receptor (Channel Blockers).
o Irreversible & Non-surmountable
o The effect of irreversible antagonists cannot be overcome by more
drug (agonist). The antagonist inactivates the receptors.
2-Functional Antagonists

Physiologic Antagonist
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•A drug that binds to a non-related receptor, producing an effect opposite to that
produced by the drug of interest.
•Its intrinsic activity is = 1, but on another receptor.
Glucocorticoid Hormones  Blood Sugar
Insulin
 Blood Sugar
 Chemical Antagonist
•A chelator (sequester) of similar agent that interacts directly with the drug being
antagonized to remove it or prevent it from binding its receptor.
•A chemical antagonist does not depend on interaction with the agonist’s receptor
(although such interaction may occur).
Heparin, an anticoagulant, acidic
If there is too much  bleeding and haemorrhaging
Protamine sulfate is a base. It forms a stable inactive complex with heparin and
inactivates it.
Receptors and signal transduction mechanism
Binding of agonist to receptors activates effectors or signaling
mechanisms of different types:
(1) Ion-channel linked receptors (Ligand-gated ion channel)
e.g. nicotinic andGABAA receptors. The response takes milliseconds.
Acetylcholine binds to nicotinic receptors
Na+ influx
depolarization
GABA binds to GABAA receptors
Cl- influx
hyperpolarization.
(2) G-protein Linked Receptors
Examples: glucagon, α and β adrenergic receptors and
muscarinic receptors. The time elapsed between binding to receptor
and cellular response is few seconds. These receptors comprise a
seven transmembrane or serpentine receptors because receptor
polypeptide chain snakes across cell membrane 7 times. When the
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agonist binds to the binding domain, G-protein will be activated to
transduce the agonist-induced signal to a variety of effector elements
(adenylcyclase, phospholipase or ion channel) located either
intracellular or in the cell membrane. These effector elements then
change the concentration of an intracellular second messenger.
Second messengers: include cAMP, Ca++ ion and phosphoinositides
and cGMP
(3) Membrane tyrosine kinase linked receptors : e.g. receptors
for insulin whichact on membrane receptors which can phosp
horylate signal transducers and activators of transcription (STAT)
molecules, which dimerize and then dissociate from the receptor to
cross the nuclear membrane and modulate gene transcription.
(4) DNA Linked receptors (intracellular receptor) e.g.
corticosteroids, vitamin D and thyroxine. Agonist binds to its
domain; the hsp 90 domain is released leaving DNA binding domain
that regulates gene transcription, translation and consequently
protein synthesis. The response has slow onset (hours) and has long
duration.
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