prof. hanan hagar. foundation...–osmotic diuretics. –purgatives used in treatment of...
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Prof. hanan Hagar
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➢Identify different targets of drug action
Ilos
Elaborate on drug binding to receptors
Differentiate between their patterns of action; agonism versus antagonism
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Pharmacodynamics is a branch of pharmacology
that deals with the study of the biochemical and
physiological effects of drugs and their mechanisms
of action.
What is Pharmacodynamics?
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What are the mechanisms of drug action?
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How drugs produce action?What are targets for drug binding ?
Receptor-mediated
mechanisms
Non receptor-mediated
mechanisms
Drugs
Drug actions
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Drugs can produce their actions by one of the
following mechanisms:
1) Receptor-mediated mechanisms (Binding with
biomolecules):
• Receptors =Biomolecules = Targets
• Targets are mostly protein in nature.
1) Non receptor-mediated mechanisms
Physiochemical properties of drugs.
What are the mechanisms of drug action?
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Non receptor–mediated mechanisms
Drugs can produce actions by:
Chemical action
– Neutralization of gastric acidity by antacids.
Physical action– Osmotic diuretics.
– Purgatives used in treatment of constipation e.g. MgSO4
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Drugs can produce actions by binding with
biomolecules (Protein Targets)
Protein targets for drug binding
o Structural protein
o Regulatory proteins
▪ Physiological receptors
▪ Enzymes
▪ Ion channels
▪ Carriers
Receptor–mediated mechanisms
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> ProteinsTARGETS
STRUCTURAL
CARRIER MOLECULE
ENZYME ION CHANNEL
RECEPTOR
REGULATORY
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Receptors
Is a special target macromolecule that binds the
drug and mediates its pharmacological actions.
Where are receptors located?
• Cell membrane.
• Cytoplasm.
• Nucleus.
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Enzymes
• The drug competes with the natural endogenous
substrate for the enzyme.
• E.g. Anticholinesterases inhibit acetylcholinesterase
thus producing cholinomimetic action.
• Neostigmine reversibly compete with ACH for acetyl
cholinesterase enzyme at motor end plate
(neuromuscular junction).
• Organophosphates irreversibly competes with ACHfor acetyl cholinesterase enzyme.
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Ion channels
• Drugs bind to alter channel function (by opening
or blockade).
• Channels are responsible for influx or outflux of
ions through cell membranes.
• They are activated by alteration in action potential.
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Ion channels
e.g. local anesthetics:
act by blocking sodium (Na+) influx through Na
channel in nerve fibers (Na channel blockers).
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> ProteinsTARGETS REGULATORY
ION CHANNEL
Local Anesthetics block Na influx through Na channel in nerve fibers. They are Na channel Blockers.
L.Anaesthesia
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Ion channels
• e.g. Sulfonylurea drugs (antidiabetic drugs):
block potassium channels in pancreatic beta cells
resulting in depolarization and opening of calcium
channels and insulin secretion.
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Carrier molecules
o Drugs bind to such molecules to alter their transport ability.
o Responsible for transport of ions and small organic molecules between intracellular compartments, through cell membranes or in extracellular fluids.
o e.g. Na pump (Na+/K+ ATPase) blocked by digoxin.
o e.g. dopamine transporter blocked by cocaine.
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Carrier molecules
Digoxin:
blocks Na efflux via Na+/K+ pump or sodium-potassium pump (Na+/K+-ATPase ); used in the treatment of heart failure.
Cocaine: o blocks transport or reuptake of (catecholamines
mainly dopamine) at synaptic cleft. o The dopamine transporter can no longer perform
its reuptake function, and thus dopamineaccumulates in the synaptic cleft producing euphoria.
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> ProteinsTARGETS REGULATORY
CARRIER MOLECULE
Digoxin blocks efflux of Na by Na pump
Digoxin
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Effect of cocaine
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Tubulin
Structure
Structural proteins
e.g. Tubulin is target for drugs
as anticancer drugs and anti
gout drugs.
Tubulin is required for
microtubules formation
(cytoskeleton).
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Tubulin
Structur
e
Structural proteins
Vincristine
Anticancer that kills cancerous
cells by inhibiting microtubule
formation and cell division.
Colchicine
o used in treatment of gout
o binds to tubulin and inhibits
microtubule formation,
preventing neutrophil motility
and decreasing inflammation
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What are the binding Forces between drugs and receptors?
– Ionic bond.
– Van-Dar-Waal.
– Hydrogen bond.
– Covalent bond.
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AffinityAbility of a drug to combine with the receptor.
D + R D-R complex Effect.
Efficacy (Intrinsic Activity) –Capacity of a drug receptor complex (D-R) to
produce an action.– is the maximal response produced by a drug (E
max).
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Agonist
is a drug that combines with receptor and elicit
a response (has affinity and efficacy).
e.g. acetylcholine (Ach) acts upon muscarinic
receptors.
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Antagonist• is a drug that combines with a receptor
without producing responses.
• It blocks the action of the agonist.
• It has affinity but no efficacy or zero efficacy.
• e.g. atropine block the action of Ach on
muscarinic receptors.
• It has similar chemical structure to an agonist.
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Agonist and Antagonist
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Agonist
Full agonist.
Partial agonist.
Full Agonist
A drug that combines with its specific receptor to
produce maximal effect by increasing its
concentration (affinity & high efficacy).
e.g. acetylcholine (Ach).
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Partial Agonist
combines with its receptor & evokes a response (submaximal effect) regardless of its concentration (affinity & partial efficacy).
• e.g. pindolol
•a beta blocker which is a partial agonist, produces less decrease in heart rate than pure antagonists such as propranolol.
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Partial Agonist: Even though the drugs may combine
with the same number of receptors, the magnitude they
can produce may differ
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Affinity is the capacity of a drug to form
a complex with the receptor(DR complex)
The value of intrinsic activity ranges from 0 to 1
Efficacy(Intrinsic activity) the ability of the drug
once bound to the receptor to trigger response
Terms Definitions
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Affinity is the capacity of a drug to form
a complex with the receptor(DR complex)
Antagonist having full affinity to the receptor but
no intrinsic activity(0) e.g. atropine
Full agonist having a full affinity to the receptor and
a maximal intrinsic activity (1) e.g. acetylcholine
Partial agonist having a full affinity to the receptor
but with low intrinsic activity (<1) e.g. pindolol
Terms Definitions
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