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Pharmacodynamics
Sites of drug action
Agonists and antagonists
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Dr Trudie Binder
Department of Pharmacology
Pharmacology
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What is a drug?
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What is a drug?
An agent that interacts with specific target molecules
in the body and produces a physiological effect
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Atropa belladonna
Deadly nightshade is
native to Europe, North
Africa and West Asia.
Is considered a toxic
plant. Symptoms of
poisoning include:
dilated pupils,
tachycardia,
hallucinations, blurred
vision, loss of balance,
confusion and paralysis.
Contains Atropine, the prototype for all anticholinergic drugs
and is a competitive inhibitor of Ach.
Clinical uses include as an antidote to poisoning by anticholinesterases.
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Digitalis Purpurea
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Willow Bark
Willow bark has been used throughout
the centuries in China and Europe to
reduce fever and inflammation.
In 1829 Scientists discovered that
salicin was the active principal
constituent. This led to the synthesis
of salicylic acid and acetyl salicylic
acid [Asprin].
New uses for Aspirin
continue to be found:
Cardioprotective: anticoagulant.
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Pharmacodynamics
Pharmacodynamics is the mechanism
by which drugs exert their effect on the
body in order for a therapeutic action
to occur.
Pharmacodynamics encompasses:
Drug-receptor interactions
General principal of drug action
Dose Response
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Receptors
The site at which a ligand (agonist or
antagonist) can attach.
The majority of drug receptors are
proteins.
Ligands may be neurotransmitters,
hormones or local factors.
Activation of receptors by a agonist
produces a response (effect).
Affinity
Selectivity [drug acts preferentially with
only one receptor]
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Types of receptor
Ligand - gated ion channels
G-protein coupled receptors
Kinase-linked receptors
Nuclear receptors
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Rang, Dale, Ritter, Moore Pharmacology 5 edition Churchill Livingstone Edinburgh 2003
Receptor Sub-types
Receptors within a given family
generally occur in several subtypes
Cholinergic - muscarinic; nicotinic
Adrenergic receptor sub-types include
2 (lungs), 1 (heart) and 1 (blood
vessels)
Development of drugs which interact
ONLY with specific receptor sub-types
has revolutionised pharmacology.
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Side effects
Because: receptors for a drug occur in
several tissue, not just the target
tissue.
Because: of non specificity of drugs.
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Regulations
Until the 1930s drugs did not need to be
tested for safety or effectiveness.
Elixir of Sulfonamide
Tragedy of 1937 led to
the requirement that
drugs be tested for safety
before they reached the
market. 107 children
died.
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Thalidomide
Thalidomide was introduced
onto the European market
as a safe sedative/hypnotic
in the late 1950s.
Many pregnant women took
it for morning sickness.
Tested on male rats only;
no teratogen testing.
Thalidomide was found
to be a teratogen which
causes birth defects.
All drugs capable of crossing
the placenta are capable of
affecting the foetus.
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Effect
DR
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Dose - Response
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ED50
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Efficacy: is a
measure of the
effectiveness of a
drug in producing a
maximum response.
Full agonists have
high efficacy;
antagonists have no
efficacy.
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chart
Measurement of the
response can be done
for example in an
organ bath - or in
whole animals (eg,
recording blood
pressure or some
other variable)
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Histamine
Acetylcholine
Drug concentration at the receptor site is not known eg, Ach - may
be metabolised by AChE - hence they cannot be used to calculate
affinity.
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Tissue Prep
Log Dose (mol/l)
high
medium
Low dose
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Drug Antagonism
An Antagonist is a drug that has
affinity for a receptor but no efficacy.
Several types of antagonism:
Competitive (or surmountable) Antagonism
Non-Competitive (or irreversible) Antagonist
Physiological Antagonism
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Competitive Antagonism
Agonists and antagonists compete for
the same receptor sites.
Maximal effect unchanged (ie
antagonism is surmountable).
Parallel shift to the right
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Competitive Antagonism
Agonist
alone
Agonist
Competitive antagonist
Agonist +
low dose
antagonist
Agonist +
higher
dose of
antagonist
Higher
High medium
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Low
Non-competitive Antagonism
Irreversible antagonists can act on the
receptor itself, binding irreversible
Cause a change in the receptor so that
the agonist can no longer bind.
A maximum effect is no longer
produced.
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Non-competitive Antagonism
Agonist
Non-competitive
antagonist
Higher High
Medium
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Low
Physiological Antagonism
Occurs when 2 agonists act on
different receptors to produce opposite
effects.
The drugs have different mechanisms
of action.
Eg bronchoconstriction due to
histamine can be treated with
adrenaline which acts as a vasodilator.
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Partial Agonists
So far we have assumed:
agonist binds to receptor = response
antagonist binds to receptor = no response
Full agonists bind to receptors and very efficiently
give a response
Partial agonists are less efficacious 1. Never achieve maximum effect.
2. Also act as an antagonist.
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Partial Agonists
Full
Agonist
Partial
Agonist
Inverse Agonists
Agonist
response
Inverse
agonist
response
constitutive
activity
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Potentiation of Agonists
Potentiation usually occurs due to the
decreased inactivation of an agonist.
Acetylcholine in the presence of
anticholinesterase (neostigmine;
physostigmine).
Noradrenaline in the presence of an
uptake blocker (cocaine, tricyclic
anti-depressants).
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Therapeutic Ratio
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Tolerance
Tolerance: The same dose of drug, on
repeated administration, produces less
effect.
Tachyphylaxis: Tolerance which
develops very rapidly.
Desensitisation: Less effect is
produced the longer the agonist
remains in contact with the receptor.
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Desensitisation
Causes of desensitisation / tolerance
Change in receptors (phosphorylation)
Down regulation of receptors
(internalization / reduced expression)
Depletion of mediators
Increased metabolic breakdown
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Questions
Define agonist and antagonist:
Distinguish between affinity, efficacy
and potency:
Define ED50
What are the main features of
competitive antagonism:
What is a partial agonist:
What is a therapeutic ratio:
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