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Introduction to Pharmacology

Pharmacodynamics
Sites of drug action
Agonists and antagonists
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Dr Trudie Binder
Department of Pharmacology

Pharmacology

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The age of Herbs, potions and


Magic
Ancient civilizations around the world have
used plant extracts as medicines.
Many of these are merely placeboes but
some ancient remedies are truly effective.
Willow bark; opium
In many cultures the administration of
remedies was accompanied by magic or
religious rituals.
An appreciation that natural products
themselves had the power to cure began
to emerge.
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Many poisonous mixtures were made.

The birth of modern Science and


Pharmacology.
The 16th and 17th centuries were notable for the
simultaneous development of physiology,
chemistry and physics.
Physiologists documented the way in which the
body functioned and chemists began to develop
the technologies which permitted extractions,
purification, and the synthesis of chemical
substances from plants.
These trends began to merge as the discipline of
Pharmacology: the study of the actions of
drugs or chemical substances on
physiological processes.
First Professor in Pharmacology was
appointed in 1847 at the Imperial Russian
University in Dorp; Estonia.
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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

The purple foxglove is native to


most of Europe.
From the leaves of this plant the
cardiac glycosides digitoxin and
digoxin were isolated. These drugs
are still used to treat heart failure.
The leaves flowers and seeds of
Digitalis are all poisonous and can
be fatal if eaten.
At the right dosage the digitalis
toxin can cause the heart to
beat more strongly preventing
heart failure.
Symptoms of Digitalis poisoning
include a low pulse rate, nausea,
vomiting, cardiac arrest and finally
death.

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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

Pharmacokinetics is what the body


does to the drug [absorption,
distribution, elimination].
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Two main types of drugs


Drugs with activity at high
concentrations -little structural
specificity. Cause physical change
(general anaesthetics).
Drugs acting at low concentrations structural specificity. Act by chemical
rather than physical interaction
(Isoprenaline).

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Agonists and Antagonist


Agonists mimic endogenous ligands.
They bind to a receptor and cause a
secondary effect.
An antagonist binds to a receptor and
prevents the action of an agonist.

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Lock and Key Model

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Agonists and Antagonists

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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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th
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.

Clinical trials were not required.


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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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Life article on thalidomide


In Britain an armless
babys play

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Drug - receptor interaction


Assumed that the effect of a drug is
proportional to the fraction of
receptors occupied.
Assumed that the maximal effects
occurs when all receptors are
occupied.
These assumptions are not always
true.

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Drug (D) + Receptor (R)

Effect

DR

1. Binding of drug to receptor - affinity


2. Response to binding - efficacy
(intrinsic activity).

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Dose - Response

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ED50 (or EC50)


The KD is a binding constant and refers
to Receptor binding sites.
Assumed: effect is proportional to
receptor occupancy and maximal
effect occurs when all receptors are
occupied.

KD becomes the ED50 ie the dose that


produces a 50% effect.

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Log Dose-Response Curve

ED50
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Potency and Efficacy


Potency: is a
measure of the drug
dosage needed to
produce a particular
therapeutic effect.
It is determined by
the strength of
binding of a drug to a
receptor or the
receptor affinity for
the drug.

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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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Dose - Response measurement


Force
transducer

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)

Addition of a known dose of drug leads to a measurable


response - so a dose-response relationship can be built up.
Within a given dose range, higher the dose the higher the
response (allow for wash-out and recovery).
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Dose Response Measurement

Sigmoidal curves although


effects downstream of drugreceptor interaction are
measured.

Histamine

Acetylcholine

Log Dose (mol/l)

Measure the effect of an


agonist on a response (BP,
contraction or relaxation of a
piece of smooth muscle)

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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Dose Response Measurement


Agonist

Tissue Prep
Log Dose (mol/l)
high

medium
Low dose

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If you plot the response


against the dose - you get a
sigmoid dose-response
curve.
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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

Log Dose (mol/l)

Higher
High medium
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Low

Agonist and antagonist compete at the


high affinity receptor sites - the agonist
can activate the receptor but the
antagonist can not. The dose-response
curve of the agonist is shifted to the
right. A high enough dose of agonist
can overcome the antagonist.

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

Log Dose (mol/l)

Higher High
Medium
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Low

Non-competitive antagonists bind


covalently to the receptor (do not
wash out). This is the equivalent of
removing a number of receptors from
the system. Therefore a max effect is
no longer produced (except in the case
of spare receptors).
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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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Drug W is a full agonist


Drug X is a competitive antagonist of drug W
Drug Y is a physiological antagonist of Drug W
Drug Z is a non-competitive antagonist of Drug W
i) Drug Y interacts with a receptor system distinct from
the receptor system of drug W
ii) The maximum effect obtained with drug W would
decrease in the presence of increasing concentrations
of drug X
iii) The maximum effect obtained with drug W would
decrease in the presence of increasing concentrations
of drug Z
iv) In the presence of drug Z the slope of the dose
response curve to drug W would show a parallel shift
to the right.
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Agonists in vivo - concept of


tone
The effect of an antagonist relies
solely on blocking the action of an
agonist which is already producing a
certain effect ie there must be an
agonist induced tone.

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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

Binding but little


response

Log Dose (mol/l)

Chart recorder pen


Highest
dose
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The dose response curve for


a partial agonist therefore
does not reach the maximal
response obtained for a full
agonist
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Inverse Agonists
Agonist
response

Some receptors are


constitutively active,
even in the absence of
any agonist.

Inverse
agonist
response

constitutive
activity

Log Dose (mol/l)

An Inverse agonist restores the


receptor to its inactive state
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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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Quantitative and Quantal


Response
Quantitative response: is measured in
gradual steps, eg fall in blood pressure
Quantal response: is all or none eg
responders or non-responders.

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Quantal Dose - Response Curves

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Therapeutic Ratio

Therapeutic ratio = LD50


ED50
Toxic Ratio = TD50
ED50
Digoxin: 2
Barbiturate: 10
Valium: almost infinite
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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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The role of pharmacodynamics in


pharmacology
Pharmacodynamics provides
information regarding dose/dosage
regimen vs response.
Factors affecting pharmacodynamics
together with pharmacokinetics are
considered when a dose is individualized
for special populations such as the elderly
Useful tool for introducing new
indications, new dosages or new
treatment populations contributing to
valuable information for drug
development.
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Things to consider when prescribing

Is the drug really necessary?


Use as few drugs as possible for as
short a time as possible
Regularly review drug therapy
Provide medication charts
Non-compliance

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