Download Pharmaco lecture 2 - pharmacology1lecnotes

How drugs Act :General principles
Lecture 2
Objectives/ Learning outcome:
 Define various targets of drug actions
 Define
receptor, types and examples
 Describe
agonist and antagonist and their
characteristics.
 Mechanism
of antagonism
 Desensitization
and Tachyphylaxis
Targets of drugs action
Drugs are effective because they bind to particular targets
proteins, a drug will not work unless it is bound..
One of the basic tenets of pharmacology is that drug
molecules must exert some chemical influence on one or
more constituents of cells in order to produce a
pharmacological response.
In order words drugs molecules must be bound to
particular constituents of cells and tissue in order to
produce an effect.
Ehrlich summed it up thus; ‘Corpora non agunt
nisi fixata’( in this context, ‘A drug will not work
unless it is bound’.
Therefore understanding the nature of these binding
sites, and the mechanisms by which the association of
drug molecules with a binding site leads to a
physiological response, constitutes the major trust of
pharmacological research.
Most drugs produce their effects by binding, in the
first instance, to protein molecules often called
“Targets”.
Classification of drug binding sites:
There are four major binding sites for drugs which are :Enzymes, Ion-channels, Carrier molecules and Receptors.
Enzymes:
Many drugs target enzymes, by competitive inhibition of
the enzyme either reversibly e.g. neostigmine on
acetylcholinerase or irreversibly e.g. aspirin, acting on
cyclooxygenase.
Ion-channels:
Drugs either open or block ion channels by directly
acting on the channels or via receptors or G-proteins
that are coupled with the channels.
Carrier molecules:
Carrier molecules are required for the transport of ions and
small organic molecules across cell membranes. e.g. of
these carrier proteins are those required for transport of: –
glucose and amino acids into cells, ions and organic
molecules by renal tubules, calcium and sodium out of
cells, and uptake of neurotransmitter precursors (e.g.
choline) neurotransmitters (e.g. noradrenaline).
Receptors:
Receptors are the sensing elements in the system of
chemical communications that coordinates the
function of all the different cells in the body
the chemical messengers being the various hormones,
transmitters and other mediators. Many therapeutically
useful drugs act either as agonist or antagonist on
receptors for known endogenous mediators.
Types of receptors:
Receptors proteins are produced by the cells that express
them, these receptor types are: i) channel-linked
(ionotropic), ii) G-protein coupled, iii) Kinase-linked, and
iv) Nuclear receptors.
i) Channel-linked
(ionotropic): These are membrane
receptors that are coupled directly to an ion-channel, e.g.
nicotinic acetylcholine and glutamate receptors.
ii) G-protein coupled (metabotropic) :Membrane
receptors, coupled to intracellular effectors system via
a G-protein e.g. muscarinic acetylcholine and
adrenergic receptors.
In many cases these intracellular domain are
enzymatic in nature (with protein Kinase or guanylate
cyclase activity). e.g. insulin and various cytokines
and growth factors.
iii) Kinase-linked: These are membrane receptors
which incorporates an intracellular protein kinase
domain in their structure.
iv) Nuclear receptors : These are receptors that
regulates gene transcription e.g. steroid hormones,
thyroid hormones and other agents such as retinoic acid
and vitamin D.
Agonist and Antagonist
Agonist:
Agonist is a substance/drug that binds to and activates a
receptor, in the process mimicking the effect of a natural
neurotransmitter or hormone.
.It
initiates changes in cell function ,thereby producing
effects of various types e.g. Phenylepherine.
Types of Agonist:
1)Full agonist: These are drugs that induces
maximum response the cells or tissues can give
in high concentration e.g. Acetylcholine.
2) Partial agonist: These are drugs that induces
only a submaximal response on the cells or tissues.
Features of Agonist:
Potency :The amount of drug that is needed to produce a
given response.
Affinity : The tendency of a drug to bind to receptors.
Efficacy :The ability of the drug to produce a desired
therapeutic effect.
Antagonist:
Antagonist is a substance that binds to and block a
receptor, thereby preventing a natural neurotransmitter
or hormones or drug from exerting its effect.
It binds to site but does not cause any action. It has
no efficacy because it generates no change in
physiological action e.g. Atropine.
Type of antagonist:
1) Antagonism by receptor block: Receptor-block
antagonism involves two important mechanisms:
Reversible and Irreversible competitive
antagonism.
Competitive Antagonism : These occurs when two
drugs compete for the same receptor site. The two
drugs compete with each other, because the
receptor can bind only one drug molecule at a
time.
Reversible antagonism:
parallel shift of the agonist log concentration-response
curve without reduction in maximal response.
rate of dissociation of the antagonist molecules is sufficiently
high that a new equilibrium is rapidly established on addition
of the agonist.
Irreversible antagonism:
Irreversible or non-equilibrium competitive antagonism
occurs when the antagonist dissociates very slowly, or not at
all, from the receptors, with the result that no change in the
antagonist occupancy takes place when the agonist is
applied.
Chemical antagonism: These is a situation where two
drugs combine in solution, as a result the effect of the active
is lost. Examples include the use of chelating agents (e.g.
dimercaprol) that bind to heavy metals and thus reduce their
toxicity.
Pharmacokinetic antagonism: Pharmacokinetic
antagonism describes the situation in which the
antagonist effectively reduces the concentration of
active drug at its site of action.
This could be through increase in metabolic degradation
of active drug, or reduction of the rate of absorption or
renal excretion e.g. Phenobarbitone induces liver
enzymes and accelerates the metabolism of warfarin.
Non-competitive antagonism: Non-competitive
antagonism describes the situation where the antagonist
blocks at some point the chain of events that leads to
production of response by the agonist.
Physiological Antagonism: Physiological antagonism is
a term used to describe the interaction of two drugs
whose opposing actions in the body tend to cancel
each other.
Desensitisation and Tachyphylasis:
Desensitisation and tachyphylasis: when a drug
given continuously or repeatedly, the effect of the drug
gradually diminishes. It occurs in a course of few
minutes.
Tolerance: gradual decrease in responsiveness
to drug, taking days or weeks to develop
Refractoriness: the loss of therapeutic
efficacy.
Drug resistance: loss of effectiveness of antimicrobial
drugs or antitumour drugs.
Many different mechanism can give rise to this type of
phenomenon. They include
 Change
in receptors

Loss of receptors

Exhaustion of mediators
 Increased
Metabolic Degradation
 Physiological
Adaptation
End Of Lecture 2
Thank You