Mechanisms of drug action
pharmacodynamics
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What the drug does to the body
This illustrates on the process of which drug alters the
body environment, either by interfering with hormones,
receptors, enzymes or other macromolecules
Mechanisms of drug action
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Drugs acting on cell membranes
Drugs acting on metabolic processes within the cell
Drugs acting outside the cell
Drugs acting on cell membrane
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Acting on receptors on cell membrane –agonists and
antagonists
Interference with selective passage of ions across the cell
membrane
Inhibition of membrane bound enzymes or pumps
Drugs acting on cell membrane
receptors
What is a cell membrane receptor?
A macromolacular complex that is embedded in the
cell membrane and functions to receive chemical
information from the extracellular compartment
and to transmit that information to the
intracellular compartment.
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Receptor down regulation
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When a receptor is continuously exposed to an agonist
the number of receptors decrease
This is known as receptor down regulation
Ex- nitrates given for angina looses its effect with time
Receptor up regulation
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Pronged contact with antagonist results in formation of
new receptors
Ex-suddern withdrawal of B blockers lead to worsening
of angina /arrythmi
Abrupt withdrawal of the drug lets circulatory NA and A
having access to the up regulated receptor number
Antagonists
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• Some drugs bind to cell surface receptors, but do not
activate the receptors to trigger a response.
• When cell surface receptors bind the drug ,
the endogenous chemical cannot bind to the
receptor and cannot trigger a response.
• The compound is said to “antagonize” or “block” the receptor
and is referred to as a receptor antagonist.
example
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β1 receptors are a sub group of adrenoceptors.
Endogenous adrenaline and nor adrenaline act on these
receptors in heart and increase heart rate and cardiac
contractility there by increasing the cardiac work load
and the blood pressure.
Propranolol is a β receptor antagonist. It binds to β1
receptors and block NA and adrenaline binding, there by
lowering cardiac contractility and BP
HOW DO DRUGS WORK BY ANTAGONIZING
CELL SURFACE RECEPTORS?
Extracellular
Compartment
Unbound Endogenous Activator (Agonist) of Receptor
Cell Membrane
Inactive Cell Surface Receptor
Intracellular
Compartment
HOW DO DRUGS WORK BY ANTAGONIZING
CELL SURFACE RECEPTORS?
Extracellular
Compartment
Bound Endogenous Activator (Agonist) of Receptor
Cell Membrane
Active Cell Surface Receptor
Intracellular
Compartment
Cellular Response
HOW DO DRUGS WORK BY ANTAGONIZING
CELL SURFACE RECEPTORS?
Displaced Endogenous Activator (Agonist) of Receptor
Extracellular
Compartment
Bound Antagonist of Receptor (Drug)
Cell Membrane
Inactive Cell Surface Receptor
Intracellular
Compartment
Agonists
•
• Some drugs bind to cell surface receptors, and
activate the receptors to trigger a response.
• The compound is said to “agonize ” the receptor
and is referred to as a receptor agonist.
Example
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The bronchioles have B2 receptors. Adrenaline act on
them to cause bronchiodilatation.
In asthma, the bronchioles constrict giving rise to
breathing difficulty
The drug used,salbutamol is a B2 receptor agonist that
bind B2 receptors and act on them to cause
bronchodilatation
Partial agonists
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Some drugs,which block the receptors and prevent
natural ligands bind can also have a mild stimulating effect
on the receptor as well.
So they have both agonist and antagonist actions
Receptor binding
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Some drugs bind receptors with weak bonds.(hydrogen
bonds,van der Waals bonds etc.)this type of binding
would be rapidly reversible and can be displaced by
increasing the endogenous substance concentration.
Some drugs bind receptors with strong bonds (covalent
bonds)and then the binding would be irriversible
Receptor binding
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Irreversible antagonism-The drug phenoxybenzamine is an
alpha receptor blocker.
In a condition where there is a tumor of the adrenal gland
which releases adrenaline(pheochomocytoma), this drug
is given during surgery
The reason is that during surgery, high amounts of
adrenaline is released to the circulation
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Adrenaline can bind to alpha receptors to increase the
blood pressure
To prevent this a drug that can block the alpha receptors
are used
However if a reversible alpha antagonist is used, it can get
displaced by high adrenaline levels,and to avoid this an
irreversible alpha receptor blocker is used
Physiological antagonism
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Drugs might not always act on the same receptor
which a physiological substance binds, in order to
counteract its action,
Anaphylactic shock is a condition where due to an
allergy, mast cells are activated and releases histamine
which acts on histamine receptors to cause
bronchoconstriction
The drug adrenaline is given as treatment and it acts
via a different receptor,the beta 2 adrenoceptor to
cause bronchodilatation.
Drugs acting on cell membrane
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Acting on receptors on cell membrane –agonists and
antagonists
Interference with selective passage of ions across
the cell membrane
Inhibition of membrane bound enzymes or pumps
Interference with selective passage of
ions across the cell membrane
Calcium channel blockers
Calcium is needed for muscle contraction.CCB drugs act
on the vascular smooth muscle and block the calcium
transport, preventing contraction of vascular smooth
muscle. This causes vasodilatation and lowering of blood
pressure
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Inhibition of membrane bound enzymes or
pumps
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Cardiac glycosides interfering with the Na+ K+ ATPase
pump of the heart muscle which causes Na+ to
accumulate within the myocardium.This Na+ is exchanges
to Ca2+, so the calcium increases in myocardium
increasing contractility of the heart muscle
Drugs acting on metabolic
processes with in the cell
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Enzyme inhibition
Inhibition of transport process that carry substances
across cells
Incorporation of larger molecules
Altering other metabolic processes
Enzyme inhibition
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Some important drugs act as enzyme inhibitors
Inhibition caused by drugs may be either reversible or
irreversible.
Drug binds to the enzyme by weak bonds in reversible
inhibition
Example for competitive enzyme inhibition
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Angiotensin II is a very potent chemical that causes rise in
BP. Angiotensin II is formed from angiotensin I by the
enzyme angiotensin converting enzyme (ACE). ACE
inhibitors are medications that slow (inhibit) the activity
of the enzyme ACE, which decreases the production of
angiotensin II. As a result, the blood vessels dilate, and
blood pressure is reduced.
Inhibition of transport process that carry
substances across cells
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Blocking anion tansport of renal tubule by probenacid can
be used to delay excretion of penicillin
Incorporation of larger molecules
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Some Anticancer drugs mimic nucleotides and bind the
nucleotide chains inhibiting DNA synthesis
Drugs acting outside the cell
Direct chemical interactions
Ex- antacids- MgOH is an antacid. In patients with gastritis
MgOH when given orally neutralizes the acids in the stomach,
with out getting absorbed into cells
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Osmosis
Ex-magnisium sulphate is a laxative which is given to treat
constipation. It is a molacule that is not absorbed into the GIT
and remains in the gut.It holds water, so stools become bulky
and constipation is relieved
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Terminology….
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Affinity—tendency of a drug to combine with a receptor,
to produce drug receptor complex and maintain it. There
is always affinity constant for specific receptors.
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Affinity may vary—it ↑ when the receptor is vacant and ↓
when the receptor is occupied.
Selectivity
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Is the ability of the drug to produce the expected
action,with out giving rise to unwanted side effects
potency
The amount of drug in relation to its effect
Ex- if Xmg of drug A has more effect than the same weight
of drug B , drug A is said to be more potent
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Lethal dose
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A lethal dose (LD) is an indication of the lethality of a
given substance. Because resistance varies from one
individual to another, the 'lethal dose' represents a dose
(usually recorded as dose per kilogram of subject body
weight) at which a given percentage of subjects will die.
Animal-based LD measurements are a commonly-used
technique in drug research..
LD values for humans are generally estimated by results
from testing on animals on human cell cultures
Toxic dose
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the dosage that may be expected to cause a toxic effects
in majority of the patients to whom it is given.
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ED50 - Median Effective Dose 50; the dose at which 50
percent of the population or sample manifests a given
effect; used with quantal dr curves
TD50 - Median Toxic Dose 50 - dose at which 50 percent
of the population manifests a given toxic effect
LD50 - Median Toxic Dose 50 - dose which kills 50
percent of the subjects
The ‘therapeutic
index’
Toxic dose
Therapeutic dose
Toxic dose
Therapeutic index =
Therapeutic dose
Thank you……