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• Anna Wiktorowska-Owczarek
Mechanisms of drug action and
the relationship between drug
concentration and its effect
• Can be defined as:
– the study of the biochemical and
physiological effects of drugs and their
mechanisms of action
– the chemical or physical interactions between
drug and target cell
Why do we want to know
mechanisms of drug action?
• Such a complete analysis provides the
basis for
– the rational therapeutic use of drug
– adverse effects
– the design of new therapeutic agents
Mechanisms of drug action
• The effects of most drugs result from their
interaction with macromolecular
components of the organism.
• These interactions initiate the biochemical
and physiological changes that the
characteristic of the response to the drug.
Mechanism of drug action
• Drug in site of action
• Drug interaction with component of the
• Alteration of function of the component
• Initiation of the biochemical and
physiological changes
Drug receptors
• Proteins form the most important class
of drug receptors.
• The term receptor denotes the
component of the organism with which
the chemical agent was presumed to
• Membrane receptors contain one or
more hydrophobic membranespanning α-helical segments, linking
the extracellular ligand-binding region
of the receptor to the intracellular
Membrane receptors contain one or
more hydrophobic membranespanning α-helical segments, linking
the extracellular ligand-binding region
of the receptor to the intracellular
domain which is involved in signalling.
Interaction with receptor
Generation of second message
Change in cellular activity
Drug receptors
• Agonist combines with receptor and
activate the receptor. Agonists initiate
changes in cell function, producing
effects of various types
• Antagonist may combine at the
same site without causing activation.
Antagonist blocks the binding of the
endogenous agonist.
Drug receptors
• Drugs acting on receptors may be
agonists or antagonists
• Agonists initiate changes in cell
function, producing effects of various
types; antagonists bind to receptors
without initiating such changes.
• Agonist potency depends on two
parameters: affinity (i.e. tendency to
bind to receptors) and efficacy (i.e.
ability, once bound, to initiate changes
which lead to effects).
Drug receptors
• For antagonists, efficacy is zero.
• Full agonists (which can produce
maximal effects) have high efficacy;
partial agonists (which can produce
only submaximal effects) have
intermediate efficacy.
Drug receptors
• Tolerance –this term is used to
describe a more gradual decrease in
responsiveness to a drug, taking days
or weeks to develope.
• Tolerance to drug effects results in a
decrease in response with repeated
• Tachyphylaxis is a medical term
describing a rapidly decreasing
response to a drug following
administration of the initial doses.
Drug receptors
• Desensitisation is used to describe
both long-term or short-term changes
in dose-response relationship arising
from a decrease in response of the
• Desensitisation can occur by a
number of mechanisms:
– Decreased receptor numbers
– Decreased receptor binding affinity
Drug targets
• Receptors (for
– adrenergic β-receptor blockers
• Enzymes
– angiotensin converting enzyme inhibitors
• Carrier molecules
– serotonin reuptake inhibitors
• Ion channels
– GABA agonists
• Idiosyncratic targets (metal ions, gastric
Types of receptors
Receptor-operated channels
G-protein-coupled receptors
Tyrosine kinase receptors
DNA-coupled receptors
Receptor-operated channels
• Subunits – 4 TMs each
• Binding of ligand  conformational
changes  opening of ion-selective pore
 membrane depolarization or
• Three states:
– open
– closed
– inactivated
• Very rapid transduction (ms)
Receptor-operated channels
• Examples
– GABAA receptor
• benzodiazepines
– nicotinic cholinergic receptor
– glycine receptor
– 5-HT3 serotonin receptor
G-protein-coupled receptors
• Membrane proteins with 7 transmembrane
helical domains
– 7-TM receptors
• N-terminal part  extracellular  binds
• C-terminal part 
intracellular  binds
G-protein-coupled receptors
• G-proteins  trimeric proteins
– three subunits: α, β, γ
– ligand binds to receptor  G-protein
separates from the receptor and α
separates from βγ dimer
– α and βγ stimulate intracellular signalling
pathways (depending on subtypes)
• adenylate cyclase (AC)  (+) or (-) 
cAMP  protein kinase A (PKA)
• phospholipase C-β (PLC) DAG, IP3
PKC, Ca2+ channel
The G-protein system
• The α-subunit binds GDP/GTP, it also
has GTPase activity. The αsubunit/GTP complex is active while
GTP is bound to it. The αsubunit/GTP complex is inactivated
when the GTP is hydrolysed to GDP.
• The β-subunits remains associated
with the γ-subunit when the receptor
is occupied and the combined βγsubunit may activate cellular enzyme.
• The γ-subunit
Second messenger systems
• Cyclic nucleotide system. This system is
based on cyclic nucleotides such as cyclic
adenosine monophosphate (cAMP), which
is synthesised from ATP via enzyme
adenylate cyclase. The cAMP is
inactivated by hydrolysis by a
phosphodiesterase enzyme to give AMP.
Second messenger systems
• The phosphatidylinositol system. This
system is based on inositol 1,4,5triphosphate (IP3) and diacylglycerol
(DAG), which are synthesised from the
membrane phospholipid
phosphatidylinositol 4,5-bis-phosphate
(PIP2), by the enzyme phospholipase Cβ.
Types of G-proteins
• Gs stimulates membrane-bound
adenylate cyclase to increase cAMP
• Gi (and Go) inhibits adenylate cyclase
to decrease cAMP
• Gq (and G12) activates phospholipase
The intracellular consequences of
receptor activation and G-protein
kinase A
Intracellular enzymes
linked to
Ion channels (Ca and K)
Contractile proteins
kinase C
Phospholipase C
Release of calcium from
sarcoplasmic reticulum
G-protein-coupled receptors
• Examples:
– adrenergic receptors
• α-adrenomimetics  vasoconstriction
– muscarinic cholinergic receptors
– dopamine receptors
• antipsychotic drugs  antagonists
Tyrosine kinase receptors
• Three domains
– extracellular (ligand binding) domain
– transmembrane domain
– intracellular (catalytic) domain  tyrosine
kinase activity
• Ligand binding 
autophosphorylation 
binding and phosphorylation
of other target proteins
Tyrosine kinase receptors
• Examples:
– insulin receptor
– epidermal growth factor receptor
– VEGF -receptor
DNA-coupled receptors
• Binding to nuclear DNA fragments when
activated by ligands
– promote or inhibit gene expression
– sometimes ligand binding causes
dissociation of inhibitory protein (e.g.,
– stay in the cytoplasm 
agonist must enter the cell
• when activated migrate to the
nucleus – slow process
DNA-coupled receptors
• Examples:
– Corticosteroids:
• Glucocorticoid receptor
• Mineralocorticoid receptor
– Thyroid hormone receptor
– Vitamin D receptor
– Retinoic acid receptor
Other sites of drug action
• Specific enzymes:
– Acetylcholinesterase (AChE) →
anticholinesterase drugs
– Cyclo-oxygenase → NSAIDs (Non
Steroidal Anti-Inflammatory Drugs )
– Angiotensin-converting enzyme → ACE
– Phosphodiesterase →
Phosphodiesterase inhibitors
Other sites of drug action
• Specific enzymes and nucleic
acid. The anticancer drugs
inhibit enzymes involved in
purine, pyrimidine or DNA
Other sites of drug action
• Specific cell membrane ion pumps.
– For example, Na/K-ATPase in the brain
is activated by the anticonvulsant
phenytoin whereas that in cardiac tissue
is inhibited by digoxin;
– K/H-ATPase (proton pump) in gastric
parietal cells is inhibited by omeprazole.
Other sites of drug action
• Ion channels
– Voltage-gated Na channels → Local
– Voltage –gated Ca channels →