Pharmacodynamics

Mechanisms of drug action

Pharmacodynamics
Biochemical, physiological effects of drugs
Mechanisms of action
Basis for rational drug therapy &
design of new drugs

Mechanisms of drug action (1)

Interaction of drugs with macromolecule

components of the organism effects
Receptor
- alters rate of body function
- modulates intrinsic physiological functions
Acceptor
Drug - receptor - function
Examples :
- hormones, growth factors, neurotransmitters
- enzymes (ACh esterase, dihydrofolate reductase)
- transport (Na/K-ATPase)
- structural (tubulin)
- nucleic acid

Mechanisms of drug action (2)

Physiological receptors
- Agonist
- Antagonist
- Negative / inverse agonist
Binding of drugs to receptors
- ionic
- hydrogen
- hydrophobic
- van der Waals
- covalent

digitalis + receptor
K+

Na+

Na+ outflow

Na K / ATP ase
ouabain

ATP

Cai++

p.n.p.ase

contractility
outside

inside

Structure-activity relationship &

drug design
Chemical structure affinity &
intrinsic activity
SAR modification
- therapeutic effect

ratio

toxic effect
- selectivity
- pharmacokinetic profile

Receptor (1)
Functional domains
1. Ligand-binding
2. Effector
cellular target(s)

Receptor occupancy

effector protein(s)
second messenger(s)
transducer(s)

Receptor (2)
Receptor - effector proteins / transducers /
second messengers - cellular targets
receptor - effector system / signal transduction
pathway
Biochemical signal amplifier

Ri

Ra

D-Ri

D-Ra

Physiological receptors
1. Enzymes
2. Ion channels
3. G protein - coupled receptor systems
4. Transcription factors

Receptors
I. Enzymes:
- Tyrosine kinase: insulin, EGF, PDGF,
lymphokines
- Serine/threonine protein kinase: TGF
- Guanylyl cyclase: ANF receptor, guanylin
receptor
- Tyrosine phosphatase
II.Ligand-gated ion channels
- Nicotinic Ach receptor
- GABAA receptor
- Glutamate, aspartate, glycine

III. G protein-coupled receptors

- Biogenic amines
- Eicosanoids
- Peptide hormones
Effectors:
- Enzymes: adenylyl cyclase, PLA2, C, D
- Ion channels: Ca++, K+, Na+
- Transport proteins
IV. Transcription factors
Cytosolic receptors: thyroid hormone, steroid,
retinoid, vitamin D

Enzymes (protein kinase)

1. Plasma membrane-bound kinase
Target proteins : enzymes (other kinases),
regulatory proteins, structural proteins
2. Tyrosine kinases : insulin, EGF, PDGF,
lymphokines
Tyrosine phosphatases
Serine/threonine kinases : TGF
Guanylyl cyclase

Cytokine receptors
1. ~ receptor tyrosine kinases
separated protein tyrosine kinase
(Janus-kinase, JAK family)
JAKs phosphorylate protein STATs
(signal transducers and activators of
transcription)
regulates transcription of specific genes

2. Ligands : growth hormones, erythropoeitin,

interferons, etc.

Ion channels
Plasma membrane-bound ion channels
Alter membrane potential or ionic
composition
Nicotinic cholinergic receptor
GABAA receptor
Glutamate, aspartate, glycine

synaptic
transmitters

Nicotinic acetylcholine receptor

Pentamer (2 chains)
Mw : 43.000 - 50.000
ACh binding to subunit causes
Nao Nai

G protein-coupled receptors
Plasma membrane-bound
Biogenic amines, eicosanoids, peptide hormones
Receptors-GTP binding to G proteins -- effector
proteins
Effector proteins :
adenylyl cyclase, phospholipase A2, C, D,
ion channels (Ca2+, K+, Na+), transport proteins
G protein subunits
Associated with generation of second messenger

G protein, regulatory cycles

Cells

G proteins

receptors

protein effectors

 Receptors
effectors / transducers
cumulative intracellular signal
Time of interactions
eg. NE + Receptor GTP binding to Gs Adenylyl cyclase
few msec

tens secs

 A receptor

Thrombin

G proteins
receptor

G protein - adenylyl cyclase

G protein - phospholipase C

Transcription factors
Receptor : soluble DNA-binding protein
Steroids, thyroid, vitamin D, retinoids
The region nearest the carboxyl terminus
binds hormone & serves a negative
regulatory control
The control region binds to nuclear DNA
to inhibit or activate gene transcription

Second messenger(s)
Characteristics
Very low concentration
Rapidly produced
Recycling mechanism

Second messenger(s)
cAMP
cGMP
Inositol trisphosphate, diacylglycerol
Ca++
NO

Phosphoinositides

 adrenergic agents

cAMP

CH & TG breakdown
HR & contractility

Vasopressin (V2)

cAMP

conservation of water
in kidney

Parathyroid

cAMP

Ca++ homeostasis

Acetylcholine
Ca++,
bradycardia, miosis,
(muscarinic receptor) phosphoinositides
etc.
Angiotensin (AT1)

Ca++,
vasoconstriction
phosphoinositides

1-adrenergic agents

Ca++,
vasoconstriction
phosphoinositides

Regulation of receptors (1)

Rs regulate physiological & biochemical
functions
Rs are subject to regulatory & homeostatic
controls
i.e. synthesis & degradation
Transducers & effector proteins are similarly
regulated

Regulation of receptors (2)

Continued stimulation by agonists
desensitization (refractoriness,
down-regulation)
Feedback inhibition
- homologous desensitization (from the stimulated
receptor)
- heterologous desensitization (from all receptors
sharing a common signalling pathway)

Regulation of receptors (3)

Homologous des. directed to the receptor
molecules itself (phosphorylation, proteolysis,
decreased synthesis, etc.)
Heterologous des. involves inhibition or loss
of one or more downstream proteins that
participate in signalling from other receptors
Supersensitization
Chronic reduction of receptor stimulation
(eg. -blocker)

Diseases resulting from receptor

malfunction

Testicular feminization syndrome deficiency of

androgen receptors
Myasthenia gravis autoimmune depletion of
nicotinic cholinergic receptors
Insulin-resistant DM autoimmune depletion of
insulin receptors
Multiple endocrine disorders deficiency of Gs
(heterozygous)
Malignancy aberrant receptors

oncogenes

Subtle mutation in receptors

activation of G
protein-coupled receptors retinitis pigmentosa,
precocious puberty, malignant hyperthyroidism.

Actions of drugs not mediated by

receptors
Binding to other molecules or ions : antacid
Colligative effects : mannitol
Structural analogs of biological chemicals :
some antiviral & anticancer agents
Desinfectants, detergent, alcohol, etc.