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 synaptic
transmitters
Glutamate, aspartate, glycine
Nicotinic acetylcholine receptor

Pentamer (2a, , g, chains)

Mw : 43.000 - 50.000

ACh binding to a 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 a, , g
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 G proteins

Thrombin 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

a1-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.