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PharmacodynamicsMechanisms 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
outside inside
ouabain
p.n.p.ase
K+ Na+
ATP
digitalis + receptor
Na+ outflow
Cai++
contractility
Na K / ATP ase
Structure-activity relationship & drug design
• Chemical structure affinity &
intrinsic activity
• SAR modification
- therapeutic effect
toxic effect
- selectivity
- pharmacokinetic profile
ratio
Receptor (1)
• Functional domains
1. Ligand-binding
2. Effector
• Receptor occupancy
cellular target(s)
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 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 breakdownHR & contractility
Vasopressin (V2) cAMP conservation of waterin kidney
Parathyroid cAMP Ca++ homeostasis
Acetylcholine Ca++, bradycardia, miosis, (muscarinic receptor) phosphoinositides etc.
Angiotensin (AT1) Ca++, vasoconstrictionphosphoinositides
1-adrenergic agents Ca++, vasoconstrictionphosphoinositides
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
• SupersensitizationChronic 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.