fds-farmakodinamik prof frans

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.