Pharmacodynamics

Mechanisms of drug action

Melva Louisa, Frans D Suyatna

Department of Pharmacology & Therapeutics

Faculty of Medicine, University of Indonesia
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 The PK – PD relationship

Pharmacokinetics Pharmacodynamics

Dosage [DRUG] - Plasma Pharmacological

Regimen Effect

How much? How

often? How long?
What form? [DRUG] - Receptors at
Target Site
 Pharmacodynamics

• Biochemical, physiological effects of drugs

• Mechanisms of drug action

• Basis for rational drug therapy & design of

new drugs

• Interaction of drugs with macromolecule

components of the organism à effects

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 Mechanisms of drug action (1)
• Receptor
- alters rate of body function
- modulates intrinsic physiological functions
• Drug - receptor - function
• Examples :
- hormones, growth factors, neurotransmitters
- enzymes (ACh esterase, dihydrofolate reductase)
- transport (Na/K-ATPase)
- etc

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 Mechanisms of drug action (2)
• Physiological receptors
- Agonist
- Antagonist
- Inverse agonist
• Binding of drugs to receptors
- ionic
- hydrogen
- hydrophobic
- van der Waals
- covalent

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Typical log concentration-effect curve
(graded ‘dose-response’ curve)
Dose-Response Relationships

• Potency
• Efficacy
 Dose-Response Functions
nEfficacy (ED50 = median effective dose)
nLethality (LD50 = median lethal dose)
nTherapeutic Index = LD50 /ED50

– The higher the TI, the safer the drug e.g.

barbiturate (TI=10)
– The lower the TI, the greater the possibility of
toxicity e.g. digitalis (TI=3),
• so death may occur if only 3mg has been
administered because the usual therapeutic dose of
cardiac glycoside is one mg.
 Structure-activity relationship &
drug design
• Chemical structure ® affinity &
intrinsic activity
• SAR modification
- toxic
ratio
therapeutic
- selectivity
- pharmacokinetic profile

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Structure activity relationship
modification

celecoxib valdecoxib rofecoxib

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 Receptor (1)

• Functional domains
1. Ligand-binding
2. Effector

Crystal structure of rhodopsin,

Membrane protein in the retina of the eye

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 Receptor (2)
cellular target(s)
effector protein(s) ®
• Receptor occupancy
second messenger(s)
transducer(s) /
intermediary cellular
signaling molecules

• Receptor - effector proteins / transducers / second

messengers - cellular targets à receptor - effector system /
signal transduction pathway
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Drug-Receptor Binding and Agonism

Ri Ra

D-Ri D-Ra

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Physiological receptors

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

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 Receptors
I. Enzymes:
- Tyrosine kinase: insulin, EGF, PDGF, lymphokines
- Serine/threonine protein kinase: TGF-Beta
- Guanylyl cyclase: ANF receptor, guanylin receptor
- Tyrosine phosphatase

II. Ligand-gated ion channels

- Nicotinic ACh receptor
- GABAA receptor
- Glutamate, aspartate, glycine

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 Receptors
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 18
 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 : TGFβ
Guanylyl cyclase
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 Ligand regulated enzyme
(tyrosine kinase) receptors

best example: Insulin receptors

Ligand
Glucose
(example: the hormone Insulin)

Insulin Receptor
Outside Transport with
Cell Protein Tyrosine Kinase

Phospholipid
Glucose Bi-layer
of Cell
Membrane

Tyrosine Kinase
activated
Inside
Cell 1. Movement of glucose
inside the cell

2. Storage of glucose as
glycogen in the liver
 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.

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 Ion channels

• Plasma membrane-bound ion channels

• Alter membrane potential or ionic composition
• Nicotinic cholinergic receptor
GABAA receptor synaptic
transmitters
Glutamate, aspartate, glycine

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 Nicotinic acetylcholine receptor

• Pentamer (2α, β, γ, δ chains)

• Mw : 43.000 - 50.000

• ACh binding to α subunit causes

Nao à Nai

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 G protein-coupled receptors
• Plasma membrane-bound
• Biogenic amines (Norepinephrine, ACh, histamine,
tyramine, dopamine, etc.) , eicosanoids (LT, PG, TX, etc.),
peptide hormones (LH, FSH, ACTH, etc.)
• 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 α, β, γ
• Associated with generation of second messenger
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G protein, regulatory cycles

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Diversity of G Protein-Coupled Receptor Signal
Transduction Pathways

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• Receptors effectors / transducers ®
cumulative intracellular signal

• Time of interactions

eg. NE + Receptor à GTP binding to Gs à Adenylyl cyclase

few msec tens secs

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 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

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Glucocorticoid Receptor Signaling
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 Second messenger(s)

Characteristics
• Very low concentration
• Rapidly produced
• Recycling mechanism

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Second messenger(s)

• cAMP
• cGMP
• Inositol trisphosphate, diacylglycerol
• Ca++
• NO

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 Second messenger
β adrenergic agents cAMP CH & TG breakdown
HR & contractility increased

Vasopressin (V2) cAMP conservation of water

in kidney

Parathyroid cAMP Ca++ homeostasis

Acetylcholine Ca++, bradycardia, miosis, etc.

(muscarinic receptor) phosphoinositides

Angiotensin (AT1) Ca++, vasoconstriction

phosphoinositides

α1-adrenergic agents Ca++, vasoconstriction

(e.g. epinephrine) phosphoinositides

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 Regulation of receptors (1)
• Receptors regulate physiological & biochemical
functions

• Receptors are subject to regulatory &

homeostatic controls
i.e. synthesis & degradation

• Transducers & effector proteins are similarly

regulated

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 Regulation of receptors (2)
• Continued stimulation by agonists à
desensitization (refractoriness, down-regulation)

• Feedback inhibition
- homologous desensitization (from the stimulated receptor)
- heterologous desensitization (from all receptors
sharing a common signaling pathway)

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 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. β-blocker)
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 Diseases resulting from receptor
malfunction
• Testicular feminization syndrome à deficiency of
androgen receptors
• Myasthenia gravisà autoimmune depletion of
nicotinic cholinergic receptors
• Insulin-resistant DM à autoimmune depletion of
insulin receptors
• Multiple endocrine disorders à deficiency of Gs
(heterozygous)
• Malignancy aberrant receptors oncogenes
• Subtle mutation in receptors activation of G protein-
coupled receptors à retinitis pigmentosa, precocious
puberty, malignant hyperthyroidism. 42
 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.

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Thank You

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