Pharmacodynamics (PD) — Drug Receptors and Mechanisms of Action

🟢 Lite — Quick Review (1h–1d)

Receptor Classification:

Type	Structure	Mechanism	Examples
Ligand-gated ion channels	Multisubunit (NMDA, GABA-A)	Ion flow on ligand binding	GABA-A (Cl⁻), NMDA (Ca²⁺), Nicotinic (Na⁺/K⁺), 5-HT3
G-protein coupled receptors (GPCR)	7-TM domain	G-protein activation	Adrenergic (α, β), muscarinic, dopamine, histamine, opioid
Tyrosine kinase receptors	Single TM	Autophosphorylation	Insulin, IGF, PDGF, VEGF, EGF
Cytokine receptors	Single TM	JAK-STAT pathway	Erythropoietin, G-CSF, interferons
Nuclear receptors	Intracellular/cytosolic	Gene transcription	Steroids, thyroid hormone, Vitamin D, retinoids
Ion channel (voltage-gated)	6-TM segments	Open on voltage change	Na⁺ channels, Ca²⁺ channels, K⁺ channels

Key Signaling Pathways:

• Gq pathway → PLC → IP3 (↑Ca²⁺) + DAG (↑PKC) → smooth muscle contraction, secretion
• Gs pathway → ↑ adenylyl cyclase → ↑ cAMP → ↑ PKA → ↑ cardiac contractility, lipolysis
• Gi pathway → ↓ adenylyl cyclase → ↓ cAMP → ↓ PKA → analgesia, sedation (opioids)

Dose-Response Relationship:

Parameter	Definition	Clinical Use
Potency	Amount of drug needed to produce effect	Dose selection
Efficacy (Emax)	Maximum effect achievable	Therapeutic ceiling
EC50	Concentration producing 50% of Emax	Affinity measure
Therapeutic index (TI)	TD50/ED50	Safety margin

Therapeutic Index:

TI = LD50 / ED50 (animals) or TD50/ED50 (humans)

• Narrow TI drugs: Lithium, digoxin, warfarin, theophylline, aminoglycosides, phenytoin

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🟡 Standard — Regular Study (2d–2mo)

G-Protein Coupled Receptors — Detailed:

Gs (Stimulatory):

• Receptor → Gsα → ↑ Adenylyl cyclase → ↑ cAMP → ↑ PKA
• Examples: β1, β2, β3 receptors, D1 receptor, H2 receptor, 5-HT4 receptor, prostaglandin receptors
• β1: Heart → ↑ HR, ↑ contractility, ↑ conduction velocity
• β2: Bronchi (bronchodilation), vasculature (vasodilation), uterus (relaxation), liver (glycogenolysis)

Gi (Inhibitory):

• Receptor → Giα → ↓ Adenylyl cyclase → ↓ cAMP
• Examples: α2 receptors, D2 receptors, μ/δ/κ opioid receptors, GABA-B receptors, 5-HT1 receptors
• α2: Presynaptic (↓ NE release), CNS (↓ sympathetic outflow)

Gq Pathway:

• Receptor → Gqα → ↑ Phospholipase C (PLC) → IP3 + DAG
• IP3 → ↑ intracellular Ca²⁺ → smooth muscle contraction, secretion, cardiac contraction
• DAG → activates Protein Kinase C
• Examples: α1 receptors, M1, M3, M5 receptors, H1 receptor, 5-HT2 receptors, V1 receptors
• M3: Smooth muscle (contraction GI, bladder), exocrine glands (salivation, lacrimation), vascular endothelium

G12/13 Pathway:

• G12/13 → RhoGEF → Rho → smooth muscle contraction, cell proliferation

Receptor Desensitization:

1. Phosphorylation — GRK (G-protein receptor kinase) → β-arrestin binding
2. Sequestration — internalization into endosomes
3. Downregulation — degradation of receptors (prolonged agonist exposure)

• Tachyphylaxis — rapid desensitization (e.g., nitrates — 24h on/off required to prevent tolerance)

Agonists vs Antagonists:

Type	Mechanism	Effect
Full agonist	Binds receptor, produces maximal response	Emax = 100%
Partial agonist	Binds receptor, produces submaximal response	Emax < 100% (ceiling effect)
Competitive antagonist	Binds same site as agonist (reversible)	Shifts dose-response curve right (↑ EC50), Emax unchanged
Non-competitive antagonist	Binds allosteric site or irreversibly	Shifts dose-response curve down (↓ Emax)
Physiological antagonist	Acts on different receptor → opposite effect	Functional antagonism

Inverse Agonist:

• Binds receptor → produces opposite effect to agonist (not just no effect)
• Example: β-carbolines (inverse agonists at benzodiazepine site on GABA-A)

Spare Receptors (Receptor Reserve):

• Maximal response achievable with <100% receptor occupancy
• Examples: β agonists in asthma, muscarinic agonists, catecholamines
• High receptor density allows amplification of signal

Affinity vs Intrinsic Activity:

Property	Definition
Affinity	How tightly drug binds to receptor (EC50 inversely related)
Intrinsic activity	Ability to activate receptor and produce response once bound
Antagonist	No intrinsic activity (even though may have affinity)

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🔴 Extended — Deep Study (3mo+)

Signal Transduction — Detailed Mechanisms:

Receptor Tyrosine Kinases (RTKs):

• Ligand binding → receptor dimerization → autophosphorylation on tyrosine residues
• Adaptor proteins (SH2, SH3 domains) → downstream pathways
• Ras-MAPK pathway: Growth factor receptors → Ras → Raf → MEK → ERK → cell proliferation
• PI3K-Akt pathway: Growth factor receptors → PI3K → Akt → cell survival, growth
• JAK-STAT pathway: Cytokine receptors → JAK → STAT → gene transcription

Nuclear Receptors — Mechanism:

1. Lipophilic ligand (steroid) crosses cell membrane
2. Binds intracellular receptor (cytosol or nucleus)
3. Receptor-hormone complex translocates to nucleus (if cytosolic)
4. Binds DNA as homodimer (or heterodimer with RXR)
5. Modulates gene transcription → protein synthesis → delayed response (hours to days)

Receptor	Ligand	Response
GR (glucocorticoid receptor)	Cortisol	Anti-inflammatory, immunosuppression
MR (mineralocorticoid receptor)	Aldosterone	Na⁺/K⁺ balance
PR (progesterone receptor)	Progesterone	Pregnancy maintenance
AR (androgen receptor)	Testosterone	Male sex characteristics
ER (estrogen receptor)	Estradiol	Female sex characteristics
TR (thyroid receptor)	T3/T4	Metabolic regulation
VDR (Vitamin D receptor)	1,25-(OH)₂D₃	Ca²⁺/phosphate absorption
PPARs	Fatty acids, thiazolidinediones	Glucose/lipid metabolism

Regulation of Drug Response:

1. Receptor upregulation — chronic blockade → ↑ receptor density (e.g., β-blockers → ↑ β-receptors → withdrawal tachycardia on abrupt discontinuation)
2. Receptor downregulation — chronic agonist → ↓ receptor density (e.g., desensitization)
3. Post-receptor changes — altered signaling cascade

Occupation Theory (Clark):

Effect = (Emax × [Drug]) / (Kd + [Drug])

• At 50% receptor occupancy: Effect = 50% of Emax
• This holds for full agonists; partial agonists show lower efficacy even at full occupancy

Efficacy vs Potency:

Feature	Efficacy (Emax)	Potency
Meaning	Maximum achievable effect	Dose required for given effect
Graph	Height of curve	Leftward shift of curve
Clinical importance	More important for therapeutic effect	Determines dosing convenience
Example	Furosemide > Thiazides (loop diuretic efficacy)	Morphine > Codeine (analgesic potency)

Quantal Dose-Response (All-or-None):

• Measures what proportion of population responds at each dose
• ED50 — dose effective in 50% of population
• TD50 — dose toxic in 50% of population
• LD50 — lethal in 50% of population
• Therapeutic window — range between ED50 and TD50
• Steep curve — small dose increase → dramatic increase in responders (toxicity risk)

Prodrugs — Activation:

Prodrug	Active metabolite	Activation site
Codeine	Morphine	CYP2D6 (polymorphic)
Tramadol	O-desmethyltramadol	CYP2D6
Clopidogrel	Active metabolite (thiol)	CYP2C19, CYP3A4, CYP1A2
ACE inhibitors (enalapril)	Enalaprilat	Ester hydrolysis
Digoxin	No prodrug	—
Piroxicam	No prodrug	—
Benznidazole	No prodrug	—

Pharmacogenetics — Key Polymorphisms:

Enzyme/ Receptor	Polymorphism	Clinical Effect
CYP2D6	Poor, ultrarapid metabolizers	Codeine: poor → no effect; ultrarapid → excessive morphine
CYP2C9	Poor metabolizers	↑ warfarin levels → bleeding
CYP2C19	Poor, ultrarapid	PPIs: poor → ↓ effect; omeprazole: ultrarapid → ↓ effect
G6PD deficiency	—	Hemolysis with primaquine, dapsone, sulfonamides
Pseudocholinesterase deficiency	—	Prolonged succinylcholine effect (scoline apnea)
Thiopurine methyltransferase (TPMT)	Deficiency	Azathioprine/6-MP → severe myelosuppression
VKORC1	Polymorphism	Warfarin dose requirement varies
β2-adrenergic receptor	Arg16Gly	Albuterol response variation

Drug-Drug Interactions via PD Mechanisms:

1. Additive effect — sum of effects (1+1=2)
2. Synergism — effect > sum (e.g., β-lactam + aminoglycoside)
3. Potentiation — one drug has no effect but enhances another
4. Antagonism — one drug reduces effect of another
   • Competitive (reversible) — atropine + pilocarpine
   • Non-competitive (irreversible) — phenoxybenzamine + epinephrine
   • Physiological — histamine + epinephrine
   • Chemical — protamine + heparin

Forskolin — direct activator of adenylyl cyclase (bypasses receptor) Sodium nitroprusside — releases NO → activates guanylyl cyclase → ↑ cGMP

Key NEET-PG Clinical Pearls:

• Propranolol + Clonidine: Clonidine (α2 agonist) withdrawal → unopposed α → hypertensive crisis; treat with phentolamine or propranolol (non-selective β-blocker without α-blocking)
• β-blocker + non-dihydropyridine CCB (verapamil, diltiazem) → avoid in heart failure (negative inotropic effect)
• Captopril + Spironolactone: Both ↑ K⁺ → severe hyperkalemia risk
• Digoxin toxicity: Treat with Digibind (digoxin-specific antibody fragments); avoid cardioversion if potassium > 5 mEq/L
• Sulbactam + Tazobactam — β-lactamase inhibitors combined with penicillins; useful for resistant organisms
• Epinephrine + Phenoxybenzamine: First give phenoxybenzamine (α-blocker) to prevent α-mediated vasoconstriction → then epinephrine produces pure β effects (used in pheochromocytoma surgery)
• Clonidine overdose: CNS depression, bradycardia, hypotension; treat with naloxone (α2-imidazoline receptor overlap)
• Inverse agonists at GABA-A: β-carbolines produce anxiety, seizures (proconvulsant); opposite of benzodiazepines

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