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M. Pharm Advanced Pharmacology - I (MPL 102T)

Unit 1: General Pharmacology

As per PCI Syllabus (12 Hours)

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SYLLABUS COVERAGE - UNIT 1

1. Pharmacokinetics - Dynamics of absorption, distribution, biotransformation, and elimination; compartment models; protein binding
2. Pharmacodynamics - Mechanism of drug action; drug concentration-effect relationships; receptors, receptor families, quantitation of drug-receptor interactions

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PART A: PHARMACOKINETICS

1.1 Definition and Scope

"Pharmacokinetics is the study of action of a drug in the body over a period of time, including processes of absorption, distribution, localization in tissues, biotransformation, and excretion."

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1.2 Drug Absorption

• Passive diffusion - Most common; drug moves down concentration gradient; governed by Fick's law
• Active transport - Carrier-mediated; against concentration gradient; requires energy (ATP); saturable and inhibitable
• Facilitated diffusion - Carrier-mediated; along concentration gradient; no energy required
• Pinocytosis/Endocytosis - For large molecules, peptides, proteins
• Paracellular transport - Through tight junctions; limited for large/charged molecules

1. Physicochemical properties of drug:
   • Molecular weight (smaller = better absorbed)
   • Lipid solubility (logP / partition coefficient)
   • Ionization: pH-partition hypothesis - only un-ionized form crosses membranes
     • Weak acids: better absorbed in acidic pH (stomach)
     • Weak bases: better absorbed in alkaline pH (intestine)
   • Dissolution rate (for solid dosage forms)
2. Route of administration:
   • IV: 100% bioavailability; no absorption phase
   • Oral: Subject to first-pass metabolism
   • Sublingual/Rectal: Bypasses hepatic first pass
   • Transdermal, IM, SC, Inhaled - variable absorption
3. Physiological factors:
   • GI motility, pH, blood flow
   • Mucosal surface area
   • P-glycoprotein (P-gp) efflux transporter - reduces absorption of many drugs (substrates: digoxin, cyclosporine)

• Fraction of administered dose reaching systemic circulation unchanged
• Absolute bioavailability = (AUC oral / AUC IV) × (Dose IV / Dose oral) × 100
• First-pass effect: Hepatic metabolism after oral absorption before reaching systemic circulation

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1.3 Drug Distribution

• Vd = Amount of drug in body / Plasma drug concentration
• Vd ~5 L: Drug confined to plasma (e.g., heparin - highly protein bound)
• Vd ~15 L: Distribution into ECF
• Vd ~40 L: Distribution throughout body water
• Vd >100 L: Extensive tissue binding (e.g., chloroquine, amiodarone)

1. Plasma protein binding (PPB)
2. Tissue binding
3. Blood flow to organs
4. Lipid solubility
5. Blood-brain barrier (BBB)
6. Placental barrier

• Most drugs bind to plasma albumin (acidic drugs) or α1-acid glycoprotein (basic drugs)
• Only free (unbound) drug is pharmacologically active
• Significance:
  • Acts as drug reservoir
  • Delays elimination
  • Prolongs duration of action
  • Drug-drug interactions at binding sites (e.g., warfarin displaced by NSAIDs → toxicity)
  • Saturable at therapeutic concentrations for some drugs
• High PPB drugs: Warfarin (99%), Phenytoin (90%), Diazepam (98%), NSAIDs (>90%)

• Formed by tight junctions of brain capillary endothelial cells + astrocyte foot processes
• Lipid-soluble, un-ionized drugs cross easily (e.g., thiopentone, benzodiazepines)
• Ionized, large molecules cannot cross under normal conditions
• Disrupted in meningitis, tumors - allows penetration of otherwise excluded drugs

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1.4 Biotransformation (Drug Metabolism)

• More polar (water-soluble) products for renal/biliary excretion
• Pharmacologically inactive products (most common)
• Active metabolites (e.g., codeine → morphine; prodrugs: enalapril → enalaprilat)
• Toxic metabolites (e.g., paracetamol → NAPQI)

• Introduce/unmask a functional group (-OH, -NH2, -SH, -COOH)
• Oxidation: Most common; mediated by CYP450 enzymes
  • CYP families: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5
  • CYP3A4 metabolizes ~50% of all drugs
• Reduction: Azo and nitro reductions
• Hydrolysis: Ester and amide hydrolysis (plasma esterases, gut bacteria)
• Product: usually more polar but still active or less active

• Conjugation of Phase I metabolite (or parent drug) with endogenous molecules
• Results in highly polar, water-soluble, usually inactive products for excretion
• Types:
  • Glucuronidation (UGT enzymes - most common; e.g., morphine-6-glucuronide is active)
  • Sulfation (SULT enzymes)
  • Acetylation (NAT enzymes; genetic polymorphism: fast/slow acetylators - e.g., isoniazid)
  • Methylation (COMT, TPMT enzymes)
  • Glutathione conjugation (protection against reactive metabolites)
  • Glycine conjugation

• Mixed-function oxidase system; located in SER of hepatocytes
• Reaction: Drug + O2 + NADPH + H+ → Oxidized drug + H2O + NADP+
• Enzyme Induction: Increased CYP synthesis → increased drug metabolism → decreased drug effect
  • Inducers: Rifampicin, Phenytoin, Carbamazepine, Phenobarbitone, Alcohol (chronic), Smoking (CYP1A2)
  • Clinical consequence: Therapeutic failure, reduced contraceptive efficacy
• Enzyme Inhibition: Competitive or mechanism-based inhibition → decreased drug metabolism → drug accumulation/toxicity
  • Inhibitors: Ketoconazole (CYP3A4), Fluoxetine (CYP2D6), Erythromycin, Cimetidine, Grapefruit juice (CYP3A4)
  • Clinical consequence: Drug toxicity, adverse effects

• CYP2D6: Extensive (EM), Poor (PM), Intermediate (IM), Ultra-rapid metabolizers (UM)
  • Affects: Codeine, Metoprolol, Tamoxifen, Antipsychotics
• CYP2C19: Affects omeprazole, clopidogrel (prodrug - PM gets less antiplatelet effect)
• NAT2 (Acetylation): Fast vs. slow acetylators
  • Slow acetylators: Isoniazid toxicity (peripheral neuropathy), Procainamide → lupus syndrome
• TPMT: Affects 6-mercaptopurine/azathioprine (poor metabolizers → bone marrow toxicity)

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1.5 Drug Elimination

1. Glomerular filtration - Free (unbound) drug; passive; GFR ~125 mL/min
2. Active tubular secretion - Against concentration gradient; carrier-mediated; saturable
   • Organic anion transporters (OAT): penicillin, methotrexate
   • Organic cation transporters (OCT): creatinine, metformin
3. Passive tubular reabsorption - Lipid-soluble, un-ionized drugs reabsorbed back

• Acidic urine enhances excretion of basic drugs (e.g., amphetamine, morphine)
• Alkaline urine enhances excretion of acidic drugs (e.g., aspirin, phenobarbital)
• Clinical use: Urine alkalinization in aspirin/barbiturate poisoning (NaHCO3 infusion)

• Large molecular weight drugs (>500 Da), conjugated metabolites
• Enterohepatic circulation: Drug excreted in bile → hydrolyzed by gut bacteria → reabsorbed → prolongs drug action (e.g., morphine, estrogens, digitoxin)

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1.6 Compartment Models (Linear and Non-Linear)

• Drug distributes instantaneously and uniformly throughout the body
• Body treated as a single homogeneous unit
• Drug follows first-order kinetics for elimination
• Equations:
  • Cp(t) = Cp0 × e^(-Ket)
  • Half-life (t½) = 0.693 / Ke
  • Vd = Dose / Cp0
  • Clearance (CL) = Ke × Vd

• Body divided into central compartment (plasma + highly perfused organs) and peripheral compartment (muscle, fat, skin)
• Biexponential decline: Distribution phase (α) + Elimination phase (β)
• Cp(t) = A·e^(-αt) + B·e^(-βt)
• More accurately describes drugs with significant tissue distribution (e.g., lidocaine, gentamicin)

• Three or more compartments for drugs with very complex distribution (e.g., amiodarone)

• Rate of elimination proportional to drug concentration
• Constant fraction (not amount) eliminated per unit time
• t½ is constant regardless of dose
• Most drugs follow this: penicillin, digoxin, benzodiazepines

• Elimination pathway becomes saturated at therapeutic concentrations
• Rate of elimination is constant (fixed amount per unit time, not fraction)
• t½ increases with increasing dose → accumulation → toxicity
• Small dose changes cause disproportionately large changes in Css
• Examples: Phenytoin (Dilantin), Aspirin at high doses, Alcohol (ethanol), Theophylline (partially)
• Michaelis-Menten equation: Rate = (Vmax × C) / (Km + C)
  • At low concentrations (C << Km): first-order kinetics
  • At high concentrations (C >> Km): zero-order kinetics
• Clinical importance: Narrow therapeutic index drugs; requires careful dose titration

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PART B: PHARMACODYNAMICS

1.7 Pharmacodynamics - Overview

1. Physical action: Mannitol (osmotic diuresis), activated charcoal (adsorption), antacids (chemical neutralization)
2. Chemical action: Chelating agents (dimercaprol, EDTA), antacids (acid neutralization), protamine (heparin neutralization)
3. Enzyme inhibition: Neostigmine (AChE inhibitor), allopurinol (xanthine oxidase), methotrexate (DHFR), aspirin (COX - irreversible), ACE inhibitors, statins (HMG-CoA reductase)
4. Ion channel modulation: Local anesthetics (Na+ channel block), nifedipine (Ca2+ channel), diazepam (GABA-Cl- channel)
5. Carrier/transporter effects: Probenecid (blocks OAT), TCAs (block NA/5-HT reuptake), metformin (OCT2)
6. Nucleic acid interaction: Alkylating agents (cyclophosphamide), intercalating agents (doxorubicin), antimetabolites

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1.8 Drug Receptors - Structural and Functional Families

Type 1: Ligand-Gated Ion Channels (Ionotropic Receptors)

• Structure: Transmembrane ion channel directly coupled to receptor
• Signal transduction: Millisecond response (direct ion flow)
• Endogenous ligands: Neurotransmitters
• Examples:
  • Nicotinic ACh receptor (nAChR): Pentameric; Na+/K+ influx; neuromuscular junction
  • GABA-A receptor: Pentameric; Cl- influx; inhibitory; modulated by benzodiazepines, barbiturates, alcohol
  • Glutamate receptors (NMDA, AMPA, Kainate): Excitatory; Ca2+/Na+ influx
  • 5-HT3 receptor: Na+/K+ channel
• Drug examples: Benzodiazepines (allosteric modulator of GABA-A), succinylcholine (nAChR agonist), vecuronium (nAChR antagonist), ketamine (NMDA antagonist)

Type 2: G Protein-Coupled Receptors (GPCRs / Metabotropic Receptors)

• Structure: Seven-transmembrane (7-TM) / heptahelical; coupled to heterotrimeric G-proteins (Gα, Gβ, Gγ)
• Signal transduction: Seconds to minutes
• Largest receptor superfamily: >800 GPCRs in humans; ~50% of drug targets
• G-protein subtypes and second messengers:
  • Gs → adenylyl cyclase ↑ → cAMP ↑ → PKA activation (e.g., β-adrenergic, D1, H2, glucagon)
  • Gi → adenylyl cyclase ↓ → cAMP ↓ → PKA inhibition (e.g., M2/M4 muscarinic, D2, α2, opioid)
  • Gq → phospholipase C ↑ → IP3 + DAG → Ca2+↑ + PKC activation (e.g., α1, M1/M3, H1, 5-HT2)
  • G12/13 → Rho-GEFs → Rho kinase (cytoskeletal changes)
• Drug examples: Salbutamol (β2 agonist - Gs), Propranolol (β antagonist), Morphine (μ-opioid - Gi), Atropine (M antagonist), Clonidine (α2 - Gi)
• Desensitization/Downregulation: Prolonged agonist exposure → receptor phosphorylation (GRKs) → β-arrestin binding → internalization → downregulation (e.g., tachyphylaxis to isoprenaline)

Type 3: Enzyme-Linked Receptors (Receptor Tyrosine Kinases - RTKs)

• Structure: Single transmembrane domain; extracellular ligand-binding domain; intracellular kinase domain
• Signal transduction: Minutes to hours; gene expression changes
• Mechanism: Ligand binding → receptor dimerization → autophosphorylation (Tyr residues) → downstream signaling (MAPK/ERK, PI3K/Akt pathways)
• Examples:
  • Insulin receptor (insulin → glucose uptake; IRS-1 → PI3K → GLUT-4 translocation)
  • Growth factor receptors: EGF-R, PDGF-R, VEGF-R
  • Cytokine receptors (JAK-STAT pathway)
• Drug examples: Imatinib (BCR-Abl kinase inhibitor), Trastuzumab (HER2), Insulin, Erlotinib (EGFR inhibitor)
• RTK-related signaling cascades:
  • RAS → RAF → MEK → ERK (MAPK pathway - proliferation)
  • PI3K → PIP3 → PDK1 → AKT → mTOR (survival, growth)

Type 4: Nuclear Receptors (Intracellular / Transcription Factor Receptors)

• Structure: Intracellular; ligand-binding domain + DNA-binding domain (zinc fingers)
• Signal transduction: Hours to days; altered gene transcription
• Mechanism: Lipid-soluble ligand diffuses into cell → binds receptor → receptor-ligand complex translocates to nucleus → binds specific DNA sequences (HRE - Hormone Response Elements) → activates/represses gene transcription
• Examples:
  • Type I (Steroid receptors): Glucocorticoid receptor (GR - cortisol), Mineralocorticoid receptor (MR - aldosterone), Androgen receptor (AR), Estrogen receptor (ER), Progesterone receptor (PR)
  • Type II (Non-steroid): Thyroid hormone receptor (TR), Retinoic acid receptor (RAR), Vitamin D receptor (VDR)
  • Orphan receptors (endogenous ligands unknown)
• Drug examples: Dexamethasone (GR), Tamoxifen (ER antagonist/partial agonist), Finasteride (AR), Thyroxine, All-trans retinoic acid (ATRA - leukemia), Calcitriol

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1.9 Quantitation of Drug-Receptor Interaction

• Drug effect proportional to fraction of receptors occupied
• E / Emax = [D] / (KD + [D])
• Dissociation constant (KD): Drug concentration at which 50% receptors are occupied; measure of receptor affinity
  • Low KD = High affinity
• Follows hyperbolic (Michaelis-Menten type) curve; linearized as Scatchard plot

• S-shaped (sigmoid) when plotted on log dose scale
• Key parameters:
  • EC50 (ED50): Drug concentration (dose) producing 50% of maximal effect; measure of potency
  • Emax: Maximum effect achievable; measure of efficacy/intrinsic activity
  • Slope: Relates to receptor reserve, cooperativity
• Potency vs Efficacy:
  • Potency: How much drug needed to produce effect (EC50); shifted by affinity + intrinsic activity
  • Efficacy (intrinsic activity, α): Maximum response a drug can produce
  • High potency ≠ high efficacy

• Population response (all-or-none endpoint)
• Yields ED50, LD50, TD50
• Therapeutic Index (TI) = LD50/ED50 (animals) or TD50/ED50 (humans)
• Certain Safety Factor (CSF) = LD1/ED99
• Wide TI = safer drug (e.g., penicillin); Narrow TI = dangerous (e.g., digoxin, warfarin, lithium, phenytoin)

1. Competitive (Surmountable) Antagonism:
   • Antagonist competes with agonist for same receptor binding site
   • Can be overcome by increasing agonist concentration
   • Parallel rightward shift of dose-response curve (Emax unchanged, EC50 increased)
   • Example: Atropine vs ACh, Propranolol vs Adrenaline, Naloxone vs Morphine
2. Non-Competitive (Insurmountable) Antagonism:
   • Antagonist binds irreversibly OR at allosteric site
   • Cannot be overcome by increasing agonist concentration
   • Emax depressed; dose-response curve shifts downward
   • Example: Phenoxybenzamine (irreversible α-blocker), Aspirin (irreversible COX inhibitor)
3. Physiological (Functional) Antagonism:
   • Two drugs produce opposing effects via different receptors/mechanisms
   • Example: Adrenaline (bronchodilator, vasopressor) antagonizes effects of histamine; Glucagon vs insulin
4. Chemical Antagonism:
   • Direct chemical interaction; inactivation
   • Example: Protamine sulfate neutralizes heparin; Dimercaprol chelates heavy metals
5. Pharmacokinetic Antagonism:
   • One drug reduces absorption/increases metabolism/excretion of another
   • Example: Rifampicin induces CYP3A4 → reduces efficacy of oral contraceptives

• Observed when maximal effect achieved at less than 100% receptor occupancy
• Results in leftward shift of dose-response curve vs receptor occupancy curve
• Amplifies sensitivity to agonists
• Example: In smooth muscle - only 1-5% of muscarinic receptors need to be occupied for maximum contraction

• pA2 value (Schild analysis): Negative log of antagonist concentration that requires doubling of agonist to produce same effect; measure of antagonist affinity
• pA2 = -log(KB); calculated from Schild plot
• Used to characterize receptor subtypes pharmacologically

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1.10 Relationship Between Drug Concentration and Effect

• Range of drug concentrations producing therapeutic effect without toxicity
• Minimum Effective Concentration (MEC) - lower limit
• Minimum Toxic Concentration (MTC) - upper limit
• Important for drugs with narrow therapeutic index

• Delay between plasma concentration and pharmacological effect
• Clockwise hysteresis: Tolerance
• Counter-clockwise hysteresis: Active metabolite formation or distribution to effect site

• Tachyphylaxis: Rapid development of tolerance on repeated doses (e.g., ephedrine, nitrates)
• Mechanisms of tolerance:
  • Receptor desensitization (phosphorylation of receptor by GRKs)
  • Receptor downregulation (internalization, decreased synthesis)
  • Physiological adaptation
  • Increased drug metabolism (pharmacokinetic tolerance)
• Sensitization/Supersensitivity: Chronic antagonist use → receptor upregulation (e.g., withdrawal of β-blockers → rebound tachycardia; denervation supersensitivity)

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SUMMARY TABLE: Unit 1 High-Yield Points

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RECOMMENDED REFERENCES

1. Goodman & Gilman's The Pharmacological Basis of Therapeutics (13th Ed.) - Brunton et al.
2. Katzung's Basic and Clinical Pharmacology (15th Ed.) - Katzung BG
3. Rang & Dale's Pharmacology (9th Ed.) - Rang HP, Ritter JM et al.
4. Essentials of Medical Pharmacology (8th Ed.) - KD Tripathi
5. Principles of Pharmacology - Golan DE et al. (mechanistic approach)
6. Pharmacokinetics Made Easy - Donald Birkett

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• Pharmacokinetics (ADME): ~6 hours - covering all four ADME processes, compartment models, linear vs non-linear kinetics, protein binding significance
• Pharmacodynamics: ~6 hours - mechanisms of drug action, receptor families (all 4 types), quantitation of drug-receptor interactions, types of agonists/antagonists, dose-response analysis