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📚 PHARMACOLOGY NOTES — UNIT I & UNIT II
🔷 UNIT I — GENERAL PHARMACOLOGY (8 Hours)
1a. Introduction to Pharmacology
Definition
Pharmacology = the science of drugs — their sources, chemistry, mechanisms of action, effects, uses, and side effects.
- Pharmacokinetics — what the body does to the drug (ADME)
- Pharmacodynamics — what the drug does to the body
Historical Landmarks
| Era | Milestone |
|---|---|
| Ancient | Herbal remedies; Dioscorides' Materia Medica |
| 17th–18th C | Experimental physiology begins (Magendie, Claude Bernard) |
| 19th C | Isolation of pure alkaloids (morphine, quinine, atropine) |
| Early 20th C | Paul Ehrlich — "magic bullet" concept; first synthetic drug (Salvarsan) |
| 1940s–50s | Penicillin introduced; rapid growth of pharmacology |
| Modern | Receptor cloning, pharmacogenomics, targeted therapy |
Scope of Pharmacology
Medical pharmacology, clinical pharmacology, toxicology, pharmacy, pharmacogenomics, pharmacovigilance, drug discovery.
Nature and Sources of Drugs
| Source | Examples |
|---|---|
| Plant | Morphine (opium), digoxin (foxglove), atropine (belladonna), quinine (cinchona) |
| Animal | Insulin (pancreas), heparin, thyroid hormone |
| Mineral | Iron, zinc, lithium, magnesium |
| Microbial | Penicillin, streptomycin |
| Synthetic | Aspirin, paracetamol, sulfonamides |
| Recombinant DNA | Insulin analogs, erythropoietin, monoclonal antibodies |
Essential Drugs Concept
WHO defines essential medicines as those that satisfy the priority health care needs of the population. They should be available at all times, in adequate amounts, in appropriate dosage forms, at a price the community can afford.
Routes of Drug Administration
Enteral (via GI tract)
- Oral — most common, convenient, economical; subject to first-pass metabolism
- Sublingual (SL) — under tongue; rapid absorption, bypasses first-pass (e.g., nitroglycerine)
- Buccal — between cheek and gum; similar to SL
- Rectal — useful when oral not possible; partial first-pass bypass
Parenteral (bypassing GI tract)
- IV (intravenous) — fastest onset, 100% bioavailability, no first-pass; cannot be recalled
- IM (intramuscular) — moderate absorption; can give depot preparations (e.g., haloperidol decanoate)
- SC (subcutaneous) — slow, sustained absorption; e.g., insulin
- Intradermal — small volumes, used for allergy testing
Topical/Local
- Skin (transdermal patches), eye drops, nasal sprays, inhalation
- Inhalation — rapid onset, local effect; e.g., salbutamol inhaler
Agonists and Antagonists
Agonist — binds receptor → activates it → produces response
- Full agonist — maximal intrinsic efficacy (e.g., morphine)
- Partial agonist — submaximal response even at full receptor occupancy (e.g., buprenorphine)
- Inverse agonist — binds receptor but produces opposite effect
Antagonist — binds receptor, no intrinsic activity, blocks agonist effect
| Type | Mechanism | Key Feature |
|---|---|---|
| Competitive (reversible) | Competes for same site as agonist | Can be overcome by ↑ agonist dose; shifts dose-response curve right; Emax unchanged |
| Non-competitive (irreversible) | Binds different site OR irreversibly | Cannot be overcome by ↑ agonist; Emax reduced |
Spare Receptors
Maximal response is achieved when only a fraction of total receptors are occupied. The "extra" receptors = spare receptors. They amplify sensitivity (low EC₅₀) without changing Emax.
Tolerance, Dependence, Addiction
| Term | Definition | Example |
|---|---|---|
| Tolerance | Reduced response to same dose over time; need higher dose for same effect | Opioids, alcohol |
| Tachyphylaxis | Rapid tolerance on repeated dosing within short period | Nitrates, ephedrine |
| Dependence | Physiological/psychological need for drug to function | Opioids, benzodiazepines |
| Addiction | Compulsive drug-seeking behavior despite harm; psychological need | Cocaine, heroin |
Idiosyncrasy & Allergy
- Idiosyncrasy — abnormal, unexpected response to a drug due to genetic differences in drug metabolism; not dose-related; e.g., G6PD deficiency → hemolysis with primaquine
- Allergy (Drug Hypersensitivity) — immune-mediated reaction; requires prior sensitization; not dose-dependent; e.g., penicillin → anaphylaxis (Type I), serum sickness (Type III)
1b. Pharmacokinetics
Membrane Transport
Drugs cross membranes by:
- Passive diffusion — most common; lipid-soluble, un-ionized drugs; down concentration gradient
- Facilitated diffusion — carrier-mediated, no energy, down gradient (e.g., glucose)
- Active transport — carrier-mediated, energy (ATP) required, against gradient (e.g., P-glycoprotein)
- Pinocytosis/endocytosis — for large molecules, insulin receptor internalization
Henderson-Hasselbalch rule: Weak acids are better absorbed in acidic environments (stomach); weak bases in alkaline environments (intestine).
Absorption
The movement of drug from site of administration into bloodstream.
Factors affecting absorption:
- Lipid solubility and ionization (pKa)
- Surface area of absorption site
- Blood flow to site
- Route of administration
- First-pass metabolism (oral route)
- Drug formulation (enteric-coated, sustained release)
Bioavailability (F) = fraction of administered dose reaching systemic circulation unchanged
- IV → F = 100%
- Oral → F < 100% due to first-pass effect
Distribution
Drug's reversible movement from blood to tissues.
Factors affecting distribution:
- Blood flow (well-perfused organs: brain, liver, kidney get drug first)
- Plasma protein binding (albumin binds acidic drugs; α₁-acid glycoprotein binds basic drugs) — only free drug is active
- Blood–brain barrier (BBB): lipophilic drugs cross; ionized drugs do not
- Volume of Distribution (Vd) = dose / plasma concentration; high Vd → drug in tissues
Metabolism (Biotransformation)
Primarily in liver (also gut wall, lung, kidney, blood).
Phase I reactions (functionalization):
- Oxidation, reduction, hydrolysis (mainly CYP450 enzymes)
- Adds/exposes polar groups (-OH, -NH₂, -COOH)
- Products may be active, inactive, or toxic
Phase II reactions (conjugation):
- Glucuronidation (most common), sulfation, acetylation, methylation, glutathione conjugation
- Usually inactivate drug; produce polar, water-soluble metabolites for excretion
Enzyme Induction:
- Drugs/substances that ↑ CYP450 enzyme synthesis → ↑ metabolism of other drugs → ↓ their effect
- Inducers: Rifampicin, carbamazepine, phenytoin, phenobarbital, chronic alcohol, St. John's Wort
- Onset: 1–2 weeks; reversible
Enzyme Inhibition:
- Drugs that block CYP450 → ↓ metabolism → ↑ plasma levels of co-administered drug → toxicity
- Inhibitors: Ketoconazole, erythromycin, clarithromycin, ritonavir, omeprazole, grapefruit juice
- Onset: rapid (within 24 hours); mechanism — competitive or irreversible
Excretion (Elimination)
Primary route = kidney. Also: bile/feces, lungs, saliva, milk, sweat.
Renal excretion involves:
- Glomerular filtration — free drug (not protein-bound) filtered; GFR ~120 mL/min
- Active tubular secretion — transporter-mediated; even protein-bound drug secreted
- Passive tubular reabsorption — lipid-soluble, un-ionized drug reabsorbed back; alkalinizing urine → ↑ excretion of weak acids (e.g., aspirin poisoning → give NaHCO₃)
Kinetics of Elimination
| Parameter | First-Order Kinetics | Zero-Order Kinetics |
|---|---|---|
| Rate of elimination | Proportional to drug concentration | Constant rate (independent of concentration) |
| Half-life | Constant | Increases with dose |
| Examples | Most drugs | Alcohol, phenytoin (at high doses), aspirin (high dose) |
Half-life (t½) = time for plasma concentration to fall by 50%
- Steady state reached in ~5 t½
- t½ = 0.693 × Vd / Cl
Clearance (Cl) = volume of plasma cleared of drug per unit time
🔷 UNIT II — GENERAL PHARMACOLOGY (12 Hours)
2a. Pharmacodynamics
Principles and Mechanisms of Drug Action
Drugs act by:
- Receptor-mediated mechanisms (most common)
- Non-receptor mechanisms: ion channels (local anesthetics), enzymes (aspirin inhibits COX), transport (furosemide inhibits NKCC2), physicochemical (antacids, mannitol)
Receptor Theories
| Theory | Key Concept |
|---|---|
| Occupancy Theory (Clark, 1926) | Response ∝ number of receptors occupied by drug |
| Rate Theory (Paton) | Response ∝ rate of drug-receptor association/dissociation |
| Induced Fit Theory | Drug induces conformational change in receptor |
| Operational Model (Black & Leff) | Incorporates efficacy; explains partial agonists |
Classification of Receptors
| Class | Mechanism | Speed | Examples |
|---|---|---|---|
| Ionotropic (Ion channel-linked) | Direct ion channel gating | Milliseconds | Nicotinic ACh-R, GABA-A, NMDA |
| G-protein coupled (GPCR / Metabotropic) | Via G-protein → 2nd messengers | Seconds | Muscarinic, adrenergic, opioid, dopamine |
| Receptor Tyrosine Kinase (RTK) | Enzyme-linked; autophosphorylation | Minutes | Insulin R, EGF-R, PDGF-R |
| JAK-STAT Receptors | Cytokine receptors linked to JAK kinases | Minutes | Cytokine receptors (IL, IFN, GH) |
| Nuclear (Transcription factor) Receptors | Regulate gene transcription | Hours-days | Steroid hormones, thyroid hormone, Vit D |
G-Protein Coupled Receptors (GPCRs) — Signal Transduction
Structure: 7 transmembrane segments; coupled to heterotrimeric G-protein (Gα, Gβ, Gγ)
Subtypes:
| G-protein | Effect | 2nd Messenger | Examples |
|---|---|---|---|
| Gs | Stimulates adenylyl cyclase | ↑ cAMP | β-adrenergic, glucagon, H₂ |
| Gi | Inhibits adenylyl cyclase | ↓ cAMP | α₂-adrenergic, M₂/M₄ muscarinic, opioid |
| Gq | Activates phospholipase C | ↑ IP₃ + DAG → ↑ Ca²⁺ + PKC | α₁-adrenergic, M₁/M₃ muscarinic |
| G₁₂/₁₃ | Activates Rho kinase | Cytoskeletal changes | Thromboxane receptors |
cAMP pathway: G-protein → adenylyl cyclase → cAMP → PKA → phosphorylation of target proteins
IP₃/DAG pathway: G-protein → PLC-β → PIP₂ → IP₃ (releases Ca²⁺ from ER) + DAG (activates PKC)
Ion Channel Receptors
- Drug binds → direct opening/closing of ion channels
- Fast synaptic transmission
- Examples: Nicotinic receptor (Na⁺/K⁺), GABA-A (Cl⁻), Glycine (Cl⁻)
- Benzodiazepines and barbiturates modulate GABA-A channel
Transmembrane Enzyme-Linked Receptors (RTK)
- Extracellular ligand-binding domain + intracellular tyrosine kinase domain
- Ligand binding → receptor dimerization → autophosphorylation → downstream signaling (MAPK, PI3K/AKT)
- Examples: Insulin receptor, VEGF-R, EGFR
- Targeted by tyrosine kinase inhibitors (imatinib, erlotinib)
JAK-STAT Receptors
- Cytokine/growth factor receptors without intrinsic kinase activity
- Associated with JAK (Janus kinase)
- Ligand → JAK activation → STAT phosphorylation → STAT dimerizes → enters nucleus → gene transcription
- Examples: IFN-α/β/γ, IL-6, erythropoietin, growth hormone receptors
- Inhibitors: Ruxolitinib (JAK1/2), tofacitinib (JAK3)
Nuclear/Transcription Factor Receptors
- Drug/hormone enters cell → binds intracellular receptor → receptor-hormone complex enters nucleus → binds DNA response element → alters gene transcription
- Slowest mechanism (hours to days)
- Examples: Glucocorticoids, mineralocorticoids, estrogen, androgen, thyroid hormone, Vitamin D, retinoic acid
Regulation of Receptors
| Type | Definition | Clinical Effect |
|---|---|---|
| Down-regulation | ↓ receptor number/sensitivity with prolonged agonist exposure | Tolerance (e.g., β-agonists in asthma) |
| Up-regulation | ↑ receptor number after prolonged antagonist use | Rebound effect on withdrawal (e.g., propranolol withdrawal → rebound tachycardia) |
| Desensitization | Receptor uncoupling from G-protein; rapid onset | Acute tolerance |
Dose-Response Relationship
Graded dose-response:
- Response increases with dose; plateau at maximum (Emax)
- EC₅₀ = concentration producing 50% of maximal response (measures potency)
- Emax = maximal effect (measures efficacy)
Quantal dose-response:
- All-or-nothing response in a population
- ED₅₀ = dose effective in 50% of population
- LD₅₀ = lethal dose in 50% of population
- Therapeutic Index (TI) = LD₅₀ / ED₅₀ (animal); higher TI = safer drug
- Therapeutic Window = range between minimum effective concentration and minimum toxic concentration
Combined Effects of Drugs
| Effect | Definition | Example |
|---|---|---|
| Synergism | Combined effect > sum of individual effects | Co-trimoxazole (sulfa + trimethoprim) |
| Additive | Combined effect = sum of individual effects | Two similar antihypertensives |
| Antagonism | One drug reduces effect of another | Naloxone + morphine |
| Potentiation | Inactive drug enhances effect of active drug | Clavulanic acid + amoxicillin |
Factors Modifying Drug Action
- Age (pediatric, geriatric pharmacology — altered PK/PD)
- Body weight / surface area
- Gender (hormonal differences, pregnancy category)
- Genetic factors (CYP polymorphisms — poor/extensive metabolizers)
- Disease states (liver/renal impairment alters PK)
- Drug interactions
- Psychological factors (placebo effect)
- Time of administration (chronopharmacology)
- Route and rate of drug administration
- Drug tolerance
2b. Adverse Drug Reactions (ADRs)
Definition: Any unintended, harmful response to a drug given at normal therapeutic doses.
WHO Classification (Type A–F):
| Type | Feature | Example |
|---|---|---|
| Type A — Augmented | Dose-dependent, predictable, pharmacological | Hypoglycemia with insulin, bleeding with warfarin |
| Type B — Bizarre | Dose-independent, unpredictable, immune/genetic | Penicillin anaphylaxis, halothane hepatitis |
| Type C — Chronic | From long-term use | Adrenal suppression with steroids |
| Type D — Delayed | Carcinogenicity, teratogenicity | Thalidomide → phocomelia |
| Type E — End of use | Withdrawal reactions | Opioid/benzodiazepine withdrawal |
| Type F — Failure | Unexpected failure of therapy | Antibiotic resistance |
Monitoring: Yellow Card system (UK), MedWatch (USA), Pharmacovigilance (WHO)
2c. Drug Interactions
Drug interactions = when one drug alters the effect of another.
Pharmacokinetic Drug Interactions
Affect ADME of one drug by another:
| Phase | Mechanism | Example |
|---|---|---|
| Absorption | Chelation, pH changes | Antacids ↓ fluoroquinolone absorption |
| Distribution | Protein binding displacement | Warfarin displaced by NSAIDs |
| Metabolism | Enzyme induction/inhibition | Rifampicin ↓ OCP efficacy (induction); Ketoconazole ↑ cyclosporine levels (inhibition) |
| Excretion | Altered renal clearance, pH | Probenecid ↓ penicillin excretion |
Pharmacodynamic Drug Interactions
Affect the action at receptor/effector site:
- Synergism: Alcohol + benzodiazepines → additive CNS depression
- Antagonism: β-blocker + β-agonist bronchodilator
- Serotonin Syndrome: SSRIs + MAO inhibitors (additive serotonergic effect)
2d. Drug Discovery and Clinical Evaluation of New Drugs
Drug Discovery Phase
- Identification of biological target (receptor, enzyme, pathway)
- High-throughput screening (HTS) of compound libraries
- Structure-Activity Relationship (SAR) studies
- Rational drug design using molecular modeling
- Lead compound identification and optimization
Preclinical Evaluation Phase
Before human testing — done in animals:
- In vitro studies (cell cultures, isolated organs)
- In vivo animal studies (rodents, non-rodents)
- Tests: acute/subacute/chronic toxicity, genotoxicity (Ames test), teratogenicity, carcinogenicity, reproductive toxicity, pharmacokinetics
Clinical Trial Phase (Human testing)
After regulatory approval (IND — Investigational New Drug application):
| Phase | Subjects | Purpose | Number |
|---|---|---|---|
| Phase I | Healthy volunteers | Safety, pharmacokinetics, dosing (ADME), MTD | 20–80 |
| Phase II | Patients with disease | Efficacy, dose optimization, short-term safety | 100–300 |
| Phase III | Large patient population | Comparative efficacy vs standard treatment (RCT) | 1000–3000+ |
| Phase IV | Post-marketing (general public) | Long-term safety, rare ADRs, new indications | Thousands |
Registration / Marketing Approval
After Phase III → NDA (New Drug Application) to regulatory authority (FDA / CDSCO in India / EMA in Europe)
Pharmacovigilance
- Continuous monitoring of drug safety after marketing
- Detects rare, long-term, or unexpected ADRs
- Methods: spontaneous reporting, prescription event monitoring, case-control studies
- WHO Programme for International Drug Monitoring (Uppsala Monitoring Centre)
- In India: National Pharmacovigilance Programme (NPvP)
🔑 Quick Revision — Key Mnemonics
- ADME = Absorption, Distribution, Metabolism, Excretion
- Competitive antagonist: "Shift right, Emax same"
- Non-competitive antagonist: "Emax drops"
- TI = LD₅₀ / ED₅₀ — higher = safer
- Phase I clinical trials = First in man = Healthy volunteers = Safety
- Type A ADR = Augmented/predictable; Type B = Bizarre/unpredictable
- Enzyme inducers (↓ effect): CRIPES — Carbamazepine, Rifampicin, Isoniazid (at high doses), Phenytoin, Ethanol (chronic), St. John's wort
- Enzyme inhibitors (↑ effect/toxicity): SICKFACES — Sodium valproate, Isoniazid, Cimetidine, Ketoconazole, Fluconazole, Alcohol (acute), Ciprofloxacin, Erythromycin, Sulfonamides
Sources: Katzung's Basic & Clinical Pharmacology 16th Ed; Lippincott Illustrated Reviews: Pharmacology
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