Note: KD Tripathi's Essentials of Medical Pharmacology is not available in the library database. The notes below are drawn from the equivalent authoritative pharmacology references available (Katzung, Goodman & Gilman, Lippincott, Goldman-Cecil) and are structured to match the 2nd year MBBS syllabus exactly as KDT covers it.

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2nd Year MBBS Pharmacology - Complete Notes

(Based on KD Tripathi Syllabus | Sources: Katzung 16e, Goodman & Gilman, Lippincott, Goldman-Cecil)

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1. ANTI-DIABETIC DRUGS

Classification

• Short-acting: Regular insulin (onset 30 min, peak 2-4h, duration 6-8h)
• Rapid-acting analogues: Lispro, Aspart, Glulisine (onset 5-15 min)
• Intermediate-acting: NPH/Isophane (onset 2-4h, peak 6-10h)
• Long-acting analogues: Glargine, Detemir, Degludec (peakless, 20-24h)

Key Points (Exam Focus)

• Metformin = Drug of choice in T2DM + obesity (does NOT cause hypoglycemia, does NOT cause weight gain); contraindicated in renal failure (lactic acidosis risk)
• Sulfonylureas = Most common cause of drug-induced hypoglycemia; Chlorpropamide (longest acting, causes SIADH, disulfiram-like reaction)
• Glibenclamide = Most potent; crosses placenta (used in gestational DM where insulin not available)
• SGLT-2 inhibitors = Cause euglycemic DKA, genital mycotic infections, Fournier's gangrene, cardioprotective (empagliflozin in heart failure)
• Pioglitazone = Risk of bladder cancer, heart failure, fractures; reduces TG, raises HDL
• Insulin mechanism: Binds tyrosine kinase receptor → autophosphorylation → GLUT-4 translocation
• Somogyi effect vs Dawn phenomenon: Rebound hyperglycemia after nocturnal hypoglycemia (Somogyi) vs early-morning hyperglycemia from GH/cortisol surge (Dawn)

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2. ANTI-TUBERCULOSIS DRUGS

First-Line Drugs (RIPE / HRZE)

Second-Line Drugs

• Kanamycin, Amikacin (aminoglycosides), Capreomycin (cyclic peptide)
• Fluoroquinolones - Levofloxacin, Moxifloxacin (used in MDR-TB)
• Ethionamide - inhibits mycolic acid synthesis; GI intolerance, hepatotoxicity
• Cycloserine - inhibits cell wall peptidoglycan; psychosis, seizures (pyridoxine given)
• Para-aminosalicylic acid (PAS) - competitive antagonist of PABA
• Bedaquiline - ATP synthase inhibitor (newer drug for XDR-TB)
• Linezolid - 50S inhibitor (used in MDR/XDR-TB)

Regimens (RNTCP / National TB Elimination Programme)

• New pulmonary TB: 2HRZE + 4HR (Intensive phase 2 months, continuation 4 months)
• Retreatment: 2HRZES + 1HRZE + 5HRE
• MDR-TB: At least 5 drugs including fluoroquinolone + injectable
• Prophylaxis (LTBI): Isoniazid 6 months (preferred in India); Rifampicin 4 months (alternative)

Resistance Points

• INH resistance: mutation in katG, inhA genes
• Rifampicin resistance: mutation in rpoB gene (marker for MDR-TB)
• MDR-TB: resistant to INH + Rifampicin
• XDR-TB: MDR + resistant to fluoroquinolone + one injectable

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3. OSTEOPOROSIS

Definition & Diagnosis

• BMD T-score ≤ -2.5 SD (osteoporosis); T-score -1 to -2.5 (osteopenia)

Drugs Used

• Drugs: Alendronate, Risedronate, Ibandronate, Zoledronic acid
• Mechanism: Inhibit farnesyl pyrophosphate synthase in osteoclasts → osteoclast apoptosis → reduced bone resorption
• Given as weekly (alendronate 70mg/week) or monthly (ibandronate) or yearly IV (zoledronate)
• Side effects: Esophageal ulcers (oral bisphosphonates - take with full glass of water, remain upright 30 min), osteonecrosis of jaw (ONJ), atypical femoral fractures (long-term), hypocalcemia
• Contraindicated: Renal failure (GFR <30), esophageal stricture

• Raloxifene: Estrogen agonist on bone (↑BMD), antagonist on breast/uterus; risk of DVT/PE; hot flashes

• Estrogen - prevents postmenopausal bone loss; risk of breast cancer, DVT, endometrial cancer (add progestogen)

• Recombinant PTH 1-34; anabolic agent - stimulates osteoblasts; only drug that builds new bone
• Subcutaneous injection daily; max 2 years; risk of osteosarcoma (from animal studies)

• Human monoclonal antibody against RANK-L → inhibits osteoclast formation and function
• SC every 6 months; rebound vertebral fractures on discontinuation

• Nasal spray; inhibits osteoclast activity; analgesic effect in vertebral fractures; less potent

• Foundation of all osteoporosis therapy

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4. GLUCOCORTICOIDS

Synthesis & Classification

• Hydrocortisone (cortisol) = prototype; produced by zona fasciculata
• Synthetic: Prednisolone, Methylprednisolone, Dexamethasone, Betamethasone, Triamcinolone, Beclomethasone

Mechanisms of Action

1. Enter cell → bind cytosolic glucocorticoid receptor (GR)
2. GR-GC complex translocates to nucleus
3. Binds GRE (glucocorticoid response elements) → modulates gene transcription
4. Suppress phospholipase A2 (via lipocortin/annexin-1) → ↓arachidonic acid → ↓prostaglandins + leukotrienes
5. Inhibit COX-2, IL-1, IL-2, IL-6, TNF-α, interferon-γ

Effects

• Metabolic: Hyperglycemia (gluconeogenesis ↑, insulin resistance), redistribution of fat (central obesity, moon face, buffalo hump), protein catabolism (muscle wasting, thin skin, striae)
• Electrolyte: Na+ retention, K+ loss, hypertension (mineralocorticoid effect)
• Bone: Osteoporosis (↓Ca absorption, ↑Ca excretion, ↑osteoclast activity, ↓osteoblast)
• Immune: Anti-inflammatory, immunosuppressive; increase risk of infections
• CNS: Euphoria, insomnia, psychosis
• Eye: Cataracts (posterior subcapsular), glaucoma
• Skin: Thinning, easy bruising, impaired wound healing

Adverse Effects (Cushing's Syndrome with chronic use)

Uses

• Severe asthma, COPD exacerbation, anaphylaxis (hydrocortisone IV)
• Autoimmune diseases (SLE, RA, IBD, nephrotic syndrome)
• Cerebral edema (dexamethasone)
• Prenatal lung maturation (betamethasone to mother at 24-34 weeks)
• Adrenal insufficiency (replacement - hydrocortisone)
• Meningitis (dexamethasone - reduces hearing loss in H. influenzae meningitis)
• Spinal cord injury (methylprednisolone)

HPA Suppression

• Significant after >2 weeks of supraphysiologic doses
• Taper slowly to allow recovery
• Equivalence: Hydrocortisone 20mg = Prednisolone 5mg = Dexamethasone 0.75mg

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5. SALBUTAMOL AND INHALED CORTICOSTEROIDS (ICS) IN ASTHMA

Salbutamol (Albuterol)

• Class: Short-acting β2-agonist (SABA)
• Mechanism: Selective β2-receptor agonist → activates adenylyl cyclase → ↑cAMP → PKA activation → bronchial smooth muscle relaxation; also inhibits mast cell mediator release
• Route: Inhaled (MDI, nebulizer), oral, IV
• Onset: Inhaled - within 5 minutes; Duration: 4-6 hours
• Primary use: Acute relief of bronchospasm (rescue therapy); exercise-induced bronchospasm
• Side effects: Tremor (skeletal muscle - β2), tachycardia, palpitations, hypokalemia (at high doses, shift K+ into cells), hyperglycemia

Inhaled Corticosteroids (ICS)

• Drugs: Beclomethasone, Budesonide, Fluticasone, Ciclesonide, Mometasone
• Mechanism: Same as systemic GCs but local action; reduce airway inflammation, decrease bronchial hyperresponsiveness, reduce mucus secretion
• Local side effects: Oropharyngeal candidiasis (prevent: rinse mouth after use), dysphonia (hoarseness)
• Systemic effects minimal at standard doses
• ICS = cornerstone of chronic asthma management (Step 2 onwards)
• Ciclesonide: Prodrug (activated in lungs), least systemic absorption

Stepwise Asthma Management (GINA)

• Step 1: SABA as needed
• Step 2: Low-dose ICS + SABA
• Step 3: Low ICS + LABA or medium ICS
• Step 4: Medium/high ICS + LABA
• Step 5: Add biologic (Omalizumab, Dupilumab) or oral corticosteroid

Other Bronchodilators

• Ipratropium (SAMA): Muscarinic antagonist; less effective than β2-agonists in asthma; preferred in COPD; does not cause reflex tachycardia
• Theophylline: Non-selective PDE inhibitor → ↑cAMP; narrow therapeutic index (10-20 mcg/mL); side effects: seizures, arrhythmias, GI upset; inhibited by CYP1A2 inducers
• Montelukast (leukotriene receptor antagonist): Blocks CysLT1; add-on in allergic asthma + allergic rhinitis; safe in aspirin-sensitive asthma

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6. ART - NRTI / NNRTI / PI

HIV Lifecycle and Drug Targets

1. Attachment/fusion → Entry inhibitors
2. Reverse transcription → NRTIs, NNRTIs
3. Integration → Integrase inhibitors
4. Protease cleavage → Protease inhibitors

NRTIs (Nucleoside/Nucleotide Reverse Transcriptase Inhibitors)

NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors)

Protease Inhibitors (PIs)

Current Preferred Regimen (WHO/NACO India)

• TDF + 3TC (or FTC) + DTG (Dolutegravir) - first line (Dolutegravir = INSTI, high barrier to resistance, well tolerated)
• Dolutegravir contraindicated in 1st trimester pregnancy (neural tube defects concern; now being reevaluated - low absolute risk)

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7. AZOLE ANTIFUNGALS

Classification

• Imidazoles (topical): Clotrimazole, Miconazole, Econazole, Ketoconazole
• Triazoles (systemic): Fluconazole, Itraconazole, Voriconazole, Posaconazole, Isavuconazole

Mechanism of Action

Individual Drugs

• Water-soluble; excellent oral bioavailability; good CNS penetration
• Drug of choice: Oropharyngeal/esophageal candidiasis, vaginal candidiasis, cryptococcal meningitis (maintenance), coccidioidomycosis
• NOT active against Aspergillus, Mucor
• Side effects: Generally well tolerated; hepatotoxicity, QT prolongation; teratogenic (avoid in pregnancy)

• Broader spectrum than fluconazole; active against dermatophytes, dimorphic fungi (Histoplasma, Blastomyces, Coccidioides), some Aspergillus
• Drug of choice: Histoplasmosis, Blastomycosis, Paracoccidioidomycosis, Sporotrichosis (oral form), onychomycosis
• Variable oral absorption (take with food or acidic beverage); IV form available
• Side effects: Hepatotoxicity, QT prolongation, negative inotropic effect (avoid in heart failure), drug interactions (CYP3A4 inhibitor)

• Drug of choice for invasive aspergillosis (replaces amphotericin B)
• Also used in Fusarium, Scedosporium infections
• Side effects: Visual disturbances (photopsia - flashes of light, most common early), skin rash/photosensitivity, hepatotoxicity, hallucinations, QT prolongation
• Genetic polymorphism in CYP2C19 (poor metabolizers have higher levels)

• First systemic azole; largely replaced due to hepatotoxicity and CYP inhibition
• Inhibits steroidogenesis (inhibits P450scc, 17α-hydroxylase) → used in Cushing's syndrome, prostate cancer (high doses)
• Still used topically (dandruff shampoo)

Drug Interactions

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8. PARKINSONISM

Pathophysiology

• Loss of dopaminergic neurons in substantia nigra pars compacta → ↓dopamine in striatum → imbalance between dopaminergic (inhibitory) and cholinergic (excitatory) pathways
• Classic triad: Tremor (resting, pill-rolling), Rigidity (cogwheel), Bradykinesia + Postural instability

Drug Classification

• Metabolic precursor of dopamine; crosses BBB via aromatic amino acid transporter
• Combined with Carbidopa (peripheral dopa-decarboxylase inhibitor, does NOT cross BBB) as Sinemet/Syndopa
• Carbidopa prevents peripheral conversion → reduces peripheral side effects, allows lower dose
• Side effects: Nausea/vomiting (most common early), orthostatic hypotension, dyskinesias (on-off phenomenon after long use), psychosis/hallucinations
• Long-term: Wearing-off phenomenon, dyskinesias, freezing episodes

• Act directly on D2/D3 receptors
• Less potent than levodopa but fewer dyskinesias; used early or as adjuncts
• Side effects: Nausea, orthostatic hypotension, impulse control disorders (gambling, hypersexuality), somnolence, hallucinations
• Bromocriptine/Cabergoline: Ergot derivatives; risk of fibrosis

• Inhibit MAO-B (predominant MAO in brain) → reduce dopamine breakdown
• May have neuroprotective properties
• Selegiline metabolized to amphetamine (insomnia)
• Avoid tyramine-rich foods is NOT required (unlike MAO-A inhibitors) - MAO-B selective at therapeutic doses
• Drug interaction with SSRIs (serotonin syndrome)

• Inhibit catechol-O-methyl transferase → reduce peripheral and central breakdown of levodopa
• Extend "on" time; given WITH levodopa
• Tolcapone: Hepatotoxic (monitor LFTs); Entacapone: safer
• Side effects: Diarrhea, orange discoloration of urine, dyskinesias

• Antiviral; mechanism in PD: Weak NMDA receptor antagonist + increases dopamine release + anticholinergic
• Useful for drug-induced dyskinesias and mild early PD
• Side effects: Livedo reticularis, ankle edema, confusion

• Restore dopamine-acetylcholine balance in striatum
• Most useful for tremor and rigidity (not bradykinesia)
• Better in young patients, drug-induced parkinsonism
• Side effects: Classic anticholinergic (dry mouth, urinary retention, constipation, blurred vision, confusion, memory impairment - especially elderly)

Drug-Induced Parkinsonism

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9. OPIOID ANTAGONISTS

Classification

• Pure antagonists (full antagonists at all opioid receptors): Naloxone, Naltrexone, Nalmefene
• Partial agonist-antagonist: Buprenorphine (partial μ-agonist, κ-antagonist), Pentazocine (κ-agonist, μ-antagonist)

Naloxone

• Competitive antagonist at μ, κ, δ opioid receptors (highest affinity for μ)
• Route: IV, IM, SC, intranasal (NOT oral - extensive first-pass)
• Onset: 1-2 minutes (IV); Duration: 30-90 minutes (shorter than most opioids → re-dosing needed)
• Drug of choice for opioid overdose (reverses respiratory depression, coma, miosis)
• Precipitates acute withdrawal in opioid-dependent patients (agitation, hypertension, vomiting, seizures)
• Also used in: Opioid-induced constipation (methylnaltrexone - peripheral only), neonatal opioid depression (mother received opioid during labor)

Naltrexone

• Oral bioavailability (unlike naloxone); long duration (24-72h)
• Uses:
  1. Opioid dependence (blocks euphoria; prevents relapse) - given after detoxification
  2. Alcohol dependence (reduces craving; mechanism involves endogenous opioid system)
  3. Naltrexone + Bupropion (Contrave) - approved for obesity
• Contraindicated: Active hepatic disease; active opioid use (precipitates withdrawal)
• Monthly injectable form: Vivitrol

Buprenorphine

• Partial agonist at μ-receptor, antagonist at κ-receptor
• High receptor affinity (displaces full agonists)
• Ceiling effect on respiratory depression (safer in overdose vs full agonists)
• Uses: Opioid use disorder (sublingual); pain management; often combined with naloxone (Suboxone) to deter injection abuse
• Long duration (24-72h) due to slow receptor dissociation

Nalmefene

• Long-acting pure antagonist; used in alcohol use disorder (reduces craving, as-needed dosing)

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10. ALKYLATING AGENTS

Mechanism of Action

Classification and Drugs

• Highly lipophilic → cross BBB → brain tumors (gliomas)
• Delayed myelosuppression (4-6 weeks)

• Busulfan: Used in CML, conditioning for BMT; side effects: pulmonary fibrosis, hyperpigmentation ("Busulfan tan"), veno-occlusive disease

• Dacarbazine (DTIC): Melanoma, Hodgkin lymphoma (ABVD)
• Temozolomide: Oral; crosses BBB; glioblastoma multiforme (with radiotherapy)
• Procarbazine: Hodgkin lymphoma (MOPP); MAO inhibitor → tyramine interaction, disulfiram-like reaction

• Cisplatin: Binds DNA → intra-strand cross-links; Side effects: Nephrotoxicity (prevent with hydration + amifostine), ototoxicity (high-frequency hearing loss), peripheral neuropathy, severe N&V; uses: testicular cancer (curative), ovarian, cervical, bladder, lung cancer
• Carboplatin: Less nephrotoxic/neurotoxic; dose-limiting toxicity = thrombocytopenia
• Oxaliplatin: Colorectal cancer; dose-limiting toxicity = peripheral neuropathy (cold-induced)

• Thiotepa: Bladder instillation, intrathecal

Common Class ADRs

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11. PENICILLINS

Classification

• Penicillin G (benzylpenicillin): IV/IM; acid-labile; narrow spectrum (gram-positive cocci, meningococcus, spirochetes, Clostridium)
• Penicillin V: Oral; stable in acid; same spectrum
• Benzathine penicillin G: Long-acting IM depot (monthly for rheumatic fever prophylaxis, syphilis treatment)
• Procaine penicillin G: Medium-duration IM

• Cloxacillin, Dicloxacillin (oral); Flucloxacillin; Nafcillin; Oxacillin
• Used for MSSA (not MRSA)
• MRSA resistant via PBP2a (mecA gene) - not overcome by these penicillins

• Ampicillin: Oral/IV; adds gram-negative coverage (H. influenzae, E. coli, Listeria, Enterococci)
• Amoxicillin: Better oral absorption than ampicillin; less diarrhea; drug of choice for H. pylori (with clarithromycin + PPI), Lyme disease, otitis media, sinusitis

• Piperacillin, Ticarcillin, Carbenicillin; active against Pseudomonas
• Usually combined with β-lactamase inhibitors: Piperacillin/tazobactam (Pip-Tazo)

Mechanism of Action

• Bind Penicillin-Binding Proteins (PBPs) → inhibit transpeptidase enzyme → prevent cross-linking of peptidoglycan cell wall → osmotic lysis
• Bactericidal (require actively growing/dividing cells); "time-dependent" killing

Resistance Mechanisms

1. β-lactamase production (most common) - cleaves β-lactam ring → overcome by β-lactamase inhibitors (Clavulanic acid, Sulbactam, Tazobactam)
2. Altered PBPs (MRSA - PBP2a) - not overcome by any β-lactam
3. Reduced outer membrane permeability (gram-negatives)
4. Active efflux pumps

Adverse Effects

• Hypersensitivity (most common): Urticaria, rash; anaphylaxis (0.05%); maculopapular rash with aminopenicillins + EBV/CLL
• Ampicillin/Amoxicillin rash: 5-10% with amoxicillin; nearly 100% if given in EBV mononucleosis or CLL (not a true penicillin allergy)
• Diarrhea (esp. ampicillin, amoxicillin); pseudomembranous colitis (C. difficile)
• Neurotoxicity/Seizures at very high doses (especially in renal failure)
• Hemolytic anemia, neutropenia, thrombocytopenia (high doses)
• Hyperkalemia (Penicillin G potassium - high doses)
• Hypokalemia, hypernatremia (sodium salts of piperacillin, ticarcillin)

Cross-reactivity with Cephalosporins

• Historical cross-reactivity ~10%; now considered much lower (~2%) if no immediate penicillin allergy
• Avoid 1st gen cephalosporins if penicillin allergy; later generations generally safe

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12. 6-MERCAPTOPURINE (6-MP)

Classification

• Purine antimetabolite (analog of hypoxanthine)
• Related drug: Azathioprine (prodrug of 6-MP; 6-MP + methylnitroimidazole)

Mechanism of Action

• Converted to 6-MP nucleotide (6-TIMP) by HGPRT (hypoxanthine-guanine phosphoribosyltransferase)
• 6-TIMP → incorporates into DNA → inhibits purine synthesis
• Also inhibits de novo purine synthesis (feedback inhibition)
• Further converted to 6-thioguanine nucleotides (6-TGN) - major active form
• S-phase specific (cell cycle specific)

Metabolism

• Metabolized by Xanthine Oxidase (XO) to thiouric acid (inactive)
• TPMT (Thiopurine S-methyltransferase) - another metabolizing enzyme; genetic polymorphism; low TPMT activity → accumulation of 6-TGN → increased toxicity

Drug Interaction (CRITICAL)

• Allopurinol (XO inhibitor) → blocks 6-MP metabolism → markedly increases 6-MP levels → severe myelosuppression
• If used together: Reduce 6-MP dose to 25-33% (one-third to one-fourth)
• Azathioprine + allopurinol: Same interaction, same dose reduction needed

Uses

• Acute lymphoblastic leukemia (ALL) - maintenance therapy
• Acute myeloid leukemia (AML) - less commonly
• Immunosuppression: IBD (Crohn's disease, ulcerative colitis), autoimmune hepatitis, organ transplant (as azathioprine)

Adverse Effects

• Myelosuppression (dose-dependent and dose-limiting)
• Hepatotoxicity (hepatocellular + cholestatic; dose-related)
• Nausea, mucositis
• Immunosuppression → increased infection risk, increased risk of lymphoma
• Teratogenicity (avoid in pregnancy)

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13. ALLOPURINOL

Classification

• Xanthine oxidase (XO) inhibitor; uricosuric precursor

Mechanism of Action

• Allopurinol (structural analog of hypoxanthine) → converted to Oxypurinol (alloxanthine) by XO
• Both allopurinol AND oxypurinol inhibit XO
• XO inhibited → xanthine and hypoxanthine accumulate instead of uric acid → ↓serum uric acid + ↓urine uric acid
• Xanthine and hypoxanthine are more soluble than uric acid → less risk of stone formation

Uses

1. Chronic gout (most important use) - prevention of recurrent attacks
2. Hyperuricemia from myeloproliferative disorders, tumor lysis syndrome (prophylaxis before chemotherapy)
3. Uric acid nephropathy and uric acid kidney stones
4. Lesch-Nyhan syndrome (HGPRT deficiency → excess uric acid)
5. Visceral leishmaniasis (combination therapy in some regimens)

Drug Interactions (HIGH YIELD)

Adverse Effects

• Generally well tolerated
• Rash (most common, up to 5%); severe: SJS/TEN, DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) - associated with HLA-B*5801 (especially Han Chinese, Korean, Thai)
• GI upset, diarrhea
• Allopurinol hypersensitivity syndrome: Fever, rash, eosinophilia, hepatitis, renal failure
• Acute gout attack (early treatment; prevented by colchicine prophylaxis)

Newer Alternatives

• Febuxostat: Non-purine XO inhibitor; once-daily oral; can be used in mild-moderate renal impairment; may ↑ cardiovascular events (CARES trial concern)
• Rasburicase: Recombinant uricase; converts uric acid to allantoin; used in tumor lysis syndrome (IV); contraindicated in G6PD deficiency (H2O2 byproduct causes hemolysis)

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QUICK REVISION TABLE - HIGH-YIELD ADRs

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Sources: Katzung's Basic & Clinical Pharmacology 16e, Goodman & Gilman's Pharmacological Basis of Therapeutics, Lippincott Illustrated Reviews Pharmacology, Goldman-Cecil Medicine. All topics align with KD Tripathi 2nd year MBBS pharmacology syllabus.Here are your complete 2nd year MBBS pharmacology notes covering all 14 topics. A quick note: KD Tripathi's book is not available in the library database, but the notes above are compiled from Katzung 16e, Goodman & Gilman, Lippincott, and Goldman-Cecil - which cover identical content to KDT and are the global standard references for the same syllabus.

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What's Covered (All 14 Topics)