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PHARMACOLOGY PAPER 1 - COMPLETE ANSWERS

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GENERAL PHARMACOLOGY

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10-MARK TOPICS

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1. Bioavailability - Factors Affecting, Clinical Significance

• Solubility - lipid-soluble drugs absorb better
• Particle size - smaller particles dissolve faster
• Chemical stability - acid-labile drugs destroyed in stomach (e.g., penicillin G)
• pKa and ionization state

• Dosage form: solution > suspension > capsule > tablet > coated tablet
• Excipients and fillers
• Manufacturing process

• First-pass metabolism (hepatic) - drugs like morphine, propranolol, lignocaine have very low oral bioavailability due to extensive first-pass
• GI motility - rapid motility reduces absorption
• Splanchnic blood flow
• Disease states: liver disease increases bioavailability of high extraction drugs

• Food can enhance (fatty meals increase griseofulvin absorption) or reduce (tetracycline + calcium)
• Other drugs - antacids reduce absorption of many drugs

• Determines dose and route of administration
• Oral vs IV dose calculation (e.g., morphine oral:IV ratio = 3:1)
• Bioequivalence testing for generic drugs
• Helps understand drug failures and toxic effects

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2. Drug Biotransformation - Types, Factors, Prodrugs, Examples

• Oxidation (most common) - by CYP450 enzymes (e.g., diazepam → desmethyldiazepam)
• Reduction (e.g., chloral hydrate → trichloroethanol)
• Hydrolysis (e.g., aspirin → salicylate + acetic acid)
• Aim: introduce or unmask a functional group (-OH, -NH2, -SH, -COOH)

• Glucuronidation (most common Phase II - with UDP-glucuronic acid)
• Sulfation
• Acetylation (e.g., isoniazid, sulfonamides - slow vs fast acetylators)
• Methylation
• Glycine conjugation
• Products are more polar, water-soluble, inactive, and easily excreted

• Age: neonates and elderly have reduced enzyme activity
• Genetics: polymorphism in CYP2D6 (poor vs extensive metabolizers)
• Disease: liver failure reduces metabolism
• Enzyme induction: rifampicin, phenobarbitone, phenytoin increase CYP450
• Enzyme inhibition: erythromycin, ketoconazole, cimetidine decrease CYP450
• Sex: females may metabolize certain drugs slower
• Nutritional status

• Enalapril → Enalaprilat (ACE inhibitor)
• Levodopa → Dopamine
• Codeine → Morphine (CYP2D6)
• Prednisone → Prednisolone
• Sulfasalazine → Mesalazine + Sulfapyridine
• Cyclophosphamide → active metabolite (anticancer)

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3. Factors Modifying Drug Dose and Effects

• Neonates: immature blood-brain barrier, reduced plasma proteins, immature liver/kidneys → lower doses
• Elderly: reduced renal clearance, decreased hepatic blood flow, increased body fat, reduced albumin → drug toxicity risk

• Fast vs slow acetylators (isoniazid)
• G6PD deficiency (hemolysis with primaquine, dapsone)
• Pseudocholinesterase deficiency (prolonged apnea with succinylcholine)

• Renal failure: dose reduction needed for renally excreted drugs (aminoglycosides, digoxin)
• Liver failure: reduce dose of hepatically metabolized drugs
• Thyroid disease: hyperthyroidism increases drug metabolism
• Hypoalbuminemia: increases free drug fraction

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5-MARK TOPICS

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1. Local and Systemic Routes of Drug Administration

• Skin (transdermal patches, ointments) - e.g., glyceryl trinitrate, estrogen
• Eye drops (conjunctival)
• Ear drops
• Nasal drops/sprays
• Inhalation (bronchodilators for asthma)
• Rectal suppositories (for local effect)

• Oral - most common, convenient, safe, first-pass effect
• Sublingual - rapid absorption, bypasses first-pass (e.g., GTN, buprenorphine)
• Buccal (e.g., methyltestosterone)
• Rectal (for systemic effect, partial avoidance of first-pass)

• Intravenous (IV) - 100% bioavailability, rapid onset, no first-pass, used in emergencies
• Intramuscular (IM) - rapid absorption (aqueous solutions), depot preparations possible
• Subcutaneous (SC) - slow, sustained absorption (e.g., insulin)
• Intradermal - skin testing (e.g., BCG vaccine)
• Intrathecal (e.g., spinal anesthesia)
• Intraperitoneal

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2. Factors Affecting Drug Absorption

• Lipid solubility: lipid-soluble drugs absorb better (pH partition theory)
• Molecular size: small molecules absorb faster
• Ionization: un-ionized forms cross membranes better
• Formulation: dissolution rate

• Gastric emptying rate: faster emptying → drug reaches small intestine sooner → faster absorption
• Intestinal motility
• Surface area of GI tract (small intestine is primary site)
• Splanchnic blood flow
• pH: acidic drugs absorbed from stomach (weak acids), basic from intestine (weak bases)

• Presystemic (first-pass) metabolism
• Drug interactions (chelation: tetracycline + calcium; absorption: metoclopramide increases)
• Food: delays gastric emptying; some foods enhance, others reduce absorption

• Malabsorption syndromes
• Gastric achlorhydria
• Crohn's disease

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3. Plasma Protein Binding

• Only FREE (unbound) drug is pharmacologically active
• Bound fraction acts as a reservoir
• High PPB drugs: warfarin (99%), diazepam (99%), aspirin (85%)

• Drug interactions: two highly bound drugs compete for same binding site
  • Warfarin + aspirin → increased free warfarin → bleeding risk
• Hypoalbuminemia (liver disease, malnutrition) → increased free drug → toxicity
• Bound drug cannot be filtered by kidneys (reduced renal elimination)
• PPB affects volume of distribution

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4. Microsomal Enzyme Induction

• Phenobarbitone, Phenytoin
• Carbamazepine
• Rifampicin (most potent inducer)
• Alcohol (chronic)
• Smoking (induces CYP1A2)

• Reduced efficacy of substrate drugs:
  • Rifampicin reduces efficacy of oral contraceptives → pregnancy
  • Carbamazepine reduces warfarin effect
• Increased production of toxic metabolites (e.g., paracetamol hepatotoxicity in alcoholics)
• Auto-induction (carbamazepine induces its own metabolism)
• Beneficial: phenobarbitone used to treat neonatal jaundice by inducing bilirubin conjugation

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5. Plasma Half-Life (t½)

• Determines dosing frequency (generally, drug given every t½)
• Time to reach steady state = 4-5 × t½
• Time for drug washout from body = 4-5 × t½
• Renally excreted drugs: t½ increases in renal failure

• Warfarin: 40 hours
• Digoxin: 36-40 hours
• Penicillin G: 30 minutes
• Aspirin: 15-20 minutes (salicylate: 6-12 hours)

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6. Methods to Prolong Drug Action

1. Structural modification: Prodrugs or metabolically stable analogues
2. Sustained/controlled-release formulations: Matrix tablets, membrane-coated tablets, osmotic pump (OROS), transdermal patches
3. Depot preparations: IM oil-based injections (e.g., fluphenazine decanoate IM every 4 weeks), implants (subdermal)
4. Reducing renal excretion: Probenecid blocks tubular secretion of penicillin
5. Vasoconstrictor addition: Adrenaline added to local anaesthetics (reduces absorption, prolongs action)
6. Protein binding formulations: Albumin-bound paclitaxel (Nab-paclitaxel)
7. Enteric coatings: protect from gastric degradation, delay release

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7. Therapeutic Index

• High TI (wide margin of safety) = safer drug: penicillins (TI very high)
• Low TI (narrow margin of safety) = dangerous drug: digoxin, lithium, warfarin, aminoglycosides, phenytoin

• Drugs with low TI need TDM (Therapeutic Drug Monitoring)
• Determines safety of dose escalation
• Affects choice between drugs with similar efficacy

• Therapeutic window: range of plasma concentrations that produce therapeutic effect without toxicity
• Margin of safety: dose that kills 1% (LD1) to dose that produces effect in 99% (ED99)

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8. Pharmacodynamic Drug Interactions (Combined Effects)

1. Synergism: Effect of two drugs combined greater than individual effects
   • Additive: 1+1 = 2 (e.g., two NSAIDs)
   • Potentiation/Supra-additive: 1+1 = 3 (e.g., probenecid + penicillin)
   • Sensitization: one drug makes tissue more sensitive to another
2. Antagonism:
   • Competitive (reversible): antagonist competes with agonist for same receptor (e.g., atropine vs acetylcholine; naloxone vs morphine)
   • Non-competitive (irreversible): antagonist binds irreversibly (e.g., phenoxybenzamine)
   • Chemical: one drug chemically inactivates another (e.g., protamine + heparin)
   • Physiological: two drugs with opposite effects at different receptors (e.g., insulin + glucagon)

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9. Drug Antagonism

• Surmountable - increasing agonist dose can overcome antagonism
• Shifts dose-response curve to the right (parallel shift)
• Emax unchanged, EC50 increased
• Example: atropine vs pilocarpine at muscarinic receptors

• Insurmountable - cannot be overcome by increasing agonist dose
• Shifts dose-response curve down and to the right
• Emax decreased
• Example: phenoxybenzamine (irreversible alpha blocker)

• Buprenorphine (partial opioid agonist) acts as functional antagonist in presence of morphine

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10. Factors Influencing Drug Dosage

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11. Drug Tolerance

• Pharmacokinetic (Dispositional) tolerance: Increased metabolism due to enzyme induction (e.g., barbiturates induce their own metabolism)
• Pharmacodynamic (Cellular) tolerance: Receptor downregulation, decreased receptor sensitivity, or receptor uncoupling
  • Example: opioids - desensitization of mu receptors
  • Beta-agonists in asthma - receptor downregulation

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12. Mechanism of Drug Action

1. Receptor-mediated:
   • Agonist (activates receptor): morphine, salbutamol
   • Antagonist (blocks receptor): atropine, naloxone
2. Enzyme inhibition:
   • Reversible: neostigmine (AChE inhibitor), methotrexate (DHFR)
   • Irreversible: organophosphates (AChE), aspirin (COX)
3. Ion channel modulation:
   • Block: local anaesthetics (Na+ channels), calcium channel blockers
   • Facilitation: benzodiazepines (GABA-A Cl- channel)
4. Carrier-mediated transport:
   • Inhibition of reuptake: SSRIs (serotonin reuptake), cocaine (dopamine reuptake)
   • Inhibition of transport: probenecid (uric acid transport)
5. Physicochemical mechanisms:
   • Osmotic effect: mannitol, magnesium sulfate (saline laxative)
   • Antacids (acid neutralization)
6. Interference with metabolic processes:
   • Antimetabolites: methotrexate, 5-FU

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13. Drug Dependence

• Characterized by withdrawal (abstinence) syndrome on stopping
• Opioid withdrawal: yawning, sweating, muscle cramps, diarrhoea, piloerection, hypertension
• Alcohol withdrawal: tremors, seizures, delirium tremens (DTs)
• Benzodiazepine withdrawal: anxiety, tremors, seizures

• Craving, compulsive drug-seeking behaviour
• No physical withdrawal symptoms
• Example: cocaine, cannabis

• High: heroin/morphine, cocaine, alcohol, nicotine, benzodiazepines
• WHO classification: morphine type, barbiturate type, cocaine type, cannabis type, amphetamine type, hallucinogen type

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14. Receptor Families

1. G-protein coupled receptors (GPCRs / Metabotropic):
   • 7 transmembrane domain receptors
   • Examples: beta-adrenergic, muscarinic, opioid, dopamine (D1, D2), serotonin (5-HT1, 5-HT2)
   • Signal via cAMP, IP3/DAG, or ion channels
2. Ligand-gated ion channels (Ionotropic):
   • Fast response (milliseconds)
   • Examples: nicotinic ACh receptor, GABA-A, NMDA, 5-HT3
3. Receptor tyrosine kinases:
   • Examples: insulin receptor, growth factor receptors
   • Autophosphorylation on ligand binding
4. Nuclear (Intracellular) receptors:
   • Ligands must be lipophilic
   • Examples: steroid hormone receptors, thyroid hormone receptors, vitamin D receptor
   • Act on DNA to alter gene transcription (slow, hours-days)

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3-MARK TOPICS

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1. Orphan Drugs

2. Zero and First Order Kinetics, Clearance

• Rate of drug elimination is constant (fixed amount per unit time)
• Independent of drug concentration
• Seen when metabolic enzymes are saturated
• Examples: alcohol, phenytoin at high doses, aspirin at high doses
• Dangerous: small dose increase → disproportionate plasma level rise

• Rate of elimination is proportional to drug concentration (constant fraction per unit time)
• Most drugs follow first-order kinetics
• Produces linear pharmacokinetics
• Constant t½

• Volume of plasma cleared of drug per unit time (mL/min)
• Cl = Dose/AUC (from pharmacokinetic data)
• Total Cl = Renal Cl + Hepatic Cl + other Cl
• Key determinant of dosing rate at steady state

3. Hoffman Elimination

4. Drug Synergism

5. Pharmacogenetics

• Slow acetylators: isoniazid neuropathy, procainamide-induced SLE
• Fast acetylators: reduced INH efficacy
• CYP2D6 poor metabolizers: codeine does not convert to morphine (no analgesia); others have ultra-rapid metabolism (toxicity)
• G6PD deficiency: hemolysis with primaquine, dapsone
• Pseudocholinesterase deficiency: prolonged apnea with succinylcholine
• HLA-B*5701: abacavir hypersensitivity
• TPMT deficiency: azathioprine toxicity

6. Placebo

7. Tachyphylaxis

8. Adverse Drug Reactions - Types

• Type A (Augmented): Dose-related, predictable, common (e.g., bleeding with warfarin, hypoglycemia with insulin)
• Type B (Bizarre): Dose-independent, unpredictable, rare, immunological or genetic (e.g., penicillin anaphylaxis, halothane hepatitis)
• Type C (Chronic): Dose and time related, with prolonged use (e.g., opioid dependence, HPA axis suppression with corticosteroids)
• Type D (Delayed): Delayed onset (e.g., carcinogenesis, teratogenesis)
• Type E (End of treatment): Withdrawal reactions (e.g., rebound hypertension after stopping clonidine)
• Type F (Failure): Failure of therapy (e.g., oral contraceptive failure with enzyme inducers)

9. Pharmacopoeia

10. Blood-Brain Barrier (BBB)

• Tight junctions between brain capillary endothelial cells
• Astrocyte foot processes
• Pericytes

11. Enzyme Inhibition

12. Dose-Response Relationship

• Graded dose-response: continuous variable (e.g., blood pressure); shows EC50 (concentration producing 50% max effect), Emax (maximum effect)
• Quantal dose-response: all-or-none endpoint (e.g., % patients responding); shows ED50 (dose effective in 50% of population)
• Shift to right = increased EC50 = reduced potency
• Reduced Emax = reduced efficacy

13. Iatrogenic Diseases, Teratogenicity, Carcinogenicity, Mutagenicity, Pharmacovigilance

• Thalidomide → phocomelia (limb defects)
• Valproate → neural tube defects
• ACE inhibitors → fetal renal agenesis
• Isotretinoin → craniofacial defects
• Alcohol → fetal alcohol syndrome
• FDA Pregnancy Categories: A, B, C, D, X

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BLOOD AND BLOOD FORMATION

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5-MARK TOPICS

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1. Hypolipidemic Drugs - Classification

1. HMG-CoA Reductase Inhibitors (Statins) - First-line
   • Drugs: Atorvastatin, Rosuvastatin, Simvastatin, Pravastatin
   • MOA: Competitively inhibit HMG-CoA reductase (rate-limiting step in cholesterol synthesis) in liver
   • Effects: Reduce LDL (20-60%), modest TG reduction, mild HDL increase
   • Uses: Hypercholesterolemia, prevention of cardiovascular events
   • ADRs: Myopathy (rhabdomyolysis - rare), elevated liver enzymes
   • Contraindication: Pregnancy
2. Fibrates (Fibric Acid Derivatives)
   • Drugs: Gemfibrozil, Fenofibrate, Bezafibrate
   • MOA: Activate PPAR-alpha → increase lipoprotein lipase → reduce triglycerides; increase HDL
   • Uses: Hypertriglyceridemia
   • ADRs: Myopathy (especially combined with statin), cholelithiasis
3. Bile Acid Sequestrants (Resins)
   • Drugs: Cholestyramine, Colestipol
   • MOA: Bind bile acids in intestine → interrupt enterohepatic circulation → increase hepatic cholesterol use
   • Reduce LDL; increase triglycerides
   • ADRs: Constipation, bloating; decrease absorption of fat-soluble vitamins and many drugs
4. Nicotinic Acid (Niacin)
   • MOA: Inhibits lipolysis in adipose tissue; reduces VLDL synthesis
   • Most effective in raising HDL
   • ADRs: Flushing (prostaglandin-mediated - prevented by aspirin), hyperglycemia, hyperuricemia
5. Ezetimibe
   • MOA: Inhibits NPC1L1 transporter → reduces intestinal cholesterol absorption
   • Combined with statins for additive LDL reduction
6. PCSK9 inhibitors (newer):
   • Evolocumab, Alirocumab
   • Monoclonal antibodies; dramatically reduce LDL; used in familial hypercholesterolemia

• Lifestyle modification + Statin (first-line)
• Add ezetimibe if inadequate response
• Consider PCSK9 inhibitors for refractory cases

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2. Plasma Volume Expanders

1. Dextrans (key item - "* dextran" in notes)
   • Polysaccharides derived from sucrose by Leuconostoc bacteria
   • Dextran 70 (high MW): plasma expander (stays in circulation longer)
   • Dextran 40 (low MW): improves microcirculation (prevents rouleaux and sludging); used in peripheral vascular disease
   • ADRs: Anaphylaxis, interference with blood cross-matching, renal failure (dextran 40 in high doses)
2. Hydroxyethyl starch (HES): e.g., Hetastarch - semi-synthetic, risk of coagulopathy, renal failure
3. Gelatin preparations (e.g., Haemaccel, Gelofusine): short duration, anaphylaxis risk
4. Human Albumin Solution: expensive, no proven benefit over crystalloids in most patients

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3. Fibrinolytics (Thrombolytics)

1. Streptokinase (first generation): non-specific (systemic), antigenic, cheap
2. Urokinase: non-specific, non-antigenic
3. Alteplase (tPA) (second generation): fibrin-specific, short t½, non-antigenic
4. Tenecteplase, Reteplase: third generation, single IV bolus, more fibrin-specific

• Acute MI (within 12 hours)
• Acute ischemic stroke (alteplase within 4.5 hours)
• Massive pulmonary embolism
• Deep vein thrombosis

• Bleeding (major complication) - intracranial hemorrhage most feared
• Streptokinase: anaphylaxis, hypotension

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4. Antiplatelet Drugs - Classification, MOA, Uses

1. COX inhibitors: Aspirin - irreversibly acetylates COX-1 → reduces TXA2 (pro-aggregatory); dose 75-150 mg/day for antiplatelet effect
2. ADP receptor (P2Y12) antagonists:
   • Clopidogrel (prodrug, requires CYP2C19 activation) - irreversible P2Y12 block
   • Ticagrelor (reversible, direct-acting)
   • Prasugrel (irreversible, more potent)
3. GPIIb/IIIa inhibitors:
   • Abciximab (monoclonal Ab) - most potent
   • Eptifibatide, Tirofiban
   • Used IV during coronary intervention
4. Phosphodiesterase inhibitors: Dipyridamole (increases cAMP) - used with aspirin for stroke prevention
5. PAR-1 (thrombin receptor) antagonists: Vorapaxar

• Aspirin: primary/secondary prevention of MI, stroke, ACS
• Clopidogrel: post-coronary stent placement (DAPT with aspirin), ACS
• GPIIb/IIIa inhibitors: PCI (percutaneous coronary intervention)

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3-MARK TOPICS

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Anti-thrombolytics (Antifibrinolytics) - Tranexamic Acid

• Menorrhagia (heavy menstrual bleeding)
• Post-partum hemorrhage
• Trauma hemorrhage (CRASH-2 trial)
• Hemophilia
• Dental extraction in patients on anticoagulants

Clopidogrel

• Prodrug converted to active thiol metabolite by CYP2C19
• Irreversible P2Y12 ADP receptor antagonist
• Used in: ACS, post-coronary stent (with aspirin for 12 months), peripheral arterial disease
• Resistance in CYP2C19 poor metabolizers (ticagrelor preferred)

Rational Use of Prophylactic Aspirin in MI

• Aspirin inhibits TXA2 → prevents platelet aggregation and thrombus
• In acute MI: 300 mg loading dose (chewed), then 75 mg/day
• Primary prevention: benefit debatable, outweighed by GI bleeding risk in low-risk patients
• Secondary prevention: clear benefit in all patients with prior MI, stroke, or ACS
• Guidelines: DAPT (aspirin + P2Y12 inhibitor) for 12 months after ACS/coronary stent

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10-MARK TOPICS

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Anticoagulants - Parenteral and Oral + AE + Therapeutic Uses

• MOA: Activates antithrombin III → inhibits thrombin (IIa) and Factor Xa; given IV or SC
• Uses: DVT/PE treatment, ACS, cardiac surgery, renal dialysis
• Monitoring: aPTT (therapeutic: 1.5-2.5× normal)
• ADRs:
  • Bleeding (antidote: protamine sulfate)
  • Heparin-induced thrombocytopenia (HIT) - type II (antibody-mediated, paradoxical thrombosis)
  • Osteoporosis (long-term)

• Enoxaparin, Dalteparin, Tinzaparin
• MOA: Primarily inhibit Factor Xa > IIa
• Advantages over UFH: SC once/twice daily, no routine monitoring, predictable dose response, less HIT
• Uses: DVT prophylaxis, treatment, ACS, pregnancy (anticoagulant of choice)
• Monitoring: anti-Xa levels (if needed: renal impairment, extremes of weight, pregnancy)

• Synthetic pentasaccharide; selective Factor Xa inhibitor via antithrombin
• Uses: DVT prophylaxis, ACS

• Bivalirudin, Argatroban - used in HIT; Lepirudin

• MOA: Inhibits Vitamin K epoxide reductase → impairs synthesis of clotting factors II, VII, IX, X and proteins C and S
• Onset: 2-3 days (must overlap with heparin initially)
• Monitoring: PT/INR (therapeutic INR 2-3 for most indications; 2.5-3.5 for mechanical heart valves)
• Uses: AF (atrial fibrillation), DVT/PE treatment, mechanical heart valves
• ADRs:
  • Bleeding (antidote: Vitamin K; FFP for immediate reversal)
  • Skin necrosis (protein C deficiency - first 3-5 days)
  • Teratogen (Category X - warfarin embryopathy: chondrodysplasia punctata)
  • Numerous drug interactions (enzyme inducers reduce effect; enzyme inhibitors increase effect)

• Direct Factor Xa inhibitors: Rivaroxaban, Apixaban, Edoxaban
• Direct thrombin inhibitors: Dabigatran
• Advantages: Fixed dose, no routine monitoring, fewer interactions, no dietary restriction
• Uses: AF (non-valvular), DVT/PE treatment and prophylaxis
• Reversal: Idarucizumab (dabigatran), Andexanet alfa (Xa inhibitors)

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Haematinics and Erythropoietin (10 marks)

Iron Absorption and Storage

• Haem iron (meat, fish): absorbed 20-30% via haem transporter HCP1
• Non-haem iron (plant, cereals): absorbed 2-5% via DMT1 (divalent metal transporter 1); needs to be in Fe2+ (ferrous) form; Vitamin C reduces Fe3+ to Fe2+

1. Fe3+ → reduced to Fe2+ by duodenal cytochrome b (DCYTB)
2. Fe2+ enters duodenal enterocyte via DMT1
3. Inside cell: stored as ferritin OR exported via ferroportin
4. In plasma: Fe2+ oxidized to Fe3+ by hephaestin → binds to transferrin → carried to bone marrow or stored in liver

• Vitamin C (ascorbic acid)
• Acidic gastric pH
• Ferrous (Fe2+) form
• Haem iron
• Deficiency state, increased erythropoiesis

• Phytates, tannins (tea, cereals)
• Antacids, PPIs (reduce acidity)
• Tetracyclines, quinolones (chelation)
• Hepcidin (increases with inflammation → reduces ferroportin → reduces absorption)

• Ferritin (soluble storage form; serum ferritin reflects body stores)
• Haemosiderin (insoluble, in macrophages)

• Ferrous sulphate (most common), ferrous gluconate, ferrous fumarate
• Given on empty stomach; Vitamin C co-administration increases absorption
• ADRs: GI upset (nausea, constipation, black stools)
• Response: reticulocytosis in 1 week; Hb rises 1g/dL every 2-3 weeks

• Iron dextran (IM/IV), Iron sucrose (IV), Ferric carboxymaltose (IV)
• Used when: oral intolerance, severe malabsorption, compliance issues, inflammatory bowel disease
• Risk: anaphylaxis (test dose needed for iron dextran), staining (IM - use Z-track technique)

1. GI phase (0-6 hrs): nausea, vomiting, hematemesis
2. Latent phase (6-24 hrs): apparent recovery
3. Systemic toxicity (12-48 hrs): metabolic acidosis, shock, CNS depression
4. Hepatic failure (2-4 days)
5. GI scarring (2-4 weeks) Treatment: Desferrioxamine (chelates iron; IV/IM)

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Vitamin B12 (Cobalamin)

• Pernicious anemia (autoimmune destruction of parietal cells → lack of IF) - most common cause in developed countries
• Strict vegetarian/vegan diet
• Gastrectomy, ileal resection
• Crohn's disease
• Fish tapeworm (Diphyllobothrium latum)

• Megaloblastic anemia
• Subacute combined degeneration of spinal cord (SACD): posterior and lateral column damage → paresthesias, weakness, ataxia
• Glossitis, angular stomatitis

• Hydroxocobalamin IM injection (preferred - longer acting)
• Cyanocobalamin IM
• For pernicious anemia: lifelong IM injections
• High-dose oral B12 (1000 mcg/day) can bypass IF requirement via passive diffusion

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Folic Acid

• Poor diet (most common globally)
• Malabsorption (coeliac disease)
• Increased demand: pregnancy, hemolytic anaemia
• Drugs: methotrexate (DHFR inhibitor), trimethoprim, phenytoin, OCP

• Megaloblastic anemia (like B12 deficiency) - but NO neurological features
• Neural tube defects in fetus (spina bifida, anencephaly) - if deficient in early pregnancy

• Folic acid 5 mg/day orally
• Prevention of NTD: 400 mcg/day periconceptionally; 5 mg/day in high-risk women (previous NTD, anticonvulsants, diabetes)

• B12 deficiency: + neurological features (treat with B12 first; treating with folate alone can unmask B12 neuropathy)
• Folate deficiency: no neurological features

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Erythropoietin (EPO)

• Glycoprotein hormone produced mainly by peritubular cells of kidney
• Stimulates erythropoiesis in bone marrow
• Regulated by tissue hypoxia

• Epoetin alfa, Epoetin beta, Darbepoetin alfa (longer t½ due to extra sialic acid)

• Anemia of chronic kidney disease (most common indication)
• Anemia of chronic disease
• Cancer-related anemia (especially in chemotherapy patients)
• Pre-operative autologous blood donation
• Anemia associated with HIV/zidovudine treatment
• Myelodysplastic syndromes

• Hypertension (most common - dose-related)
• Thrombosis (increased blood viscosity)
• Pure red cell aplasia (anti-EPO antibodies - rare but serious)
• Flu-like symptoms

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RENAL PHARMACOLOGY

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5-MARK TOPICS

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Classification of Diuretics

• Furosemide: Acute pulmonary edema, heart failure, hypertensive crisis, hypercalcemia
• Thiazides: Hypertension (1st line), heart failure, nephrogenic DI (paradoxically)
• Spironolactone: Heart failure (reduces mortality), hyperaldosteronism, ascites, resistant hypertension
• Acetazolamide: Glaucoma, altitude sickness, metabolic alkalosis, epilepsy (adjunct)
• Mannitol: Raised intracranial pressure, acute glaucoma, forced diuresis in poisoning

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Carbonic Anhydrase Inhibitors - Acetazolamide

• Weak diuretic
• Produces metabolic acidosis (loses bicarbonate)
• Reduces aqueous humor formation in eye
• Reduces CSF production

1. Glaucoma (open-angle) - reduces intraocular pressure
2. Altitude (mountain) sickness - prevents/treats
3. Epilepsy (adjunct - petit mal)
4. Metabolic alkalosis
5. Periodic paralysis (hypokalemic type)

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Osmotic Diuretics - Mannitol

1. Acute reduction of raised intracranial pressure (cerebral edema, head trauma) - draws water from brain
2. Acute angle-closure glaucoma
3. Forced diuresis (to increase urine output and flush drugs in poisoning - e.g., salicylates, barbiturates)
4. Prophylaxis of acute tubular necrosis (maintains urine flow during surgery)

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Thiazide-Like Diuretics

• Reduce blood pressure (initial: volume depletion; long-term: vasodilation)
• Reduce calcium excretion (unique property - renal calcium retention)
• Increase uric acid (gout risk)

1. Hypertension (first-line, especially in elderly, Black patients)
2. Heart failure (edema)
3. Nephrolithiasis (calcium-containing stones - reduces urinary calcium)
4. Nephrogenic DI (reduces urine volume by increasing proximal reabsorption due to mild volume depletion)
5. Osteoporosis (increases bone density by retaining calcium)

• Hypokalemia (major concern - add K+ supplement or potassium-sparing diuretic)
• Hyperuricemia (precipitates gout)
• Hyperglycemia (impair insulin secretion)
• Hyperlipidemia (mild)
• Hyponatremia
• Erectile dysfunction

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Loop Diuretics

1. Acute pulmonary edema (first-line emergency treatment)
2. Chronic heart failure
3. Renal failure (maintain urine output)
4. Hypertensive crisis
5. Hypercalcemia (increases urinary calcium excretion - unlike thiazides)
6. Nephrotic syndrome
7. Ascites (with spironolactone)

• Hypokalemia (most important ADR - can precipitate arrhythmias with digoxin)
• Hyponatremia, hypomagnesemia
• Ototoxicity (high-dose IV: tinnitus, deafness - especially with aminoglycosides)
• Hyperuricemia
• Metabolic alkalosis
• Hypocalcemia (unlike thiazides)

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Potassium-Sparing Diuretics

• MOA: Competitive antagonist of aldosterone receptor in collecting duct → less Na reabsorption and less K excretion
• Uses: Heart failure (reduces mortality - RALES trial), hypertension (especially primary hyperaldosteronism, resistant hypertension), ascites in cirrhosis, nephrotic syndrome
• ADRs: Hyperkalemia (most dangerous - avoid with ACE inhibitors in renal failure), gynecomastia (anti-androgen effect), menstrual irregularity
• Eplerenone: newer, more selective → less gynecomastia

• MOA: Directly block epithelial sodium channel (ENaC) in collecting duct → Na retention of K
• Uses: As add-on to thiazides or loop diuretics (to prevent K loss); Liddle syndrome (amiloride)
• ADRs: Hyperkalemia; triamterene can cause renal stones

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Antidiuretic Hormone (ADH) Antagonists - Vasopressin

• Produced in hypothalamus, stored/released from posterior pituitary
• V1 receptors: vasoconstriction
• V2 receptors: water reabsorption in collecting duct (via aquaporin-2 insertion)

1. Diabetes insipidus (DI):
   • Central DI: Desmopressin (DDAVP) - intranasal/oral/SC
   • Vasopressin tannate (IM)
2. Nocturnal enuresis: Desmopressin
3. Haemophilia A and vWD: Desmopressin (releases vWF and Factor VIII from endothelium)
4. Variceal bleeding (portal hypertension): Terlipressin, octreotide

• Tolvaptan, Conivaptan
• Produce aquaresis (free water excretion without electrolyte loss)
• Uses: SIADH, hyponatremia, polycystic kidney disease (tolvaptan)

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CARDIOVASCULAR SYSTEM

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10-MARK TOPICS

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1. ACE Inhibitors

• Vasodilation (arterial > venous)
• Reduce cardiac preload and afterload
• Reduce aldosterone → reduce K loss
• Cardiac remodeling prevention (reduce fibrosis)

1. Hypertension (first-line; especially in diabetics with proteinuria)
2. Heart failure (first-line - reduce mortality; Consensus trial, SOLVD trial)
3. Post-MI (all patients; especially with LV dysfunction)
4. Diabetic nephropathy (renoprotective - reduce proteinuria via efferent arteriolar dilation)
5. Chronic kidney disease
6. Left ventricular hypertrophy regression

• Dry cough (most common - due to bradykinin accumulation; switch to ARB)
• Angioedema (rare but serious - laryngeal edema; switch to ARB - also contraindicated in hereditary angioedema)
• Hyperkalemia
• First-dose hypotension
• Renal impairment (bilateral renal artery stenosis - absolute contraindication)
• Teratogenic (pregnancy: fetal renal agenesis, Potter sequence)

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2. Angiotensin Receptor Blockers (ARBs)

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3. Organic Nitrates

• Glyceryl trinitrate (GTN/nitroglycerin): short-acting sublingual (onset 2-3 min; t½ 2-8 min); transdermal patch; IV
• Isosorbide dinitrate: intermediate-acting oral
• Isosorbide mononitrate: long-acting oral (active form; no first-pass)

• Venodilation → reduce preload → reduce cardiac work
• Coronary artery dilation → relieve coronary spasm
• Arterial dilation at higher doses → reduce afterload
• Dilate coronary collaterals

1. Angina pectoris (GTN sublingual for acute attack)
2. Prophylaxis of angina (isosorbide mononitrate)
3. Acute heart failure/pulmonary edema (IV GTN)
4. Hypertensive crisis (IV)
5. Esophageal spasm, biliary colic

• Headache (meningeal vasodilation) - most common
• Postural hypotension, flushing, tachycardia (reflex)
• Methemoglobinemia (high doses)

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4. Calcium Channel Blockers (CCBs)

1. Dihydropyridines (DHP): Mainly vascular selectivity
   • Amlodipine, Nifedipine, Felodipine, Nicardipine, Nimodipine (cerebral)
   • Potent vasodilators; minimal cardiac depression
2. Non-dihydropyridines:
   • Phenylalkylamines: Verapamil - cardiac selective; reduces HR, AV conduction, myocardial contractility
   • Benzothiazepines: Diltiazem - intermediate; reduces HR and causes vasodilation

• Hypertension: All CCBs (especially amlodipine - long-acting DHP; preferred in Black patients and elderly)
• Angina: All three types; Nimodipine for vasospastic (Prinzmetal) angina; verapamil/diltiazem for stable angina with contraindication to beta-blockers
• Arrhythmias: Verapamil, diltiazem - SVT, rate control in AF
• Hypertrophic cardiomyopathy: Verapamil
• Raynaud phenomenon: DHP (nifedipine)
• Subarachnoid hemorrhage: Nimodipine (prevents cerebral vasospasm)

• DHPs: ankle edema (most common), flushing, headache, reflex tachycardia (nifedipine)
• Verapamil/Diltiazem: bradycardia, heart block, constipation (verapamil), negative inotropic effect
• Verapamil + beta-blocker: severe bradycardia/heart block - dangerous combination

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5. Cardiac Glycosides

1. Positive inotropic effect: Inhibits Na-K-ATPase → intracellular Na increases → less Na-Ca exchange → intracellular Ca increases → stronger contractions
2. Negative chronotropic and dromotropic effects: Increase vagal tone (direct and via baroreceptors) → slow heart rate, slow AV conduction; therapeutic effect in AF

1. Heart failure with reduced ejection fraction (HFrEF): reduces symptoms, reduces hospitalizations (but NOT mortality)
2. Atrial fibrillation (AF)/Atrial flutter: rate control (slows ventricular response)

• GI: Nausea, vomiting, anorexia (early signs)
• CNS: Visual disturbances (yellow-green vision, halos), confusion
• Cardiac: All arrhythmias possible; Bigeminy (coupled beats), AV block, VT/VF

• Stop digoxin, correct K+ and Mg2+
• Atropine for bradycardia/AV block
• Digoxin-specific antibody fragments (DigiFab) for severe toxicity

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5-MARK TOPICS

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1. Sodium Nitroprusside

1. Hypertensive emergencies (most important use; achieves rapid BP control)
2. Acute aortic dissection (with beta-blocker)
3. Acute heart failure with hypertension
4. Controlled hypotension during surgery

• Cyanide then converted to thiocyanate by rhodanase (requires thiosulfate)
• Antidote: Sodium thiosulfate (given prophylactically in prolonged infusions); hydroxocobalamin (binds cyanide)

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2. Classification

1. Diuretics (thiazides, loop, K-sparing)
2. ACE inhibitors / ARBs / ARNI (sacubitril/valsartan)
3. Beta-blockers
4. Calcium channel blockers
5. Alpha-blockers (prazosin, doxazosin)
6. Centrally acting (clonidine, methyldopa)
7. Vasodilators (hydralazine, minoxidil)
8. Aldosterone antagonists (spironolactone)

1. Nitrates (organic)
2. Beta-blockers
3. Calcium channel blockers
4. K-channel openers (nicorandil)
5. If channel blocker (ivabradine)
6. Late sodium current blocker (ranolazine)

• Class I: Na channel blockers (Ia: quinidine, procainamide, disopyramide; Ib: lignocaine, mexiletine; Ic: flecainide, propafenone)
• Class II: Beta-blockers (propranolol, metoprolol)
• Class III: K channel blockers - prolong repolarization (amiodarone, sotalol, ibutilide)
• Class IV: Calcium channel blockers (verapamil, diltiazem)
• Adenosine, Digoxin (unclassified)

1. Diuretics (symptomatic relief)
2. ACE inhibitors / ARBs / ARNI
3. Beta-blockers (carvedilol, bisoprolol, metoprolol succinate)
4. Aldosterone antagonists (spironolactone, eplerenone)
5. Cardiac glycosides (digoxin)
6. SGLT2 inhibitors (empagliflozin, dapagliflozin)
7. Hydralazine + isosorbide dinitrate (if ACEi/ARB intolerant)

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3. Pharmacotherapy of Acute MI

• M - Morphine (pain relief, reduces anxiety, venodilation)
• O - Oxygen (only if SpO2 <94%)
• N - Nitroglycerin/Nitrates (sublingual or IV)
• A - Aspirin 300 mg chewed + Clopidogrel/Ticagrelor (DAPT)
• B - Beta-blockers (reduce HR, myocardial O2 demand; reduce mortality; oral metoprolol)

• Primary PCI (preferred if available within 90 min): Balloon angioplasty + stent
• Thrombolysis (if PCI not available within 2 hours): Streptokinase, Alteplase, Tenecteplase (within 12 hours)

• Aspirin (lifelong) + Clopidogrel/Ticagrelor (12 months)
• Beta-blocker (lifelong) - reduces reinfarction and mortality
• ACE inhibitor/ARB (lifelong) - prevents LV remodeling
• Statin (high-intensity; atorvastatin 80 mg)
• Aldosterone antagonist (if EF <35% or HF)

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4. Lignocaine (Lidocaine)

• IV only (extensive first-pass if oral)
• Short t½ (~1-2 hrs)
• Metabolized by liver (reduce dose in liver disease)

1. Ventricular arrhythmias especially post-MI (VT, VF) - IV
2. Local anaesthesia (2% lignocaine)

• Perioral numbness, tinnitus, dizziness
• Convulsions
• Respiratory arrest
• Cardiac: AV block, hypotension

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5. Amiodarone

1. Most serious, life-threatening arrhythmias when other drugs fail
2. VT, VF (IV for resuscitation)
3. AF/Flutter (conversion and maintenance)
4. SVT refractory to other drugs
5. WPW syndrome

• Pulmonary toxicity (most serious - pulmonary fibrosis/pneumonitis)
• Thyroid: Hyperthyroidism OR hypothyroidism (contains 37% iodine by weight)
• Hepatotoxicity (elevated liver enzymes)
• Corneal microdeposits (most common; reversible; rarely affects vision)
• Photosensitivity (blue-grey skin discoloration)
• Peripheral neuropathy
• Bradycardia, heart block
• Prolongs QT interval (torsades de pointes - rare)

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6. Adenosine

• Drug of choice for SVT (AVNRT, AVRT) - terminates 90%+ of SVTs
• Diagnostic tool (reveals underlying atrial rhythm by unmasking P waves during AV block)
• Pharmacological stress testing (adenosine thallium scan)

• Flushing, chest tightness (very brief)
• Transient dyspnea, nausea
• Bradycardia, AV block (transient)
• Bronchospasm (contraindicated in asthma)

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3-MARK TOPICS

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Beta-Blockers in Angina and Hypertension

• Reduce heart rate and myocardial contractility → reduce cardiac O2 demand
• Increase diastolic filling time → improve coronary perfusion
• Prevent exercise-induced tachycardia
• Drugs: propranolol, metoprolol, atenolol, bisoprolol

• Initially: reduce cardiac output
• Long-term: reduce renin secretion → reduce Angiotensin II
• Also: central sympatholysis
• Drugs: atenolol, bisoprolol (cardioselective - β1 selective), carvedilol (also α-blocker)
• Contraindicated in: asthma, COPD (non-selective), bradycardia, heart block, vasospastic angina (Prinzmetal), LPAD; diabetes (mask hypoglycemia warning signs)

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Centrally Acting Sympatholytics - Clonidine

1. Hypertension (oral)
2. Refractory hypertension
3. Migraine prophylaxis
4. Menopausal hot flushes
5. Opioid/nicotine withdrawal
6. Attention deficit hyperactivity disorder (ADHD)
7. Epidural analgesia (adjunct)

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Vasodilators

• MOA: Direct arteriolar vasodilator (mechanism not fully clear; may involve K channel opening or NO release)
• Uses: Hypertension (especially in pregnancy combined with methyldopa/labetolol), HF (combined with isosorbide in patients intolerant of ACEi/ARBs)
• ADRs: Reflex tachycardia, fluid retention (must combine with diuretic + beta-blocker); drug-induced lupus (slow acetylators, high doses)

• Opens K channels → hyperpolarization → vasodilation
• Uses: Severe refractory hypertension; topical for alopecia
• ADRs: Reflex tachycardia, fluid retention, hypertrichosis (hirsutism)

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CHEMOTHERAPY

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10-MARK TOPICS

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1. Fluoroquinolones (pg 416 in notes)

• 1st: Nalidixic acid (urinary only)
• 2nd: Ciprofloxacin, Ofloxacin (broad-spectrum - Gram-negative excellent coverage)
• 3rd: Levofloxacin (respiratory fluoroquinolone - good Gram-positive including Streptococcus)
• 4th: Moxifloxacin, Gatifloxacin (excellent coverage including atypicals and anaerobes; NOT for UTI)

• UTI (ciprofloxacin - Gram-negative)
• Respiratory infections (levofloxacin, moxifloxacin)
• Typhoid/enteric fever (ciprofloxacin)
• Anthrax (ciprofloxacin - drug of choice)
• Gonorrhea (azithromycin + ceftriaxone now preferred due to resistance)
• Tuberculosis: Levofloxacin, moxifloxacin (second-line)
• Pseudomonal infections (ciprofloxacin)

• GI (nausea, vomiting)
• CNS (convulsions, insomnia - contraindicated in epilepsy)
• Arthropathy/Tendinopathy (Achilles tendon rupture - especially with steroids; avoid in children and pregnancy)
• QT prolongation (moxifloxacin especially)
• Photosensitivity
• Interactions: chelation with antacids/Ca2+/Mg2+/Fe2+ (take 2 hours apart)

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2. Beta-Lactam Antibiotics

• Narrow spectrum; IV/IM only; t½ 30 min
• Uses: Streptococcal, meningococcal, syphilis, gas gangrene (Clostridium)
• Preparations: Procaine penicillin G (long-acting IM - single daily), Benzathine penicillin G (very long-acting - monthly IM for rheumatic fever prophylaxis)

• Ampicillin, Amoxicillin - extended spectrum (Gram-positive + some Gram-negative: H. influenzae, E. coli, Listeria)
• Amoxicillin better absorbed orally
• Amoxicillin + Clavulanate (Co-Amoxiclav/Augmentin) - covers beta-lactamase producers

• Cloxacillin, Flucloxacillin, Dicloxacillin - Beta-lactamase stable; for MSSA infections

• 1st gen (Cephalexin, Cefazolin): Gram-positive coverage; surgical prophylaxis
• 2nd gen (Cefuroxime): G+/G- coverage; respiratory infections
• 3rd gen (Cefotaxime, Ceftriaxone, Ceftazidime): Expanded Gram-negative; meningitis, gonorrhea, pneumonia, Typhoid, Salmonella; Ceftriaxone can be given OD; Ceftazidime covers Pseudomonas
• 4th gen (Cefepime): broader Gram-negative including Pseudomonas + better G+ than 3rd
• 5th gen (Ceftaroline): MRSA activity

• Imipenem (+ cilastatin - prevents renal inactivation), Meropenem, Ertapenem
• Broadest spectrum: Gram-positive (MSSA, Streptococcus), Gram-negative (Pseudomonas), anaerobes; NOT MRSA or Enterococcus faecium
• Uses: Severe sepsis, complicated intra-abdominal infections, nosocomial pneumonia
• ADRs: Seizures (imipenem), carbapenem resistance (major global threat)

• Aztreonam - narrow spectrum (ONLY Gram-negative aerobic bacilli)
• Safe in penicillin allergy (no cross-reactivity)
• Uses: Gram-negative infections in penicillin-allergic patients

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3. Macrolide Antibiotics

• Alternative to penicillin in penicillin-allergic patients
• Community-acquired pneumonia (atypical coverage)
• Clarithromycin: H. pylori eradication (triple therapy), MAC prophylaxis in HIV
• Azithromycin: STIs (Chlamydia - single dose 1g), CAP, MAC prophylaxis; long t½ (once weekly)
• Whooping cough (pertussis)
• Diphtheria

• GI (most common - nausea, vomiting, diarrhea) - especially erythromycin (prokinetic via motilin agonism)
• Hepatotoxicity (erythromycin estolate - cholestatic jaundice)
• QT prolongation (all macrolides - especially azithromycin)
• CYP450 inhibition (erythromycin, clarithromycin) → drug interactions (statins → myopathy; warfarin → bleeding; carbamazepine → toxicity)
• Hearing loss (high-dose erythromycin IV)

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4. Antitubercular Drugs - Rifampicin, Isoniazid

• MOA: Inhibits bacterial DNA-dependent RNA polymerase (β-subunit) → stops transcription
• Spectrum: TB, leprosy (with dapsone), Meningococcal prophylaxis, MRSA (combination), Brucellosis
• ADRs: Red-orange coloration of urine, saliva, tears, sweat (harmless - warn patient); hepatotoxicity; influenza-like syndrome (intermittent therapy); potent enzyme inducer (reduces efficacy of: OCP, warfarin, antiretrovirals, methadone)

• MOA: Inhibits mycolic acid synthesis (InhA enzyme) - essential component of mycobacterial cell wall; bactericidal in actively dividing TB
• ADRs: Peripheral neuropathy (most common - pyridoxine/B6 deficiency; prevent with pyridoxine 10 mg/day); hepatotoxicity; SLE-like syndrome (slow acetylators); CNS toxicity (convulsions)
• Slow acetylators: higher plasma levels → more ADRs
• INH is used alone for latent TB prophylaxis (6-9 months)

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5. Antimalarial Drugs - Chloroquine

• MOA: Accumulates in parasite's food vacuole → inhibits haem polymerase → toxic haem accumulates → kills parasite
• Effective against: Blood schizonts of P. vivax, P. malariae, P. ovale; sensitive P. falciparum strains
• Uses: Treatment of uncomplicated malaria (where sensitive), malaria prophylaxis, rheumatoid arthritis, SLE (anti-inflammatory/immunomodulatory), COVID-19 (tested but not proven)
• ADRs:
  • Retinopathy/Corneal deposits (most serious - dose-related; regular ophthalmologic monitoring needed)
  • GI: nausea, vomiting
  • Acute overdose: Dangerous; cardiac arrhythmias, convulsions
  • Hemolysis in G6PD deficiency
  • Contraindicated in: Psoriasis, epilepsy, G6PD deficiency (relative)
• Resistance: widespread P. falciparum resistance - use ACTs (artemisinin-based combination therapies) instead

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5-MARK TOPICS (Chemotherapy)

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• MOA: Bind 30S ribosome → misreading of mRNA → bactericidal; concentration-dependent killing
• Uses: Serious Gram-negative infections, Tuberculosis (streptomycin), endocarditis (synergy with penicillin)
• ADRs: Ototoxicity (irreversible, dose-related - cochlear and vestibular), nephrotoxicity (reversible usually), neuromuscular blockade
• Monitor: Drug levels (peak and trough), renal function, audiometry

• MOA: Bind 30S ribosome, inhibit aminoacyl-tRNA binding; bacteriostatic
• Uses: Chlamydia, Rickettsia, Mycoplasma, Brucellosis, Lyme disease, acne, H. pylori (alternate), malaria prophylaxis (doxycycline)
• ADRs: GI, photosensitivity, tooth discoloration and bone growth inhibition in children (<8 yrs), hepatotoxicity; chelation with Ca2+/Mg2+/Al3+ - reduced absorption

• MOA: Inhibit ergosterol synthesis (inhibit CYP51/14-alpha demethylase) → altered fungal cell membrane permeability
• Fluconazole: Candidiasis (oropharyngeal, esophageal, vulvovaginal, systemic), Cryptococcal meningitis
• Itraconazole: Aspergillus, Blastomycosis, Histoplasma, nail fungus
• Voriconazole: Aspergillosis (drug of choice), rare mold infections
• ADRs: Hepatotoxicity, drug interactions (CYP450 inhibition - ketoconazole, fluconazole), QT prolongation

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3-MARK TOPICS (Chemotherapy)

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• Uncomplicated P. falciparum: Artemisinin-based Combination Therapy (ACT) - e.g., Artemether + Lumefantrine (Coartem), Artesunate + Amodiaquine
• Severe P. falciparum (IV): IV Artesunate (preferred) or IV Quinine + Doxycycline
• P. vivax/P. ovale: Chloroquine (blood stages) + Primaquine (liver hypnozoites - radical cure; check G6PD first)

• 6-Mercaptopurine: Inhibits de novo purine synthesis; used in ALL maintenance, IBD (Crohn's, UC). Metabolized by TPMT → check for TPMT deficiency (→ toxicity). Azathioprine → converted to 6-MP. Interaction: Allopurinol inhibits xanthine oxidase → increases 6-MP levels (reduce dose by 75%)
• 6-Thioguanine: ALL, AML

• Mild/moderate: Oral Vancomycin (1st line) or Fidaxomicin
• Alternative: Oral Metronidazole (now second-line due to inferior cure rates)
• Severe/recurrent: Fidaxomicin, Bezlotoxumab (monoclonal antibody - reduces recurrence), Fecal Microbiota Transplant (FMT)

• Neuraminidase inhibitors (antiinfluenza drugs)
• MOA: Inhibit influenza neuraminidase → prevent viral release from host cells and spread
• Oseltamivir (Tamiflu): Oral; use within 48 hours of symptom onset; reduces illness by ~1 day; important for high-risk patients (elderly, immunocompromised, pregnant)
• Zanamivir (Relenza): Inhaled; for patients with renal failure
• Uses: Treatment and prophylaxis of Influenza A and B

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Study Tip: The notes reference KD Tripathi's Essentials of Medical Pharmacology textbook page numbers throughout. For each topic, the depth of answer should match the mark allocation: 10-mark answers need full classification + MOA + uses + ADRs; 5-mark answers need 2-3 key subsections; 3-mark answers need a focused paragraph.