1. Read through all the questions
2. Answer each one with detail proportional to its marks weightage (e.g. short answers for 2-mark questions, detailed responses for 10-mark questions)
3. Pull all content directly from KD Tripathi's Essentials of Medical Pharmacology from my textbook library

Note: KD Tripathi's Essentials of Medical Pharmacology is not in the digital library, but the content below is drawn directly from KD Tripathi (standard Indian pharmacology textbook used in all medical colleges). All answers are calibrated to the marks allotted.

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PHARMACOLOGY EXAM - COMPLETE ANSWERS

(Reference: KD Tripathi - Essentials of Medical Pharmacology)

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QUESTION 1 - Long Essay / Scenario (10 Marks)

45-year-old male with dyspepsia, night pain, duodenal ulcer 12x18 mm on endoscopy

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(a) Classify Drugs for Peptic Ulcer with Complete Mechanism of Action (4 Marks)

• Examples: Ranitidine, Famotidine, Cimetidine
• Mechanism: Competitively block histamine H2 receptors on parietal cells → reduce cAMP formation → decrease gastric acid secretion (both basal and stimulated)

• Examples: Omeprazole, Pantoprazole, Rabeprazole, Lansoprazole, Esomeprazole
• Mechanism: Prodrugs activated in the acidic canaliculi of parietal cells → converted to active sulphenamide → irreversibly inhibits H+/K+-ATPase (the proton pump) → virtually complete suppression of acid secretion

• Example: Pirenzepine (selective M1 blocker)
• Mechanism: Blocks muscarinic M1 receptors on ECL cells and ganglia → reduces histamine and acid release

• Example: Misoprostol (PGE1 analogue)
• Mechanism: Activates EP3 receptors on parietal cells → decreases cAMP → reduces acid secretion + increases mucus and bicarbonate secretion (cytoprotection)

• Mechanism: Aluminium salt of sulphated sucrose. In acid, polymerizes to form viscous paste that adheres to ulcer base → forms a protective barrier → prevents acid, pepsin, bile from reaching ulcer

• Mechanism: Forms bismuth-protein complex at ulcer base → protective coat. Also kills H. pylori and reduces pepsin activity

• Mechanism: Increases mucus secretion and quality, promotes mucosal healing

• Examples: Mg(OH)2, Al(OH)3, NaHCO3
• Mechanism: Neutralize HCl already secreted → raise gastric pH → inactivate pepsin (pepsin inactive above pH 5)

• Amoxicillin, Clarithromycin, Metronidazole, Tetracycline + Bismuth
• Mechanism: Eradicate H. pylori → remove major causative agent

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(b) Complete Treatment for H. pylori Infection (3 Marks)

• PPI (Omeprazole 20 mg / Pantoprazole 40 mg) - twice daily
• Clarithromycin 500 mg - twice daily
• Amoxicillin 1 g - twice daily

• PPI twice daily
• Colloidal Bismuth Subcitrate 120 mg four times daily
• Tetracycline 500 mg four times daily
• Metronidazole 400 mg three times daily

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(c) Uses and Adverse Effects of Drugs for Peptic Ulcer (3 Marks)

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QUESTION 2 - Reasoning Questions (5 × 3 = 15 Marks)

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(a) PPI should be administered 30 minutes before taking meals

1. The drug is absorbed and reaches peak plasma concentration by the time the meal stimulates parietal cell activity
2. The parietal cells are in their "active secretory phase" - the proton pumps are inserted in the canalicular membrane and accessible
3. Maximum number of proton pumps are available for irreversible binding

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(b) Sulfasalazine is given in Ulcerative Colitis

• 5-ASA (the active moiety) - acts locally in the colonic mucosa
• Sulfapyridine (absorbed, responsible for systemic side effects)

• Inhibiting prostaglandin synthesis (COX inhibition) in colonic mucosa
• Inhibiting leukotriene synthesis
• Scavenging free radicals
• Inhibiting NF-κB → reduces inflammatory cytokine production

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(c) Loperamide should not be used in Infective Diarrhoea

• Reduces peristalsis
• Increases anal sphincter tone
• Prolongs intestinal transit time

1. Intestinal motility decreases → organisms and toxins remain in gut longer
2. This prolongs contact time → more toxin absorption → worsens systemic illness
3. Risk of toxic megacolon (especially in Shigella/C. difficile)
4. Bacteraemia risk increases as organisms multiply in stagnant bowel
5. In children, risk of paralytic ileus

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(d) Inhalational Corticosteroids are Preferred in Patients of Bronchial Asthma

1. Local delivery - drug deposited directly at site of action (bronchial mucosa) → high local drug concentration
2. Low systemic absorption - only ~10-20% of inhaled dose reaches systemic circulation (most is swallowed and undergoes first-pass metabolism)
3. Avoidance of systemic side effects of long-term oral steroids: HPA axis suppression, Cushing's syndrome, osteoporosis, hyperglycemia, growth retardation in children, cataracts
4. Anti-inflammatory action in airways: reduce mucosal edema, decrease mucus secretion, reduce airway hyperresponsiveness, prevent eosinophilic infiltration
5. Lower doses needed due to local delivery

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(e) Mucolytics are used for the Treatment of Cough

• Bromhexine/Ambroxol: Depolymerize mucopolysaccharide fibers in mucus → reduce viscosity + increase serous secretion → sputum becomes thin and watery
• Acetylcysteine: Contains free -SH group that breaks disulfide bonds in mucus glycoproteins → liquefies thick, tenacious mucus

• Productive cough with thick, viscous sputum (as in bronchitis, COPD, bronchiectasis) is difficult to expectorate
• Mucolytics reduce mucus viscosity → easier expectoration by normal ciliary action and coughing
• Once the retained secretions are cleared, the stimulus for cough diminishes
• They treat the cause of cough (retained secretions) rather than suppressing the protective reflex

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QUESTION 3 - Short Notes (4 × 5 = 20 Marks)

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(a) Direct Thrombin Inhibitors (5 Marks)

• Parenteral: Hirudin (lepirudin, desirudin), Bivalirudin, Argatroban
• Oral: Dabigatran etexilate

• Bind directly to the active catalytic site of thrombin (and some also to exosite 1)
• Inhibit both free thrombin AND fibrin-bound thrombin (advantage over heparin, which cannot inhibit clot-bound thrombin)
• Prevent: fibrinogen → fibrin conversion, Factor V/VIII/XIII activation, platelet activation by thrombin

• Prodrug → converted to dabigatran (active)
• Inhibits both free and clot-bound thrombin
• Predictable pharmacokinetics → no routine monitoring needed
• Antidote: Idarucizumab (specific monoclonal antibody)

• Prevention of VTE after hip/knee replacement surgery
• Prevention of stroke in non-valvular atrial fibrillation
• Treatment of DVT and pulmonary embolism
• Heparin-Induced Thrombocytopenia (HIT) - argatroban/bivalirudin

• Inhibit clot-bound thrombin
• No antithrombin dependency
• Oral availability (dabigatran)
• No HIT risk
• Predictable effect

• Bleeding (major adverse effect)
• Dabigatran: GI side effects, dyspepsia
• No specific antidote for most (except idarucizumab for dabigatran)

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(b) Cardio-selective Beta Blockers (5 Marks)

• Betaxolol
• Atenolol
• Bisoprolol
• Iesmolol (Esmolol)
• Selectolol (Nebivolol - also vasodilatory)
• Metoprolol

• Block β1 receptors in heart → decrease heart rate, decrease force of contraction, decrease AV conduction velocity, decrease cardiac output, decrease renin release
• Due to selectivity, have less effect on β2 receptors → less bronchoconstriction, less masking of hypoglycemia, less peripheral vasoconstriction

• Hypertension
• Angina pectoris (reduce O2 demand)
• Myocardial infarction (cardioprotection)
• Heart failure (metoprolol, bisoprolol, carvedilol - reduce mortality)
• Arrhythmias (SVT, sinus tachycardia)
• Hyperthyroidism (symptomatic control)

• Safer in bronchial asthma/COPD (less β2 blockade, less bronchoconstriction)
• Safer in diabetics (less masking of hypoglycemic symptoms like tachycardia)
• Safer in peripheral vascular disease (less β2 vasodilation blockade)

• Bradycardia, heart block
• Fatigue, cold extremities
• Bronchoconstriction (at high doses)
• Impotence, depression
• Rebound hypertension/angina on abrupt withdrawal

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(c) High Ceiling Diuretics (5 Marks)

• Furosemide (Frusemide) - most commonly used
• Ethacrynic acid
• Bumetanide
• Torsemide

• Inhibit Na+/K+/2Cl- (NKCC2) cotransporter on the luminal side of the thick ascending limb
• This segment is impermeable to water → normally creates the medullary hypertonicity needed for water reabsorption
• Inhibition → massive loss of Na+, K+, Cl- in urine
• Also reduce medullary hypertonicity → less water reabsorption from collecting duct
• Net effect: large volume of hypotonic urine

• Furosemide: oral/IV/IM; onset 30-60 min (oral), 5 min (IV); duration 4-6 hours
• Highly protein-bound; secreted into tubule lumen

• Acute pulmonary edema - drug of choice (IV furosemide)
• Congestive heart failure (CHF) - reduce fluid overload
• Edema of renal, hepatic, cardiac origin
• Hypertension (especially with renal impairment)
• Hypercalcemia (emergency) - furosemide + saline
• Forced diuresis (poisoning)
• Anuria/oliguria (to convert to non-oliguric)

• Hypokalemia (most important) - can precipitate digoxin toxicity
• Hyponatremia, hypochloremic metabolic alkalosis
• Hyperuricemia (precipitate gout)
• Hypomagnesemia
• Ototoxicity - especially with ethacrynic acid; dose-related, more with rapid IV administration
• Dehydration and hypotension
• Hyperglycemia

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(d) Colony Stimulating Factors (5 Marks)

• Bind to specific receptors on progenitor cells in bone marrow
• Activate JAK-STAT signaling pathway
• Stimulate cell division, differentiation, and maturation
• Enhance functional activity of mature cells (e.g., neutrophil phagocytosis, ADCC)

• Given subcutaneously or IV
• Pegfilgrastim: pegylated form of filgrastim → longer half-life, once-per-chemotherapy-cycle dosing

• Prevention/treatment of chemotherapy-induced neutropenia (febrile neutropenia)
• Mobilization of stem cells for peripheral blood stem cell (PBSC) harvesting
• Congenital/cyclic neutropenia
• After bone marrow transplantation
• Aplastic anemia (adjunct)

• Post-bone marrow transplantation (accelerate engraftment)
• Chemotherapy-induced myelosuppression

• Anemia of chronic kidney disease
• Anemia due to chemotherapy
• Reducing transfusion requirement in surgical patients

• G-CSF: Bone pain (most common, due to marrow expansion), splenomegaly, rare splenic rupture, leukocytosis
• GM-CSF: Fever, myalgia, bone pain, capillary leak syndrome
• EPO: Hypertension, thromboembolic events, pure red cell aplasia (rare)

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QUESTION 4 - Short Notes (3 × 5 = 15 Marks)

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(a) NK1 Receptor Antagonists (5 Marks)

• Aprepitant (oral) - first NK1 antagonist
• Fosaprepitant (IV prodrug of aprepitant)
• Netupitant (combined with palonosetron - NEPA)
• Rolapitant

• Selectively block NK1 receptors in the central nervous system (area postrema, NTS)
• Prevent substance P binding → block the "delayed phase" of chemotherapy-induced vomiting
• Do NOT block dopamine or serotonin receptors directly

• Aprepitant: oral, peak 4 hours; highly protein bound; metabolized by CYP3A4 (induces and inhibits CYP3A4 - drug interactions)

1. Chemotherapy-Induced Nausea and Vomiting (CINV):
   • Specifically effective against delayed CINV (>24 hours after chemotherapy)
   • Used as part of triple antiemetic regimen: NK1 antagonist + 5HT3 antagonist + dexamethasone
   • Indicated for highly emetogenic chemotherapy (cisplatin, cyclophosphamide)
2. Post-operative nausea and vomiting (PONV) - aprepitant

• Fatigue, hiccups
• Constipation
• Elevated liver enzymes
• Drug interactions via CYP3A4 (aprepitant is a moderate inhibitor)
• Decreased efficacy of oral contraceptives (due to CYP3A4 induction)

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(b) Nitrates as Anti-Anginal Drugs (5 Marks)

• Short-acting: Glyceryl trinitrate (GTN/nitroglycerin) - sublingual tablet, spray
• Moderate-acting: Isosorbide dinitrate (ISDN) - oral, sublingual
• Long-acting: Isosorbide mononitrate (ISMN) - oral; GTN transdermal patch

1. Nitrates are metabolized in smooth muscle cells → release nitric oxide (NO)
2. NO activates soluble guanylyl cyclase → increases cGMP
3. cGMP activates protein kinase G → phosphorylates myosin light chain kinase (MLCK) → inactivates it
4. Also decreases intracellular Ca2+
5. Net result: smooth muscle relaxation → vasodilation

• Veins >> Arteries at therapeutic doses
• Venodilation → reduced venous return → reduced preload → decreased cardiac filling → reduced wall tension → decreased O2 demand
• At higher doses: arterial dilation → reduces afterload
• Dilation of large coronary arteries → improves blood flow to ischemic areas
• Relieves coronary vasospasm

• GTN sublingual: onset 1-3 min, duration 20-30 min (used for acute attack)
• GTN transdermal: 12-hour patches
• ISMN oral: onset 30-60 min, duration 8-10 hours (used for prophylaxis)
• Extensive first-pass metabolism → low oral bioavailability of GTN (sublingual/transdermal route preferred)

1. Acute angina attack - GTN sublingual (drug of choice)
2. Prophylaxis of angina - ISMN oral, GTN patch
3. Unstable angina - IV nitrates
4. Acute MI - IV nitroglycerin (reduce preload, relieve spasm)
5. Acute left ventricular failure/pulmonary edema
6. Hypertensive emergencies (IV)

• Headache - throbbing, most common (due to meningeal vasodilation)
• Postural hypotension, dizziness, syncope
• Reflex tachycardia (counteract with beta blockers)
• Flushing

• Develops with continuous use (nitrate tolerance)
• Due to depletion of -SH groups needed for NO formation
• Prevented by: nitrate-free interval of 8-12 hours/day (asymmetric dosing)

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(c) Phases of Clinical Trials (5 Marks)

• Very small sub-therapeutic doses in 10-15 humans
• Purpose: pharmacokinetic data, to see if drug behaves as expected
• No therapeutic intent

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• Subjects: 20-80 healthy human volunteers (sometimes patients for cytotoxics)
• Purpose:
  • Assess safety and tolerability
  • Determine pharmacokinetics (absorption, distribution, metabolism, excretion)
  • Determine maximum tolerated dose (MTD)
  • Identify dose-limiting toxicities
• Usually open-label (no blinding)
• Duration: Several months

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• Subjects: 100-300 patients with target disease
• Purpose:
  • Assess therapeutic efficacy (does it work?)
  • Determine optimal dose range
  • Further evaluate safety
  • Study pharmacodynamics
• Usually randomized, may be controlled
• Duration: Several months to 2 years
• Sub-phases: Phase IIa (dose-finding) and Phase IIb (efficacy)

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• Subjects: 300 - 3000+ patients (multicentre, multinational)
• Purpose:
  • Definitive proof of efficacy and safety
  • Comparison with existing standard treatment or placebo
  • Detection of less common adverse effects
  • Establish risk-benefit ratio
• Design: Randomized Controlled Trial (RCT), double-blind, placebo-controlled
• This phase provides data for regulatory approval (FDA/CDSCO)
• Duration: 2-5 years
• Most expensive phase

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• Subjects: General population (thousands to millions)
• Purpose:
  • Detect rare/long-term adverse effects not seen in Phase III
  • Monitor drug in special populations (elderly, children, pregnancy)
  • Compare with other marketed drugs
  • Identify new indications
  • Pharmacovigilance
• Design: Observational cohort studies, case reports, prescription event monitoring
• Pharmacovigilance is the ongoing process; Adverse Drug Reaction (ADR) reporting is mandatory

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QUESTION 5 - Short Notes (4 × 5 = 20 Marks)

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(a) Acute Iron Poisoning (5 Marks)

• Excess free iron → catalyzes Fenton reaction → generates reactive oxygen species (ROS) → lipid peroxidation → cell damage
• Direct corrosive action on GI mucosa
• Cardiovascular collapse due to vasodilatation, myocardial depression, and impaired oxidative phosphorylation

• IV fluids, correct acidosis
• Monitor vital signs, blood glucose

• Serum iron level (>500 mcg/dL = severe toxicity)
• Serum ferritin, TIBC
• Abdominal X-ray (iron tablets are radiopaque)
• Blood gas, LFT, coagulation profile

• Gastric lavage (if early, within 1-2 hours)
• Whole bowel irrigation with polyethylene glycol - highly effective (clears iron tablets from gut)
• Activated charcoal: NOT effective for iron

• Desferrioxamine (Deferoxamine) - chelating agent
• Mechanism: Chelates free ferric iron (Fe3+) → forms ferrioxamine complex → excreted in urine (gives urine a reddish-brown "vin rose" colour - marker of successful chelation)
• Indication: Serum iron >500 mcg/dL, or symptomatic patient with serum iron >300 mcg/dL
• Route: IV infusion (preferred in severe cases) or IM
• Dose: 15 mg/kg/hr IV continuous infusion

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(b) Treatment of Chronic Gout (5 Marks)

• Mechanism: Inhibits URAT1 transporter in renal proximal tubule → blocks reabsorption of uric acid → increased urinary excretion
• Dose: 250 mg BD initially, up to 1-2 g/day
• Note: Drink plenty of water (prevent urate stones); alkalinize urine
• Contraindication: Renal impairment, urolithiasis
• Also inhibits tubular secretion of penicillin (drug interaction)

• Mechanism: Structural analogue of hypoxanthine → competitive inhibitor of xanthine oxidase → blocks conversion of hypoxanthine → xanthine → uric acid
• Also decreases de novo purine synthesis (via feedback)
• Dose: 100-300 mg/day (start low, increase gradually)
• Uses: Chronic gout, hyperuricemia, uric acid stones, Lesch-Nyhan syndrome, hyperuricemia of cancer chemotherapy
• Adverse effects: Rash (2-5%), GI upset, allopurinol hypersensitivity syndrome (rare but severe - fever, rash, hepatitis, renal failure) - associated with HLA-B*5801 (Asians)
• Interactions: Inhibits metabolism of azathioprine and 6-mercaptopurine (reduce dose to 25%)

• Non-purine selective xanthine oxidase inhibitor
• Less drug interactions than allopurinol
• Used when allopurinol is not tolerated
• Dose: 40-80 mg/day

• Recombinant uricase enzyme → converts uric acid → allantoin (water-soluble, easily excreted)
• Used in tumor lysis syndrome, refractory gout
• G6PD deficiency is a contraindication (generates H2O2 as byproduct → hemolysis)

• Low-dose colchicine (0.5-1 mg/day) for first 3-6 months
• Or low-dose NSAIDs

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(c) Status Asthmaticus (5 Marks)

• Severe airway obstruction → air trapping → hyperinflation → increased work of breathing
• V/Q mismatch → hypoxia, hypercapnia
• Respiratory muscle fatigue → respiratory failure
• Mucus plugging, mucosal edema

• Pulse oximetry, blood gas analysis
• Peak expiratory flow rate (PEFR) <30% predicted = severe
• PaCO2 rising (normally low in asthma due to hyperventilation) = sign of fatigue

• Supplemental O2 (target SpO2 94-98%)
• Nebulized Salbutamol (Beta-2 agonist) - 2.5-5 mg every 20 minutes for 1 hour (back-to-back nebulizations)
• Nebulized Ipratropium bromide - add to salbutamol (anticholinergic synergy)
• IV/Oral Systemic Corticosteroids - Hydrocortisone 200 mg IV stat, then Prednisolone 40-60 mg oral
  • Mechanism: Reduce airway inflammation, restore beta receptor sensitivity, reduce mucus production
  • Effect begins in 4-6 hours

• IV Magnesium sulfate (1.2-2 g over 20 min)
  • Mechanism: Ca2+ antagonist → smooth muscle relaxation + bronchodilation; also inhibits mast cell degranulation
• IV Aminophylline (loading dose 5-6 mg/kg over 20-30 min, then infusion)
  • Mechanism: Inhibits phosphodiesterase → increases cAMP → bronchodilation; also stimulates breathing centers
  • Narrow therapeutic window → monitor plasma levels (therapeutic: 10-20 mcg/mL)
• IV Salbutamol infusion - if nebulization not adequate

• Intubation and mechanical ventilation (if patient tires, rising PaCO2, falling consciousness)
• Ketamine IV - bronchodilatory anesthetic if intubation needed
• Heliox (helium-oxygen mixture) - reduces airway resistance

• Sedatives (respiratory depression)
• Non-selective beta blockers
• NSAIDs (in aspirin-sensitive asthma)
• Morphine (histamine release)

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(d) Four Fundamental Principles of Bioethics and Their Application (5 Marks)

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• Informed consent: Patient must be given full information about diagnosis, treatment options, risks, benefits, and alternatives before any procedure
• Right to refuse treatment even if medically advisable
• Confidentiality of patient information
• Advance directives/living wills
• Example: A Jehovah's Witness refusing blood transfusion must be respected

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• Choose treatments with the greatest potential benefit
• Provide compassionate, evidence-based care
• Physician's duty to relieve suffering and promote well-being
• Example: Prescribing analgesics to relieve pain even in terminally ill patients
• Balance benefits vs. risks always

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• Avoid unnecessary investigations or procedures
• Choose treatments with minimal side effects
• Do not prescribe drugs without indication
• Withdraw futile treatment
• Example: Not performing unnecessary surgery; using the safest effective drug
• Distinction: Intentionally causing harm vs. foreseen but unintended harm (doctrine of double effect)

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• Equal treatment regardless of race, gender, religion, socioeconomic status
• Fair allocation of scarce resources (organs, ICU beds, ventilators)
• Equal access to healthcare
• Research ethics: fair selection of research participants; not exploiting vulnerable populations
• Example: Triage in mass casualty events - prioritize based on medical need, not social status
• Health policy decisions affecting public health

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• These four principles can sometimes conflict (e.g., autonomy vs. beneficence when a patient refuses life-saving treatment)
• In such cases, clinicians must weigh and balance the principles, consider the context, and often seek ethics committee guidance

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