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PHARMACOLOGY 2 - CHEMOTHERAPY EXAM ANSWERS

🔴 RED (HIGH PRIORITY) QUESTIONS FIRST

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🔴 Q5. Fluoroquinolones - MOA, Adverse Reactions, Therapeutic Uses [5M]

Classification of Fluoroquinolones

Mechanism of Action (MOA)

• Inhibit bacterial DNA Gyrase (Topoisomerase II) - primary target in gram-negative bacteria
• Inhibit Topoisomerase IV - primary target in gram-positive bacteria
• DNA gyrase prevents relaxation of supercoiled DNA needed for transcription and replication
• Topoisomerase IV is needed for separation of replicated chromosomal DNA in daughter cells
• Result: Bactericidal - blocks DNA synthesis → cell death
• Concentration-dependent killing with prolonged post-antibiotic effect

Adverse Effects (ADRs)

1. GI (most common) - nausea, vomiting, diarrhea
2. CNS - headache, dizziness, insomnia, seizures (avoid in epilepsy)
3. Tendinopathy/Tendon rupture - especially Achilles tendon (hallmark ADR, due to Mg chelation)
4. Phototoxicity - sparfloxacin > lomefloxacin (avoid sun exposure)
5. QTc prolongation - moxifloxacin, sparfloxacin (avoid with other QT-prolonging drugs)
6. Cartilage damage - contraindicated in children under 12 years and pregnancy
7. Hepatotoxicity - trovafloxacin (withdrawn)
8. Hyperglycemia/Hypoglycemia - gatifloxacin (withdrawn)
9. Drug interactions - absorption reduced by antacids (Al/Mg), iron, zinc (chelation)

Therapeutic Uses

FQ NOT used for systemic infection: Norfloxacin (poor systemic bioavailability, excreted in urine only) FQ NOT used for UTI: Moxifloxacin (excreted in feces, poor urinary levels)

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🔴 Q4/4.3. Aminoglycosides - Classification, MOA, ADRs, Uses [3M/5M]

Classification

Common Properties

• All are polycationic (positively charged)
• All are poorly absorbed orally (given IV/IM)
• All are renally excreted (dose adjust in renal failure)
• All exhibit concentration-dependent killing
• All have prolonged post-antibiotic effect (PAE) - allows once-daily dosing

Mechanism of Action

1. Enter bacterial cell via oxygen-dependent active transport (hence inactive against anaerobes)
2. Bind irreversibly to 30S ribosomal subunit (specifically 16S rRNA of 30S)
3. Cause misreading of mRNA → incorporation of wrong amino acids → abnormal/non-functional proteins
4. Also cause premature termination of translation
5. Abnormal proteins are inserted into cell membrane → membrane disruption → enhanced aminoglycoside uptake → rapid cell death
6. Bactericidal in action

Adverse Effects (High-Yield!)

Memory: ON (Oto + Nephro) + NMB for aminoglycosides

Therapeutic Uses

• Severe gram-negative infections (sepsis, pneumonia, UTI) - with beta-lactam
• Streptomycin: TB (2nd line), Plague, Brucellosis, Tularemia
• Gentamicin: Synergy with penicillin for Infective Endocarditis (IE)
• Tobramycin: Pseudomonas infections
• Amikacin: MDR gram-negative infections, MDR-TB
• Neomycin: Topical (skin infections), bowel sterilization before surgery

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🔴 Q11. Beta-Lactam MOA in Gram-Positive Bacteria + Two Important ADRs [3M]

Mechanism of Action in Gram-Positive Bacteria

1. Beta-lactam antibiotics (penicillins, cephalosporins) contain a beta-lactam ring
2. They are structural analogs of D-Ala-D-Ala (terminal dipeptide of peptidoglycan precursor)
3. Bind irreversibly to Penicillin-Binding Proteins (PBPs) - which are transpeptidases
4. Inhibit transpeptidation - the final step in bacterial cell wall (peptidoglycan) synthesis
5. Prevent cross-linking of peptidoglycan chains → weak cell wall
6. Bacteria continue to synthesize peptidoglycan → autolysins are activated → cell lysis and death
7. Why more effective in gram-positive: Gram-positive bacteria have a thick peptidoglycan layer (no outer membrane barrier), so drug easily reaches PBPs
8. Bactericidal + time-dependent killing (efficacy depends on time concentration > MIC)

Two Important Adverse Reactions

1. Hypersensitivity/Allergy (Most important, most common)
   • Ranges from urticaria/rash to anaphylaxis (life-threatening)
   • Mediated by IgE (Type I) for anaphylaxis
   • Cross-reactivity between penicillins and cephalosporins (~1-2%)
   • Test: Intradermal skin test before administering
   • Management: Epinephrine for anaphylaxis
2. Neurotoxicity (Seizures)
   • High doses of penicillin G can cause epileptiform convulsions
   • Especially with intrathecal administration or in renal failure
   • Mechanism: GABA antagonism

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🔴 Q13/13.1. First Line Anti-TB Drugs + Adverse Effects + Rifampicin Details [5M]

First Line Drugs for Pulmonary TB (RIPE Mnemonic)

Treatment Regimen for Drug-Sensitive Pulmonary TB (NTEP)

• Intensive phase (2 months): 2HRZE (Rifampicin + INH + PZA + Ethambutol) - daily
• Continuation phase (4 months): 4HR (Rifampicin + INH) - daily
• Total: 6 months for new cases

Rifampicin - Detailed (for Q13.1)

• Hepatotoxicity (most serious) - monitor LFTs
• Orange-red discoloration of urine, tears, saliva, sputum (harmless, warn patients)
• Enzyme inducer (CYP450) - reduces efficacy of OCP, warfarin, corticosteroids, antifungals, antiretrovirals
• Flu-like syndrome (intermittent therapy)
• Thrombocytopenia, hemolytic anemia (intermittent)
• GI symptoms

Pyridoxine added to regimen: Because INH depletes pyridoxal phosphate (Vitamin B6) → peripheral neuropathy. Especially required in: elderly, pregnant, alcoholics, diabetics, malnourished. Rifampicin contraindicated with OCP: Rifampicin is a powerful enzyme inducer (CYP3A4) → increases OCP metabolism → reduced plasma levels → contraceptive failure. Use barrier contraception.

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🔴 Q14. MDR-TB - Definition + NTEP 2021 Shorter and Longer Oral Regimens [5M]

Definition

NTEP 2021 Drug Classification for MDR-TB

Shorter Oral Regimen (9-12 months) - BPaL + M

• BPaL regimen: Bedaquiline + Pretomanid + Linezolid (± Moxifloxacin)
• Duration: 6-9 months
• For fluoroquinolone-susceptible MDR-TB
• Pretomanid inhibits mycolic acid synthesis and respiratory function

Longer Oral Regimen (18-20 months)

• At least 3 (preferably all 3) Group A drugs + Group B drugs
• Regimen: Moxifloxacin/Levofloxacin + Bedaquiline + Linezolid + Clofazimine + Cycloserine
• Total duration: 18-20 months (at least 15-17 months after culture conversion)
• Amikacin added in initial phase if needed (injectable)

BPaL (Bedaquiline-Pretomanid-Linezolid) Regimen

• All-oral, shorter regimen
• Bedaquiline: inhibits mycobacterial ATP synthase (blocks energy production)
• Pretomanid: inhibits mycolic acid synthesis + kills anaerobic bacteria (targets dormant bacilli)
• Linezolid: 50S ribosome inhibitor

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🔴 Q15. Drugs for Leprosy + Lepra Reactions + Management [3M]

Classification of Leprosy

• Paucibacillary (PB): TT, BT types (< 5 skin lesions, smear -ve)
• Multibacillary (MB): BB, BL, LL types (> 5 skin lesions, smear +ve)

Drugs Used (MDT - Multi-Drug Therapy per WHO)

• Dapsone 100 mg daily (self-administered)
• Rifampicin 600 mg monthly (supervised)

• Dapsone 100 mg daily
• Rifampicin 600 mg monthly
• Clofazimine 300 mg monthly + 50 mg daily

Lepra Reactions

Continue anti-leprosy drugs during lepra reactions - never stop!

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🔴 Q13 (First line TB) + Q16. Treatment of Specific Patients [5M]

Q16. Antibiotic Treatment for Specific Patients

• WHO MDT for PB: Rifampicin 600 mg once monthly (supervised) + Dapsone 100 mg daily for 6 months

• Safe antibiotics in pregnancy: Nitrofurantoin (avoid near term), Cephalosporins (safest), Amoxicillin
• Drug of Choice: Cephalexin (1st gen cephalosporin) OR Amoxicillin-clavulanate
• Avoid: Fluoroquinolones (cartilage damage), Tetracyclines, TMP-SMX (folate antagonist in 1st tri), Nitrofurantoin (hemolysis near term)

• Drug of Choice: Cefazolin + Metronidazole (covers aerobes + anaerobes)
• Given as single dose 30-60 minutes before incision
• Rationale: Colorectal surgery involves gram-negative enteric bacteria (E.coli) and anaerobes (Bacteroides fragilis) → need broad spectrum cover

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🔴 Q19. Classify Antimalarial Drugs + Drug Therapy of Severe Falciparum Malaria [5M]

Classification of Antimalarial Drugs

Drug Therapy: Severe and Complicated Falciparum Malaria

• Artesunate 2.4 mg/kg IV at 0, 12, 24 hours, then once daily until patient can take oral therapy
• Mechanism: Activated by heme → free radicals → alkylation of parasite proteins → rapid parasite death
• Fastest acting antimalarial - reduces parasitemia within hours

• Quinine dihydrochloride 20 mg/kg loading dose in 5% dextrose over 4 hours, then 10 mg/kg every 8 hours
• Always add Doxycycline or Clindamycin (to prevent recrudescence)
• Monitor for: Hypoglycemia (quinine stimulates insulin), QT prolongation, Cinchonism

• Dexamethasone: NOT recommended (worsens outcome in cerebral malaria)
• Mannitol for raised ICP in cerebral malaria
• IV glucose for hypoglycemia
• Blood transfusion for severe anemia
• Anticonvulsants for seizures (diazepam IV)

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🔴 Q20. HIV PEP Drugs + Needle Prick Prevention [5M]

Post-Exposure Prophylaxis (PEP) for HIV

PEP Regimen (NACO/WHO 2021 Guidelines)

• TDF (Tenofovir disoproxil fumarate) + 3TC (Lamivudine) + DTG (Dolutegravir)
• OR TDF + 3TC + LPV/r (Lopinavir/ritonavir) - alternate

• AZT (Zidovudine) + 3TC + LPV/r
• AZT + 3TC + EFV (Efavirenz)

Drug Mechanisms

Rationale for Boosted PI (Lopinavir/ritonavir)

• Ritonavir inhibits CYP3A4 → reduces metabolism of lopinavir → increases lopinavir plasma levels
• Low dose ritonavir acts as "pharmacokinetic booster" not as antiretroviral

Measures to Prevent Needle-Prick Injury

1. No recapping of needles (single-hand scoop technique only if necessary)
2. Dispose sharps immediately in puncture-proof sharp containers
3. Never bend or break needles
4. Use safety-engineered devices (retractable needles)
5. Wear gloves during procedures
6. Keep sharps containers at point of use (never overfill beyond 3/4 full)
7. Training and awareness programs
8. Hepatitis B vaccination for healthcare workers

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🔴 Q22. Three Systemic Antifungal Drugs and Their Therapeutic Uses [3M]

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🔴 Q23. Classify Anthelmintic Drugs + Therapeutic Uses [3M]

Classification and Uses

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🔴 Q24. Albendazole - MOA and Uses [3M]

Mechanism of Action

1. Binds to β-tubulin of helminths → inhibits its polymerization → prevents microtubule formation
2. Interferes with glucose uptake (inhibits fumarate reductase → impairs glucose metabolism → ATP depletion)
3. Result: Immobilization and death of parasite
4. Active against larval and adult forms
5. Spectrum: Broad - nematodes, some cestodes (cysticercus, hydatid), Giardia

Therapeutic Uses

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🔴 Q25. General Principles of Cancer Chemotherapy [5M]

Principles

• Cell-Cycle Specific (CCS): Kill only dividing cells in specific phase - antimetabolites (S phase), vinca alkaloids (M phase)
• Cell-Cycle Non-Specific (CCNS): Kill cells in any phase - alkylating agents, antibiotics

• Each dose of drug kills a constant fraction (not a constant number) of cells
• E.g., a drug that kills 99.9% (3-log kill) of 10⁹ cells leaves 10⁶ cells
• Rationale for multiple cycles of chemotherapy

• Drugs from different classes with different mechanisms → synergism
• Prevent/delay resistance
• Reduced dose of each drug → less toxicity
• Cover different phases of cell cycle

• Bone marrow suppression (myelosuppression) - most common, dose-limiting: neutropenia, thrombocytopenia, anemia
• GI toxicity - nausea, vomiting, mucositis, diarrhea
• Alopecia (hair loss) - reversible
• Gonadal toxicity - sterility
• Teratogenicity - avoid in 1st trimester
• Immunosuppression - opportunistic infections
• Secondary malignancy - alkylating agents (leukemia)

• Decreased drug uptake (MDR - P-glycoprotein overexpression)
• Increased drug efflux
• Increased target enzyme
• Altered target (topoisomerase mutations)
• Increased DNA repair

• High growth fraction tumors (ALL, Burkitt's, choriocarcinoma) - respond well
• Slow-growing solid tumors (colon, breast) - respond poorly
• Tumor size: smaller tumors respond better

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🔴 MISCELLENOUS - Q1. Pharmacotherapy of Scabies [3M]

Treatment

• MOA: Blocks voltage-gated sodium channels in nerve cell membrane → prolonged depolarization → paralysis and death of parasite
• Apply from neck down, leave for 8-12 hours, wash off; repeat after 1 week
• Safe in children (> 2 months) and pregnancy

• MOA: Toxic to Sarcoptes scabiei mite
• Apply after bath x 3 nights, wash off on 4th morning
• ADR: Skin irritation, rarely CNS stimulation if absorbed

• MOA: Enhances GABA-mediated Cl⁻ influx → hyperpolarization → paralysis of mite
• 200 mcg/kg single dose, repeat after 2 weeks
• Used for crusted (Norwegian) scabies and when topical fails

• Treat all household contacts simultaneously
• Wash clothes and bedding in hot water
• Sulfur 6% ointment (safe in infants < 2 months and pregnancy)
• Treat secondary bacterial infection with antibiotics

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🔴 MISCELLENOUS - Q2. Pharmacotherapy of Psoriasis [3M]

Topical (for mild-moderate)

Systemic (for moderate-severe)

Biologics (severe/refractory)

• Anti-TNF-α: Etanercept, Adalimumab, Infliximab
• Anti-IL-17: Secukinumab, Ixekizumab
• Anti-IL-12/23: Ustekinumab

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🔴 MISCELLENOUS - Q3. Drug Therapy for Acne Vulgaris [3M]

Pathogenesis (briefly)

Treatment (Stepwise)

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🔴 MISCELLENOUS - Q4. Fat-Soluble Vitamins + Nutritional Blindness [3M]

Fat-Soluble Vitamins: A, D, E, K

Vitamin A Deficiency and Nutritional Blindness

1. Night blindness (Nyctalopia) - earliest
2. Conjunctival xerosis
3. Bitot's spots (triangular foamy patches on conjunctiva)
4. Corneal xerosis
5. Keratomalacia - corneal melting → permanent blindness

Prevention and Treatment of Nutritional Blindness (National Programme)

• 6-11 months: Vitamin A 1 lakh IU single oral dose
• 12-59 months: Vitamin A 2 lakh IU every 6 months
• Lactating mothers: 1 lakh IU within 6 weeks of delivery
• Dietary diversification (dark green leafy vegetables, orange fruits)
• Food fortification (sugar, oil, milk with Vitamin A)

• Day 1: Age-specific dose of Vitamin A
• Day 2: Repeat same dose
• Day 14 (or at discharge): Repeat same dose
• Dose: < 6 months - 50,000 IU; 6-12 months - 1,00,000 IU; > 12 months - 2,00,000 IU

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OTHER QUESTIONS (Non-Red) - Quick Reference

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Q1-Q3. Antimicrobial Resistance, PAE, Conc vs Time-Dependent Killing [3M each]

1. Enzymatic inactivation (beta-lactamase destroys beta-lactam ring)
2. Altered target (PBP mutation - MRSA; DNA gyrase mutation - FQ resistance)
3. Decreased permeability (porin mutations - Pseudomonas)
4. Active efflux pumps (tetracyclines)
5. Alternate pathway (MRSA - acquired new PBP2a)

• Continued suppression of bacterial growth after drug concentration falls below MIC
• Clinical significance: Allows less frequent dosing; basis for once-daily aminoglycosides
• Good PAE: Aminoglycosides, Fluoroquinolones (both have prolonged PAE against gram-negative)
• Minimal PAE: Beta-lactams (requires continuous concentration above MIC)

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Q7. Amoxicillin vs Penicillin G - Spectrum Difference + Clinical Uses of Amoxicillin [5M]

• UTI (E. coli - if sensitive)
• Otitis media, Sinusitis (H. influenzae)
• Typhoid (non-MDR strains - though fluoroquinolones preferred)
• H. pylori eradication (triple/quadruple therapy)
• Dental prophylaxis for endocarditis
• LRTI
• Amoxicillin + Clavulanate: Beta-lactamase producing organisms, animal bites

Q8. Rationale for Combining Penicillin with Probenecid [3M]

• Probenecid inhibits tubular secretion of penicillin (OAT transporter in proximal tubule)
• Reduces renal elimination → increases plasma levels and prolongs duration of penicillin
• Used when high tissue levels required (gonorrhea treatment, IE)
• Also used for gout (inhibits tubular reabsorption of urate)

Q9. Semisynthetic Penicillins - Classification + Uses [5M]

Q10. 3rd Gen Cephalosporins + Typhoid Pharmacotherapy [3M]

• Uncomplicated: Cefixime 400 mg/day x 10-14 days OR Azithromycin 500 mg/day x 7 days
• Complicated/severe: Ceftriaxone 2g IV daily x 10-14 days OR Ciprofloxacin (if sensitive)
• MDR Typhoid: Ceftriaxone + Azithromycin
• Chloramphenicol (historical DOC, now resistance high)
• Duration: 10-14 days

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Q12 (CASE: TB) Key Points

• 2HRZE (Intensive) / 4HR (Continuation)
• Isoniazid → Peripheral neuropathy; Rifampicin → Hepatotoxicity + orange urine; Pyrazinamide → Gout/Hyperuricemia; Ethambutol → Optic neuritis

• Yes required! For: Wife + both children (< 5 years contacts) - all close household contacts
• Isoniazid Preventive Therapy (IPT): INH 5 mg/kg/day (max 300 mg) for 6 months
• All children < 5 years and HIV-positive contacts must receive prophylaxis

Q18. Rationale: Primaquine + Chloroquine in P. vivax [3M]

• Chloroquine: Kills erythrocytic (blood) schizonts → eliminates the acute attack
• Primaquine: Kills hypnozoites (dormant liver stage specific to P. vivax and P. ovale) → prevents relapse; also gametocidal
• Both are needed because:
  • Chloroquine alone → treats acute attack but relapse occurs in 2-3 months (from hypnozoites)
  • Primaquine alone → no action on erythrocytic stage (cannot treat acute attack)
  • Combined → radical cure (cure + prevention of relapse)
• Precaution: Check G6PD status before primaquine → can cause hemolytic anemia in G6PD deficiency

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Q21 (CASE: Hepatic Amoebiasis) Key Points

1. Metronidazole (DOC for hepatic amoebiasis)
   • MOA: Activated by ferredoxin-type protein in anaerobic organisms → forms free radicals → DNA strand breaks
   • ADR: Metallic taste, nausea, disulfiram-like reaction with alcohol, peripheral neuropathy
2. Chloroquine (alternate if metronidazole fails)
   • Concentrates in liver → active against hepatic amoebae

• Diloxanide furoate (DOC for asymptomatic intestinal carriage) or Iodoquinol
• Use in hepatic amoebiasis: To eliminate intestinal cysts (to prevent reinfection/transmission) - always follow metronidazole with luminal amebicide

• Complete alcohol avoidance during treatment AND for 48 hours after completing course
• Metronidazole inhibits acetaldehyde dehydrogenase → accumulation of acetaldehyde → disulfiram-like reaction: flushing, headache, nausea, vomiting, tachycardia, hypotension

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Q26. Drug Combination Rationales [3M]

• TMP blocks DHFR (dihydrofolate reductase) - step 2 in folate synthesis
• Sulfonamide blocks DHPS (dihydropteroate synthase) - step 1 in folate synthesis
• Sequential blockade of same pathway → synergism (combined effect > sum of individual)
• 50x more potent together than alone

• Amoxicillin is a beta-lactam antibiotic - kills bacteria
• Clavulanate is a beta-lactamase inhibitor (BLI) - no antibacterial activity of its own (suicide inhibitor)
• Protects amoxicillin from beta-lactamase enzyme produced by resistant bacteria
• Extends amoxicillin's spectrum to include BLPB (beta-lactamase producing bacteria): S. aureus, H. influenzae, Moraxella, E. coli

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Q27. Vinca Alkaloids [3M]

• Vincristine: Peripheral neurotoxicity (dose-limiting) - paresthesias, areflexia, autonomic neuropathy; minimal myelosuppression
• Vinblastine: Myelosuppression (dose-limiting); less neurotoxicity
• Both: Alopecia, constipation (autonomic neuropathy), local tissue damage (vesicant - extravasation must be avoided)

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MALARIA CASES - Quick Summary

• ACT: Artemether 80 mg + Lumefantrine 480 mg (AL) BD x 3 days (Coartem)
• OR Artesunate-Mefloquine or Artesunate-Sulfadoxine-Pyrimethamine
• Plus single dose Primaquine 0.25 mg/kg (gametocidal - to prevent transmission)

• Chloroquine 25 mg/kg over 3 days + Primaquine 0.25 mg/kg/day x 14 days (radical cure)
• If CQ-resistant vivax: Artemether-Lumefantrine + Primaquine

• Artemisinin: Rapid action (reduces parasitemia quickly), short half-life
• Partner drug (Lumefantrine, Mefloquine): Longer half-life, clears residual parasites
• Prevents resistance (never use artemisinin monotherapy)

• Chloroquine-sensitive areas: Chloroquine 300 mg weekly (1 week before to 4 weeks after)
• Chloroquine-resistant areas: Mefloquine / Atovaquone-Proguanil (Malarone) / Doxycycline

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QUICK REVISION TABLE - All RED Questions at a Glance

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