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🧠 Section I: Central Nervous System (CNS) - PYQs

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Chapter: Alcohols

• Explain why Ethyl alcohol is used in methyl alcohol poisoning. (2022 / 2024 August)

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Chapter: Sedatives and Hypnotics

• What are the reasons behind Drug Automatism seen with Barbiturates? (2019 March)
• Three differences between Barbiturates and Benzodiazepines. (2021 / 2024 August)
• Why benzodiazepines are preferred over barbiturates as sedative hypnotics. (2023 Feb New)

• Z compounds. (2018 Winter)

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Chapter: Antiepileptic Drugs

• Classify Antiepileptic drugs. Describe mechanism of action, therapeutic uses and adverse effects of Phenytoin sodium. Mention newer antiepileptic drugs. (2021)
• Classify Antiepileptic drugs based on their Mechanism of Action. Write Uses and Adverse Effects of Phenytoin. (2023 June Old)
• A 40-year male presenting with jerking of limbs and convulsions... Classify anti-epileptic drugs, write mechanism of Sodium Valproate, five non-epileptic uses, and treatment of status epilepticus. (2025 Jan)

• Compare phenytoin sodium and valproic acid as anti-epileptic drugs. (2017)
• Discuss the mechanism of action, therapeutic uses and unwanted effects of phenytoin. (2022)
• Why sodium valproate is called a broad-spectrum antiepileptic drug. (2023 Feb New)

• In case of phenytoin sodium why do we see a change in elimination kinetics from first order to zero order? Point out clinical significance. (2017)
• Absence seizures (Write two suitable drugs). (2018 Winter / 2023 Feb Old)
• Adverse effects of Phenytoin. (2019 March)
• Enumerate non-epileptic uses of carbamazepine. (2023 Feb New)
• Write basis of use of valproate in epilepsy. (2024 April)

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Chapter: Antiparkinsonian Drugs

• A 47-year-old man with resting tremors, slow movement, diminished facial expressions... Explain the rationale/advantages of combining levodopa with carbidopa, classify antiparkinsonian drugs, and discuss dopamine agonists vs levodopa/carbidopa. (2024 April)

• Drugs for treatment of Drug-Induced Parkinsonism. (2019 March)
• Explain briefly the pharmacological basis for combining Carbidopa with Levodopa. (2021 / 2025 Jan)
• Explain why Bromocriptine is effective even after Levodopa fails in Parkinsonism. (2022)
• Explain why pyridoxine should be avoided in patients on Levodopa Therapy. (2023 Feb Old)
• What is on-off phenomena and which drugs are combined to overcome this effect. (2023 Feb New)
• Why Levodopa is not used in drug-induced parkinsonism? (2023 June New)

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Chapter: Antipsychotic Drugs (Neuroleptics)

• Classify Antipsychotic drugs and write their important adverse effects and drug-drug interactions. (2018 Summer)
• A 19-year-old man with acute psychosis secondary to schizophrenia... Pharmacological basis of Haloperidol, advantages of atypical over typical antipsychotics, and typical antipsychotic ADRs with treatment. (2023 June New)
• A 45-year male diagnosed with schizophrenia... Classify antipsychotics, enumerate longer-acting injectables (LAI), write mechanism/uses/ADRs of Haloperidol, and compare Haloperidol vs Olanzapine. (2024 August)

• Enumerate atypical antipsychotic drugs and describe their advantages over typical antipsychotics. (2018 Summer / 2018 Winter / 2023 Feb Old / 2023 June Old / 2024 April / 2025 Jan)
• Compare and contrast between typical and atypical antipsychotic agents. (2023 Feb Old)
• Classify Anti-Psychotic Drugs. Write in brief about adverse drug reactions of Anti-Psychotic Drugs. (2022)

• Weight neutral antipsychotics. (2018 Winter)
• Enumerate extrapyramidal side effects of typical neuroleptics. (2023 Feb New)
• Rationale of using Samidorphan with Olanzapine in Schizophrenia. (2025 Jan)

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Chapter: Antidepressants & Anti-Anxiety Drugs

• Why are SSRIs preferred drugs for treatment of Depression? (2019 March / 2023 June New / 2024 April)
• Enumerate SSRIs & write rationale for use of Fluoxetine in depression. (2024 April / 2025 Jan)

• Mention two selective serotonin reuptake inhibitors (SSRIs) used as anti-depressants. (2017)
• Enumerate drugs for treatment of Mania / Rationale of Lithium in Mania. (2017 / 2019 March / 2022)

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Chapter: Opioid Analgesics and Antagonists

• Enumerate Opioid analgesics. Briefly describe their mechanism of action, uses and side effects. (2020)

• Uses of Opioid / Therapeutic uses and adverse effects of Morphine. (2017 / 2021)

• Opioid antagonists. (2018 Winter)
• Write two suitable drugs for opioid deaddiction. (2023 Feb Old / 2023 Feb New)
• Why Morphine is contraindicated in Head injury patients? (2023 June New / 2024 April)
• Write two contraindications of Morphine. (2023 June Old)

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1. Phenytoin - mechanism, uses, ADRs, kinetics (most repeated)
2. Atypical vs Typical Antipsychotics - asked almost every year
3. Levodopa + Carbidopa combination - rationale (2021, 2024, 2025)
4. SSRIs in depression - asked 3+ times
5. Sodium Valproate - broad-spectrum basis, non-epileptic uses

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🧠 CNS PHARMACOLOGY - COMPLETE PYQ ANSWERS

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CHAPTER 1: ALCOHOLS

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Q. Why is Ethyl Alcohol used in Methyl Alcohol (Methanol) poisoning? (2022 / 2024 August)

• Formaldehyde → then to Formic acid (formate)

• Severe metabolic acidosis (high anion gap)
• Optic nerve toxicity → blindness
• Can be fatal

• Ethanol has 10-20x higher affinity for alcohol dehydrogenase (ADH) than methanol
• When ethanol is given, it competitively inhibits the metabolism of methanol by ADH
• Methanol is then excreted unchanged in the urine/breath rather than being converted to toxic formate
• This buys time for methanol to be eliminated (naturally or via hemodialysis)

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CHAPTER 2: SEDATIVES AND HYPNOTICS

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Q. What are the reasons behind Drug Automatism seen with Barbiturates? (2019 March)

1. Narrow therapeutic index - small difference between therapeutic and toxic dose
2. Sedation before hypnosis - barbiturates cause progressive CNS depression; in the sedated state, the patient loses judgment and memory
3. Anterograde amnesia - barbiturates cause amnesia during the sedated state, so the patient doesn't remember taking the drug
4. No ceiling effect - unlike benzodiazepines, higher doses cause progressively deeper CNS depression (no safety plateau)
5. Prolonged half-life - especially with long-acting barbiturates like phenobarbitone; repeated doses accumulate

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Q. Three Differences Between Barbiturates and Benzodiazepines (2021 / 2024 August)

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Q. Why are Benzodiazepines preferred over Barbiturates as sedative-hypnotics? (2023 Feb New)

1. Safety in overdose - BZDs have a ceiling effect; even large doses rarely cause fatal respiratory depression when taken alone. Barbiturates cause dose-dependent respiratory depression and death.
2. Specific antidote - Flumazenil reverses benzodiazepine effects; no antidote for barbiturates.
3. Less enzyme induction - barbiturates induce CYP450 and cause many drug interactions; BZDs do not.
4. Lower abuse potential - physical dependence with barbiturates is severe; BZDs have lower but still significant dependence.
5. No hangover (shorter-acting BZDs) - agents like temazepam/triazolam have appropriate duration.
6. Anxiolytic at sub-hypnotic doses - BZDs reduce anxiety without excessive sedation; barbiturates are sedating across all doses.
7. Muscle relaxation without loss of consciousness - BZDs achieve this; barbiturates cause generalized CNS depression.

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Q. Z-Compounds (2018 Winter)

• Zolpidem - binds selectively to BZ1 (ω1) receptors; primarily hypnotic with minimal anxiolytic/anticonvulsant effects
• Zaleplon - ultra-short acting; useful for sleep-onset insomnia
• Zopiclone / Eszopiclone - short-to-intermediate acting; also has anxiolytic properties

• More selective (BZ1 receptors) → less muscle relaxation and amnesia
• Less disruption of sleep architecture
• Fewer rebound effects

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CHAPTER 3: ANTIEPILEPTIC DRUGS

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LONG ANSWER: Classify Antiepileptic Drugs. MOA, Uses, ADRs of Phenytoin. Mention newer AEDs. (2021 / 2023)

Classification of Antiepileptic Drugs (by Mechanism of Action)

• Phenytoin, Carbamazepine, Valproate, Lamotrigine, Lacosamide, Oxcarbazepine

• Ethosuximide, Valproate

• Increase GABA-A activity: Benzodiazepines (clonazepam), Phenobarbitone, Topiramate
• GABA transaminase inhibitors (increase GABA levels): Vigabatrin
• GABA reuptake inhibitors: Tiagabine

• Felbamate, Topiramate, Perampanel (AMPA antagonist)

• Valproate (Na⁺ block + T-Ca²⁺ block + GABA enhancement → broad-spectrum)
• Levetiracetam (binds SV2A synaptic vesicle protein - unique mechanism)

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Phenytoin Sodium

• Phenytoin blocks voltage-gated sodium channels by prolonging their inactivated state
• In rapidly firing neurons, more channels are in the inactivated state; phenytoin selectively binds these
• This is called use-dependent (frequency-dependent) block - it preferentially suppresses abnormally firing (epileptic) neurons without affecting normal neuronal activity
• Net effect: reduces sustained, high-frequency, repetitive firing of neurons

1. Grand mal (tonic-clonic) seizures - drug of choice (historically)
2. Focal (partial) seizures - with or without secondary generalization
3. Status epilepticus - IV phenytoin/fosphenytoin (second-line after benzodiazepines)
4. Prevention of seizures post-neurosurgery or head trauma
5. Non-epileptic uses:
   • Cardiac arrhythmias - especially digoxin-induced arrhythmias (ventricular)
   • Trigeminal neuralgia (second-line to carbamazepine)

• Nystagmus (earliest sign of toxicity)
• Diplopia, ataxia, vertigo
• Sedation, confusion, cognitive impairment

• Gingival hyperplasia (20-30% - due to inhibition of collagen metabolism in fibroblasts)
• Hirsutism (especially in young females)
• Megaloblastic anemia (due to folate deficiency - phenytoin impairs folate absorption)
• Osteomalacia (due to increased vitamin D metabolism via CYP induction)
• Peripheral neuropathy
• Coarsening of facial features

• Steven-Johnson syndrome (severe skin reaction)
• Aplastic anemia, hepatotoxicity
• Teratogenicity - "fetal hydantoin syndrome" (cleft palate, digital hypoplasia, cardiac defects)
• Lupus-like syndrome

• Hypotension and cardiac arrhythmias (due to propylene glycol vehicle)
• Use fosphenytoin (prodrug) for IV use - safer

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Newer Antiepileptic Drugs

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Q. Compare Phenytoin Sodium and Valproic Acid as Antiepileptic Drugs (2017)

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Q. Why is Sodium Valproate called a Broad-Spectrum Antiepileptic? (2023 Feb New)

1. Blocks voltage-gated Na⁺ channels (use-dependent) → effective in tonic-clonic and focal seizures
2. Blocks T-type Ca²⁺ channels in thalamic neurons → effective in absence seizures
3. Enhances GABA - inhibits GABA transaminase (enzyme that breaks down GABA) + increases GABA synthesis → raises brain GABA levels → general seizure suppression
4. Reduces neuronal excitability by multiple pathways

• Tonic-clonic (grand mal)
• Absence (petit mal)
• Myoclonic
• Atonic (drop attacks)
• Focal (partial) seizures
• Juvenile myoclonic epilepsy (drug of choice)

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Q. Phenytoin: Change from First-Order to Zero-Order Kinetics - Clinical Significance (2017)

• Phenytoin is metabolized by CYP2C9 (and 2C19) hepatic enzyme
• These enzymes have a limited capacity
• At low plasma concentrations - first-order kinetics (enzyme is not saturated)
• As the dose increases and plasma levels rise, the enzymes become saturated
• Once saturated, a constant amount (not fraction) is eliminated per unit time → zero-order (capacity-limited) kinetics

1. Small dose increases cause disproportionately large rises in plasma concentration → risk of sudden toxicity (nystagmus, ataxia, confusion)
2. Narrow therapeutic window (10-20 mcg/mL) is easily crossed
3. Therapeutic drug monitoring (TDM) is mandatory - blood levels must be measured regularly
4. Half-life increases with increasing dose (unlike typical drugs)
5. Drug interactions are unpredictable because enzyme saturation amplifies effects of inhibitors

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Q. Drugs for Absence Seizures (2018 Winter / 2023 Feb Old)

1. Ethosuximide - drug of choice for pure absence seizures; blocks T-type Ca²⁺ channels in thalamus; does NOT work for other seizure types
2. Sodium Valproate - drug of choice when absence occurs with other seizure types (tonic-clonic); multiple mechanisms

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Q. Adverse Effects of Phenytoin (2019 March)

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Q. Non-Epileptic Uses of Carbamazepine (2023 Feb New)

1. Trigeminal neuralgia - drug of choice (reduces paroxysmal nerve pain by Na⁺ channel block)
2. Glossopharyngeal neuralgia
3. Bipolar disorder - mood stabilizer (especially when lithium fails or is contraindicated)
4. Diabetic neuropathy (neuropathic pain)
5. Alcohol withdrawal (prevents withdrawal seizures)
6. Post-herpetic neuralgia
7. Restless leg syndrome

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Q. Basis of Use of Valproate in Epilepsy (2024 April)

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LONG ANSWER: Status Epilepticus - Treatment (2025 Jan)

• ABC (Airway, Breathing, Circulation)
• IV access, O₂, glucose (if hypoglycemic), vitals monitoring

• Lorazepam IV 4 mg (drug of choice - longer CNS effect than diazepam) OR
• Diazepam IV 10 mg OR
• Midazolam IM (if no IV access)
• Can repeat once after 5-10 min

• Phenytoin/Fosphenytoin IV (20 mg/kg) - fosphenytoin preferred (less cardiotoxic)
• OR Valproate IV (30-40 mg/kg)
• OR Levetiracetam IV (60 mg/kg)

• Propofol infusion (first choice)
• Midazolam infusion
• Thiopentone/Phenobarbitone
• ICU admission, EEG monitoring

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CHAPTER 4: ANTIPARKINSONIAN DRUGS

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LONG ANSWER: Classify Antiparkinsonian Drugs. Rationale of Carbidopa + Levodopa. Dopamine Agonists. (2024 April)

Classification of Antiparkinsonian Drugs

1. Levodopa + Carbidopa (Sinemet) - gold standard
2. Dopamine agonists: Bromocriptine, Pramipexole, Ropinirole, Cabergoline, Rotigotine
3. MAO-B inhibitors: Selegiline, Rasagiline (prevent dopamine breakdown)
4. COMT inhibitors: Entacapone, Tolcapone (prevent L-DOPA breakdown peripherally)
5. Amantadine (increases DA release + weak NMDA antagonist + antimuscarinic)

• Trihexyphenidyl (Benzhexol), Biperiden, Procyclidine, Orphenadrine

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Rationale / Advantages of Combining Levodopa with Carbidopa

• Levodopa is a dopamine precursor that crosses the blood-brain barrier (BBB) - dopamine itself cannot
• When given alone, >95% of levodopa is converted to dopamine in peripheral tissues by dopa decarboxylase (aromatic amino acid decarboxylase, AAAD) before it reaches the brain
• This peripheral dopamine causes: nausea, vomiting, hypotension, cardiac arrhythmias
• Very large doses of levodopa are required (3-5g/day) to get adequate brain levels

• A peripheral AAAD inhibitor that does NOT cross the BBB
• When combined with levodopa, it blocks the conversion of levodopa to dopamine in the periphery
• More levodopa reaches the brain intact → converts to dopamine in the striatum

1. Levodopa dose reduced by 75% (from ~3-5g/day to ~300-750mg/day)
2. Peripheral side effects greatly reduced (less nausea, vomiting, cardiac effects)
3. Faster onset of therapeutic effect
4. Less interference by pyridoxine (Vit B6) - B6 activates peripheral AAAD; carbidopa blocks this interaction

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Why Pyridoxine (Vit B6) Should Be Avoided in Patients on Levodopa (Without Carbidopa) (2023 Feb Old)

• Pyridoxine (Vit B6) is a cofactor for dopa decarboxylase (AAAD)
• It enhances the peripheral conversion of levodopa → dopamine before it crosses the BBB
• This means more levodopa is destroyed peripherally and less reaches the brain
• Result: reduced therapeutic effect of levodopa
• If carbidopa is given with levodopa, this interaction is abolished (because AAAD is already inhibited)

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Dopamine Agonists vs Levodopa/Carbidopa

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Q. Drugs for Drug-Induced Parkinsonism (2019 March)

1. Stop the causative drug (if possible)
2. Anticholinergics - Trihexyphenidyl (Benzhexol), Biperiden - these are the drugs of choice
3. Amantadine

• The parkinsonian symptoms are caused by blockade of dopamine receptors (D2) by the offending drug
• Levodopa increases synaptic dopamine, but the receptors are already blocked
• Levodopa cannot override the receptor blockade → ineffective
• Moreover, adding levodopa may worsen the psychiatric condition being treated by the antipsychotic

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Q. Explain Why Bromocriptine is Effective Even After Levodopa Fails (2022)

• Bromocriptine is a dopamine receptor agonist - it directly stimulates D2 (and D1) receptors in the striatum
• It does NOT require conversion to dopamine; it acts directly on the receptor
• Levodopa can fail because:
  1. Loss of nigrostriatal nerve terminals - as disease progresses, there are fewer neurons to convert levodopa → dopamine
  2. Down-regulation of dopamine receptors with long-term levodopa use
  3. On-off phenomenon - erratic response to levodopa
• Bromocriptine bypasses the need for functional presynaptic terminals since it stimulates receptors directly
• It has a longer half-life than levodopa → more stable receptor stimulation
• Also effective for: lactation suppression (D2 agonist reduces prolactin), acromegaly (GH suppression)

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Q. What is the On-Off Phenomenon? Which Drugs Overcome It? (2023 Feb New)

• "ON" phase: Drug is working - patient has good motor control (may have dyskinesias)
• "OFF" phase: Sudden, unpredictable loss of drug effect - patient becomes akinetic, rigid, may "freeze"
• The transitions between ON and OFF can be abrupt and unpredictable ("wearing off" is more predictable; true on-off is random)

1. COMT inhibitors (Entacapone, Tolcapone) - given with levodopa; block peripheral breakdown of L-DOPA → prolong its action; Stalevo = levodopa + carbidopa + entacapone
2. MAO-B inhibitors (Selegiline, Rasagiline) - reduce central dopamine breakdown → smooth response
3. Long-acting dopamine agonists (Pramipexole, Ropinirole) - provide steady dopaminergic stimulation
4. Extended-release carbidopa/levodopa (Rytary) - slower release → more stable levels
5. Continuous intraduodenal levodopa infusion (Duodopa)
6. Deep Brain Stimulation (DBS) of subthalamic nucleus (surgical)

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CHAPTER 5: ANTIPSYCHOTIC DRUGS (NEUROLEPTICS)

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LONG ANSWER: Classify Antipsychotics. ADRs. Drug-Drug Interactions. (2018 Summer / 2022 / 2024 August)

Classification of Antipsychotic Drugs

• Haloperidol, Fluphenazine, Trifluoperazine

• Perphenazine, Loxapine

• Chlorpromazine, Thioridazine

• Haloperidol decanoate, Fluphenazine decanoate

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Mechanism of Action - Haloperidol (Typical Antipsychotic)

• Primarily blocks D2 receptors (dopamine receptor antagonism) in four key dopamine pathways:
  1. Mesolimbic pathway - reduces positive symptoms (hallucinations, delusions) - therapeutic
  2. Mesocortical pathway - may worsen negative symptoms (flat affect, social withdrawal)
  3. Nigrostriatal pathway - causes extrapyramidal side effects (EPS)
  4. Tuberoinfundibular pathway - blocks dopamine inhibition of prolactin → hyperprolactinemia

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Adverse Drug Reactions of Typical Antipsychotics

• Acute dystonia (within hours-days): Involuntary muscle spasms, torticollis, oculogyric crisis; treat with anticholinergics (benztropine) or IV diazepam
• Akathisia (within days-weeks): Subjective restlessness, compulsion to move; treat with propranolol or benzodiazepines
• Parkinsonism (weeks-months): Tremor, rigidity, bradykinesia; treat with trihexyphenidyl
• Tardive Dyskinesia (TD) (months-years): Repetitive involuntary oral-facial movements (lip smacking, tongue protrusion); largely irreversible; treat with clonazepam, tetrabenazine, or switch to clozapine

• Hyperthermia, muscle rigidity, altered consciousness, autonomic instability
• Elevated CK, leukocytosis
• Treatment: Stop antipsychotic; dantrolene, bromocriptine, supportive care

• Hyperprolactinemia → galactorrhea, amenorrhea, gynecomastia, sexual dysfunction
• Weight gain (especially low-potency agents and SGAs like olanzapine, clozapine)
• Glucose intolerance

• Dry mouth, constipation, urinary retention, blurred vision (more with low-potency agents)

• QT prolongation (thioridazine, ziprasidone) → risk of Torsades de Pointes
• Postural hypotension (alpha-1 blockade)

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Drug-Drug Interactions of Antipsychotics

1. Additive CNS depression with alcohol, opioids, sedatives, antihistamines
2. QT prolongation - avoid with other QT-prolonging drugs (erythromycin, quinolones, TCAs)
3. Anticholinergic excess - combined with TCAs, antihistamines → urinary retention, ileus
4. Reduced efficacy when combined with CYP inducers (rifampicin, carbamazepine, phenytoin) - increased metabolism of antipsychotic
5. CYP inhibitors (fluoxetine, fluvoxamine) increase levels of haloperidol, clozapine
6. Antidiabetic drugs - atypical antipsychotics worsen glycemic control
7. Lithium + antipsychotics - additive risk of neurotoxicity; monitor

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Q. Atypical Antipsychotics - Enumerate + Advantages over Typical (Repeated: 2018 S/W, 2023, 2024, 2025)

1. Less EPS - due to lower D2 receptor occupancy + 5-HT2A antagonism (serotonin blockade in nigrostriatal pathway releases dopamine to counteract D2 block); aripiprazole (partial agonist) has minimal EPS
2. Less tardive dyskinesia - significantly lower risk
3. Treat negative symptoms (apathy, social withdrawal, flat affect) - typical agents do not; atypicals improve these via 5-HT2A antagonism in mesocortical pathway
4. Less hyperprolactinemia - except risperidone/amisulpride; quetiapine and clozapine cause minimal prolactin rise
5. Effective in treatment-resistant schizophrenia - especially clozapine (gold standard for TRS)
6. Better cognitive outcomes - some evidence for cognitive improvement
7. Reduce suicide risk - clozapine has specific anti-suicidal benefit (FDA-approved indication)
8. Less anticholinergic effects (compared to low-potency typical agents)

• More metabolic side effects (weight gain, diabetes, dyslipidemia) - olanzapine, clozapine
• Clozapine risk of agranulocytosis (1%), myocarditis, seizures
• QT prolongation (ziprasidone)
• More expensive

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Q. Weight-Neutral Antipsychotics (2018 Winter)

1. Aripiprazole - partial D2 agonist; weight-neutral or slight loss
2. Ziprasidone - minimal weight gain
3. Lurasidone - low metabolic burden
4. Haloperidol (typical) - minimal weight effect
5. Amisulpride - relatively weight-neutral

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Q. Extrapyramidal Side Effects (EPS) of Typical Neuroleptics (2023 Feb New)

1. Acute dystonia - hours to days; involuntary muscle contractions; treated with anticholinergics
2. Akathisia - days to weeks; motor restlessness; treated with propranolol/BZDs
3. Parkinsonism - weeks to months; tremor/rigidity/bradykinesia; treated with anticholinergics/amantadine
4. Tardive dyskinesia - months to years; oro-facial movements; difficult to reverse; treat with tetrabenazine/switch to clozapine

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Q. Rationale of Samidorphan with Olanzapine in Schizophrenia (2025 Jan)

• Olanzapine is highly effective for schizophrenia but causes significant weight gain and metabolic syndrome (via histamine H1 and serotonin 5-HT2C antagonism → increased appetite/food intake)
• Samidorphan is an opioid receptor antagonist (mu and kappa opioid receptors)
• Opioid receptor activation in the hypothalamus increases appetite and food intake
• Samidorphan blocks opioid receptors → reduces the weight gain associated with olanzapine
• The combination (Lybalvi = olanzapine/samidorphan) maintains the antipsychotic efficacy of olanzapine while mitigating its metabolic side effects
• Samidorphan does not affect olanzapine's antipsychotic mechanism

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CHAPTER 6: ANTIDEPRESSANTS & ANTI-ANXIETY DRUGS

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Q. Why are SSRIs Preferred for Depression? (2019 March / 2023 / 2024)

1. Effective in all subtypes of depression (MDD, dysthymia, PMDD)
2. Also effective for anxiety disorders, OCD, PTSD, panic disorder, bulimia

1. Safe in overdose - no cardiotoxicity (TCAs cause fatal arrhythmias in overdose)
2. No anticholinergic effects - no dry mouth, constipation, urinary retention, sedation, cognitive impairment (unlike TCAs)
3. No need for dietary restrictions - MAOIs require tyramine-free diet (risk of hypertensive crisis); SSRIs do not
4. Weight-neutral (unlike TCAs which cause weight gain) - most SSRIs
5. No cardiac conduction problems (unlike TCAs - prolong QRS, QT)
6. Less sedation - patients can work and drive
7. Once daily dosing - improves compliance

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Q. SSRIs - Enumerate (2017) / Fluoxetine rationale (2024 / 2025)

1. Fluoxetine (Prozac)
2. Sertraline
3. Paroxetine
4. Fluvoxamine
5. Escitalopram
6. Citalopram

• Potent, selective SERT inhibitor → increases synaptic serotonin
• Longest half-life (~2-3 days; active metabolite norfluoxetine ~7-9 days) → least withdrawal symptoms on discontinuation
• Effective for MDD, OCD, bulimia nervosa, panic disorder
• Weekly dosing formulation available (compliance advantage)
• Relatively activating (less sedating) - useful in depressed patients with fatigue/psychomotor retardation
• Generally well-tolerated; main side effects: GI upset (nausea), sexual dysfunction, insomnia, headache
• Inhibits CYP2D6 - important drug interaction (increases levels of TCAs, metoprolol, codeine)

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Q. Drugs for Mania / Rationale of Lithium in Mania (2017 / 2019 / 2022)

1. Lithium - gold standard, but slow onset (5-7 days); use for mild-moderate acute mania
2. Haloperidol / Olanzapine - for rapid behavioral control
3. Valproate (sodium valproate) - faster than lithium; preferred when rapid control needed
4. Carbamazepine - second-line mood stabilizer
5. Benzodiazepines (lorazepam) - adjunct for acute agitation

1. Lithium (drug of choice), Valproate, Lamotrigine (especially for bipolar depression), Quetiapine

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1. Inhibits inositol monophosphatase and inositol polyphosphate 1-phosphatase → depletes inositol → reduces signaling through phosphatidylinositol (PI) pathway (important in the "inositol depletion hypothesis")
2. Inhibits glycogen synthase kinase-3 (GSK-3) - a serine/threonine kinase involved in neuronal signaling and circadian rhythm regulation
3. Modulates cAMP signaling - reduces receptor-coupled adenylyl cyclase activity
4. Reduces dopamine and norepinephrine release (relevant to reducing mania)
5. Neuroprotective effects - promotes neuronal survival, increases BDNF
6. Li⁺ is a monovalent cation that mimics Na⁺/K⁺ but is handled differently in cells → alters membrane ion dynamics

• Narrow therapeutic index (0.6-1.2 mEq/L therapeutic; >1.5 mEq/L toxic)
• Toxicity: Tremor, polyuria/polydipsia (nephrogenic DI), hypothyroidism, GI effects, nausea
• Severe toxicity: Coarse tremor, confusion, convulsions, cardiac arrhythmias
• Renally excreted; NSAIDs and thiazides reduce lithium excretion → increase levels → toxicity

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CHAPTER 7: OPIOID ANALGESICS AND ANTAGONISTS

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LONG ANSWER: Enumerate Opioids, Mechanism, Uses, Side Effects (2020)

Opioid Classification

• Morphine, Heroin (diacetylmorphine), Fentanyl, Methadone, Pethidine (meperidine), Oxycodone, Hydromorphone

• Codeine, Tramadol (weak opioid + SNRI), Buprenorphine (partial agonist - ceiling effect)

• Pentazocine, Nalbuphine, Butorphanol (agonist at kappa, antagonist/partial at mu)

• Naloxone (IV, short-acting), Naltrexone (oral, long-acting), Nalmefene

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Mechanism of Action of Opioids

• Mu (μ) - analgesia (spinal + supraspinal), euphoria, respiratory depression, constipation, dependence, miosis, antitussive
• Kappa (κ) - spinal analgesia, sedation, dysphoria, miosis
• Delta (δ) - analgesia, mood modulation

1. Inhibit adenylyl cyclase → decrease cAMP
2. Open K⁺ channels → hyperpolarization → reduce neuronal firing
3. Close voltage-gated Ca²⁺ channels → reduce neurotransmitter release (presynaptically)
4. Net effect: Decreased nociceptive transmission in spinal cord (dorsal horn) and brain

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Therapeutic Uses of Morphine (2017 / 2021)

1. Severe acute pain - post-operative, trauma, MI ("drug of choice" for MI pain: reduces preload/afterload + anxiety)
2. Chronic cancer pain - WHO analgesic ladder step 3
3. Acute pulmonary edema - reduces anxiety, decreases preload (venodilation), reduces respiratory drive (reduces sensation of dyspnea)
4. Cough suppression (antitussive) - codeine preferred (less addictive)
5. Diarrhea - loperamide (peripheral only), codeine
6. Preanesthetic medication - reduces anxiety, provides analgesia
7. Balanced anesthesia - with other agents

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Adverse Effects of Morphine / Opioids

• Sedation, drowsiness, euphoria
• Respiratory depression (reduced sensitivity of respiratory center to CO₂) - most dangerous effect
• Nausea and vomiting (stimulates CTZ - chemoreceptor trigger zone)
• Miosis (pinpoint pupils) - even in addicts; due to mu/kappa receptor stimulation of Edinger-Westphal nucleus
• Physical dependence and addiction

• Constipation (reduces GI motility - increases sphincter tone, reduces peristalsis) - does not develop tolerance
• Delayed gastric emptying
• Biliary spasm (increases biliary duct pressure - painful in biliary colic)

• Hypotension (histamine release + vasodilation)

• Urinary retention (ureter/bladder sphincter tone)
• Pruritus (histamine release)
• Tolerance and dependence develop to most effects (except constipation and miosis)

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Q. Why is Morphine Contraindicated in Head Injury? (2023 / 2024)

1. CO₂ retention: Morphine causes respiratory depression → PaCO₂ rises
2. Cerebral vasodilation: Elevated PaCO₂ causes cerebral vasodilation → increases cerebral blood flow and ICP (intracranial pressure)
3. Dangerous in head injury: Already elevated ICP in head injury is further worsened → brainstem herniation risk
4. Miosis masks neurological assessment - pupillary responses are critical for monitoring neurological deterioration; morphine-induced miosis interferes with this
5. Sedation makes neurological assessment (GCS) unreliable
6. Nausea/vomiting from morphine can raise ICP (Valsalva effect)

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Q. Two Contraindications of Morphine (2023 June Old)

1. Head injury / Raised ICP (as above)
2. Bronchial asthma / Respiratory depression - morphine causes bronchoconstriction (histamine release) + depresses respiratory drive; can be fatal in asthmatics

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Q. Opioid Antagonists (2018 Winter)

1. Naloxone (Narcan)
   • Given IV/IM/intranasal
   • Short half-life (~30-60 min); opioid effects outlast it → repeated doses or infusion needed
   • Used for: acute opioid overdose (emergency), reversal of opioid-induced respiratory depression
   • Causes rapid opioid withdrawal in dependent patients (precipitation of withdrawal)
2. Naltrexone
   • Oral; long half-life (~24h; metabolite 72h)
   • Used for: Maintenance treatment of opioid dependence (prevents relapse; blocks euphoria), alcohol dependence (reduces craving by blocking endorphin-mediated reward)
   • Patient must be opioid-free for 7-10 days before starting
3. Methylnaltrexone / Alvimopan - peripheral opioid antagonists (do not cross BBB)
   • Used to treat opioid-induced constipation without reversing central analgesia
4. Nalmefene - similar to naltrexone; also used for alcohol dependence

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Q. Two Drugs for Opioid De-Addiction (2023 Feb Old / New)

1. Methadone - long-acting oral opioid agonist (mu)
   • Maintenance therapy: substitutes for heroin/morphine (prevents withdrawal symptoms)
   • Reduces cravings, allows social rehabilitation
   • Long half-life (~24-36h) → once daily dosing; smooth levels (less euphoria/withdrawal)
2. Buprenorphine (+ Naloxone = Suboxone)
   • Partial mu agonist + kappa antagonist
   • Ceiling effect on respiratory depression → safer than methadone in overdose
   • Naloxone added to deter IV abuse (naloxone is poorly bioavailable sublingually, so no effect when taken correctly; if injected, naloxone causes withdrawal)
   • High affinity for mu receptors → blocks heroin/morphine euphoria

• Naltrexone - for relapse prevention (antagonist)
• Clonidine - alpha-2 agonist; manages autonomic symptoms of withdrawal (sweating, tachycardia, diarrhea) but not craving

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🦠 SECTION V: CHEMOTHERAPY OF MICROBIAL INFECTIONS

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CHAPTER 1: GENERAL PRINCIPLES OF ANTIMICROBIAL THERAPY

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LONG ANSWER: Rationale for Multi-Drug Regimens in Microbial Infections (2019 March)

Short Answer: Justification for Co-administration of Antimicrobials with Examples (2017)

Advantages (Indications) of Combination Antimicrobial Therapy

• Two drugs together produce greater effect than the sum of each alone
• Classic example: Beta-lactam + Aminoglycoside for Gram-negative infections and enterococcal endocarditis
  • Beta-lactam disrupts cell wall → increases aminoglycoside entry into cell → synergistic bactericidal kill
• Example: Ampicillin + Gentamicin for Enterococcus faecalis endocarditis

• When drugs act at different targets, a resistant mutant to drug A is unlikely to simultaneously be resistant to drug B
• Most important rationale in tuberculosis - simultaneous resistance to 4 drugs is virtually impossible
• Example: HRZE regimen (Isoniazid + Rifampicin + Pyrazinamide + Ethambutol) for TB

• When organism is unknown and the infection is life-threatening, combinations provide coverage of multiple likely pathogens until culture results return
• Example: Piperacillin-tazobactam + Vancomycin in sepsis (covers Gram-negatives + MRSA)
• Example: Cefotaxime + Ampicillin in neonatal meningitis (Gram-negatives + Listeria)

• Some infections involve multiple organisms that no single drug can cover
• Example: Intra-abdominal infection needs cover for aerobes + anaerobes → Metronidazole + Cephalosporin
• Example: Aspiration pneumonia - mixed anaerobes + aerobes

• HIV-TB co-infection: needs anti-TB drugs + antiretrovirals simultaneously

• By using sub-maximal doses of two drugs that have synergistic action, each individual drug's toxic dose is avoided
• Example: Amphotericin B + Flucytosine for cryptococcal meningitis

Disadvantages of Combination Therapy

1. Antagonism - bacteriostatic drug (tetracycline) + bactericidal drug (penicillin) → first drug slows growth → second drug less effective (bactericidal drugs require actively growing cells)
2. Increased adverse effects and toxicity
3. Increased cost
4. Risk of superinfection / Clostridioides difficile colitis (broad-spectrum disrupts normal flora)
5. Promotes antimicrobial resistance via selection pressure if given unnecessarily

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Short Answer: Mechanisms of Antimicrobial Resistance with Examples (2020)

Mechanisms of Bacterial Resistance

• Bacteria produce enzymes that destroy or inactivate the antibiotic
• Beta-lactamases - break the beta-lactam ring of penicillins and cephalosporins (e.g., ESBL-producing E. coli destroys 3rd-gen cephalosporins)
• Aminoglycoside-modifying enzymes (acetyltransferases, phosphotransferases, nucleotidyltransferases) - modify aminoglycosides → reduce ribosome binding
• Chloramphenicol acetyltransferase - inactivates chloramphenicol

• Mutation changes the target such that the drug no longer binds effectively
• PBP (Penicillin-Binding Protein) mutations - MRSA has altered PBP2a (mecA gene) → very low affinity for beta-lactams → methicillin resistance
• Ribosomal mutations - altered 30S ribosome → streptomycin resistance in TB (rpsL gene mutation)
• DNA gyrase / topoisomerase IV mutations → fluoroquinolone resistance
• Altered cell wall precursors (D-Ala-D-Lac instead of D-Ala-D-Ala) → vancomycin resistance in VRE (Enterococcus)

• Reduced uptake: Gram-negative bacteria alter outer membrane porin proteins → reduced entry of beta-lactams (e.g., Pseudomonas aeruginosa OprD loss → carbapenem resistance)
• Efflux pumps: Active export of drug from the cell
  • Tetracycline resistance via Tet efflux pumps
  • Multidrug efflux pumps (e.g., MexAB-OprM in Pseudomonas) - export multiple unrelated antibiotics → MDR
  • Macrolide resistance (mef gene) via efflux

• Bacteria develop alternative metabolic pathway not inhibited by the drug
• Sulfonamide resistance - some bacteria can use exogenous folic acid from environment, bypassing the need for synthesis (so sulfonamide that blocks synthesis has no effect)
• MRSA uses PBP2a (a different PBP) to bypass the blocked PBPs

• Resistance spreads between bacteria by:
  • Plasmids (R-factors) - most important mechanism of spread; conjugation
  • Transposons (jumping genes)
  • Bacteriophages (transduction)
  • Transformation (uptake of free DNA)

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CHAPTER 2: SULFONAMIDES, COTRIMOXAZOLE, AND QUINOLONES

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Short Answer: Mechanism and Adverse Effects of Sulfonamides (2024 August)

Mechanism of Action

• Bacteria must synthesize their own folic acid (they cannot take it up from the environment)
• Sulfonamides competitively inhibit dihydropteroate synthetase - the enzyme that incorporates PABA into dihydrofolic acid
• Result: Bacteria cannot synthesize folic acid → cannot make purines, thymidine, certain amino acids → bacteriostatic effect
• Human cells are not affected because they cannot synthesize folate and rely on dietary folate

Adverse Effects of Sulfonamides

1. Hypersensitivity reactions - most common; rashes, urticaria, drug fever; severe: Stevens-Johnson syndrome (erythema multiforme major), toxic epidermal necrolysis
2. Crystalluria and renal damage - sulfonamides precipitate in acidic urine forming crystals → renal tubular obstruction; prevented by adequate hydration + alkalinizing urine
3. Hematological:
   • Hemolytic anemia (especially in G6PD-deficient patients)
   • Agranulocytosis, aplastic anemia (rare)
   • Megaloblastic anemia (folate antagonism)
4. Kernicterus in newborns - displace bilirubin from plasma albumin binding → bilirubin enters brain → brain damage; contraindicated in neonates
5. Hepatotoxicity - rare; hepatitis, cholestasis
6. Nausea, vomiting, anorexia

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Q. Rationale of Combining Trimethoprim with Sulfamethoxazole (Co-trimoxazole) (2021)

• Sulfonamide (Sulfamethoxazole) blocks step 1: PABA → Dihydrofolic acid (inhibits dihydropteroate synthetase)
• Trimethoprim blocks step 2: Dihydrofolic acid → Tetrahydrofolic acid (inhibits dihydrofolate reductase - 50,000x more selective for bacterial enzyme than human enzyme)

1. Synergistic bactericidal effect - sequential blockade of the same pathway; each drug alone is bacteriostatic, but together they are often bactericidal
2. Reduced emergence of resistance - resistance to both drugs simultaneously is very rare; a mutant resistant to one drug is still susceptible to the other
3. Broader spectrum than either alone
4. Lower doses of each drug required → reduced individual drug toxicity

• Urinary tract infections (E. coli, Proteus)
• Pneumocystis jirovecii pneumonia (PCP) - drug of choice (treatment and prophylaxis)
• Traveler's diarrhea, typhoid (less common now), MRSA skin infections
• Toxoplasmosis prophylaxis

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CHAPTER 3: BETA-LACTAM ANTIBIOTICS

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LONG ANSWER: Classify Cephalosporins. Therapeutic Uses and Adverse Effects (2018 Winter / 2020 / 2022 / 2024)

Classification of Cephalosporins (by Generation)

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Ceftriaxone - Uses and Adverse Effects

1. Bacterial meningitis (Streptococcus pneumoniae, Neisseria meningitidis, H. influenzae) - drug of choice
2. Community-acquired pneumonia (CAP)
3. Typhoid fever (drug of choice - 3rd gen cephalosporins)
4. Gonorrhea (Neisseria gonorrhoeae) - single dose 500mg IM
5. Septicemia, septic arthritis, osteomyelitis
6. Prophylaxis in surgical procedures
7. Advantage: Once daily dosing (long half-life ~8h); good tissue penetration including CSF

1. Hypersensitivity - most common; rashes, urticaria, anaphylaxis; ~1-3% cross-reactivity with penicillin allergy (especially older cephalosporins)
2. GI effects - nausea, vomiting, diarrhea; Clostridioides difficile colitis (especially with broad-spectrum agents)
3. Nephrotoxicity - mild; potentiated by aminoglycosides
4. Ceftriaxone-specific: Biliary sludge/pseudolithiasis (ceftriaxone precipitates in bile as calcium salt; more common in children); avoid in neonates (displaces bilirubin → kernicterus)
5. Bleeding tendency - some cephalosporins (cefamandole, cefoperazone) have MTT side chain → inhibit Vit K metabolism → hypoprothrombinemia
6. Disulfiram-like reaction with alcohol (MTT-containing cephalosporins)
7. Pain at injection site (IM); thrombophlebitis (IV)

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Q. Classify Antimicrobials Acting on Bacterial Cell Wall. Indications for Vancomycin (2019 Sept)

Cell Wall-Active Antimicrobials

• Penicillins: Natural (Penicillin G/V), Antistaphylococcal (Cloxacillin, Dicloxacillin), Aminopenicillins (Ampicillin, Amoxicillin), Antipseudomonal (Piperacillin, Ticarcillin), Carboxypenicillins
• Cephalosporins (1st-5th generation - as above)
• Carbapenems: Imipenem-cilastatin, Meropenem, Ertapenem, Doripenem - broadest spectrum beta-lactams
• Monobactams: Aztreonam - Gram-negative only (useful in penicillin allergy)
• Beta-lactamase inhibitors (given with penicillins): Clavulanic acid, Sulbactam, Tazobactam, Avibactam

• Vancomycin (IV), Teicoplanin - inhibit cell wall synthesis by binding D-Ala-D-Ala terminus of peptidoglycan precursors

• Daptomycin (Gram-positive only; disrupts cell membrane)

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Indications for Vancomycin

1. MRSA infections (Methicillin-Resistant Staphylococcus aureus) - bacteremia, endocarditis, pneumonia, osteomyelitis - vancomycin is drug of choice
2. Clostridioides difficile colitis - oral vancomycin (not absorbed; acts locally) - first-line for severe disease
3. Penicillin-allergic patients with serious infections requiring cell-wall-active drugs - e.g., pneumococcal meningitis in severe penicillin allergy
4. Staphylococcal endocarditis due to penicillin-resistant or MRSA strains
5. Febrile neutropenia with suspected MRSA
6. Gram-positive prosthetic valve endocarditis
7. CNS infections (meningitis, VP shunt infections) due to resistant Gram-positive organisms

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Q. Beta-Lactamase Inhibitors (2025 Jan)

• Beta-lactamases are bacterial enzymes that break the beta-lactam ring → inactivate penicillins/cephalosporins
• Beta-lactamase inhibitors bind irreversibly to the enzyme (suicide inhibitors) → permanently inactivate it
• Combined with a beta-lactam → protect it from enzymatic destruction

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Q. Two Antipseudomonal Penicillins (2023 June Old)

1. Piperacillin (usually given as Piperacillin-Tazobactam)
2. Ticarcillin (usually given as Ticarcillin-Clavulanic acid)

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Q. Mechanisms of Bacterial Resistance to Beta-Lactam Antibiotics (2023 June Old)

1. Beta-lactamase production (most common) - enzymes that hydrolyze the beta-lactam ring; encoded on plasmids or chromosomes; includes ESBL (Extended-Spectrum Beta-Lactamases) and carbapenemases (KPC, NDM, OXA-48)
2. Altered Penicillin-Binding Proteins (PBPs) - mutated PBPs have reduced affinity for beta-lactams; classic example: MRSA (PBP2a encoded by mecA gene) → resistant to all standard beta-lactams
3. Reduced outer membrane permeability - loss of porin channels (OprD in Pseudomonas) → carbapenem resistance; especially relevant in Gram-negative organisms
4. Efflux pumps - active export of beta-lactam before it reaches PBP (e.g., MexAB-OprM in Pseudomonas)

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Q. Why is Cilastatin Combined with Imipenem? (2024 August)

• Imipenem is rapidly hydrolyzed in the renal tubules by dehydropeptidase-I (DHP-I) - a brush border enzyme
• This destroys >70% of the drug before it can be excreted as active drug in urine
• Inadequate urinary drug levels → ineffective for urinary tract infections
• The nephrotoxic metabolites (formed by DHP-I) can cause tubular necrosis

• A specific competitive inhibitor of DHP-I (not an antibiotic itself; has no antimicrobial activity)
• Blocks the enzyme → prevents imipenem breakdown in kidney tubules
• Benefits:
  1. Maintains adequate urinary concentrations of imipenem (active drug) → effective for UTI
  2. Prevents accumulation of toxic metabolites → reduces nephrotoxicity
  3. Increases systemic half-life of imipenem (less wastage)
• Note: Meropenem, ertapenem, and doripenem are stable to DHP-I → do NOT require cilastatin

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CHAPTER 4: AMINOGLYCOSIDES AND MACROLIDES

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LONG ANSWER: Uses and Adverse Effects of Gentamicin (2017)

Mechanism of Action of Aminoglycosides

• Bind to the 30S ribosomal subunit (specifically 16S rRNA) → cause misreading of mRNA → production of aberrant, non-functional proteins → cell death
• Also disrupt bacterial cell membrane integrity (particularly at higher concentrations)
• Bactericidal and show concentration-dependent killing (higher peak = better killing)
• Post-antibiotic effect (PAE) - bacterial suppression continues for hours after drug levels drop → once-daily dosing is rational

Uses of Gentamicin

1. Gram-negative septicemia - including E. coli, Klebsiella, Proteus, Enterobacter, Serratia - often combined with beta-lactam for synergy
2. Hospital-acquired / Ventilator-associated pneumonia (Gram-negative)
3. Urinary tract infections (complicated; refractory to other drugs)
4. Endocarditis - combined with penicillin/ampicillin for synergy against Streptococcus viridans and Enterococcus
5. Pelvic inflammatory disease (with metronidazole and ampicillin)
6. Intra-abdominal infections (with metronidazole)
7. Eye infections - gentamicin eye drops for bacterial conjunctivitis, keratitis
8. Burns / Wound infections - topical cream
9. Perioperative prophylaxis in GI/GU surgery

Adverse Effects of Aminoglycosides (All shared) (2023 / 2024 / 2025)

• Accumulate in endolymph/perilymph of the inner ear → damage hair cells (irreversible)
• Vestibulotoxicity (vertigo, ataxia, nystagmus, loss of balance) - most with Streptomycin, Gentamicin
• Cochleotoxicity (tinnitus, high-frequency hearing loss → progressive deafness) - most with Neomycin, Kanamycin, Amikacin
• Exacerbated by: loop diuretics (furosemide, ethacrynic acid), pre-existing hearing loss, prolonged use

• Accumulate in proximal renal tubular cells → cell damage
• Manifests as: rising serum creatinine, reduced GFR, non-oliguric renal failure
• Most nephrotoxic: Neomycin, Tobramycin, Gentamicin
• Potentiated by: vancomycin, amphotericin B, cisplatin, NSAIDs, pre-existing renal disease
• Usually reversible on stopping drug

• At very high doses (e.g., intraperitoneal irrigation or rapid IV) → inhibit Ca²⁺ entry at neuromuscular junction → curare-like flaccid paralysis → respiratory arrest
• Reversible with IV calcium gluconate or neostigmine
• Risk highest in patients on general anesthesia or with myasthenia gravis

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Short Answer: Classify Macrolides. Mechanism + Four Uses (2022)

Classification of Macrolides

• Azithromycin (Z-pack) - longest half-life, single-dose regimens
• Clarithromycin - best CNS/intracellular penetration
• Roxithromycin, Dirithromycin

Mechanism of Action

• Bind reversibly to the 50S ribosomal subunit (23S rRNA, peptidyl transferase center)
• Block translocation of the peptidyl-tRNA → inhibit peptide chain elongation → bacteriostatic
• (At high concentrations: bactericidal against highly susceptible organisms like S. pneumoniae)

Four Uses of Macrolides

1. Community-acquired pneumonia (CAP) - Streptococcus pneumoniae, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella - macrolides cover "atypical" organisms that beta-lactams miss; azithromycin commonly used
2. Atypical pneumonia - Mycoplasma, Legionella, Chlamydophila - drugs of choice
3. Upper respiratory tract infections - pharyngitis (Group A Strep), sinusitis - alternative to penicillin in penicillin allergy
4. H. pylori eradication - clarithromycin is a component of triple therapy (clarithromycin + amoxicillin + PPI)
5. Other uses: Pertussis (whooping cough) - azithromycin; STIs (Chlamydia trachomatis) - azithromycin single 1g dose; MAC (Mycobacterium avium complex) in HIV patients; diphtheria carriers

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CHAPTER 5: ANTITUBERCULAR AND ANTILEPROSY DRUGS

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LONG ANSWER: Classify TB Drugs. RNTCP/NTEP Regimens. ADRs of First-Line Drugs. (2023 / 2024 / 2025)

Classification of Antitubercular Drugs

• Injectable agents: Amikacin, Capreomycin, Kanamycin (Group A)
• Fluoroquinolones: Levofloxacin, Moxifloxacin (DNA gyrase inhibition) - Group A
• Newer drugs: Bedaquiline (inhibits ATP synthase), Delamanid (inhibits mycolic acid synthesis), Linezolid, Clofazimine (Group B/C)
• Older second-line: Ethionamide, Prothionamide, PAS (para-aminosalicylic acid), Cycloserine

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NTEP (National TB Elimination Programme) Regimens for Drug-Susceptible TB

• 2HRZE / 4HR = 2 months HRZE + 4 months HR (total 6 months)
• All drugs given daily (not intermittent - changed from DOTS thrice-weekly)

• 2HRZE / 10HR = 2 months HRZE + 10 months HR (total 12 months)

• First send for DST (Drug Sensitivity Testing)
• Empirically: 2HRZES / 1HRZE / 5HRE or based on DST results

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Adverse Effects of First-Line Antitubercular Drugs

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Basis of Combination Therapy in TB (2025 Jan)

1. Prevention of resistance - TB bacilli exist in multiple compartments (cavities, macrophages, necrotic tissue) and in different metabolic states; each drug targets different bacterial populations; a mutant resistant to one drug is still killed by the other drugs - combined effect prevents survival of resistant mutants
2. Different bacterial populations:
   • Rapidly multiplying bacilli (cavities) → killed by INH + Rifampicin
   • Slowly multiplying/dormant (macrophages, acidic environment) → killed by Pyrazinamide
   • Persisters (all populations) → Rifampicin is most important sterilizing drug
3. Shorter course: Combination allows 6-month regimens vs. 18+ months with single drugs

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New Drugs for MDR-TB / XDR-TB (2018 / 2019) and Drugs for MDR + XDR (2024)

1. Bedaquiline (Sirturo) - diarylquinoline; inhibits mycobacterial ATP synthase → depletes energy; active against MDR and XDR-TB; FDA approved 2012; used in BPaL regimen
2. Delamanid (Deltyba) - nitroimidazole; inhibits synthesis of methoxy-mycolic acid and keto-mycolic acid in cell wall; FDA approved 2014
3. Pretomanid - nitroimidazole (similar to delamanid); used in BPaL regimen (Bedaquiline + Pretomanid + Linezolid) - approved 2019 for XDR-TB

• Levofloxacin or Moxifloxacin + Bedaquiline + Linezolid (core components)

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DOTS Regimen for Defaulters (Cat Regimen) (2019 March)

• If treated for <1 month prior: Restart full Cat 1 treatment (2HRZE/4HR)
• If defaulted after completing IP (2 months) but before CP: Resume from where left off after sputum smear
• Sputum culture and Drug Sensitivity Testing (DST) is now mandatory for all previously treated patients before restarting treatment, to identify resistance
• Retreatment with Category II (2HRZES/1HRZE/5HRE) is given only if DST not available and prior treatment confirmed

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Multidrug Therapy (MDT) of Paucibacillary Leprosy (2022)

• Paucibacillary (PB): 1-5 skin lesions; skin smear negative; fewer bacilli
• Multibacillary (MB): >5 skin lesions; skin smear positive; more bacilli

• Rifampicin 600 mg - once monthly (supervised)
• Dapsone 100 mg - daily (self-administered)
• Duration: 6 months

• Rifampicin 600 mg - monthly (supervised)
• Clofazimine 300 mg - monthly (supervised) + Clofazimine 50 mg daily
• Dapsone 100 mg - daily
• Duration: 12 months

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CHAPTER 6: ANTIFUNGAL, ANTIVIRAL, AND ANTIPROTOZOAL DRUGS

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LONG ANSWER: Classify Antimalarials. MOA, Pharmacological Actions, Uses, ADRs of Chloroquine (2022)

Classification of Antimalarial Drugs

1. 4-Aminoquinolines: Chloroquine, Hydroxychloroquine, Amodiaquine
2. 8-Aminoquinolines: Primaquine, Tafenoquine (act on liver forms + gametocytes)
3. Quinoline methanol: Quinine, Mefloquine
4. Artemisinin compounds (Sesquiterpene lactones): Artesunate, Artemether, Dihydroartemisinin
5. Antifolates:
   • DHPS inhibitors: Sulfadoxine, Dapsone
   • DHFR inhibitors: Pyrimethamine, Proguanil
   • Combinations: Sulfadoxine-Pyrimethamine (SP/Fansidar), Atovaquone-Proguanil (Malarone)
6. Others: Atovaquone, Halofantrine, Lumefantrine

• Blood schizonticidals (kill asexual erythrocytic forms - treat acute attacks): Chloroquine, Quinine, Mefloquine, Artemisinin compounds, Lumefantrine
• Tissue schizonticidals (kill liver stages - prevent relapse): Primaquine, Tafenoquine (for P. vivax/ovale hypnozoites)
• Causal prophylactics (kill hepatic pre-erythrocytic forms - prevent initial infection): Proguanil, Primaquine
• Gametocytocidals (kill sexual forms - prevent transmission): Primaquine (all species), Artemisinin compounds (P. falciparum)

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Chloroquine - Mechanism of Action

1. Accumulation in food vacuole: Chloroquine is a weak base; it passively enters the parasite's acidic food vacuole and becomes protonated (ion trapping) → concentrates 1000x in vacuole
2. Inhibits hemozoin (malaria pigment) formation: The parasite digests hemoglobin → releases free heme (toxic). Normally, the parasite polymerizes heme into insoluble hemozoin (non-toxic) via heme polymerase. Chloroquine inhibits heme polymerase → free heme accumulates → forms ferriprotoporphyrin IX-chloroquine complex → toxic to the parasite membrane → kills it

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Pharmacological Actions and Therapeutic Uses of Chloroquine

1. Chloroquine-sensitive P. vivax, P. ovale, P. malariae - drug of choice for acute attack and prophylaxis (where sensitive)
2. Chloroquine-sensitive P. falciparum (some regions)
3. Prophylaxis of malaria in chloroquine-sensitive areas (300mg base weekly)
4. Combined with Primaquine to prevent relapse in P. vivax/ovale (primaquine kills hypnozoites in liver)

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Adverse Effects of Chloroquine

• Nausea, vomiting, abdominal discomfort
• Headache, dizziness
• Pruritus (especially in dark-skinned Africans - very common; antihistamines used)
• Corneal deposits (reversible, visual disturbance - halos around lights)

• Retinopathy (chloroquine maculopathy) - most serious long-term effect; irreversible damage to retinal cells → permanent visual loss; related to total cumulative dose; requires regular ophthalmological monitoring
• Bleaching of hair
• Skin pigmentation changes (blue-black)
• Peripheral neuropathy, myopathy
• Ototoxicity (rare)
• Exacerbation of psoriasis, porphyria cutanea tarda

• Cardiac arrhythmias (QRS widening, QT prolongation), hypotension → potentially fatal
• Seizures, visual disturbances

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Q. Artemisinin - Important Features (2017)

1. Source: Derived from Artemisia annua (sweet wormwood plant); used in traditional Chinese medicine for 2000 years; isolated by Tu Youyou (Nobel Prize 2015)
2. Chemical nature: Sesquiterpene lactone with an endoperoxide bridge (trioxane ring) - this bridge is essential for activity
3. Mechanism: Activated by heme iron within the parasite's food vacuole → forms carbon-centered free radicals → alkylate parasite proteins, membranes, and hemoglobin → kill parasites
4. Spectrum: Active against ALL species of Plasmodium; most effective against P. falciparum (including multi-drug resistant); also kills gametocytes → reduces transmission
5. Speed of action: FASTEST acting antimalarial (reduces parasitemia by 10,000-fold per cycle); acts on all erythrocytic stages including ring forms (which chloroquine/quinine miss)
6. Short half-life (~1-3 hours): Cannot be used as monotherapy (rapid clearance → recrudescence); MUST be given as Artemisinin-based Combination Therapy (ACT)
7. Derivatives: Artesunate (IV/IM/oral - most water-soluble), Artemether (IM/oral - in Coartem with lumefantrine), Dihydroartemisinin (active metabolite)
8. ACT examples:
   • Artemether + Lumefantrine (Coartem) - first-line for uncomplicated falciparum malaria
   • Artesunate + Amodiaquine, Artesunate + Mefloquine, Artesunate + SP
   • IV Artesunate = drug of choice for severe/complicated falciparum malaria (replaced IV quinine)
9. Adverse effects: Minimal; GI disturbance, rare neurological effects at very high doses; generally very safe
10. No resistance (yet, for practical purposes) - though partial artemisinin resistance now reported in Southeast Asia (kelch13 mutations); hence always use in combination

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Q. Treatment / Prophylaxis of Chloroquine-Resistant Falciparum Malaria (2018 / 2023 / 2024)

Treatment of Uncomplicated Chloroquine-Resistant P. falciparum:

• Artemether + Lumefantrine (Coartem) - 6-dose regimen over 3 days; WHO/NTEP recommended
• Artesunate + Amodiaquine (ASAQ)
• Artesunate + Mefloquine (in Southeast Asia)
• Artesunate + SP (Sulfadoxine-Pyrimethamine) - where SP still sensitive

• Quinine + Doxycycline (7-day course) - still effective
• Atovaquone-Proguanil (Malarone) - well-tolerated; useful in travelers

Treatment of Severe/Complicated Falciparum Malaria:

• IV Artesunate - drug of choice (superior to IV quinine in large RCTs - AQUAMAT, SEAQUAMAT)
• If artesunate unavailable: IV Quinine + Doxycycline

Prophylaxis for Chloroquine-Resistant Areas:

• Atovaquone-Proguanil (Malarone) - once daily; start 1-2 days before, during, and 7 days after travel
• Mefloquine - once weekly; start 2-3 weeks before travel
• Doxycycline - once daily; start 1-2 days before travel

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Q. Primaquine - Rationale of Use (2025 Jan)

1. Only drug that kills hypnozoites (dormant liver stages) in P. vivax and P. ovale - thus prevents true relapses
2. Acts as a gametocytocidal agent against all Plasmodium species - kills sexual forms → reduces transmission
3. G6PD testing mandatory before use - primaquine causes dose-dependent hemolytic anemia in G6PD-deficient patients

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Q. Adverse Effects of Quinine as Antimalarial (2019 March)

1. Cinchonism (most characteristic syndrome of quinine toxicity): Tinnitus (ringing in ears), headache, nausea, vomiting, blurred vision, dizziness; occurs at therapeutic doses
2. Hypoglycemia - quinine is a potent stimulator of insulin release (especially with IV use and falciparum malaria which itself causes hypoglycemia) - monitor blood glucose
3. Cardiac effects - QT prolongation → risk of arrhythmias; hypotension (rapid IV infusion)
4. Hemolytic anemia - especially in G6PD-deficient patients; Blackwater fever (massive hemolysis → hemoglobinuria → renal failure) - rare
5. Visual and auditory toxicity at high doses - amblyopia (visual disturbances), deafness
6. Oxytocic effect - mild uterine stimulation; avoid in pregnancy except for life-threatening malaria

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Q. Drugs for Amebiasis / Metronidazole Indications (2019 Sept / 2025 Jan)

Drugs for Amebiasis

1. Luminal amebicides (act in intestinal lumen - treat asymptomatic cyst passers):
   • Diloxanide furoate (drug of choice for asymptomatic luminal amoebiasis)
   • Paromomycin (aminoglycoside - not absorbed)
   • Iodoquinol
2. Tissue amebicides (act in gut wall + extraintestinal sites):
   • Metronidazole - most important; drug of choice for invasive intestinal and extraintestinal amoebiasis (amoebic dysentery, liver abscess)
   • Tinidazole, Secnidazole, Ornidazole (similar to metronidazole; better tolerated)

• Amoebic dysentery / amoebic liver abscess: Metronidazole 400-800mg TID × 7-10 days → FOLLOWED by a luminal amebicide (diloxanide furoate) to eliminate cysts from gut
• Asymptomatic cyst passer: Diloxanide furoate alone

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Therapeutic Uses of Metronidazole (Indications)

1. Amoebiasis - intestinal and hepatic (amoebic liver abscess)
2. Giardiasis - drug of choice (Giardia lamblia)
3. Trichomoniasis - drug of choice (Trichomonas vaginalis) - treat both partners simultaneously
4. Anaerobic bacterial infections - bacteroides, Fusobacterium, Clostridium, Prevotella; used for:
   • Intra-abdominal infections (with cephalosporin/aminoglycoside)
   • Pelvic inflammatory disease
   • Aspiration pneumonia, lung abscess
   • Dental/oral infections
5. C. difficile colitis (pseudomembranous colitis) - oral metronidazole (mild-moderate); oral vancomycin or fidaxomicin preferred for severe disease
6. H. pylori eradication - triple therapy (metronidazole/amoxicillin + clarithromycin + PPI)
7. Bacterial vaginosis (Gardnerella vaginalis) - oral or topical
8. Treatment of ampicillin-induced diarrhea (C. difficile) (2019 March)

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Q. Drugs for Fungal Infections (2017)

1. Used locally (topical, skin): Clotrimazole (topical cream/lotion/powder for tinea, candidiasis)
2. Used systemically: Fluconazole (oral/IV - systemic candidiasis, cryptococcal meningitis, oropharyngeal candidiasis)

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Q. Antiretrovirals (ARVs) - NRTI and NNRTI Examples (2017)

• Zidovudine (AZT/ZDV), Lamivudine (3TC), Tenofovir (TDF), Emtricitabine (FTC), Abacavir (ABC), Stavudine, Didanosine

• Efavirenz, Nevirapine, Rilpivirine, Doravirine, Etravirine

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Q. Drugs for Preventing Vertical Transmission of HIV (Mother to Foetus) (2019 / 2022 / 2025)

• All HIV-positive pregnant women start lifelong ART (regardless of CD4 count or clinical stage)
• Preferred first-line regimen during pregnancy:
  • TDF + 3TC (or FTC) + DTG (Tenofovir + Lamivudine + Dolutegravir)
  • Or TDF + 3TC + EFV (Efavirenz - established regimen; avoid DTG in 1st trimester if neural tube defect risk is concern, though current data supports DTG use throughout pregnancy)

• Nevirapine syrup (NVP) given to newborn once daily for 6 weeks (if mother on ART) or 12 weeks (if high risk)
• AZT (Zidovudine) may be added to NVP for high-risk infants

1. Maternal ART suppresses viral load to undetectable → minimal transmission risk
2. Avoid breastfeeding (or if breastfeeding, continue maternal ART + infant NVP)
3. Caesarean section in cases of high viral load (reduces intrapartum exposure)
4. Avoid invasive procedures during labor

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CHAPTER 7: ANTHELMINTIC DRUGS

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Short Answer: Albendazole (2021)

• Binds to beta-tubulin of helminths → inhibits tubulin polymerization → disrupts microtubule formation → impairs glucose uptake by the worm → depletes glycogen stores → worm is immobilized and dies

1. Roundworm (Ascaris lumbricoides) - drug of choice
2. Hookworm (Ancylostoma, Necator) - drug of choice (with mebendazole)
3. Pinworm (Enterobius vermicularis)
4. Whipworm (Trichuris trichiura)
5. Strongyloidiasis - alternative to ivermectin
6. Hydatid disease (Echinococcus granulosus) - long-term albendazole; adjunct to surgery
7. Neurocysticercosis (Taenia solium) - with praziquantel and dexamethasone
8. Giardiasis - alternative to metronidazole
9. Lymphatic filariasis - in combination with ivermectin or DEC

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Q. Two Uses of Ivermectin (2017)

1. Onchocerciasis (River blindness) - drug of choice; kills microfilariae of Onchocerca volvulus; given as annual/biannual single dose in mass drug administration programs
2. Lymphatic filariasis - used in combination with albendazole or DEC; kills microfilariae of Wuchereria bancrofti and Brugia
3. Strongyloidiasis - drug of choice (Strongyloides stercoralis)
4. Scabies (oral ivermectin) - especially crusted (Norwegian) scabies
5. Head lice (Pediculosis) - topical or oral

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Q. Drugs for Hookworm Infestation (2021)

1. Albendazole 400mg single dose - also covers Ascaris, pinworm
2. Mebendazole 100mg BD × 3 days (or 500mg single dose) - alternative
3. Pyrantel pamoate (depolarizing neuromuscular blocker of helminths)

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