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QUICK REFERENCE INDEX

GASTROINTESTINAL SYSTEM (Q1-21)

RESPIRATORY SYSTEM (Q1-13)

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• Questions asking to "Define X + Classify + Discuss Drug Y" follow a pattern: Definition (1-2 marks) → Classification with examples (2-3 marks) → Mechanism of Action (3 marks) → Therapeutic Uses (2 marks) → Adverse Effects (2 marks) = 10 marks
• Always write drug names in both generic and class names
• For adverse effects, always mention the MOST IMPORTANT/UNIQUE ones first (e.g., EPR for metoclopramide, antiandrogenic effects for cimetidine, constipation for aluminium hydroxide)
• ORS question always comes - memorize the exact composition (Na+ 75, K+ 20, Cl- 65, Citrate 10, Glucose 75, Osmolarity 245)

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CNS PHARMACOLOGY - ALL 19 LONG ANSWER QUESTIONS

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UNIT I - ANTIEPILEPTIC DRUGS

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Q1. Classify antiepileptic drugs. Describe Phenytoin - mechanism of action, pharmacokinetics, therapeutic uses, adverse effects, and drug interactions.

Classification of Antiepileptic Drugs (AEDs)

• Hydantoins: Phenytoin, Fosphenytoin
• Barbiturates: Phenobarbitone, Primidone
• Iminostilbenes: Carbamazepine, Oxcarbazepine
• Valproic acid: Sodium Valproate
• Succinimides: Ethosuximide
• Benzodiazepines: Diazepam, Clonazepam, Lorazepam, Clobazam
• Newer drugs: Lamotrigine, Levetiracetam, Gabapentin, Pregabalin, Topiramate, Vigabatrin, Zonisamide

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PHENYTOIN (Diphenylhydantoin)

Mechanism of Action

• Neurons fire by opening sodium (Na+) channels rapidly.
• Phenytoin selectively blocks voltage-gated Na+ channels in the inactivated (closed) state.
• It prolongs the inactivated state of Na+ channels → slows recovery → reduces the ability of neurons to fire at high frequencies.
• This is called "use-dependent" or "frequency-dependent" blockade - it preferentially blocks rapidly firing (epileptic) neurons without affecting normal neurons.
• Result: Stabilizes neuronal membranes, prevents spread of seizure discharge.
• At high concentrations: Also inhibits Ca2+ channels and modulates GABA.

Simple way to remember: "Phenytoin locks the sodium door so the neuron can't keep firing repeatedly."

Pharmacokinetics (Very Important - Non-linear kinetics!)

Key point for exam: Phenytoin shows Michaelis-Menten (non-linear/zero-order) kinetics at therapeutic doses. This means even a small dose increase can suddenly cause toxic levels - making plasma level monitoring mandatory.

Therapeutic Uses

1. Generalized tonic-clonic seizures - drug of choice (with valproate)
2. Partial (focal) seizures - simple and complex
3. Status epilepticus - IV phenytoin or fosphenytoin (given after IV benzodiazepines)
4. Post-neurosurgical seizure prophylaxis
5. Trigeminal neuralgia (second-line after carbamazepine)
6. Cardiac arrhythmias - specifically digoxin-induced ventricular arrhythmias (rarely used now; superseded by lignocaine/amiodarone)
7. NOT effective for: Absence seizures (may worsen them), myoclonic seizures

Adverse Effects

1. Gingival hyperplasia (gum overgrowth) - ~20% of patients; due to altered collagen metabolism; characteristic adverse effect of phenytoin; prevented by good oral hygiene
2. Hirsutism (increased body/facial hair) - especially troublesome in women
3. Coarsening of facial features
4. Megaloblastic anaemia - folate deficiency (reduces folate absorption + increases folate metabolism); treated with folic acid
5. Osteomalacia - induces CYP enzymes → increases Vitamin D metabolism → reduces calcium absorption; treated with Vit D
6. Peripheral neuropathy - with long-term use

1. Nystagmus - first sign of toxicity (plasma level >20 mcg/mL)
2. Ataxia (loss of balance) - level >30 mcg/mL
3. Mental confusion, diplopia - level >40 mcg/mL
4. Encephalopathy, coma - very high levels

1. Skin rashes - maculopapular; rarely Stevens-Johnson syndrome
2. Hepatotoxicity (rare)
3. Lymphadenopathy

1. Cardiovascular toxicity - hypotension, bradycardia, cardiac arrhythmias (due to propylene glycol solvent); must give slowly (<50 mg/min)
2. Purple glove syndrome - local thrombophlebitis at IV site

1. Fetal hydantoin syndrome - cleft palate, cardiac defects, facial abnormalities, nail/digital hypoplasia; Category D in pregnancy

Drug Interactions (Phenytoin is a major CYP enzyme INDUCER)

• Oral contraceptive pills (OCP) → contraceptive failure
• Warfarin → reduced anticoagulation → clotting risk
• Corticosteroids → reduced effect
• Cyclosporine → transplant rejection risk
• Digoxin → reduced levels

• Cimetidine, Isoniazid, Fluconazole, Sulphonamides (inhibit CYP2C9)
• Valproate (displaces phenytoin from protein binding + inhibits metabolism)

• Carbamazepine, Phenobarbitone (induce metabolism)
• Rifampicin

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Q2. Describe Sodium Valproate - mechanism of action, pharmacokinetics, therapeutic uses, adverse effects, and precautions.

Sodium Valproate (Valproic Acid)

Think of valproate as the "broad spectrum" antiepileptic - it works in almost all types of epilepsy.

Mechanism of Action (Multiple mechanisms - valproate's strength)

1. Na+ channel blockade (like phenytoin) - reduces repetitive firing
2. Potentiates GABA (inhibitory neurotransmitter):
   • Inhibits GABA transaminase (the enzyme that breaks down GABA) → increases GABA levels
   • Enhances GABA synthesis (activates glutamic acid decarboxylase)
   • Increases GABA release
3. Blocks T-type Ca2+ channels in thalamus (like ethosuximide) → effective for absence seizures
4. Reduces glutamate excitability

Memory tip: Valproate = "GABA booster + Na channel blocker + Ca channel blocker" = Broad spectrum drug

Pharmacokinetics

Therapeutic Uses - BROAD SPECTRUM

1. ALL types of epilepsy:
   • Generalized tonic-clonic seizures
   • Absence seizures - drug of choice (with ethosuximide)
   • Myoclonic seizures - drug of choice
   • Partial seizures
   • Juvenile myoclonic epilepsy - drug of choice
2. Bipolar disorder (Mood stabilizer) - especially acute mania and maintenance
3. Migraine prophylaxis - reduces frequency of attacks
4. Neuropathic pain (adjunct)
5. Status epilepticus (IV valproate - alternative to phenytoin)

Adverse Effects

1. Nausea, vomiting, GI upset - take with food; enteric-coated forms reduce this
2. Increased appetite and weight gain

Precautions

• Monitor LFTs before and during treatment (hepatotoxicity)
• Monitor CBC (thrombocytopenia)
• Avoid in liver disease
• Avoid/caution in women of childbearing age - prescribe folic acid 5 mg if essential
• Do NOT stop abruptly
• Watch for drug interactions (valproate inhibits CYP enzymes - raises levels of phenobarbitone, lamotrigine)

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Q3. Describe the management of Status Epilepticus. Discuss the drugs used and their rationale.

Status Epilepticus (SE)

Step-by-Step Management

• ABC (Airway, Breathing, Circulation)
• Oxygen, IV access, blood glucose
• Check glucose: If hypoglycemia → IV 50% dextrose

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"BZD is the FASTEST way to stop a seizure"

• Benzodiazepines enhance GABA activity at GABA-A receptors → open Cl- channels → hyperpolarize neurons → rapidly terminate seizures
• Work within 1-3 minutes
• Lorazepam preferred (longer duration of action 12-24 hrs vs. diazepam 20-30 min)
• Rectal diazepam (Diazepam rectal) - used in children, community settings when IV not available
• Midazolam IM/intranasal - if IV access not available (onset 5 min)

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• Blocks Na+ channels → prevents sustained repetitive firing
• Fosphenytoin is water-soluble prodrug of phenytoin - safer IV route (less cardiovascular toxicity, can give faster at 150 PE/min)
• Both require cardiac monitoring during infusion (hypotension, arrhythmias)
• Phenytoin: Give in SALINE only (precipitates in dextrose)

• IV Valproate 30 mg/kg - safe in children, no cardiovascular side effects, good for absence/myoclonic SE
• IV Levetiracetam - newer, well-tolerated, no cardiac monitoring needed

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• IV Phenobarbitone 20 mg/kg at 100 mg/min (effective but causes heavy sedation)
• IV Anaesthetic agents:
  • Propofol (drug of choice for refractory SE)
  • Thiopentone sodium (barbiturate anaesthetic)
  • Midazolam infusion
  • Ketamine (NMDA antagonist - increasing use)
• All require mechanical ventilation + EEG monitoring

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Q4. Classify antiepileptic drugs and discuss the pharmacological treatment of different types of epilepsy.

Pharmacological Treatment by Seizure Type

Memory aid: "Carbamazepine and Phenytoin are SODIUM channel blockers - NEVER use for myoclonic or absence seizures (they worsen these)." Valproate is SAFE for ALL types.

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UNIT II - OPIOID ANALGESICS

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Q5. Classify opioid analgesics. Describe Morphine - mechanism of action, pharmacological actions, therapeutic uses, adverse effects, contraindications, and toxicity.

Classification of Opioid Analgesics

• Natural: Morphine, Codeine (from opium poppy - Papaver somniferum)
• Semi-synthetic: Heroin (diacetylmorphine), Oxycodone, Hydromorphone, Buprenorphine, Nalbuphine
• Synthetic: Pethidine (Meperidine), Fentanyl, Methadone, Tramadol, Pentazocine

• Pure agonists: Morphine, Codeine, Pethidine, Fentanyl, Methadone, Tramadol
• Partial agonists: Buprenorphine (mu partial agonist)
• Mixed agonist-antagonists: Pentazocine, Nalbuphine, Butorphanol (kappa agonist + mu antagonist)
• Pure antagonists: Naloxone, Naltrexone, Methylnaltrexone

• Strong: Morphine, Fentanyl, Pethidine, Methadone
• Moderate: Codeine, Tramadol, Oxycodone
• Mild: Dextropropoxyphene

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MORPHINE (Prototype Opioid)

Mechanism of Action

Think: Morphine mimics the brain's own painkillers (endorphins)

• Activates opioid receptors (G-protein coupled receptors):
  • Mu (μ) receptors - mainly responsible for: analgesia, euphoria, respiratory depression, dependence, miosis, constipation, decreased GI motility
  • Kappa (κ) receptors - analgesia, sedation, dysphoria, miosis
  • Delta (δ) receptors - analgesia, mood modulation
• At receptor level (Gi-coupled):
  1. Reduces cAMP → reduced neuronal excitability
  2. Opens K+ channels → hyperpolarization → reduced firing
  3. Closes voltage-gated Ca2+ channels → reduced neurotransmitter release
• In pain pathways:
  • Spinal cord: Reduces substance P release → reduces pain transmission
  • Brain (periaqueductal gray, thalamus): Activates descending inhibitory pathways

Pharmacological Actions (System by System)

1. Analgesia - raises pain threshold; reduces pain perception and emotional response to pain. Works on both acute and chronic pain; visceral pain better than somatic pain.
2. Euphoria/Dysphoria - intense feeling of well-being → contributes to abuse
3. Sedation and drowsiness
4. Respiratory depression - reduces sensitivity of respiratory center to CO2 → MOST DANGEROUS effect; dose-dependent
5. Miosis (pin-point pupils) - stimulates Edinger-Westphal nucleus of oculomotor nerve; diagnostic sign of opioid toxicity; does NOT develop tolerance
6. Suppression of cough (antitussive) - acts on cough center in medulla
7. Nausea and vomiting - stimulates CTZ (chemoreceptor trigger zone)
8. Truncal rigidity at high doses (reduces cough in anesthesia)

Therapeutic Uses

1. Severe pain - post-operative pain, trauma, cancer pain (step 3 of WHO analgesic ladder), MI pain (IV morphine - reduces pain and anxiety)
2. Acute pulmonary edema - IV morphine relieves breathlessness by: vasodilation (reduces preload), sedation, analgesia (reduces anxiety)
3. Dyspnoea in terminal illness/cancer
4. Preanaesthetic medication - reduces anxiety, provides sedation
5. Cough suppression - codeine preferred (weaker opioid)
6. Diarrhea (codeine, loperamide preferred)
7. Balanced anesthesia (fentanyl preferred for intraoperative use)
8. Intrathecal/Epidural - post-operative analgesia with minimal systemic side effects

Adverse Effects

1. Nausea, vomiting (CTZ stimulation)
2. Constipation (most common; no tolerance develops)
3. Respiratory depression (dose-related; most dangerous)
4. Sedation, drowsiness, mental clouding
5. Urinary retention
6. Pruritus (histamine release; especially with IV/spinal morphine)
7. Miosis (pin-point pupils)
8. Tolerance (need increasing doses for same effect)
9. Physical and psychological dependence (addiction)
10. Withdrawal syndrome on abrupt discontinuation

Contraindications

1. Head injury, raised intracranial pressure (ICP) - CO2 retention from respiratory depression causes cerebral vasodilation → raises ICP further; also miosis masks neurological assessment
2. Bronchial asthma - bronchoconstriction (histamine release) + respiratory depression
3. Hypothyroidism (myxedema) - enhanced respiratory depression
4. Hepatic failure - reduced metabolism → accumulation
5. Renal failure - accumulation of active metabolite morphine-6-glucuronide
6. Acute pancreatitis, biliary colic - biliary spasm worsens pain
7. Labor - neonatal respiratory depression (use cautiously; have naloxone ready)
8. Pheochromocytoma - histamine-induced catecholamine release
9. Patients on MAO inhibitors (serotonin syndrome with pethidine; morphine also dangerous)

Toxicity (Opioid Overdose)

"Coma + Pin-point pupils (miosis) + Respiratory depression"

1. Airway, Breathing - secure airway, O2, assisted ventilation
2. Naloxone (Narcan) - specific antidote:
   • Pure opioid antagonist (competes at mu receptors)
   • IV 0.4-2 mg; repeat every 2-3 minutes (up to 10 mg)
   • Short half-life (30-90 min) → may need repeated doses or infusion (as morphine's half-life is longer)
   • Precipitates acute withdrawal in dependent patients
3. Gastric lavage (if oral ingestion, alert patient)
4. Supportive care

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Q6. Describe acute opioid poisoning. Discuss clinical features and management.

This is covered within Q5 (Toxicity section) above in detail. Expanded version:

Acute Opioid Poisoning

Clinical Features

1. Coma (deep unconsciousness, unresponsive to stimuli)
2. Pin-point pupils (miosis) - characteristic; bilateral; even in coma
3. Respiratory depression - slow, shallow, irregular breathing → apnea → death from respiratory failure

• Bradycardia, hypotension
• Hypothermia, cold clammy skin
• Cyanosis (lips, nail beds - due to hypoxia)
• Pulmonary edema (non-cardiogenic)
• Muscle flaccidity
• Urinary retention
• Decreased bowel sounds (GI depression)
• Death from respiratory failure + aspiration pneumonia

Management

• Open airway, position patient
• Oxygen via face mask (100%)
• IV access, monitor ECG, SpO2, BP

• IV Naloxone 0.4-2 mg (adult)
• Repeat every 2-3 minutes if no response (up to 10 mg total)
• Response: Pupil dilation, respiratory rate increases, consciousness returns (within 1-2 minutes)
• Infusion: Since naloxone half-life (30-90 min) << morphine half-life → give 2/3 of effective reversal dose as hourly infusion
• In neonatal opioid depression: Naloxone 0.01 mg/kg IV/IM
• Caution: Naloxone precipitates acute withdrawal in opioid-dependent patients (agitation, tachycardia, seizures, vomiting)

• Assisted ventilation (intubation if GCS <8 or SpO2 not maintained)
• IV fluids for hypotension
• Treat pulmonary edema (diuretics, positive pressure ventilation)
• Gastric lavage (if oral, conscious/intubated patient)
• Activated charcoal (if oral within 1 hour)
• Maintain body temperature (warming blankets)

• Continuous monitoring for 24 hours (risk of re-narcotization as naloxone wears off)

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Q7. Classify opioid antagonists and discuss their therapeutic uses.

Classification of Opioid Antagonists

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

• Methylnaltrexone (Relistor) - SC/oral
• Naloxegol - oral
• Alvimopan - oral (GI only)

• Buprenorphine (mu partial agonist, kappa antagonist)
• Nalbuphine, Pentazocine (kappa agonists, mu antagonists)

Therapeutic Uses

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UNIT III - ANTIPSYCHOTIC DRUGS

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Q8. Classify antipsychotic drugs. Describe Chlorpromazine - mechanism of action, pharmacological actions, therapeutic uses, adverse effects, and precautions.

Classification of Antipsychotic Drugs

• Low potency: Chlorpromazine (CPZ), Thioridazine
• Medium potency: Trifluoperazine
• High potency: Fluphenazine, Perphenazine

• Clozapine (prototype - "gold standard" for refractory schizophrenia)
• Risperidone, Olanzapine, Quetiapine, Ziprasidone, Aripiprazole, Amisulpride, Paliperidone

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CHLORPROMAZINE (CPZ) - Prototype Typical Antipsychotic

Mechanism of Action

"CPZ is a DIRTY DRUG - it blocks everything!"

Pharmacological Actions

1. Antipsychotic: Reduces positive symptoms (hallucinations, delusions, thought disorder, agitation) in schizophrenia
2. Sedation (H1 blockade) - strong; not the same as sleep
3. Antiemetic (D2 blockade at CTZ)
4. Reduces body temperature (poikilothermia - body temp follows environment)
5. Catalepsy (waxy flexibility) at high doses
6. Does NOT cause analgesia but potentiates analgesics

Therapeutic Uses

1. Schizophrenia - reduces positive symptoms (hallucinations, delusions, agitation); less effective for negative symptoms
2. Acute mania (adjunct to lithium/valproate)
3. Antiemetic - drug/radiation-induced nausea; NOT motion sickness (requires anticholinergic)
4. Premedication before anesthesia - sedation, antiemetic, potentiates analgesia
5. Hiccups (intractable hiccups) - chlorpromazine specifically approved for this
6. Anxiety and agitation in psychotic patients
7. Potentiation of analgesics and anesthetics - reduces narcotic dose needed
8. Tetanus (muscle rigidity management - adjunct)
9. Hypothermia (induces deliberate hypothermia in surgery - "lytic cocktail")

Adverse Effects

Memory tip for EPR timing: "ADD To Tardive" = Acute dystonia → Akathisia → Drug-induced Parkinsonism → Tardive dyskinesia (chronological order)

• Sedation (strong with CPZ - low potency phenothiazines)
• Orthostatic hypotension (alpha blockade) - especially on first dose or IV use
• Anticholinergic effects - dry mouth, constipation, urinary retention, blurred vision, tachycardia
• Hyperprolactinaemia - galactorrhoea, amenorrhoea, gynecomastia
• Weight gain (H1 blockade + 5-HT blockade)
• Cholestatic jaundice (hypersensitivity reaction)
• Photosensitivity - sunburn; reddish-purple skin discolouration with chronic use
• Corneal and lens deposits (thioridazine → retinal pigmentation/pigmentary retinopathy; risk of blindness)
• Cardiac: QT prolongation (especially thioridazine → withdrawn for this)
• Neuroleptic Malignant Syndrome (NMS) - rare but life-threatening:
  • Features: Fever (hyperthermia >40°C), severe muscle rigidity, altered consciousness, autonomic instability (tachycardia, BP fluctuations)
  • Treatment: STOP antipsychotic, IV dantrolene (muscle relaxant), bromocriptine (D2 agonist), supportive care (cooling, IV fluids)
• Agranulocytosis - rare with typical; common with clozapine

Precautions

• Avoid IV injection rapidly (hypotension)
• Use with caution in epilepsy (lowers seizure threshold)
• Avoid in comatose patients or with CNS depressants (additive sedation)
• Caution in liver disease, BPH, glaucoma, cardiac disease
• Protect from sun (photosensitivity)
• Monitor blood count (rare agranulocytosis)
• Do not abruptly discontinue

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Q9. Classify atypical antipsychotic drugs. Discuss their advantages, therapeutic uses, and adverse effects.

Why "Atypical"?

1. Blocking 5-HT2A receptors in addition to D2 receptors (5-HT2A blockade partially reverses D2-related EPR and improves negative symptoms)
2. Fewer or no extrapyramidal side effects at therapeutic doses
3. Effective against BOTH positive AND negative symptoms
4. Less hyperprolactinaemia (except risperidone/paliperidone)

Advantages Over Typical Antipsychotics

Therapeutic Uses

1. Schizophrenia (first-line; most guidelines recommend atypicals as first choice)
2. Refractory schizophrenia - Clozapine (when 2+ antipsychotics fail)
3. Bipolar disorder - Olanzapine, Quetiapine (acute mania + maintenance)
4. Major depression with psychotic features - augmentation with Quetiapine, Aripiprazole
5. Autism - Risperidone, Aripiprazole (FDA approved for irritability in autism)
6. Tourette syndrome - Haloperidol, Pimozide
7. Dementia-related agitation (cautiously; increased mortality risk in elderly)
8. Borderline personality disorder (adjunct)

Adverse Effects of Atypical Antipsychotics

• Weight gain - olanzapine and clozapine cause the most weight gain
• Hyperglycaemia, diabetes mellitus (type 2)
• Dyslipidemia (raised triglycerides, reduced HDL)
• This metabolic syndrome increases cardiovascular risk significantly

• Agranulocytosis - 1-2% (potentially fatal); mandatory regular WBC monitoring (weekly for 6 months, then fortnightly)
• Seizures (lowers seizure threshold; dose-related)
• Hypersalivation (sialorrhoea) - paradoxical (M4 receptor agonism)
• Myocarditis, cardiomyopathy (rare but serious)
• Sedation, weight gain (extensive)

• Most likely atypical to cause EPR and hyperprolactinaemia (at higher doses)

• Cataracts (lens opacity) - annual slit lamp exam recommended
• Sedation, orthostatic hypotension

• QTc prolongation - avoid in cardiac patients

• Partial D2 agonist (unique); akathisia; nausea; weight-neutral

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Q10. Compare typical and atypical antipsychotic drugs.

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UNIT IV - ANTIDEPRESSANT DRUGS

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Q11. Classify antidepressant drugs. Discuss SSRIs - mechanism of action, therapeutic uses, adverse effects, and advantages over older antidepressants.

Classification of Antidepressants

• Tertiary amines: Amitriptyline, Imipramine, Clomipramine, Doxepin
• Secondary amines: Nortriptyline, Desipramine

• Irreversible non-selective: Phenelzine, Tranylcypromine, Isocarboxazid
• Reversible MAO-A selective (RIMA): Moclobemide

• NaSSA: Mirtazapine
• NDRI: Bupropion (Wellbutrin)
• SARI: Trazodone
• Melatonin agonist: Agomelatine
• SMS (Serotonin modulator and stimulator): Vortioxetine

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SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs)

"SSRIs keep serotonin working longer in the synapse"

Mechanism of Action

• Normally after serotonin (5-HT) is released into the synapse, it is pumped back into the presynaptic neuron by the SERT (serotonin transporter) - a reuptake pump.
• SSRIs selectively block SERT → serotonin cannot be reuptaken → it accumulates in the synapse → prolonged activation of postsynaptic 5-HT receptors.
• Over 2-4 weeks of continuous therapy: Desensitization of presynaptic 5-HT1A autoreceptors occurs → further increases serotonin transmission.
• This explains the 2-4 week delay before therapeutic antidepressant effects appear (even though the reuptake is blocked from day 1).

Simple analogy: "SERT is a vacuum cleaner pulling serotonin back. SSRIs break the vacuum cleaner - serotonin stays in the synapse longer and does its job better."

Therapeutic Uses

1. Major depressive disorder (MDD) - FIRST-LINE (drug of choice for most patients)
2. Anxiety disorders:
   • Generalized anxiety disorder (GAD) - Escitalopram, Paroxetine
   • Panic disorder - Paroxetine, Fluoxetine, Sertraline
   • Social anxiety disorder - Sertraline, Paroxetine
   • OCD (Obsessive-Compulsive Disorder) - Fluoxetine, Sertraline, Fluvoxamine (DOC for OCD), Paroxetine
   • PTSD (Post-traumatic stress disorder) - Sertraline (FDA approved), Paroxetine
3. Bulimia nervosa - Fluoxetine (only FDA-approved for this)
4. Premenstrual dysphoric disorder (PMDD) - Fluoxetine, Sertraline
5. Premature ejaculation - Dapoxetine (short-acting SSRI specifically for this)
6. Neuropathic pain (adjunct)
7. Hot flushes in menopausal women (non-hormonal)

Adverse Effects

1. GI effects (most common, especially early):
   • Nausea, diarrhoea, vomiting, anorexia
   • Take after food; improves after 1-2 weeks
2. Sexual dysfunction - reduced libido, anorgasmia, delayed ejaculation (very common ~30-40%; most troublesome; persists)
3. Insomnia, agitation, restlessness (especially fluoxetine - most activating)
4. Headache
5. Weight changes - initial weight loss → long-term weight gain (paroxetine gains most weight)
6. Serotonin syndrome (when combined with other serotonergic drugs - MAOIs, tramadol, triptans):
   • Triad: Altered mental status + Autonomic instability (hyperthermia, tachycardia, sweating) + Neuromuscular abnormalities (tremor, clonus, hyperreflexia)
   • Treatment: STOP drug, cyproheptadine (5-HT antagonist), supportive care
7. Hyponatraemia (SIADH - inappropriate ADH secretion) - especially in elderly
8. Bleeding tendency - serotonin is required for platelet activation; SSRIs reduce platelet serotonin → increased bleeding risk; caution with NSAIDs/warfarin
9. QTc prolongation - Citalopram and Escitalopram at high doses
10. Suicidal ideation (Black box warning in <25 years, especially early treatment - first 1-2 weeks; monitor closely)
11. Discontinuation syndrome (abrupt withdrawal): Dizziness, sensory disturbances ("electric shocks/brain zaps"), irritability, nausea; especially with paroxetine (shortest half-life); Fluoxetine has least discontinuation syndrome (longest half-life ~4-6 days; self-tapering)

Advantages Over Older Antidepressants (TCAs and MAOIs)

Bottom line: SSRIs are the first-line choice because they are equally effective but FAR SAFER than TCAs and MAOIs.

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Q12. Classify atypical antidepressants and discuss their mechanism of action, therapeutic uses, and adverse effects.

Atypical Antidepressants

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1. Mirtazapine (NaSSA - Noradrenergic and Specific Serotonergic Antidepressant)

• Blocks alpha-2 adrenergic autoreceptors and heteroreceptors → removes the "brake" on norepinephrine and serotonin release → increases both NE and 5-HT in synapse.
• Blocks 5-HT2 and 5-HT3 receptors (but NOT 5-HT1A) → this is why it has no sexual dysfunction or GI side effects (unlike SSRIs).
• Blocks H1 histamine receptors → strong sedation.
• Does NOT inhibit reuptake.

• Depression, especially with:
  • Insomnia (uses sedation therapeutically; give at night)
  • Weight loss/anorexia (increases appetite)
  • Anxiety
  • Vomiting (5-HT3 blockade)
• Prevention of chemotherapy-induced nausea (5-HT3 blockade)

• Sedation (most common; due to H1 blockade; actually a benefit in insomnia)
• Weight gain and increased appetite (H1 blockade)
• Dry mouth (mild anticholinergic)
• NO sexual dysfunction
• NO GI side effects (5-HT3 blockade)
• Agranulocytosis (very rare)

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2. Bupropion (NDRI - Norepinephrine-Dopamine Reuptake Inhibitor)

• Blocks reuptake of norepinephrine AND dopamine (NOT serotonin).

• Major depression (comparable to SSRIs in efficacy)
• Smoking cessation (Zyban - reduces nicotine craving via dopamine pathways)
• ADHD (off-label; increases dopamine)
• Depression in patients with sexual dysfunction on SSRIs (bupropion has NO sexual side effects)
• Depression with weight gain concerns (weight-neutral to weight loss)

• Seizures (dose-related; lowers seizure threshold; contraindicated in epilepsy, bulimia nervosa, eating disorders)
• Insomnia, agitation, restlessness, headache
• Dry mouth
• NO sexual dysfunction
• NO weight gain (may cause weight loss)
• NO sedation

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3. Trazodone (SARI - Serotonin Antagonist and Reuptake Inhibitor)

• Inhibits serotonin reuptake + blocks 5-HT2A receptors and H1 receptors.

• Depression with insomnia (strong sedative - good for sleep)
• Often used at LOW doses for insomnia even in non-depressed patients
• Sexual dysfunction caused by SSRIs

• Sedation (major; useful in insomnia)
• Priapism (prolonged painful penile erection) - rare but characteristic; emergency urological condition
• Orthostatic hypotension
• Dry mouth

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4. Venlafaxine / Duloxetine (SNRI)

• Major depression
• GAD, panic disorder, social anxiety (venlafaxine, duloxetine)
• Neuropathic pain, fibromyalgia, diabetic neuropathy - duloxetine (FDA approved)
• Stress urinary incontinence - duloxetine
• Hot flushes in menopausal women

• Nausea, sweating, dry mouth, dizziness
• Hypertension (NE effect) - especially venlafaxine at high doses; monitor BP
• Sexual dysfunction (serotonergic)
• Discontinuation syndrome

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5. Agomelatine

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Q13. Write a detailed note on MAO Inhibitors - classification, mechanism of action, therapeutic uses, adverse effects, and drug interactions.

MAO Inhibitors (MAOIs)

"MAOIs boost monoamines by stopping their destruction"

• MAO-A - metabolizes norepinephrine, serotonin, tyramine (in gut/liver)
• MAO-B - metabolizes dopamine, phenylethylamine, tyramine

Classification

Mechanism of Action

• Inhibit MAO enzyme in nerve terminals → reduced breakdown of NE, 5-HT, dopamine → increased monoamine levels in synapse → antidepressant effect.
• Irreversible MAOIs: Form covalent bond with MAO → enzyme is permanently inactivated until new enzyme is synthesized (2+ weeks after stopping drug → reason for 2-week washout period before starting other drugs).
• Moclobemide (RIMA): Reversibly inhibits MAO-A; safer tyramine profile.
• Selegiline: At low doses, selectively inhibits MAO-B → used in Parkinson's disease (preserves dopamine); at high doses, also inhibits MAO-A → antidepressant use.

Therapeutic Uses

1. Treatment-resistant depression - when SSRIs/TCAs fail
2. Atypical depression (depression with: mood reactivity, weight gain, hypersomnia, leaden paralysis, interpersonal rejection sensitivity) - MAOIs may be superior
3. Panic disorder, social phobia (phenelzine)
4. Parkinson's disease - Selegiline + Rasagiline (MAO-B inhibitors; slow dopamine breakdown; neuroprotective)
5. Bulimia nervosa, PTSD (phenelzine; less commonly used)

Adverse Effects

1. Insomnia, agitation
2. Orthostatic hypotension (most common)
3. Weight gain
4. Sexual dysfunction
5. Peripheral neuropathy (pyridoxine deficiency - phenelzine; treat with B6)

This is the most important MAOI adverse effect in exams!

• Normally, dietary tyramine (in aged cheese, red wine, cured meats, fermented foods) is metabolized by MAO-A in the gut wall and liver before reaching systemic circulation.
• MAOIs block this first-pass metabolism → tyramine enters systemic circulation → displaces NE from nerve terminals → massive NE release → severe, potentially fatal hypertensive crisis.
• Features: Severe pounding headache, palpitations, flushing, neck stiffness, hypertension (BP can reach >200/120), intracranial haemorrhage, death.
• Treatment: IV Phentolamine (alpha-blocker) or IV Nifedipine/Labetalol.
• Prevention: Strict low-tyramine diet while on MAOIs (and 2 weeks after stopping).

Drug Interactions (Potentially Fatal)

Washout rules: Stop MAOI → wait 14 days before starting SSRI. Stop fluoxetine (long half-life) → wait 5 WEEKS before starting MAOI.

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Q14. Compare Tricyclic Antidepressants (TCAs) and SSRIs.

Bottom line: TCAs and SSRIs are equally effective for depression but SSRIs win on SAFETY, TOLERABILITY, and BREADTH of use.

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UNIT V - MOOD STABILIZERS

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Q15. Describe Lithium - mechanism of action, pharmacological effects, therapeutic uses, adverse effects, toxicity, monitoring, and management of toxicity.

LITHIUM (Prototype Mood Stabilizer)

"Lithium is the gold standard for Bipolar Disorder - but it's a double-edged sword: incredibly effective but needs careful monitoring"

Mechanism of Action

1. Inositol Depletion Hypothesis (Most Important):
   • Lithium inhibits inositol monophosphatase and inositol polyphosphate 1-phosphatase enzymes.
   • These enzymes are needed to recycle inositol (for the phosphatidylinositol second messenger system - IP3/DAG pathway).
   • Lithium blocks inositol recycling → depletes free inositol → reduces IP3/DAG signaling → dampens overactive neuronal transmission in mania.
   • This effect is "use-dependent" - affects most those neurons firing most rapidly (like in mania).
2. Protein Kinase C (PKC) inhibition - reduces neuronal excitability
3. GSK-3β (Glycogen Synthase Kinase-3β) inhibition - neuroprotective; mood-stabilizing
4. Increases serotonin synthesis and release - contributes to antidepressant effect
5. Mimics Na+ in some cells (similar ionic radius) → alters Na+/K+ transport → reduces neuronal hyperexcitability

Pharmacological Effects

• Antimanic - reduces symptoms of mania in 7-14 days
• Antidepressant - prevents depressive episodes (less effective for acute depression)
• Mood stabilizer - prevents BOTH manic and depressive recurrences in bipolar disorder
• Anti-suicidal - reduces suicidal behavior in bipolar and major depression
• No sedation, no tolerance, no dependence

Therapeutic Uses

1. Acute mania - treats current manic episode (onset 7-14 days; antipsychotics/BZD used for rapid control meanwhile)
2. Maintenance/Prophylaxis in Bipolar Disorder (Type I & II) - drug of choice; prevents recurrences of BOTH mania and depression
3. Augmentation in treatment-resistant depression (add to antidepressant)
4. Cluster headache prophylaxis
5. Neutropenia - lithium stimulates granulopoiesis (increases WBC count)
6. SIADH - causes nephrogenic diabetes insipidus → reduces free water retention

Adverse Effects

1. Fine tremor of hands (most common; dose-related; treat with propranolol)
2. Polyuria and polydipsia (nephrogenic diabetes insipidus - reduces renal response to ADH)
3. Weight gain (increased appetite)
4. Nausea, vomiting, diarrhea (take with food)
5. Hypothyroidism (common with long-term use - lithium inhibits thyroid hormone synthesis and release); check TFTs regularly; treat with levothyroxine if needed
6. Goitre (due to compensatory TSH rise)
7. Acne, psoriasis exacerbation
8. Hair loss (alopecia)
9. Metallic taste in mouth
10. Oedema (ankle)
11. Cognitive dulling (memory issues - "cognitive blunting")
12. Leukocytosis (mild; benign - WBC 10,000-14,000)

• Ebstein's anomaly (downward displacement of tricuspid valve) - cardiac malformation; Category D in first trimester

Lithium Toxicity

"Lithium is a drug with one of the narrowest therapeutic windows in medicine"

• Dehydration (vomiting, diarrhea, exercise, hot weather) → reduced renal blood flow → increased Li reabsorption
• Salt restriction (Na+ depletion → kidneys compensate by reabsorbing more Na+/Li+)
• NSAIDs (reduce GFR, increase Li retention - most common drug interaction)
• Thiazide diuretics (reduce NaCl reabsorption → kidneys reabsorb more Li+; can raise levels by 50%)
• ACE inhibitors, ARBs (reduce renal clearance of Li)
• Loop diuretics (less dangerous; Na+ loss doesn't proportionally increase Li+ retention as much)

Monitoring of Lithium

Management of Lithium Toxicity

1. STOP lithium immediately
2. IV fluids (Normal saline) - rapidly rehydrate; saline loading promotes lithium excretion
3. NO thiazides (worsen lithium retention)
4. Hemodialysis - definitive treatment for severe toxicity (Li >2.5 mEq/L, seizures, coma, renal failure); Li is dialyzable
5. Supportive: Anticonvulsants for seizures, cardiac monitoring
6. Sodium polystyrene sulphonate - cation exchange resin (sometimes used to bind lithium in gut if oral)
7. Monitor serum lithium levels every 4-6 hours until safe

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Q16. Classify drugs used in Bipolar Disorder and discuss their therapeutic role.

Classification of Drugs Used in Bipolar Disorder

• Lithium (gold standard)
• Sodium Valproate (Valproic acid)
• Carbamazepine / Oxcarbazepine

• Olanzapine, Quetiapine, Risperidone, Aripiprazole, Ziprasidone, Asenapine, Lurasidone

• Lorazepam, Clonazepam (rapid control of agitation)

Therapeutic Role

• First-line: Lithium OR Valproate OR atypical antipsychotic (Olanzapine, Quetiapine, Risperidone)
• Add benzodiazepine (lorazepam) for immediate sedation/agitation control
• Valproate preferred over lithium when: rapid cycling, mixed episodes, substance use comorbidity
• Carbamazepine: Alternative when lithium+valproate fail

• Quetiapine (FDA approved) - most evidence
• Lamotrigine - effective for bipolar depression; mood stabilizer
• Lurasidone (with lithium or valproate)
• Note: Antidepressants ALONE are controversial (may trigger manic switch); use only with a mood stabilizer

• Lithium - reduces both manic AND depressive recurrences; also reduces suicide risk
• Valproate - better for rapid cycling bipolar (4+ mood episodes/year)
• Lamotrigine - better for preventing depressive episodes
• Olanzapine, Quetiapine, Aripiprazole - maintenance atypical antipsychotics

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UNIT VI - ANXIOLYTICS AND SEDATIVE-HYPNOTICS

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Q17. Classify antianxiety drugs. Describe Benzodiazepines - mechanism of action, pharmacological actions, therapeutic uses, adverse effects, and precautions.

Classification of Antianxiety Drugs

• Short-acting: Triazolam, Midazolam, Alprazolam (short-to-intermediate)
• Intermediate-acting: Temazepam, Lorazepam, Oxazepam
• Long-acting: Diazepam, Clonazepam, Chlordiazepoxide

• SSRIs: Escitalopram, Paroxetine, Sertraline
• SNRIs: Venlafaxine, Duloxetine
• TCAs: Imipramine (panic disorder)

• Hydroxyzine (Atarax) - acute anxiety; no dependence

• Propranolol (situational anxiety - performance anxiety, stage fright - reduces palpitations/tremor)

• Phenobarbitone, Pentobarbitone, Thiopentone (now mainly for epilepsy/anaesthesia)

• Pregabalin/Gabapentin (GABAergic; for GAD)
• Meprobamate (obsolete)
• Chloral hydrate (obsolete hypnotic)

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BENZODIAZEPINES (BZDs)

"BZDs make GABA work better - like adding a power booster to the brain's brake system"

Mechanism of Action

• GABA-A receptor is the main inhibitory neurotransmitter receptor in the brain. It is a ligand-gated Cl- ion channel.
• GABA-A receptor has binding sites for: GABA itself, benzodiazepines, barbiturates, neurosteroids, ethanol, picrotoxin.
• BZDs bind to a specific allosteric site (between alpha and gamma subunits) on the GABA-A receptor - the BZD recognition site.
• When GABA binds its site AND a BZD also binds its site: BZD increases the FREQUENCY of Cl- channel opening (in response to GABA) → more Cl- enters → hyperpolarization → reduced neuronal excitability.

Important distinction:

• BZDs: increase FREQUENCY of Cl- channel opening (need GABA to be present)
• Barbiturates: increase DURATION of Cl- channel opening (can act without GABA at high doses)
• BZDs do NOT replace GABA - they enhance its effect (modulatory)
• This is why BZDs are SAFER than barbiturates - they have a "ceiling effect" and require GABA

Pharmacological Actions

1. Anxiolytic (anti-anxiety) - reduces subjective anxiety; limbic system (amygdala, hippocampus)
2. Sedation - drowsiness; reduces alertness; dose-dependent
3. Hypnotic (sleep) - larger doses; reduce sleep latency, reduce REM sleep (may cause vivid dreams/nightmares on withdrawal), increase stage 2 NREM sleep
4. Anticonvulsant/Anti-epileptic - clonazepam, diazepam; effective for all seizure types; IV diazepam/lorazepam = first-line for status epilepticus
5. Muscle relaxant (central) - diazepam; reduces spasticity by acting on interneurons in spinal cord; useful in muscle spasm, tetanus
6. Anterograde amnesia - inability to form new memories during drug action; useful for pre-procedure sedation (endoscopy), also misuse potential (date rape drug)
7. No analgesia - BZDs do NOT relieve pain directly; may reduce anxiety component of pain
8. Minimal cardiovascular/respiratory depression at therapeutic doses (advantage over barbiturates)

Therapeutic Uses

1. Anxiety disorders - GAD (short-term), panic disorder, social anxiety (clonazepam, alprazolam)
2. Insomnia - short-term (nitrazepam, temazepam, triazolam, midazolam); NOT recommended long-term (dependence)
3. Epilepsy:
   • Status epilepticus (IV diazepam, lorazepam) - first-line
   • Chronic epilepsy (clonazepam) - myoclonic, absence
   • Febrile convulsions (rectal diazepam)
4. Acute alcohol withdrawal - chlordiazepoxide or diazepam (prevent DTs and withdrawal seizures)
5. Muscle relaxation - diazepam for muscle spasm, spasticity, tetanus, back pain
6. Pre-operative sedation / premedication - midazolam (anterograde amnesia, sedation, anxiolysis)
7. Procedural sedation - IV midazolam (endoscopy, dental procedures)
8. Acute mania (adjunct with mood stabilizer for rapid sedation)
9. Night terrors, sleepwalking - clonazepam
10. Restless legs syndrome - clonazepam

Adverse Effects

1. Sedation, drowsiness (most common) - impairs driving, operating machinery
2. Anterograde amnesia - cannot form new memories after taking drug
3. Ataxia, coordination problems (especially elderly - falls)
4. Respiratory depression - at high doses, especially with alcohol or opioids; less than barbiturates
5. Tolerance - develops to sedative and hypnotic effects (less to anxiolytic); need increasing doses
6. Physical and psychological dependence - major problem with long-term use; develops even at therapeutic doses after 2-4 weeks
7. Withdrawal syndrome (on abrupt discontinuation after regular use):
   • Features: Rebound anxiety (worse than before), insomnia, tremor, sweating, tachycardia, seizures (severe cases), confusion
   • Always taper gradually when stopping
8. Paradoxical reactions - excitement, aggression, hostility (rare; especially in elderly/children)
9. Hangover effect - residual sedation next morning (long-acting BZDs)

• Relatively SAFE alone - causes sedation, ataxia, slurred speech, but rarely fatal alone
• Combined with alcohol/opioids = DANGEROUS respiratory depression
• Antidote: Flumazenil (competitive BZD antagonist at GABA-A receptor) - IV 0.2 mg; short half-life (reversal may not last) - repeat doses needed

Precautions

• Short-term use only (2-4 weeks for anxiety/insomnia)
• Gradual dose tapering to avoid withdrawal
• Avoid in: Respiratory disease (COPD, sleep apnoea), liver failure, elderly (half-life prolonged → falls), pregnancy (category D - neonatal floppy infant syndrome)
• Avoid combination with alcohol, opioids, CNS depressants
• LOT preferred in elderly: Lorazepam, Oxazepam, Temazepam (no active metabolites; shorter half-life; safer in liver disease)
• Addictive potential - schedule H/H1 drug

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Q18. Compare Benzodiazepines and Barbiturates.

Key memory point: Barbiturates killed patients in overdose (small margin between sedative and lethal dose). BZDs replaced them for anxiety/insomnia because BZDs are much SAFER.

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Q19. Compare Benzodiazepines and Buspirone in the treatment of anxiety disorders.

Buspirone

• Activates 5-HT1A autoreceptors (presynaptically) → reduces serotonin release → anxiolytic effect
• Also has weak D2 antagonist properties
• Does NOT interact with GABA-A receptors (completely different mechanism from BZDs)

Clinical Bottom Line

"Use BZDs for IMMEDIATE relief; use Buspirone for LONG-TERM anxiety management without dependence"

• BZDs are ideal when you need rapid control (acute panic attack, procedural anxiety, short-term situational anxiety).
• Buspirone is ideal for chronic GAD where long-term daily therapy is needed and addiction/dependence is a concern.
• SSRIs/SNRIs are now actually the first-line for most chronic anxiety disorders (buspirone and BZDs are second-line).

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EXAM TIPS SUMMARY