CNS Pharmacology - Antidepressants, Antipsychotics, and Anticonvulsants

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CNS Pharmacology — Key Facts for FMGE Core concept: Antidepressants work primarily by increasing synaptic serotonin and/or norepinephrine; antipsychotics block dopamine D2 receptors High-yield point: SSRIs are first-line for depression due to better safety/tolerability; atypicals have lower extrapyramidal side effects than typicals ⚡ Exam tip: TCAs cause anticholinergic effects, orthostatic hypotension, and cardiac toxicity; SSRIs are much safer but can cause serotonin syndrome

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CNS Pharmacology — FMGE Study Guide

Antidepressants

Tricyclic Antidepressants (TCAs)

Examples: Amitriptyline, nortriptyline, imipramine, desipramine, clomipramine

Mechanism:

• Block reuptake of serotonin (5-HT) and norepinephrine (NE) → ↑ synaptic levels
• Also block: H1 histamine, muscarinic (M1), α1 adrenergic, 5-HT2 receptors

Pharmacokinetics:

• Highly lipophilic, wide distribution
• Hepatic metabolism (CYP450) → active metabolites
• Nortriptyline is metabolite of amitriptyline; desipramine is metabolite of imipramine

Adverse effects (due to receptor blockade):

• Anticholinergic: Dry mouth, constipation, urinary retention, blurred vision, tachycardia, confusion (worse in elderly - urinary retention, glaucoma)
• α1 blockade: Orthostatic hypotension, dizziness
• Histamine H1 blockade: Sedation, weight gain
• Cardiac: Prolonged QRS, QT prolongation, arrhythmias, tachycardia
• Seizures: Lower seizure threshold (dose-dependent)
• Sedation: Amitriptyline most sedating; desipramine least

Toxicity:

• Anticholinergic symptoms: Hyperthermia, mydriasis, flushed skin, urinary retention, altered mental status
• Cardiac arrhythmias (widened QRS, prolonged QT) → can be fatal
• Treatment: Sodium bicarbonate (narrows QRS by increasing protein binding), supportive care

Uses:

• Major depression (second-line after SSRIs)
• Neuropathic pain (amitriptyline, nortriptyline)
• Migraine prophylaxis
• OCD (clomipramine)
• Enuresis (imipramine - rarely used now)
• Chronic pain syndromes

Selective Serotonin Reuptake Inhibitors (SSRIs)

Examples: Fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine

Mechanism: Selectively block 5-HT reuptake → ↑serotonin in synaptic cleft

Pharmacokinetics:

• All inhibit CYP2D6 (except sertraline at high dose); fluoxetine also inhibits CYP3A4, CYP2C19
• Long half-life of fluoxetine (4-6 days including active metabolite norfluoxetine)

Adverse effects:

• GI: Nausea, diarrhea (sertraline), dyspepsia
• Sexual dysfunction: Decreased libido, anorgasmia, erectile dysfunction (very common - affects compliance)
• CNS: Headache, insomnia or somnolence, anxiety
• Serotonin syndrome (with MAOIs, tryptophan, linezolid, meperidine): Hyperthermia, rigidity, hyperreflexia, myoclonus, altered mental status
• Discontinuation syndrome: Paroxetine and venlafaxine (short half-lives) - dizziness, paresthesias, vivid dreams
• SIADH/hyponatremia: Especially in elderly (increased ADH secretion)
• Bleeding: Increased bleeding risk (platelet 5-HT) - especially with NSAIDs, warfarin

Uses:

• Major depressive disorder (first-line)
• Panic disorder, social anxiety disorder
• Generalized anxiety disorder
• OCD (fluoxetine, sertraline, fluvoxamine)
• Bulimia (fluoxetine)
• PTSD
• Premenstrual dysphoric disorder

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

Examples: Venlafaxine, duloxetine, desvenlafaxine

Mechanism: Block 5-HT and NE reuptake

Adverse effects: Similar to SSRIs + ↑NE → ↑BP, tachycardia; discontinuation syndrome

Uses: Depression, GAD, diabetic neuropathy, chronic musculoskeletal pain

Atypical Antidepressants

Bupropion:

• NE and dopamine reuptake inhibitor (NDRI)
• No sexual dysfunction, no weight gain
• Contraindicated in eating disorders, seizure disorders
• Used for depression with sexual dysfunction, ADHD, smoking cessation

Mirtazapine:

• Blocks α2 autoreceptor (↑NE and 5-HT release) + blocks 5-HT2, 5-HT3
• Sedation, appetite stimulation, weight gain
• Useful for depressed patients with insomnia and weight loss

Trazodone:

• 5-HT2A antagonist + weak 5-HT reuptake inhibition
• Causes significant sedation
• Used for insomnia (low dose) and depression

MAO Inhibitors (MAOIs) - rarely used now due to diet/drug interactions:

• Phenelzine, tranylcypromine, isocarboxazid: Non-selective MAO inhibition
• Dietary restriction: Tyramine-containing foods (aged cheese, red wine, fermented foods) → hypertensive crisis (tyramine displaces NE)
• Drug interactions: Meperidine (serotonin syndrome), sympathomimetics, SSRIs (wait 2 weeks between drugs)
• Uses: Atypical depression, refractory cases

Antipsychotics (Neuroleptics)

Typical (First-Generation)

Examples: Haloperidol, chlorpromazine, fluphenazine, perphenazine, thioridazine

Mechanism: Predominantly D2 receptor blockade (mesolimbic pathway → antipsychotic effect)

Adverse effects (due to D2 blockade in other pathways):

• Extrapyramidal symptoms (EPS) (striatum - nigrostriatal pathway):
  • Acute dystonia (hours): Sustained muscle contraction (oculogyric crisis, torticollis) - treat with anticholinergic (trihexyphenidyl)
  • Akathisia (days-weeks): Inability to sit still, inner restlessness - treat with beta-blocker or BZD
  • Parkinsonism (weeks-months): Bradykinesia, rigidity, tremor - treat with anticholinergic or amantadine
  • Tardive dyskinesia (months-years): Involuntary choreoathetoid movements (orofacial - lip smacking, tongue protrusion) - irreversible; stop drug immediately; treat with tetrabenazine, VMAT2 inhibitor
• Hyperprolactinemia (tuberoinfundibular pathway): Galactorrhea, amenorrhea, erectile dysfunction, gynaecomastia (D2 blockade → ↑prolactin)
• Neuroleptic malignant syndrome (rare but life-threatening): High fever, muscle rigidity, autonomic instability, elevated CK - treat with dantrolene, bromocriptine

Atypical (Second-Generation)

Examples: Clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone

Mechanism: D2 + 5-HT2A blockade (serotonin modulation reduces EPS)

Adverse effects:

• Metabolic syndrome: Weight gain, hyperlipidemia, diabetes (clozapine > olanzapine > risperidone > others)
• Myocarditis: Clozapine (can be fatal)
• Agranulocytosis: Clozapine (requires WBC monitoring)
• Sedation: Olanzapine, quetiapine
• EPS: Much lower than typicals (but not zero)
• Hyperprolactinemia: Risperidone > others
• QT prolongation: Ziprasidone, thioridazine
• Orthostatic hypotension: Risperidone, clozapine

Uses of Antipsychotics

• Schizophrenia: Positive symptoms (hallucinations, delusions) respond well; negative symptoms (flat affect, social withdrawal) respond less
• Bipolar disorder: Acute mania, maintenance
• Psychotic depression: With antidepressant
• Delirium: Haloperidol (first-generation) preferred for delirium due to low anticholinergic effects
• Tourette syndrome: Haloperidol, pimozide
• Nausea: Prochlorperazine, chlorpromazine

Anticonvulsants

Phenytoin

Mechanism: Blocks voltage-gated Na channels (stabilizes neuronal membranes)

Uses: Tonic-clonic seizures, focal seizures, status epilepticus (IV)

Adverse effects:

• Gingival hyperplasia (25%): More common in children
• Hirsutism: Aesthetic concern
• Osteomalacia: ↓Vitamin D metabolism
• Megaloblastic anemia: ↓Folate absorption
• Peripheral neuropathy: ↓Folate, B12
• Ataxia, nystagmus, diplopia: CNS toxicity (dose-related)
• Teratogenicity: Fetal hydantoin syndrome (craniofacial anomalies, nail hypoplasia)
• Cushing syndrome: Enzyme induction → ↓cortisol clearance
• SLE-like syndrome: With hydantoin

Pharmacokinetics:

• Zero-order at therapeutic concentrations → narrow TI
• Highly protein bound (90%); displaced by other highly protein-bound drugs
• Enzyme inducer (CYP450) → many drug interactions
• IV must be given slowly (cardiac depression, hypotension)

Carbamazepine

Mechanism: Blocks Na channels; also enhances GABA

Uses: Tonic-clonic, focal seizures, trigeminal neuralgia (first-line), bipolar disorder

Adverse effects:

• Aplastic anemia, agranulocytosis: Hematological monitoring required
• SIADH: Hyponatremia (water retention)
• Stevens-Johnson syndrome: HLA-B*1502 association (test before starting in Asian patients)
• Enzyme inducer: Similar drug interactions to phenytoin
• Dizziness, ataxia, diplopia

Valproic Acid

Mechanism: Blocks Na channels, ↑GABA, ↓excitatory transmission

Uses: Absence seizures, myoclonic, tonic-clonic, bipolar, migraine prophylaxis

Adverse effects:

• Hepatotoxicity: Especially in children <2 years
• Pancreatitis
• Teratogenicity: Neural tube defects (spina bifida) - avoid in pregnancy
• Weight gain, tremor, hair loss
• Hyperammonemia: Can cause encephalopathy even with normal liver tests

Benzodiazepines (Anticonvulsant use)

• Clonazepam: Absence, myoclonic seizures
• Diazepam/lorazepam: Status epilepticus (IV)
• Clobazam: Seizure clusters

Ethosuximide

• First-line for absence seizures only
• Mechanism: Blocks T-type Ca²⁺ channels in thalamic neurons
• Adverse effects: GI upset, headache, rash, SLE-like syndrome

Gabapentin/Pregabalin

• Gabapentin: Structurally related to GABA; used for neuropathic pain, focal seizures, restless leg syndrome
• Pregabalin: Similar but better pharmacokinetics; Schedule V controlled

Levetiracetam

• Newer antiepileptic; mechanism unclear
• Few drug interactions
• Used for partial onset, generalized tonic-clonic seizures
• Adverse effects: Behavioral changes (irritability, depression), somnolence

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