CNS Pharmacology — Sedative-Hypnotics, Antiepileptics, and Antipsychotics
🟢 Lite — Quick Review (1h–1d)
Sedative-Hypnotics (Benzodiazepines & Z-drugs):
| Drug | Half-life | Active Metabolite | Key Use |
|---|---|---|---|
| Diazepam | Long (20-100h) | Yes (desmethyldiazepam) | Status epilepticus, alcohol withdrawal |
| Lorazepam | Intermediate | No | ICU sedation, seizures |
| Midazolam | Short | No | Pre-medication, induction |
| Alprazolam | Short | No | Panic disorder, anxiety |
| Zolpidem | Short (~2.5h) | No | Insomnia (non-BZD) |
Antiepileptics — Monotherapy:
| Drug | Mechanism | Key Side Effects | Notes |
|---|---|---|---|
| Phenytoin | Na+ channel block | Gingival hyperplasia, hirsutism, peripheral neuropathy | Non-linear kinetics |
| Carbamazepine | Na+ channel block | Aplastic anemia, SIADH, Stevens-Johnson | Auto-inducer |
| Valproate | Multiple | Hepatotoxicity, teratogenicity, pancreatitis | Broad spectrum |
| Levetiracetam | SV2A modulation | Behavioral changes, somnolence | Newer agent |
| Phenobarbital | GABA-A potentiation | Sedation, dependence, megaloblastic anemia | Oldest AED |
Antipsychotics:
- Typical (First-gen): Haloperidol, Chlorpromazine, Fluphenazine
- Side effects: Extrapyramidal symptoms (EPS), tardive dyskinesia, hyperprolactinemia
- Atypical (Second-gen): Risperidone, Olanzapine, Quetiapine, Clozapine
- Side effects: Metabolic syndrome (weight gain, DM2), sedation
🟡 Standard — Regular Study (2d–2mo)
GABA Receptor Pharmacology:
- Benzodiazepines bind at α-γ interface of GABA-A receptor → ↑ Cl- channel opening frequency
- Barbiturates bind at β subunit → ↑ Cl- channel opening duration
- Key differences:
- BZDs: anxiolytic, anticonvulsant, muscle relaxant, amnestic (allosteric modulators)
- Barbiturates: same effects BUT no ceiling — respiratory depression risk is dose-dependent
- BZD antagonist: Flumazenil
- Barbiturate overdose: NO specific antagonist — support respiration
Benzodiazepine Pharmacology:
| Property | Diazepam | Lorazepam | Midazolam |
|---|---|---|---|
| Route | PO, IV, IM, PR | PO, IV, IM | IV, IM, IN |
| Onset | Fast (IV) | Intermediate | Very fast |
| Half-life | Long | Intermediate | Short |
| Active metabolites | Yes | No | No |
| Use in liver disease | Caution | Preferred | Preferred |
Barbiturate Pearls:
- Phenobarbital: longest-used AED; also used in neonatal seizures
- Thiopental: ultra-short acting; used for induction of anesthesia
- Mephobarbital, pentobarbital: intermediate/sleep induction
Antiepileptic Mechanisms:
| Mechanism | Drugs | Clinical Use |
|---|---|---|
| Na+ channel block | Phenytoin, Carbamazepine, Oxcarbazepine, Lamotrigine, Topiramate | Focal seizures, tonic-clonic |
| Ca2+ channel block (T-type) | Ethosuximide, Valproate | Absence seizures |
| GABA enhancement | Phenobarbital, Benzodiazepines, Tiagabine, Vigabatrin | Multiple seizure types |
| Glutamate block (NMDA/AMPA) | Topiramate, Felbamate, Lamotrigine | Adjunct therapy |
| SV2A modulation | Levetiracetam, Brivaracetam | Adjunct for focal/generalized |
Antiepileptic Teratogenicity (NEET HIGH-YIELD):
- Valproate — neural tube defects (spina bifida), facial dysmorphism, developmental delay → AVOID in pregnancy
- Phenytoin — fetal hydantoin syndrome (craniofacial, nail hypoplasia)
- Carbamazepine — neural tube defects (lower risk than valproate)
- Lamotrigine — considered safer in pregnancy (but still requires folate)
- B6 (folic acid) supplementation recommended for all women of childbearing age on AEDs
First-line AEDs by Seizure Type:
- Focal onset: Carbamazepine, Lamotrigine, Levetiracetam
- Generalized tonic-clonic: Valproate, Lamotrigine
- Absence: Ethosuximide, Valproate (if comorbid generalized)
- Myoclonic: Valproate, Levetiracetam
- Status epilepticus: IV Lorazepam or IV Diazepam (if Lorazepam unavailable)
Dopamine Pathways & Antipsychotics:
| Pathway | Effect when blocked | Symptoms |
|---|---|---|
| Mesolimbic | ↓ Positive symptoms | Hallucinations, delusions (THERAPEUTIC) |
| Mesocortical | ↑ Negative/cognitive symptoms | Flat affect, anhedonia (WORSENING) |
| Nigrostriatal | Extrapyramidal symptoms | Parkinsonism, dystonia, akathisia |
| Tuberoinfundibular | Hyperprolactinemia | Galactorrhea, amenorrhea, gynecomastia |
EPS Side Effects (Nigrostriatal blockade):
| EPS Type | Onset | Features | Treatment |
|---|---|---|---|
| Acute dystonia | Hours-days | Muscle spasm (head, neck, eyes) | Benztropine, diphenhydramine |
| Akathisia | Days-weeks | Inner restlessness, pacing | Beta-blocker, benzodiazepine |
| Parkinsonism | Weeks-months | Bradykinesia, rigidity, tremor | Anticholinergics, amantadine |
| Tardive dyskinesia | Months-years | Involuntary movements (orofacial) | Stop drug ASAP; valbenazine, deutetrabenazine |
Atypical vs Typical Antipsychotics:
| Feature | Typical (Haloperidol) | Atypical (Risperidone) |
|---|---|---|
| D2 selectivity | High (mesolimbic + nigrostriatal) | Moderate + 5-HT2A antagonism |
| EPS risk | High | Lower |
| Metabolic effects | Lower | Higher (especially clozapine, olanzapine) |
| Negative symptoms | Minimal benefit | Some benefit |
| Hyperprolactinemia | High | Dose-dependent |
Key Antipsychotic Drugs:
| Drug | Unique Feature | Notable Side Effects |
|---|---|---|
| Haloperidol | First-line typical; high potency | EPS, QT prolongation |
| Clozapine | Gold standard for refractory schizophrenia | Agranulocytosis (weekly WBC), myocarditis, metabolic |
| Risperidone | Popular atypical | Dose-dependent EPS, hyperprolactinemia |
| Olanzapine | Good for agitation | Marked weight gain, DM2, sedation |
| Quetiapine | Low EPS | Sedation, metabolic (lower than olanzapine) |
| Aripiprazole | Partial D2 agonist | Activation, less metabolic |
Antidepressant Classes:
| Class | Mechanism | Side Effects | Examples |
|---|---|---|---|
| TCA | NE + serotonin reuptake inhibition | Anticholinergic (dry mouth, constipation, urinary retention), cardiac | Amitriptyline, imipramine |
| SSRI | Selective 5-HT reuptake inhibition | GI upset, sexual dysfunction, serotonin syndrome | Fluoxetine, sertraline, escitalopram |
| SNRI | 5-HT + NE reuptake inhibition | Similar to SSRI + ↑ BP | Venlafaxine, duloxetine |
| MAOI | Monoamine oxidase inhibition | Tyramine reaction (hypertensive crisis), serotonin syndrome | Phenelzine, tranylcypromine |
| Atypical | Mixed | Variable | Bupropion (seizure risk at high dose), mirtazapine (sedation, weight gain) |
Serotonin Syndrome (SSRIs + MAOIs + meperidine, linezolid, methylene blue):
- Features: Hyperthermia, muscle rigidity, hyperreflexia, autonomic instability, altered mental status
- Treatment: Cyproheptadine (5-HT antagonist), cooling, ICU
🔴 Extended — Deep Study (3mo+)
Benzodiazepine Dependence & Withdrawal:
- Chronic use → tolerance (especially sedation, not respiratory depression)
- Abrupt cessation → withdrawal: anxiety, insomnia, tremor, seizures
- Flumazenil — competitive antagonist at BZD binding site; used for BZD overdose
- Zolpidem/zaleplon: non-BZD hypnotics; similar mechanism but shorter acting; some cross-reactivity with BZD receptors
Phenytoin Non-linear Kinetics (Michaelis-Menten):
- At therapeutic doses: first-order kinetics
- At toxic doses: zero-order (saturated metabolism)
- Small dose increase → disproportionate plasma level increase
- Saturable hepatic metabolism
- Target therapeutic range: 10-20 μg/mL
Carbamazepine Auto-induction:
- Induces own metabolism (CYP3A4, CYP2C9)
- Plasma levels DECREASE over first few weeks of therapy
- Also induces hepatic enzymes more broadly
- Key interactions: ↓ OCPs, ↓ warfarin, ↓ many drugs
Levetiracetam & Brivaracetam:
- SV2A protein modulation (synaptic vesicle glycoprotein)
- Novel mechanism — fewer drug interactions
- Broad-spectrum AED (focal and generalized seizures)
- Behavioral side effects in children (irritability, mood changes)
- No enzyme induction or inhibition
Clozapine Monitoring (REMS Program):
- Weekly WBC/ANC monitoring (first 6 months), then biweekly, then monthly
- Stop if ANC < 1000 or WBC < 3000
- Risk of myocarditis, seizures (dose-dependent), metabolic syndrome
- Reserved for treatment-resistant schizophrenia (failed 2 other antipsychotics)
Aripiprazole Mechanism:
- Partial D2 agonist (not pure antagonist like typicals)
- Partial 5-HT1A agonist + 5-HT2A antagonist
- “Dopamine stabilizer” — blocks in hyperdopaminergic states, stimulates in hypodopaminergic states
- Lower EPS and hyperprolactinemia compared to other atypicals
- Activation side effects (akathisia, insomnia) in some patients
Antipsychotic Metabolic Monitoring (Atypical, especially Clozapine/Olanzapine):
- Baseline + quarterly: weight, BMI, blood pressure, fasting glucose, lipids
- Recommended: switch to lower-metabolic-risk agent if significant weight gain/DM
NEET PG Key Pearls:
- Diazepam + lorazepam — preferred for status epilepticus (IV)
- Ethosuximide — ONLY for absence seizures; NOT for other seizure types
- Valproate — broad spectrum; teratogenic (neural tube defects); avoid in women of childbearing age unless absolutely necessary
- Clozapine — only for refractory cases; agranulocytosis risk; requires WBC monitoring
- Flumazenil — BZD antagonist; do NOT use in patients with seizure history on chronic BZDs (can precipitate seizures)
- Serotonin syndrome — SSRIs + MAOIs or meperidine = contraindicated
- EPS treatment — benztropine or diphenhydramine for acute dystonia; amantadine for parkinsonism
- Tardive dyskinesia — stop offending drug immediately; consider tetrabenazine
- Bupropion — contraindicated in eating disorders, seizure disorders (lowers seizure threshold)
- Carbamazepine — induces hepatic enzymes; reduces OCP efficacy → use alternative contraception
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