Pharmacology chapters
Antipsychotics and antidepressants
Drugs for psychosis, depression and bipolar disorder: typical and atypical antipsychotics with their extrapyramidal and metabolic effects and neuroleptic malignant syndrome; SSRIs, tricyclics, MAO inhibitors and newer antidepressants with serotonin syndrome and tricyclic overdose; and lithium with its narrow therapeutic range.
- Antipsychotics block D2 receptors in the mesolimbic pathway (reducing positive symptoms); blocking D2 in the nigrostriatal pathway causes extrapyramidal effects (acute dystonia within days, akathisia, parkinsonism, tardive dyskinesia after years) and in the tuberoinfundibular pathway causes hyperprolactinaemia; typicals (haloperidol, chlorpromazine) cause more EPS, atypicals (risperidone, olanzapine, clozapine) more weight gain and diabetes, and clozapine (for resistant schizophrenia) can cause agranulocytosis.
- Neuroleptic malignant syndrome: fever, rigidity, confusion, autonomic instability and raised CK → stop the drug, cool, dantrolene or bromocriptine.
- SSRIs (fluoxetine, sertraline) are first-line antidepressants; tricyclics (amitriptyline) have anticholinergic, α-blocking and antihistamine effects and are deadly in overdose (arrhythmias with wide QRS: give sodium bicarbonate); MAOIs react with tyramine (cheese reaction); combining serotonergic drugs causes serotonin syndrome; lithium has a narrow therapeutic range (toxicity: tremor, ataxia, confusion; raised by thiazides, NSAIDs, ACE inhibitors and dehydration).
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Antipsychotics
Dopamine pathways
| Pathway | Function | Effect of D2 blockade |
|---|---|---|
| Mesolimbic | Emotion, reward | Antipsychotic effect (reduces positive symptoms: hallucinations, delusions) |
| Mesocortical | Cognition, motivation | May worsen negative symptoms |
| Nigrostriatal | Movement | Extrapyramidal side effects |
| Tuberoinfundibular | Dopamine inhibits prolactin | Hyperprolactinaemia: galactorrhoea, amenorrhoea, gynaecomastia, sexual dysfunction |
The chemoreceptor trigger zone also has D2 receptors, so many antipsychotics are antiemetics (prochlorperazine).
Typical vs atypical
| Feature | Typical (first-generation) | Atypical (second-generation) |
|---|---|---|
| Examples | Haloperidol (high potency), chlorpromazine (low potency), fluphenazine (depot) | Clozapine, risperidone, olanzapine, quetiapine, aripiprazole (partial agonist) |
| Receptors | Mainly D2 | D2 plus 5-HT2A blockade |
| Extrapyramidal effects | More (especially high-potency haloperidol) | Fewer (risperidone dose-dependent) |
| Negative symptoms | Little effect | Somewhat better |
| Metabolic effects | Less | Weight gain, diabetes, dyslipidaemia (especially olanzapine, clozapine) |
Low-potency typicals (chlorpromazine) have more anticholinergic, α-blocking (postural hypotension) and antihistamine (sedation) effects; chlorpromazine also causes cholestatic jaundice, photosensitivity and corneal/lens deposits.
Extrapyramidal side effects
| Effect | Timing | Features | Treatment |
|---|---|---|---|
| Acute dystonia | Hours to days | Muscle spasms: torticollis, oculogyric crisis, trismus; young men, high-potency drugs | Anticholinergic (procyclidine IM/IV, benztropine) or antihistamine |
| Akathisia | Days to weeks | Inner restlessness, cannot sit still | Reduce dose; propranolol, benzodiazepine |
| Parkinsonism | Weeks | Tremor, rigidity, bradykinesia | Reduce dose; anticholinergic (not levodopa) |
| Tardive dyskinesia | Months to years | Involuntary lip-smacking, chewing, tongue movements; often irreversible | Stop or switch (clozapine); tetrabenazine; anticholinergics worsen it |
Anticholinergics help acute dystonia and parkinsonism but worsen tardive dyskinesia.
Other serious adverse effects
- Neuroleptic malignant syndrome (NMS): rare and life-threatening; high fever, severe rigidity ("lead-pipe"), confusion, autonomic instability (labile BP, sweating), raised creatine kinase, myoglobinuria and renal failure. Treatment: stop the drug, cooling, fluids, dantrolene (muscle relaxant) and/or bromocriptine (dopamine agonist).
- Clozapine: agranulocytosis (regular blood count monitoring), myocarditis, seizures, hypersalivation, constipation, weight gain. Reserved for treatment-resistant schizophrenia; reduces suicide risk.
- QT prolongation (haloperidol, others): torsades de pointes.
- Lowered seizure threshold.
- Higher stroke and death risk in elderly people with dementia.
Antidepressants
Classes
| Class | Examples | Mechanism | Notes |
|---|---|---|---|
| SSRIs | Fluoxetine, sertraline, citalopram, escitalopram, paroxetine | Block serotonin reuptake | First-line for depression and anxiety disorders, OCD, bulimia; safer in overdose |
| SNRIs | Venlafaxine, duloxetine | Block serotonin and noradrenaline reuptake | Depression, anxiety, neuropathic pain (duloxetine); raise BP |
| Tricyclics (TCAs) | Amitriptyline, imipramine, clomipramine, nortriptyline | Block serotonin and noradrenaline reuptake; also block muscarinic, α1 and H1 receptors and sodium channels | Neuropathic pain, migraine prophylaxis, nocturnal enuresis (imipramine), OCD (clomipramine); dangerous in overdose |
| MAO inhibitors | Phenelzine, tranylcypromine (irreversible); moclobemide (reversible MAO-A); selegiline (MAO-B, Parkinson's) | Block breakdown of monoamines | Atypical depression; many interactions |
| Others | Mirtazapine (α2 antagonist: sedation, weight gain), bupropion (dopamine and noradrenaline; smoking cessation), trazodone | Various | (none specific) |
Antidepressants take 2–4 weeks for mood to improve (side effects come first). In young people, monitor for suicidal thoughts early in treatment.
SSRI adverse effects
Nausea and gut upset, headache, insomnia or anxiety early on, sexual dysfunction, hyponatraemia (elderly), bleeding risk (especially with NSAIDs, aspirin, warfarin), QT prolongation (citalopram); discontinuation symptoms (paroxetine, venlafaxine). Fluoxetine has a very long half-life.
Tricyclic adverse effects and overdose
- Anticholinergic: dry mouth, constipation, urinary retention, blurred vision, confusion.
- α1 block: postural hypotension. H1 block: sedation, weight gain.
- Sodium channel block: cardiotoxicity.
Overdose ("the 3 Cs": coma, convulsions, cardiotoxicity): anticholinergic signs, seizures, coma, hypotension and arrhythmias with wide QRS on ECG. Treatment: airway support, activated charcoal if early, IV sodium bicarbonate (for wide QRS, arrhythmias or acidosis), benzodiazepines for seizures. Avoid flumazenil and physostigmine.
MAOI interactions
- Tyramine in cheese, cured meats, red wine, yeast extract → hypertensive crisis (the "cheese reaction"), because MAO in the gut and liver normally breaks tyramine down. Treat with phentolamine.
- With SSRIs, pethidine, tramadol, linezolid, dextromethorphan → serotonin syndrome. Leave a wash-out gap when switching (longer after fluoxetine).
Serotonin syndrome
Caused by too much serotonergic activity (SSRIs, SNRIs, MAOIs, TCAs, tramadol, pethidine, linezolid, triptans, St John's wort, MDMA), especially in combination. Develops within hours.
- Neuromuscular: clonus (inducible, ocular), hyperreflexia, tremor, myoclonus.
- Autonomic: fever, sweating, tachycardia, diarrhoea, dilated pupils.
- Mental: agitation, confusion.
Treatment: stop the drugs, supportive care, benzodiazepines, cyproheptadine (5-HT2A antagonist).
| Feature | Serotonin syndrome | Neuroleptic malignant syndrome |
|---|---|---|
| Drug | Serotonergic drugs | Antipsychotics (dopamine blockers) |
| Onset | Hours | Days |
| Muscles | Clonus, hyperreflexia | Lead-pipe rigidity, slow reflexes |
| Pupils | Dilated | Normal |
| Treatment | Cyproheptadine | Dantrolene, bromocriptine |
Lithium
Uses: bipolar disorder (prevention and treatment of mania), adjunct in resistant depression; reduces suicide risk.
- Narrow therapeutic range: usually about 0.4–1.0 mmol/L (the exact target depends on the indication and local guidance), checked 12 hours after the dose.
- Excreted by the kidney; handled like sodium. Low sodium, dehydration, thiazides, NSAIDs, ACE inhibitors and ARBs raise lithium levels.
Adverse effects:
- Short term: fine tremor, thirst, polyuria, nausea, weight gain.
- Long term: hypothyroidism (goitre), nephrogenic diabetes insipidus (polyuria), reduced kidney function, hyperparathyroidism (hypercalcaemia).
- Pregnancy: Ebstein anomaly (small absolute risk).
Toxicity: coarse tremor, ataxia, slurred speech, confusion, vomiting and diarrhoea, seizures, coma, arrhythmias. Treatment: stop lithium, IV fluids, haemodialysis for severe toxicity.
Other mood stabilisers: valproate, carbamazepine, lamotrigine (bipolar depression), atypical antipsychotics.
Expect: dopamine pathways and side effects, typical vs atypical antipsychotics, acute dystonia vs tardive dyskinesia and their treatment, clozapine and agranulocytosis, neuroleptic malignant syndrome and its treatment, SSRIs as first-line, tricyclic receptor effects and overdose with sodium bicarbonate, MAOI cheese reaction, serotonin syndrome vs NMS, lithium range, drugs that raise lithium, and lithium adverse effects (hypothyroidism, nephrogenic DI).
Quick revision
- Antipsychotic effect: mesolimbic D2. EPS: nigrostriatal. Prolactin: tuberoinfundibular.
- Acute dystonia: procyclidine. Tardive dyskinesia: late, irreversible, worse with anticholinergics.
- Clozapine: resistant schizophrenia; agranulocytosis.
- NMS: fever, rigidity, high CK; dantrolene, bromocriptine.
- SSRIs first-line; TCA overdose: wide QRS → sodium bicarbonate.
- MAOI + tyramine → hypertensive crisis. Serotonin syndrome: clonus; cyproheptadine.
- Lithium: narrow range; raised by thiazides, NSAIDs, ACE inhibitors, dehydration; causes hypothyroidism and nephrogenic DI.
Written by The House Job from standard pharmacology references (Katzung's Basic and Clinical Pharmacology).
FAQ
Which dopamine pathway causes extrapyramidal side effects?
The nigrostriatal pathway.
How is neuroleptic malignant syndrome treated?
Stop the antipsychotic, cool and rehydrate the patient, and give dantrolene and/or bromocriptine.
How is tricyclic antidepressant overdose treated?
Supportive care, activated charcoal if early, intravenous sodium bicarbonate for a wide QRS or arrhythmias, and benzodiazepines for seizures.
Which drugs increase lithium levels?
Thiazide diuretics, NSAIDs, ACE inhibitors and ARBs, and dehydration or low sodium intake.