Antidepressants include SSRIs (fluoxetine, sertraline, escitalopram), SNRIs (venlafaxine, duloxetine), TCAs (amitriptyline, nortriptyline, imipramine, clomipramine, doxepin), MAOIs (phenelzine, tranylcypromine), and atypicals such as bupropion and mirtazapine. SSRIs and SNRIs can cause serotonin syndrome when combined with other serotonergic agents, producing the classic triad of autonomic instability, neuromuscular hyperactivity (clonus, hyperreflexia), and altered mental status, with cyproheptadine used for severe cases; triptans should also be avoided with serotonergic agents for the same reason. MAOIs require dietary restriction of tyramine-rich foods such as aged cheese, cured meats, and wine to prevent hypertensive crisis. TCA overdose produces the anticholinergic-cardiac-CNS triad of mydriasis and dry skin, wide QRS with ventricular tachycardia, and seizures or coma, with QRS widening treated by sodium bicarbonate. Bupropion lowers the seizure threshold and is contraindicated in seizure and eating disorders but is useful for smoking cessation. Mirtazapine causes sedation and weight gain via H1 and 5-HT2C antagonism but has fewer sexual side effects. Lithium toxicity manifests as tremor, confusion, ataxia, and seizures, with hemodialysis for severe cases. Anxiolytics and sedatives include benzodiazepines, which are positive allosteric modulators at the GABA-A receptor increasing the frequency of chloride channel opening and reversed by flumazenil (which can precipitate seizures in chronic users). Benzodiazepine withdrawal requires a slow taper with a long-acting agent such as diazepam or chlordiazepoxide to avoid seizures, delirium, and death; flumazenil is contraindicated. Barbiturates (phenobarbital, thiopental) are GABA-A agonists and CYP450 inducers with overdose treated supportively. Buspirone is a 5-HT1A partial agonist for generalized anxiety disorder that lacks sedation, dependence, and respiratory depression but takes 1-2 weeks for effect. Zolpidem is a non-benzodiazepine selective for the BZ-1 subtype, with minimal muscle relaxation and less dependence, though overdose is still reversed by flumazenil.
Neurodegenerative and related CNS therapy centers on neurotransmitter modulation. In Parkinson disease, levodopa is combined with carbidopa, a peripheral DOPA decarboxylase inhibitor that reduces peripheral conversion to dopamine, increasing CNS availability and decreasing peripheral side effects. Selegiline selectively inhibits MAO-B at low doses for early disease. Benztropine is a muscarinic antagonist for tremor and rigidity, while amantadine increases dopamine release and blocks NMDA receptors, particularly useful for levodopa-induced dyskinesias. For Alzheimer disease, donepezil is an acetylcholinesterase inhibitor (causing bradycardia, syncope, GI upset, and vivid dreams) and memantine is an uncompetitive NMDA antagonist for moderate-to-severe disease. Riluzole modestly prolongs survival in ALS by inhibiting glutamate release and NMDA effects. Sumatriptan is a 5-HT1B/1D agonist producing cranial vasoconstriction, contraindicated in CAD, Prinzmetal angina, and uncontrolled hypertension. Spasticity can be reduced with dantrolene (a direct ryanodine receptor blocker acting on muscle), baclofen (a GABA-B receptor agonist acting in the spinal cord), or tizanidine (a central α2 agonist used especially in multiple sclerosis and spinal cord injury with LFT monitoring). Other CNS agents include ondansetron, a 5-HT3 antagonist for chemotherapy-induced and postoperative nausea, now carrying an FDA warning for QT prolongation, and metoclopramide, a D2 antagonist prokinetic with risk of extrapyramidal symptoms and tardive dyskinesia, with acute dystonia responsive to diphenhydramine or benztropine.
The autonomic nervous system drugs span muscarinic agents. Atropine is a muscarinic antagonist used for symptomatic bradycardia and preoperatively to dry secretions, with classic anticholinergic effects (mydriasis, hyperthermia, dry mouth, urinary retention). Bethanechol is a direct muscarinic agonist for postoperative urinary retention and neurogenic ileus, contraindicated in mechanical obstruction. Pilocarpine is a direct muscarinic agonist used in open-angle glaucoma and acute angle-closure glaucoma (after laser peripheral iridotomy) to produce miosis and open the trabecular meshwork. Organophosphates irreversibly inhibit acetylcholinesterase, producing the DUMBBBELS syndrome of diarrhea, urination, miosis, bronchospasm, bradycardia, emesis, lacrimation, salivation, and sweating, treated with atropine plus pralidoxime, which regenerates acetylcholinesterase before aging occurs but does not reverse CNS effects.
Neuromuscular pharmacology centers on junctional agents. Succinylcholine is a depolarizing NMJ blocker with Phase I block that releases potassium and is contraindicated in hyperkalemia, denervation injuries, burn patients, malignant hyperthermia history, and muscular dystrophy. Malignant hyperthermia is triggered by succinylcholine or volatile anesthetics in patients with RyR1 mutations, producing sustained calcium release and hyperthermia and rigidity, treated with dantrolene. Non-depolarizing agents such as vecuronium, rocuronium, and cisatracurium are reversed by sugammadex (a cyclodextrin that binds rocuronium) or by neostigmine combined with glycopyrrolate to prevent muscarinic effects. Myasthenia gravis is diagnosed with the short-acting AChE inhibitor edrophonium and treated chronically with pyridostigmine, immunosuppressants, and thymectomy. Lambert-Eaton syndrome features antibodies to presynaptic voltage-gated calcium channels with strength improving on repeated stimulation (opposite of myasthenia), often associated with small cell lung cancer and treated with 3,4-diaminopyridine. Botulinum toxin cleaves SNARE proteins to block acetylcholine release at the NMJ, used for spasticity, blepharospasm, strabismus, migraine prophylaxis, and cosmetic indications, but is also responsible for foodborne botulism. Tetrodotoxin blocks voltage-gated sodium channels on nerves (classically from puffer fish), producing ascending paralysis and respiratory failure with no specific antidote, requiring supportive care only.