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Neuro & Psych Pharmacology

Name: Neuro & Psych Pharmacology
Creator: Veli Bakalov, MD

Mechanisms and signature toxicities across the CNS drug classes

Neurology & Psychiatry·Pharmacology·5 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Phenytoin: Na⁺ channel blocker with zero-order kinetics; gingival hyperplasia, hirsutism, nystagmus, folate-related megaloblastic anemia, P-450 induction, fetal hydantoin syndrome and SJS.
Carbamazepine is first-line for trigeminal neuralgia (SIADH, agranulocytosis, SJS with HLA-B*15:02); valproate causes hepatotoxicity, pancreatitis and neural tube defects.
Ethosuximide (thalamic T-type Ca²⁺ blocker) is first-line for absence seizures; status epilepticus gets an IV benzodiazepine first, then phenytoin or fosphenytoin.
Local anesthetics block Na⁺ channels (pain lost first) and need higher doses in acidic, infected tissue; amides have two i's (lidocaine, bupivacaine).
Malignant hyperthermia (RYR1; volatile anesthetics or succinylcholine) and NMS are both treated with dantrolene, which blocks the ryanodine receptor.
Carbidopa blocks peripheral DOPA decarboxylase without entering the CNS, increasing central levodopa and reducing nausea and hypotension.
EPS timeline: acute dystonia in hours (benztropine), akathisia in days, parkinsonism in weeks, tardive dyskinesia in months (VMAT2 inhibitor); clozapine requires ANC monitoring for agranulocytosis.
Serotonin syndrome (clonus, hyperreflexia) is treated with cyproheptadine; TCA overdose (wide QRS) with sodium bicarbonate; MAOI plus tyramine causes hypertensive crisis.
Benzodiazepines increase GABA-A opening frequency and barbiturates increase duration; flumazenil reverses benzodiazepines only; lithium causes nephrogenic DI, hypothyroidism and Ebstein anomaly.

Antiepileptics

Sodium-channel blockers. Phenytoin, carbamazepine and valproate (in part) block voltage-gated Na⁺ channels and so limit rapid, repetitive firing. Phenytoin is an older agent for focal and tonic-clonic seizures (valproate, lamotrigine and levetiracetam are now first-line) and, as IV fosphenytoin, a second-step drug in status epilepticus. It follows zero-order (saturable) kinetics, so a small dose increase can cause a large jump in serum level. Phenytoin and carbamazepine both induce cytochrome P-450, whereas valproate inhibits it.

Absence and status epilepticus. Ethosuximide blocks thalamic T-type Ca²⁺ channels and is first-line for absence (petit mal) seizures. Status epilepticus is aborted first with an IV benzodiazepine (lorazepam or diazepam), and then a longer-acting agent (phenytoin or fosphenytoin) is loaded to prevent recurrence.

Antiepileptics: use and signature toxicity

Drug	Mechanism	Key use	Signature toxicity
Phenytoin	Na⁺ channel block; zero-order kinetics	Status epilepticus (as fosphenytoin); older tonic-clonic agent	Gingival hyperplasia, hirsutism, nystagmus and ataxia, megaloblastic anemia (folate), P-450 induction, fetal hydantoin syndrome, SJS
Carbamazepine	Na⁺ channel block	Focal seizures; first-line for trigeminal neuralgia	SIADH, agranulocytosis or aplastic anemia, SJS (HLA-B*15:02 in Asians), neural tube defects
Valproate	Na⁺ channel block and ↑ GABA	Broad spectrum; first-line for tonic-clonic and myoclonic	Hepatotoxicity, pancreatitis, neural tube defects, weight gain, tremor
Ethosuximide	Thalamic T-type Ca²⁺ channel block	First-line for absence	GI upset, SJS
Lamotrigine	Na⁺ channel block	Focal and generalized seizures	SJS, especially with rapid titration
Benzodiazepines	↑ GABA-A opening frequency	First drug for status epilepticus	Sedation, respiratory depression

Ethosuximide targets T-type Ca²⁺ channels in absence seizures ("the sux blocks the T").

Anesthetics and opioids

Local anesthetics. These weak bases cross the axon membrane in their un-ionized form, then block voltage-gated Na⁺ channels from inside. Small, myelinated, rapidly firing fibers are blocked first, so sensation is lost in the order pain → temperature → touch → pressure. Infected, acidic tissue ionizes more of the drug, which then cannot penetrate, so larger doses are needed. The esters are procaine, benzocaine and tetracaine, and their PABA-related metabolites make allergy more likely. The amides are lidocaine, bupivacaine and mepivacaine, which have two i's in the name. Bupivacaine is the most cardiotoxic.

Inhaled anesthetics. These are halothane, isoflurane, sevoflurane and N₂O. Potency tracks with lipid solubility. The more lipid-soluble the agent, the lower its MAC (minimum alveolar concentration that keeps 50% of patients from moving on incision) and the more potent it is. Low blood/gas solubility means faster onset and recovery. Halothane is hepatotoxic.

Malignant hyperthermia. In patients with an RYR1 (ryanodine receptor) mutation, volatile anesthetics or succinylcholine (alone or together) trigger uncontrolled Ca²⁺ release from the sarcoplasmic reticulum. The result is hyperthermia, muscle rigidity, rising end-tidal CO₂ and high CK. Treat with dantrolene, which blocks the ryanodine receptor and halts that release. Dantrolene also treats neuroleptic malignant syndrome.

IV induction agents.

Propofol: rapid onset and offset; antiemetic; can cause hypotension.
Ketamine: NMDA antagonist producing dissociative anesthesia; raises cerebral blood flow and sympathetic tone; can cause emergence hallucinations.
Etomidate: hemodynamically stable but suppresses adrenal steroid synthesis (inhibits 11β-hydroxylase).
Thiopental: barbiturate with very rapid onset; its effect ends by redistribution out of the brain.

Opioids. Morphine, fentanyl and heroin are μ-receptor agonists. They cause analgesia, respiratory depression, miosis and constipation, and naloxone reverses an overdose.

Parkinson disease drugs

Oral levodopaCrosses the blood-brain barrier; dopamine itself cannot
Carbidopa addedBlocks peripheral DOPA decarboxylase but does not enter the CNS
More levodopa reaches the brainLess peripheral nausea and hypotension
Central conversion to dopamineImproves bradykinesia and rigidity

Levodopa limits. Long-term use leads to on-off fluctuations and dyskinesias.

Dopamine agonists: pramipexole and ropinirole (non-ergot) and bromocriptine (ergot). They can cause impulse-control disorders such as gambling.
MAO-B inhibitors: selegiline and rasagiline block central dopamine breakdown.
COMT inhibitors: entacapone (peripheral) and tolcapone (also central) prolong the effect of levodopa.
Amantadine: increases dopamine release and treats levodopa-induced dyskinesias.
Antimuscarinics: benztropine mainly improves tremor.

Antipsychotics

Typicals: potency sets the side effects. Typical antipsychotics are D2 antagonists. High-potency agents (haloperidol, fluphenazine, trifluoperazine) cause more extrapyramidal symptoms (EPS) and hyperprolactinemia. Low-potency agents (chlorpromazine, thioridazine) cause more anticholinergic, antihistamine (sedation) and α1-blocking (orthostatic hypotension) effects. Chlorpromazine causes corneal deposits, and thioridazine causes retinal deposits.

Hours: acute dystoniaOculogyric crisis, torticollis; treat with benztropine or diphenhydramine
Days: akathisiaInner restlessness
Weeks: parkinsonismBradykinesia, rigidity, tremor
Months: tardive dyskinesiaOrofacial choreiform movements, often irreversible; VMAT2 inhibitors such as valbenazine

Neuroleptic malignant syndrome (NMS). NMS causes fever, lead-pipe rigidity, autonomic instability, altered mental status and very high CK. Stop the drug and give dantrolene or bromocriptine. The mnemonic is FEVER: Fever, Encephalopathy, Vitals unstable, Elevated enzymes (CK), Rigidity.

Atypicals. Risperidone, olanzapine, quetiapine, ziprasidone and aripiprazole (a D2 partial agonist) act on 5-HT2A as well as D2. They cause fewer EPS, but they carry metabolic syndrome (weight gain, hyperglycemia, dyslipidemia), which is worst with olanzapine and clozapine. Risperidone raises prolactin. Clozapine is reserved for refractory schizophrenia. It requires ANC monitoring for agranulocytosis and can also cause seizures and myocarditis.

Antidepressants, lithium and sedative-hypnotics

Antidepressant classes

Class	Examples	Signature toxicity / note
SSRIs	Fluoxetine, sertraline	First-line; GI upset, sexual dysfunction, serotonin syndrome
SNRIs	Venlafaxine, duloxetine	Also treat neuropathic pain
TCAs	Amitriptyline, nortriptyline	Overdose: 3 C's (Convulsions, Coma, Cardiotoxicity with wide QRS) plus anticholinergic effects; treat with sodium bicarbonate
MAOIs	Phenelzine, tranylcypromine	Hypertensive crisis with tyramine (aged cheese, wine); serotonin syndrome with other serotonergic drugs

TCAs block cardiac Na⁺ channels. Sodium bicarbonate overcomes that block and narrows the QRS.

Drug-induced hyperthermia syndromes

Feature	Serotonin syndrome	NMS	Malignant hyperthermia
Trigger	Serotonergic drugs (SSRI, MAOI, tramadol)	D2 blockers	Volatile anesthetics, succinylcholine
Onset	Hours	Days to weeks	During anesthesia
Neuromuscular sign	Clonus, hyperreflexia	Lead-pipe rigidity	Generalized rigidity
Treatment	Cyproheptadine (5-HT2 antagonist), cooling, benzodiazepines	Stop drug; dantrolene or bromocriptine	Dantrolene

Lithium. Lithium, used for bipolar maintenance, has a narrow therapeutic index. Its classic adverse effects are tremor, nephrogenic diabetes insipidus, hypothyroidism and Ebstein anomaly (it is a teratogen). Lithium is cleared by the kidney, so thiazides, NSAIDs and ACE inhibitors can raise its level into the toxic range.

Benzodiazepines vs barbiturates. Both potentiate GABA-A chloride channels. Benzodiazepines increase the frequency of channel opening, whereas barbiturates increase its duration. Barbiturates are more lethal in overdose. Flumazenil reverses benzodiazepines only and does not reverse barbiturates.

Frenzodiazepines increase frequency, and barbiDURATes increase duration.