5.2 Antiepileptics & Neurologic Agents

Choosing an Antiepileptic by Seizure Type

Drug selection is driven by seizure classification, and this is a reliable exam angle:

Valproate is the most effective agent for generalized epilepsies, but it is contraindicated in women of childbearing potential wherever an alternative exists because of teratogenicity (neural tube defects, neurodevelopmental harm); international regulators require a pregnancy-prevention program when it must be used.

Two cross-cutting points apply to almost all antiepileptics. First, pregnancy counseling: enzyme-inducing agents (carbamazepine, phenytoin) reduce hormonal contraceptive efficacy, and all women on antiepileptics who may conceive should receive high-dose folic acid (5 mg daily) preconception and through the first trimester, with the fewest effective agents at the lowest effective dose. Second, baseline and periodic monitoring matters: full blood count and liver function for carbamazepine and valproate (valproate causes hepatotoxicity, pancreatitis, and thrombocytopenia), and awareness that abrupt withdrawal of any antiepileptic can trigger rebound seizures - adherence counseling is a recurring pharmacist role.

The High-Yield Antiepileptics

Carbamazepine

Carbamazepine blocks voltage-gated sodium channels and is first-line for focal seizures and trigeminal neuralgia. Three facts dominate exam questions:

• CYP3A4 autoinduction - it induces its own metabolism, so plasma concentrations fall over the first 2-4 weeks and the dose often needs upward adjustment; it also reduces the effectiveness of hormonal contraceptives, warfarin, and many other substrates.
• Hyponatremia (SIADH-like) - check sodium if the patient becomes confused or lethargic.
• HLA-B*1502 - patients of Han Chinese, Thai, and other Southeast Asian ancestry carrying this allele have a greatly elevated risk of Stevens-Johnson syndrome / toxic epidermal necrolysis; screen before starting in at-risk populations.

Phenytoin

Phenytoin exhibits nonlinear (Michaelis-Menten) kinetics: once metabolizing enzymes saturate, elimination switches from first-order to zero-order, so a small dose increase (even 25-50 mg) can produce a large, disproportionate jump in plasma level. Target 10-20 mg/L. Signs of toxicity follow a roughly dose-related sequence: nystagmus first, then ataxia, diplopia, sedation, and encephalopathy. Chronic adverse effects include gingival hyperplasia (meticulous dental hygiene), hirsutism, coarsened facies, folate deficiency, and osteomalacia. Phenytoin is highly protein-bound and a potent enzyme inducer, creating many interactions; in hypoalbuminemia or renal failure, interpret total levels with an albumin correction or measure free drug. IV phenytoin must be given slowly (max 50 mg/min) because of hypotension and arrhythmia risk from its propylene glycol diluent.

Levetiracetam

Levetiracetam binds the synaptic vesicle protein SV2A, has minimal drug interactions, no required level monitoring, and renally-adjusted dosing - a convenient broad-spectrum option. Its characteristic drawback is behavioral adverse effects: irritability, agitation, depression, and occasionally psychosis, particularly in patients with prior psychiatric history.

Gabapentinoids

Gabapentin and pregabalin bind the alpha-2-delta subunit of voltage-gated calcium channels. They are used for focal seizure adjuncts but mainly for neuropathic pain; both are renally cleared (dose-adjust in CKD), cause sedation and weight gain, and have recognized misuse and dependence potential, which matters for UAE controlled-medicine dispensing rules.

Status Epilepticus

Convulsive status epilepticus (seizure activity beyond 5 minutes) is a medical emergency treated in stages:

1. First-line - a benzodiazepine: IV lorazepam (or diazepam) in hospital; buccal midazolam or rectal diazepam out of hospital. Repeat once if the seizure continues.
2. Second-line - a longer-acting antiepileptic: IV phenytoin (or fosphenytoin), levetiracetam, or valproate - the ESETT trial showed these three are broadly equivalent.
3. Refractory status: general anesthesia with agents such as midazolam, propofol, or thiopental infusion in intensive care.

Parkinson's Disease

Parkinson's disease reflects dopaminergic loss in the substantia nigra. Levodopa, always combined with a peripheral dopa-decarboxylase inhibitor (carbidopa or benserazide) to reduce peripheral side effects, remains the most effective symptomatic treatment. With long-term use most patients develop motor fluctuations - end-of-dose "wearing off" and unpredictable "on-off" phenomena - plus peak-dose dyskinesias. Other classes:

• Dopamine agonists (pramipexole, ropinirole, rotigotine patch) - useful initial therapy in younger patients to delay levodopa; watch for impulse-control disorders (gambling, hypersexuality), somnolence, and hallucinations.
• MAO-B inhibitors (selegiline, rasagiline, safinamide) - mild symptomatic benefit; avoid with SSRIs/pethidine because of serotonin syndrome risk.
• COMT inhibitors (entacapone, opicapone) - extend levodopa's half-life to smooth wearing-off; entacapone discolors urine orange.
• Anticholinergics (trihexyphenidyl) - help tremor in young patients but are avoided in the elderly (confusion, urinary retention).

Alzheimer's Disease

Donepezil (with rivastigmine and galantamine) is an acetylcholinesterase inhibitor for mild-to-moderate Alzheimer's disease; it modestly improves cognition without altering disease progression. Cholinergic adverse effects - nausea, diarrhea, bradycardia (caution with conduction disease), and vivid dreams - are class dose-limiting. Memantine, an NMDA-receptor antagonist, is used for moderate-to-severe disease and is better tolerated, with dizziness and confusion the main effects. Neither class is curative; pharmacist counseling on realistic expectations is examinable.

Multiple Sclerosis (Concept Level)

Multiple sclerosis is managed with disease-modifying therapies (interferon beta, glatiramer acetate, fingolimod, ocrelizumab, natalizumab) that reduce relapse frequency, plus acute relapses treated with high-dose IV methylprednisolone. For the DHA assessment, concept-level familiarity suffices: know that these agents modify disease course, that natalizumab carries progressive multifocal leukoencephalopathy risk, and that supportive drugs (e.g., baclofen for spasticity) manage symptoms.