Newer Anticonvulsants

Definition and general advantages. The second- and third-generation antiseizure medications — lamotrigine, levetiracetam, topiramate, gabapentin, pregabalin, oxcarbazepine, zonisamide, lacosamide, brivaracetam, perampanel, eslicarbazepine and cenobamate. Their advantages over phenytoin, carbamazepine, phenobarbitone and valproate are fewer cytochrome P450 interactions, linear (first-order) kinetics, low protein binding, a wider therapeutic index, and no need for routine level monitoring — all particularly valuable in polypharmacy.

Mechanisms of action. Sodium-channel blockade — lamotrigine, oxcarbazepine, eslicarbazepine; slow inactivation of sodium channels — lacosamide; SV2A synaptic vesicle protein binding — levetiracetam and brivaracetam; α2δ calcium-channel subunit binding — gabapentin and pregabalin; AMPA receptor antagonism — perampanel; multiple mechanisms — topiramate and zonisamide.

Key drugs and their place. Levetiracetam — broad spectrum, intravenous form available, no significant interactions, renal dose adjustment; the workhorse drug in geriatrics. Lamotrigine — broad spectrum, mood-stabilising, best tolerability, but needs slow titration. Lacosamide — focal seizures, IV available. Oxcarbazepine — focal seizures, better tolerated than carbamazepine. Topiramate — broad spectrum and also effective in migraine. Gabapentin and pregabalin — weak antiseizure agents, mainly used for neuropathic pain.

Adverse effects to name. Lamotrigine — rash and Stevens–Johnson syndrome if titrated too fast (halve the dose when combined with valproate). Levetiracetam — irritability, aggression, depression and psychosis. Topiramate — cognitive slowing, word-finding difficulty, weight loss, renal stones, acute glaucoma and metabolic acidosis. Oxcarbazepine and eslicarbazepine — hyponatraemia. Perampanel — serious psychiatric and behavioural reactions (boxed warning). Lacosamide — dizziness and PR interval prolongation. Zonisamide — stones and oligohidrosis. Gabapentinoids — oedema, sedation, weight gain and misuse potential.

Geriatric considerations. These agents are preferred over the older drugs in old age because they do not induce CYP450 enzymes and therefore do not compromise warfarin, DOACs, statins, antihypertensives, antiarrhythmics or chemotherapy, and they cause less bone loss. However, levetiracetam, gabapentin, pregabalin and lacosamide all require dose reduction for creatinine clearance, and every agent can cause dizziness, ataxia and falls. Sedative and anticholinergic burden must be counted under the AGS Beers Criteria.

Limitations. They are substantially more expensive — a major issue in Indian practice — and parenteral formulations are limited. Importantly, they do not achieve higher seizure-freedom rates than the older drugs: SANAD II showed that levetiracetam was neither clinically superior nor cost-effective compared with lamotrigine for focal epilepsy, and valproate remained best for generalised epilepsy. Evidence in the very old and the frail remains sparse.

Cenobamate — the newest third-generation agent for drug-resistant focal epilepsy. It has a dual mechanism — inhibition of the persistent sodium current plus positive allosteric modulation of GABA-A receptors — and produces unusually high seizure-freedom rates in adjunctive trials (around 20% at the highest dose, far above the usual 2–5% for add-on agents). Two cautions are examinable: it must be titrated very slowly over at least 12 weeks starting at 12.5 mg daily to avoid DRESS (drug reaction with eosinophilia and systemic symptoms), and it induces CYP3A4 and inhibits CYP2C19, so interactions must be rechecked — a real consideration in the polypharmacy of old age. Brivaracetam, eslicarbazepine and perampanel are currently under study in older populations.