Page 449 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 24 Antiseizure Drugs 435

had been difficult to achieve. There is little information on ANTISEIZURE DRUGS IN
antiseizure drug withdrawal in seizure-free adults. Withdrawal
is believed to be more likely to be successful in patients with DEVELOPMENT
generalized epilepsies who exhibit a single seizure type, whereas Several potential new antiseizure drugs are in late clinical develop-
longer duration of epilepsy, an abnormal neurologic exami- ment; these are Staccato (thermal aerosol inhaled) alprazolam, for
nation, an abnormal EEG, and certain epilepsy syndromes, acute repetitive seizures; intranasal midazolam, for acute repetitive
including juvenile myoclonic epilepsy, are associated with seizures; allopregnanolone, for status epilepticus; ganaxolone,
increased risk of recurrence. Drugs are generally withdrawn for status epilepticus and rare epilepsy syndromes; cannabidiol,
slowly over a 1- to 3-month period or longer. Abrupt cessa- for epileptic encephalopathies and focal seizures; cannabidiva-
tion may be associated with return of seizures and even a risk rin, for focal seizures; cenobamate (YKP3089), for focal seizures;
of status epilepticus. Some drugs are more easily withdrawn fenfluramine, for Dravet’s syndrome; and stiripentol, for Dravet’s
than others. Physical dependence occurs with barbiturates and syndrome. Other drugs are in earlier stages of development;
benzodiazepines, and there is a well-recognized risk of rebound current information can be found on the Epilepsy Foundation
seizures with abrupt withdrawal. website at http://www.epilepsy.com/etp/pipeline_new_therapies.

SUMMARY ANTISEIZURE DRUGS

Mechanism
Type, Drug of Action Pharmacokinetics Clinical Applications Toxicities, Interactions
SODIUM CHANNEL BLOCKERS
• Carbamazepine Sodium channel Rapidly absorbed orally, with Focal and focal-to-bilateral Toxicity: Nausea, diplopia, ataxia,
blocker bioavailability 75–85% • peak levels in tonic-clonic seizures; hyponatremia, headache • Interactions:
4–5 h • plasma protein binding 75% trigeminal neuralgia Phenytoin, valproate, fluoxetine, verapamil,
• extensively metabolized in liver, in macrolide antibiotics, isoniazid,
part to active carbamazepine-10, propoxyphene, danazol, phenobarbital,
11-epoxide • t 1/2 of parent in adults primidone, many others
initially 25–65 h, decreasing to
12–17 h with autoinduction
• Oxcarbazepine: Similar to carbamazepine; 100% bioavailability; 1-2 h t 1/2 but active metabolites with t 1/2 of 8-12 h; fewer interactions reported
• Eslicarbazepine acetate: Similar to oxcarbazepine but shown to be effective when given once daily and may be more rapidly converted to the active metabolite
• Lamotrigine Sodium channel Nearly complete (~90%) absorption Focal seizures, generalized Toxicity: Dizziness, headache, diplopia, rash
blocker • peak levels in 1–3 h • protein binding tonic-clonic seizures, absence • Interactions: Valproate, carbamazepine,
55% • extensively metabolized; no seizures, other generalized oxcarbazepine, phenytoin, phenobarbital,
active metabolites • t 1/2 8–35 h seizures; bipolar depression primidone, succinimides, sertraline,
topiramate
• Lacosamide Sodium channel Complete absorption • peak levels in Focal seizures Toxicity: Dizziness, headache, nausea • small
blocker, slow 1–2 h • protein binding <30% • no active increase in PR interval • Interactions:
blocking kinetics metabolites • t 1/2 12–14 h Minimal
• Phenytoin, Sodium channel Absorption is formulation dependent Focal seizures, tonic-clonic Toxicity: Diplopia, ataxia, gingival
fosphenytoin blocker • highly bound to plasma proteins • no seizures hyperplasia, hirsutism, neuropathy
active metabolites • dose-dependent • Interactions: Phenobarbital, carbamazepine,
elimination, t 1/2 12–36 h isoniazid, felbamate, oxcarbazepine,
• fosphenytoin is for IV, IM routes topiramate, fluoxetine, fluconazole, digoxin,
quinidine, cyclosporine, steroids, oral
contraceptives, others
(continued)