Anticonvulsants
In general, anticonvulsants are:
- Well absorbed orally
- Highly protein bound
- Hepatically metabolised by CYP450 enzymes, and induce their own metabolism (as well as that of other drugs)
- Renally eliminated
- Interact with each other
| Property | Phenytoin | Sodium Valproate | Carbamazepine | Levetiracetam |
|---|---|---|---|---|
| Uses | GTCS, partial seizures, trigeminal neuralgia, ventricular arrhythmias | Partial seizures | Antiepileptic, trigeminal neuralgia | GTCS, partial seizures, myoclonic seizures, seizure prophylaxis |
| Presentation | Capsules, syrup, solution. IV formulation incompatible with dextrose. | Tablets, syrup, solution | Tablets, suppositories, syrup | Tablets, oral liquid, IV liquid |
| Route of Administration | PO, IV, IM | PO, IV | PO | PO, IV (over 15 minutes) |
| Dosing | 15-20mg.kg-1 load, aiming plasma levels 10-20mcg.ml-1 | 300-1250mg BD | 50-800mg BD | Typically 1g loading, then 500mg BD increasing up to 1.5g BD. Dose adjusted in renal impairment. |
| Mechanism of Action | Stabilises Na+ channels in their inactive state, inhibiting generation of further action potentials. | Stabilises Na+ channels in their inactive state and potentiates GABA | Stabilises Na+ channels in their inactive state and potentiates GABA | Unknown, but different to other antiepileptics and may be related to inhibition of N-type Ca2+ currents |
| Absorption | Slow PO absorption. PO bioavailability 90% | PO bioavailability 100% | 95% PO bioavailability | Near 100% PO bioavailability |
| Distribution | Highly protein bound | Highly protein bound | Highly protein bound | Nil significant protein binding, VD ~0.5L.kg-1 |
| Metabolism | Hepatic hydroxylation with highly individual variation in dosing. Obeys first-order kinetics in the therapeutic range, and zero-order kinetics just above the therapeutic range. Metabolised by CYP450. Induces warfarin, benzodiazepines, OCP metabolism. Inhibited by metronidazole, chloramphenicol, isoniazid. Genetic polymorphism results in reduced metabolism in 5-15% of patients. | Hepatic to inactive and active metabolites | Hepatic | Hepatic hydrolysis to inactive metabolites |
| Elimination | Renal elimination of inactive metabolites and active drug | Renal elimination of metabolites and active drug | Renal elimination | Renal of active drug (major route) and metabolite (minor route) |
| CVS | ↓ BP, heart block, and asystole with rapid administration, antiarrhythmic properties | Antiarrhythmic | ||
| CNS | ↑ Seizure threshold, paraesthesia, ataxia, nystagmus, slurred speech, tremor, vertigo. | ↑ Seizure threshold | ↑ Seizure threshold | ↑ Seizure threshold, anxiolytic. Minimal ↓ in seizure threshold on cessation. |
| Renal | Water retention from ADH-like effects | Rarely precipitates AKI | ||
| GIT | Hepatotoxicity (idiosyncratic). Nausea and vomiting. | Hepatotoxicity. | ||
| Haeme | Aplastic anaemia and other blood dyscrasias | Thrombocytopenia, leukopenia (requires regular testing) | Thrombocytopenia | |
| Immune | Rash | SJS | ||
| Metabolic | Hyperammonaemia | |||
| Other | Requires monitoring due to narrow therapeutic window and significant pharmacokinetic variation. Gum hyperplasia. Teratogenic. May precipitate porphyria. |
Reduces efficacy of aminosteroids. Teratogenic. |
References
- Peck TE, Hill SA. Pharmacology for Anaesthesia and Intensive Care. 4th Ed. Cambridge University Press. 2014.
- Smith S, Scarth E, Sasada M. Drugs in Anaesthesia and Intensive Care. 4th Ed. Oxford University Press. 2011.
- CICM March/May 2010
- Petkov V. Essential Pharmacology For The ANZCA Primary Examination. Vesselin Petkov. 2012.
- Levetiracetam - Drug Information. FDA. 2009.