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Tolerability of Newer and Older Anticonvulsants

A Comparative Review

  • Comparative Review
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Summary

This review provides a comparison of conventional [phenobarbital (phenobarbitone), phenytoin, primidone, carbamazepine, ethosuximide and valproic acid (sodium valproate)] and newer (felbamate, oxcarbazepine, zonisamide, vigabatrin, gabapentin and lamotrigine) anticonvulsants.

The advantages and disadvantages of the older agents are well documented, because they have been administered to large numbers of patients for prolonged periods of time. A complete assessment of the adverse effects of the newer agents is not yet possible because of the relative lack of experience with them, such that the potential for infrequent adverse reactions or reactions occurring only after long term use is unknown.

Common early adverse effects (i.e. acute toxicity) mainly affect the CNS. Sedation or drowsiness are associated with phenobarbital, primidone and zonisamide, and sometimes with vigabatrin and gabapentin, usually transiently with the latter 2 drugs. Dizziness, vertigo, diplopia and motor incoordination characterise the acute toxicity of phenytoin and carbamazepine, and can occur when lamotrigine is coadministered with carbamazepine. Drug-induced stupor or coma is a rare adverse effect of valproic acid and vigabatrin. The initiation of treatment with several anticonvulsants can be followed by an increase in seizure frequency. However, true drug-induced seizures tend to only occur in patients with particular epileptic syndromes.

Gastrointestinal disturbances are more frequent after initiation of primidone, valproic acid and ethosuximide than other anticonvulsants. Leucopenia and increases in liver enzyme levels are frequent with all anticonvulsants, but usually are without clinical significance.

Rare early adverse reactions mainly involve a hypersensitivity syndrome, most often limited to a skin rash. Skin eruptions have been reported to occur with all the anticonvulsants, and are probably benign in most cases. However, potentially fatal reactions are possible. Toxic acute fulminant liver failure has been associated with exposure to valproic acid, mainly in polymedicated infants with particular epilepsies, and to felbamate.

CNS effects after long term administration of anticonvulsants are common. Sedation, drowsiness, fatigue and dizziness are common consequences of phenobarbital, primidone and zonisamide therapy. Other anticonvulsants usually produce minimal sedation. Lamotrigine may cause insomnia in adults. Phenytoin may slow motor functioning. Occasionally, phenytoin and valproic acid have been responsible for a subacute encephalopathy presenting as a reversible dementia. Movement disorders of various types are also a rare adverse reaction to all conventional anticonvulsants, although only valproic acid-induced tremor is of clinical significance. Behavioural changes and acute psychosis may result from the use of barbiturates, valproic acid and vigabatrin.

Anticonvulsant-related leucopenia has various significance. Aplastic anaemia has been reported secondary to many conventional drugs and to felbamate, usually in polymedicated patients. Thrombocytopenia or platelet dysfunction has only been associated with valproic acid. Connective tissue disorders are a possible consequence of prolonged exposure to barbiturates or phenytoin. They have not been reported with carbamazepine or the new drugs.

Increases in bodyweight are a prevalent adverse effect of valproic acid and vigabatrin, and have also been noted in patients exposed to gabapentin. Immunological disorders have to date not been associated with the newer drugs, but this may be a result of the limited experience with these agents.

Phenobarbital, primidone, phenytoin and carbamazepine have been reported to induce clinical, and more often biological, signs of osteomalacia, while oxcarbazepine has not. Hyponatraemia may be a complication of carbamazepine and oxcarbazepine therapy. The other older and newer anticonvulsants do not modify electrolyte levels.

All conventional anticonvulsants are metabolised in the liver, which leads to numerous more or less clinically significant drug-drug interactions. Phenytoin, phenobarbital, primidone and carbamazepine are enzyme-inducers, and valproic acid is an enzyme-inhibitor Phenytoin and valproic acid are also highly protein-bound. Obviously, the newer agents will be easier to prescribe because of no or minimal drug-drug interactions.

The older anticonvulsants are also all weak teratogenic agents. No conclusions can be drawn concerning the teratogenic potential of the newer drugs in humans, although animal data suggest that they are devoid of this effect.

To date, there has been insufficient experience with new drugs in elderly patients to compare their tolerability with that of conventional agents in this patient population. Elderly patients often receive multiple medications for systemic illnesses. Therefore, they may benefit greatly from drugs, such as vigabatrin and gabapentin, that are unlikely to cause drug interactions, as well as from drugs with moderate protein binding, such as lamotrigine, Limited data suggest that the newer drugs are well tolerated in this age group, even in the presence of some decrease in hepatic or renal function.

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  1. Department of Neurology, University Hospital, Bordeaux, France

    Pierre Loiseau

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Loiseau, P. Tolerability of Newer and Older Anticonvulsants. CNS Drugs 6, 148–166 (1996). https://doi.org/10.2165/00023210-199606020-00006

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