Drug Treatment of the Epilepsies

The term epilepsy applies to a group of disorders that are characterized by sudden and transient episodes (seizures) of motor (convulsions), sensory, autonomous or psychic origin. The seizures are usually correlated with abnormal and excessive discharges in the brain and can be visualized on the electroencephalogram (EEG). 

The epilepsies are estimated to affect 20-40 million individuals worldwide and are more common in children than in adults. They are classified into two broad groups primary or idiopathic epilepsy is the term applied to those types for which no specific cause can be identified, and secondary or symptomatic epilepsy arises when the symptoms are associated with trauma, neoplasm, infection, cerebrovascular disease or some other physically induced lesion of the brain. Seizures that accompany severe metabolic disturbances are not classified as epilepsy. 

For the purpose of drug treatment, the epilepsies are classified according to the seizure type. The classification generally used is based on that proposed by the Commission on Classification and Terminology of the International League against Epilepsy. The main groups are  

Fundamentals of Psychopharmacology. Third Edition. By Brian E. Leonard 2003 John Wiley Sons, Ltd. ISBN 0 471 52178 7 

Partial (focal) seizures, or seizures initiated locally in the brain. These include  

---

The anticonvulsant primidone (1035) resembles phenobarbital but lacks the 2-oxo substituent. It was introduced in 1952 and has remained a valuable drug for controlling grand mal and psychomotor epilepsy. As might be expected, primidone is metabolized to yield phenobarbital (1034 X = 0) and C-ethyl-C-phenylmalondiamide (1036), both of which have marked anticonvulsant properties however, primidone does have intrinsic activity and an appropriate mixture of its metabolites has only a fraction of its activity (73MI21303). Primidone may be made in several ways, of which desulfurization by Raney nickel of the 2-thiobarbiturate (1034 X = S) or treatment of the diamide (1036) with formic acid (at 190 °C) seem to be the most satisfactory (54JCS3263). 

French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs II treatment of refractory epilepsy, report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2005 62 1261-1273. 

In addition to epilepsy, neuronal death due to the toxic effects of glutamate has also been implicated in cerebral ischaemia associated with multi-infarct dementia and possibly Alzheimer s disease. With the plethora of selective excitatory amino acid receptor antagonists currently undergoing development, some of which are already in clinical trials, one may expect definite advances in the drug treatment of neurodegenerative disorders in the near future. 

Drugs that may cause cognitive disorders in the elderly. Med Let 2000 42 111-112. Faught E. Epidemiolgy and drug treatment of epilepsy in elderly people. Drugs Aging 1999 15 255-269. 

Anticonvulsant action In anaesthetic dose all barbiturates e.g. phenobarbitone, mephobarbitone possess anticonvulsant action. Phenobarbitone is drug of choice for the treatment of grandmal epilepsy (details are given in chapter Antiepileptic drugs ). 

Side effects. Many of the side effects reported to occur with topiramate have been found in patients receiving other antiepileptic drugs concurrently. Such side effects as ataxia, confusion, dizziness, fatigue, somnolence, memory disturbance, depression and agitation appear to be less frequent in those patients receiving topiramate as a monotherapy. Weight loss has been reported in many patients this effect may be due to drug induced anorexia. Topiramate has proven efficacious in the treatment of severe epilepsy. 

Seizures have been classified into two broad groups, partial (or focal), and generalized. Choice of drug treatment is based on the classification of the epilepsy being treated (Figure 15.2). 

Therapeutic drug monitoring is as essential as clinical and biochemical monitoring in the drug treatment of epilepsy. 

Bromide (1857) was the first drug to be used for the treatment of epilepsy, but it is now obsolete. Phenobarbital, introduced in 1912, controlled patients resistant to bromides. The next success was the discovery in 1938 of phenytoin (a hydantoin) which is structurally related to the barbiturates. Since then many other drugs have been discovered, but phenytoin still remains a drug of choice in the treatment of major epilepsy. Over the past ten years there has been a dramatic increase in the number of new anticonvulsant drugs (vigabatrin, gabapentin, lamotrigine, topiramate, oxcarbazepine, levetiracetam), but none has been shown to be superior to the major standard anticonvulsants (phenytoin, carbamazepine and sodium valproate). 

The direct costs of epilepsy include the cost of the drug, treatment of adverse events, emergency room visits, drug levels, laboratory tests, physician visits, rehabilitation, and transportation. Indirect costs include the costs associated with time lost from work, the inability to get a job, decreased productivity, and mortality. 

The ability of conotoxins to selectively block ion channels and neuronal receptors has led to their development into therapeutic agents. So far, most conotoxin applications as therapeutics have been concentrated on the treatment of different forms of pain. The first drug of marine origin is based on the w-conotoxin MVIIA for the treatment of chronic pain (see helow). Other therapeutic applications of conotoxins include treatment of schizophrenia, epilepsy, neuromuscular disorders, certain types of cancer, urinary dysfunction, Parkinson s disease, Alzheimer s disease, stroke, and related hrain injuries. Other uses include muscle relaxants, anesthetics, and antiseizure compounds. As the demand for new painkillers and other neuropharmacological agents is expected to increase, the value of the discovery and testing of new conotoxins is expected to continue to expand. 

---