Epilepsy antiepileptics

Epilepsy Antiepileptic drugs, surgery Medication serum concentrations, sedation, cognitive abilities, liver function tests, blood dyscrasias, bleeding abnormalities, CNS toxicities, rashes, seizure counts, other drug-specific adverse effects... 

Bialer M, Johannessen SI, Kupferberg HJ et al (2001) Progress report on new antiepileptic drugs a summary of the Fifth Eilat Conference (EILAT V). Epilepsy Res 43(1) 11—5 8... 

All such animal procedures suffer from the obvious and basic problem that laboratory animals do not behave like humans and that humans cannot reliably interpret their reactions and behaviour. Thus we know that Parkinson s disease is caused by a degeneration of the dopaminergic nigrostriatal tract but its lesion in animals does not produce any condition which resembles human Parkinsonism, except in primates, even though there are functional tests (e.g. rotational movements) which readily establish that loss of dopamine function and also respond to its augmentation (Chapter 15). By contrast, there are many ways, e.g. electrical stimulation and the administration of certain chemicals, to induce convulsions in animals and a number of effective antiepileptic drugs have been introduced as a result of their ability to control such activity. Indeed there are some tests, as well as animals with varied spontaneous seizures, that are even predictive of particular forms of epilepsy. But then convulsions are a very basic form of activity common to most species and epileptic seizures that are characterised by behavioural rather than motor symptoms are more difficult to reproduce in animals. 

Figure 16.7 The structure of some established antiepileptic drugs (AEDs) and some newer ones. Note that while the structures of phenytoin and ethosuximide are similar and also close to that of phenobarbitone, they are effective in different forms of epilepsy. Vigabatrin, progabide and gabapentin are clearly related to GABA. Muscimol is a GABAa agonist but is not an effective antiepileptic drug...

Children and women with epilepsy have unique problems related to the use of antiepileptic drugs. 

Cortical function is modulated by many other neurotransmitters. However, their role in the pathophysiology of epilepsy and in the action of antiepileptic drugs is not yet well known. 

The ultimate outcome goal for any patient with epilepsy is elimination of all seizures without any adverse effects of the treatment. An effective treatment plan would allow the patient to pursue a normal lifestyle with complete control of seizures. Specifically, the treatment should enable the patient to drive, perform well in school, hold a reasonable job, and function effectively in the family and community. However, due to the intractability of the seizures or sensitivity to antiepileptic drugs (AEDs), many patients are not able to achieve these outcomes. In these cases, the goal of therapy is to provide a tolerable balance between reduced seizure severity and/or frequency and medication adverse effects that optimizes the individual s ability to have a lifestyle as nearly normal as possible. 

BC, a 22-year-old woman, was diagnosed 2 years ago with juvenile myoclonic epilepsy. She has been treated with valproate 1500 mg/day. Since starting valproate she has gained 45 pounds (20.5 kg), continues to have occasional myoclonic jerks, had a generalized tonic-clonic seizure 3 months ago, and is sexually active. Additionally, she complains of easily falling asleep during the day. Due to adverse effects, poor seizure control, and the risk of birth defects with valproate, the decision is made to switch to a different antiepileptic drug. 

French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs I treatment of new onset 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 1252-1260. 

Calcium channels have been shown to play a role in epilepsy as well [23]. Currently used antiepileptic drugs exhibit a wide spectrum of activity, including modulation of voltage-gated sodium and calcium channels. T-type calcium channels have been demonstrated to play an important role in absence epilepsy, a specific form of epilepsy characterized by brief lapses in consciousness correlated with spike-and-wave discharges in the electroencephalogram [14,24-28]. Ethosuximide 1 has been shown to block T-type calcium channels and is used clinically to treat absence epilepsy [25]. Several selective small-molecule T-type calcium channel antagonists have demonstrated efficacy in rodent epilepsy models (vide infra). 

FIGURE 52-1. Algorithm for treatment of epilepsy. (AED, antiepileptic drug QOL, quality of life.)... 

Data from Fought Pharmacokinetic considerations in prescribing antiepileptic drugs. Epilepsia 2001 42(Suppl 4) 19-23 Leppik IE. Contemporary Diagnosis and Management of the Patient with Epilepsy, 6th ed. Newton, PA Handbooks in Health Care, 2006.02-149 and Bourgeois BED. Pharmacokinetics and pharmacodynamics of antiepiieptic drugs. In WyllieE. ed. The Treatment of Epilepsy, 4th ed. Philadelphia Lippincott Williams 8 Wilkins, 2006 656-669. 

Krogsgaard-Larsen, P., Falch, E., Larsson, O. M., and Schousboe, A. (1987) GABA uptake inhibitors relevance to antiepileptic drug research. Epilepsy Res. 1,77-93. 

Treatment of epilepsy is often more complex in the elderly (Tallis et al. 2002). Plasma concentration of antiepileptic drugs that are adequate for younger patients may be toxic for older adults. Clinical response, and not only plasma concentration of the drug, is more important in the elderly for evaluation of antiepileptic treatment. 

Valproic acid (dipropylacetic acid) is a single branched chain carboxylic acid that is structurally unlike any of the other drugs used in the treatment of bipolar disorder or epilepsy. The amide derivative, valproamide, is available in Europe as a more potent form of valproate. Valproate was first developed in Erance as an antiepileptic agent in 1963. As an antiepileptic agent, it was shown to be active against a variety of epilepsies without causing marked sedation. 

In assessing the risk benefit ratio, it is also necessary to consider the benefit for the child resulting from adequate therapeutic treatment of its mother. For instance, therapy with antiepileptic drugs is indispensable, because untreated epilepsy endangers the infant at least as much as does administration of anticonvulsants. 

The mechanism of antiepileptic drags is not sufficiently clear, as the etiology of epilepsy is not yet completely understood. 

Acetazolamide is used for epilepsy in the absence of attacks and also in conjunction with other antiepileptic drugs. The most common synonym of this drag is diamox. 

Epilepsy, monotherapy Indicated for conversion to monotherapy in adults with partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (AED). 

Although low risks of teratogenesis, including risk of neural tube defects have been reported for several antiepileptics it should be realized that uncontrolled epilepsy poses far more risks for the fetus. 

Vigabatrin is a new antiepileptic for use in epilepsy unresponsive to other therapy. It is an irreversible inhibitor of GABA-transaminase, the enzyme responsible for inactivation of the neurotransmitter GABA and it has shown efficacy against partial and secondarily generalized seizures. The principal unwanted effects are psychiatric disorders, including depression and psychosis, in a small number of patients. 

At present, the primary indication for vigabatrin is in the treatment of patients with partial seizures, but it appears to be an effective and generally well tolerated antiepileptic medication for other seizure types as well. It should not be used in patients with absence epilepsy or with myoclonic seizures. Vigabatrin is not approved as an AED in the United States, although it is approved in many other countries. 

It is now generally accepted that the specific antiepileptic action of ethosuximide (and the older agent tri-methadione, no longer employed) against absence epilepsy is its ability to reduce the low-threshold calcium current (LTCC) or T (transient) current. These currents underlie the 3-Hz spike wave discharges that are characteristic of absence epilepsy. A blockade of... 

Several examples of non-oxicam-type 1,2-thiazine-containing small molecule enzyme inhibitors have been disclosed. The landmark work in this area involves the antiepileptic drug sulthiame 10, first discovered and approved for use over 30 years ago. Interest in this carbonic anhydrase inhibitor has been renewed by recent work on its efficacy in treatment of both childhood benign and focal epilepsies <2002MI469>. 

Murialdo, G., Galimberti, C.A., Magri, E, Sampaolo, P., Copello, E, Gianelli, M.V., Gazzerro, E., Rollero, A., Deagatone, C., Manni, R., Ferrari, E., Polleri, A., and Tartara, A. (1997) Menstrual cycle and ovary alterations in women with epilepsy on antiepileptic therapy. / Endocrinol Invest 20 519-526. 

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