Felbamate

PROLOGUE

This paper describes the format and content on the topic "Antiepileptic Drugs." This topic is covered during the first semester for second professional year PharmD students in the required course Principles of Drug Action III (PHA 442). The topic uses approximately three 50-minute didactic lectures and an hour of student presentation on a case history.

DIDACTIC LECTURES

A brief but comprehensive understanding of epilepsy is provided before the drugs are covered in didactic lecture. Epilepsy affects about 20-40 million people worldwide. It is more common in children than adults, with an incidence of about eight per 1000 children under the age of seven years. Epilepsy is the second most common neurological disorder, after stroke. Epilepsy is a disorder of the central nervous system characterized by excessive electrical discharge. A typical seizure may include brief and periodic episodes of change in the normal state of consciousness, loss of muscle tone, and sensory and behavioral alterations. Seizures could be nonepileptic if evoked in the normal brain by treatments, such as electric shock or chemical convulsants, or epileptic when occurring without evident provocation. About a hundred years ago, John Hughlings Jackson, the father of the modern concept of epilepsy, proposed that the seizures were caused by "occasional, sudden, excessive, rapid, and local discharge of gray matter" and a generalized convulsion resulted when normal brain tissue is invaded by the seizure activity initiated in the abnormal focus. Jackson's concept remains unchanged and has been substantiated by the electrical proof. In some cases of epilepsy, a seizure may be associated with presence of an infection, tumor, stroke, or birth injury. However, in other cases, it may be associated with a biochemical and/or physiological defect in the brain of the patient with epilepsy presumably due to an imbalance of excitatory and inhibitory neurotransmitters. This imbalance of neurotransmitters may be a result of structural pathology or genetic factors or stress(1-3).

Among the ancient cultures, epilepsy was considered due to possession by spirits and gods and treated by trephening, cupping, and herbal and animal extracts. Epilepsy does not shorten life or cause insanity or subnormal intelligence. Some famous individuals such as religious leaders: Moses, St. Paul, Luther, and Mohammad; military geniuses: Alexander the Great, Julius Caesar, Napoleon, and the Duke of Wellington; writers and poets: Socrates, Dante, Lord Byron, Flaubert, Guy de Maupassant, and Dostoyevsky; and musicians and painters Beethoven, Berlioz, Paganini, and Van Gogh had epilepsy(4).

Seizure Classification

More than 40 distinct epileptic symptoms have been identified and broadly classified into partial and generalized seizures (Table I). The partial seizures account for about 60 percent of all epilepsies and commonly are due to a lesion in some part of the cortex, tumors, developmental malformations, trauma, stroke, and infections. These lesions are evident on brain imaging. Partial seizures are those associated with discharge that begins locally and often remains localized. Partial seizure may produce relatively simple symptoms without loss of consciousness, such as involuntary muscle contractions, abnormal sensory experiences or autonomic discharge, or they may cause more complex effects on consciousness, mood and behavior, often termed psychomotor epilepsy.

An epileptic focus in the motor cortex results in attacks, sometimes called Jacksonian epilepsy, consisting of repetitive jerking of a particular muscle group, which spreads and may involve much of the body for about two minutes before ending. The patient does not lose consciousness, though he or she may lose voluntary control of the affected parts of the body. In psychomotor epilepsy, which is often associated with a focus in the temporal lobe, the attack may consist of stereotyped movements such as rubbing or patting movements, or much more complex behavior such as dressing, walking, or hair-combing. The seizure usually lasts for a few minutes, after which the patient recovers with no recollection of the event. The behavior during the seizure can be bizarre and accompanied by a strong emotional response(1,5).

The generalized epilepsies account for approximately 40 percent of all epilepsies and etiology is normally genetic. Generalized seizures involve the whole brain, including the reticular system, thus producing abnormal electrical activity throughout both hemispheres. Immediate loss of consciousness is characteristic of generalized seizures. The main categories are tonic-clonic seizures (grand mal) and absences (petit mal). A tonic-clonic seizure consists of an initial strong contraction of the whole musculature, causing a rigid extensor spasm. Respiration stops and defecation, micturition, and salivation often occur. This tonic phase lasts for about one minute and is followed by a series of violent, synchronous jerks that gradually ends in about 2-4 minutes. The patient stays unconscious for a few more minutes and then gradually recovers, feeling ill and confused. Injury may occur during the convulsive episode.

Absence seizures occur in children; they are much less dramatic but may occur more frequently (many seizures each day) than tonic-clonic seizures. The patient abruptly ceases whatever he/she was doing, sometimes stopping speaking in mid-sentence, and stares vacantly for a few seconds, with little or no motor disturbance. The patient is unaware of his/her sursoundings and recovers abruptly with no aftereffects. A particularly severe kind of epilepsy (Lennox-Gastaut syndrome) that occurs in children is associated with progressive mental retardation, possibly a reflection of excitotoxic neurodegeneration. Pharmacologically there is a clear distinction between drugs that are effective in absence seizures and those that are effective in other types of epilepsy, though most drugs show little selectivity with respect to the other clinical subdivisions. With optimal drug therapy, epilepsy is controlled completely in about 75 percent of patients, and about 10 percent continue to have seizures at intervals of one month or less, which severely disrupts their life and work. There is therefore a need to improve the efficacy of therapy(1,5). The clinical aspects of certain generalized seizures are highly correlated with experimental seizures produced in animals by subcutaneous pentylenetetrazol injections, and partial seizures correlated with experimental seizures produced by maximal electroshock (MES) test.

ANTISEIZURE DRUGS

Available antiepileptic drugs control seizures in about two-thirds of the patients. In 1857, Sir Charles Locock, the attending physician for the birth of Queen Victoria's children, suggested potassium bromide for the treatment of epilepsy. Phenobarbital was introduced in 1912, and later, in 1938, phenytoin was found to be effective in experimental seizures. Significant progress was made both in the development of experimental models and in methods for screening and testing of new epileptic drugs in the period 1935 to 1960. Thirteen new antiepileptic drugs were developed during this period, but in the last 30 years, only a relatively few new epileptic drugs have been developed. For a long period it was thought that a single drug would be able to treat all forms of epilepsy, but the current consensus is that it is quite unlikely that a wide variety of epilepsies can be managed with one drug. Drugs used in the treatment of two major seizure types, partial and generalized, are quite distinct in their clinical profiles(2).

GENERAL MECHANISM OF ACTION OF ANTISEIZURE DRUGS

In order to bring normal balance between excitatory and inhibitory postsynaptic potential, antiseizure drugs may use one or more of the following mechanisms (1, 2).

1. Enhancement of GABA-mediated inhibition.

The drug may act directly on the GABA-receptor-chloride channel complex (e.g., benzodiazepines, barbiturates), and inhibit the metabolism of GABA (e.g., vigabatrin, valproate) or increase the release of GABA (e.g., gabapentin). This mechanism provides protection against generalized and focal seizures.

2. Suppression of rapid repetitive firing.

This mechanism of action of antiseizure drugs (e.g., phenytoin, carbamazepine, valproate, lamotrigine) involves the prolongation and the closing of inactivation gate of Na+ channels, thus reducing the ability of neurons to fire at high frequencies. This mechanism provides protections against maximal electric shock in animals and focal seizures in humans.

3. Reduction of current through T-type Ca++ channels. A low threshold Ca++ current (T-type) governs oscillatory responses in thalamic neurons. Reduction of this current by antiseizure drugs (e.g., ethosuximide, dimethadione, valproate) explains the mechanism of action against absence seizures.

4. Reduction of excitatory glutaminergic neurotransmission. Some antiseizure drugs (e.g., phenobarbital, topiramate) block the AMPA receptor and some (Felbamate, remacemide, an investigational drug) block NMDA receptors.

The understanding of these basic mechanisms has resulted in the development of many new antiseizure drugs. Chemical structures of various antiseizure drugs are given in Figure 1. Clinical uses, mechanism of action, side effects, and other characteristics of these antiseizure drugs are presented in Table II and Table III. The drugs) of choice for various types of seizures are listed in Table I(1-8).

STATUS EPILEPTICUS

The most common, generalized tonic-clonic status epilepticus is a life threatening emergency requiring immediate cardiovascular, respiratory, and metabolic management along with antiepileptic drugs. Intravenous injection of 20-30 mg of diazepam or lorazapam is followed by a long acting drug such as phenytoin (15-20 mg/kg). Intravenous phenytoin (15-20 mg/kg) alone successfully treats 41-90 percent of patients. Intravenous phenobarbital (20 mg/kg in adults) is also effective in treatment of status epilepticus. Other drugs such as lidocaine have been also recommended. General anesthesia is usually necessary in high resistant cases(2).

TERATOGENECITY

Children born to mothers taking antiseizure drugs have an increased risk (~ two fold) of congenital malformations. Use of phenytoin during pregnancy has been implicated in Fetal Hydantoin Syndrome (skeletal, CNS, limb, and orofacial defects). Similar anomalies are also observed with use of phenobarbital and carbamazepine during pregnancy. Pregnant women taking valproate have 1-2 percent risk of having a child with spina bifida. Topiramate has shown teratogenic effects in animals.

It is important to minimize the use of antiseizure drugs during pregnancy in both number and dosages. Maternal seizures, however, should not go unchecked. The risk of the pregnant mother having a full blown seizure and having brain injury (hypoxia) are much higher than having a fetus with congenital defects. Thus, the risk to benefit ratio should be seriously considered. However, the pregnant mother taking antieptileptic drugs) should be closely monitored(2).

WITHDRAWAL AND OTHER CONDITIONS

Abrupt withdrawal of antiseizure drugs may increase seizure frequency and severity in patients with epilepsy. Some drugs are more easily withdrawn than others. Barbiturates and benzodiazepines are difficult to discontinue; weeks or months may be required to taper off. Anti-absence seizure drugs are easier to withdraw than drugs for partial or generalized tonic-clonic seizures(2). Some antiseizure drugs are effective in treating other conditions. Their efficacy and conditions are listed in Table IV(2).

CLASS ACTIVITY

Case Study

A group of 4-5 students were randomly assigned to a case study. A group leader was also chosen by lottery. Guidelines for presentations were as follows:

1. Group Leader will coordinate the preparation and presentation of the topic. A well-organized and coordinated presentation will earn points for each presenter.

20 points per student (15 points individual and five points for group effort)

2. Group Leader will submit an outline of the topic to the instructor for review, approval, and suggestions. This should be done at least a week before the presentation.

3. Appropriate handouts, overheads, and/or electronic displays should be used. They should be of good quality and easy to read. Appropriate references should be included in the handouts.

4. Each presenter will prepare at least one question based on the material described for discussion at the end of the presentation. The question can be of any style used in this class.

Case History

R.J., a 28-year-old female high school math teacher, was driving back from her vacation. She stopped at a rest area, where she fell down on the floor with tonic-clonic seizures. After several minutes, she recovered from her seizures and informed the people who tried to help her in the rest area that she was diagnosed with epilepsy at the age of four and was on medication. She had stopped taking the medication as she was planning to get pregnant.

1. What drug(s) was (were) used by R.J.?

2. Discuss the pathophysiology and classification of epilepsy.

3. Discuss the various drugs with their mechanism of action and side effects for different types of epilepsy.

4. Why did R.J. stop her medication before her pregnancy?

5. Discuss the use and effects of antiepileptic drugs during pregnancy.

6. Discuss the development of newer antiepileptic drugs.

Students were tested on subject materials from didactic lectures and case history discussions. The author believes in providing a firm foundation and a broad picture of the topic area rather than all minute details. Students appreciate this approach as evidenced by their evaluations.

Acknowldgements. The author thanks Dr. Xiangming Guan for drawing the chemical structures and Ms. Nancy Allbee and Ms. Tracy Scriver for typing the manuscript.

References

(1) McNamara, J.O., "Drugs effective in the therapy of epilepsies," In Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed., (edit. Hardman, Limbird, Molinoff, Rudden, and Gilman, Goodman), New York NY (1996) pp. 461-486.

(2) Porter, R.J. and Meldrum, B.S., Antiseizure Drugs in Basic and Clinical Pharmacology (Edit. Katzung) McGraw Hill, New York NY (2001) pp. 395-417.

(3) Dwivedi, C. and Smar, M.W., "Antiepileptic Agents - Recent Developments," Exp. Opin. They Patent., 4, 139-444(1994).

(4) Gerald, M.C., Pharmacology: An Introduction to Drugs, 2nd ed., Prentice Hall, New Jersey (1981) pp. 211-219.

(5) Rand, H.P., Dale, M.M., Ritter, J.M., and Gardner, P. Pharmacology, Churchill, Livingston, New York NY (1995) pp. 596-608.

(6) Medical Letter, "Drugs for Epilepsy," 37, 37-40(1995).

(7) Medical Letter, "Two New Drugs for Epilepsy," 42, 33-35(2000).

(8) Gold Standard Multmedia, www.gsm.com.

Chandradhar Dwivedi1

College of Pharmacy, South Dakota State University, Box 2202C, Brookings SD 57007-0099

1Distinguished Professor of Pharmacology.

Am. J Pharm. Educ., 65, 197- 202(2001); received 1/16/01, accepted 4/3/01.

Copyright American Association of Colleges of Pharmacy Summer 2001
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