Antiepileptic drugs prof.MUDr Jiřina Martínková, CSc 2006/2007

1. Antiepileptic drugs prof.MUDr Jiřina Martínková, CSc 2006/2007

2. Antiepileptic drugs Epilepsyaffects 0.5-1% of the population. It may develop after brain damage (trauma, infection or tumour growth), or other kinds of neurological disease, including various inherited neurological syndromes. Epilepsy is treated mainly with drugs. Current antiepileptic drugs are effective in controlling seizures in about 75% of patients, their use is often limited by adverse effects

3. Antiepileptic drugs The characteristic event in E. is the seizure, which is associated with the episodic high-frequency discharge of impulses by a group of neurones in the brain. What starts as a local abnormal discharge may then spread to other areas of the brain. The site of the primary discharge and the extend of its spread determines the symptoms that are produced, which range from a brief relapse of attention to a full-blown convulsive fit lasting for several minutes. Abnormal electrical activity during a seizure can be detected by EEG recording from electrodes distributed over the surface of the scalp.

4. Types of epilepsy Two major categories: partial and generalized, simple (consciousness is not lost), complex (consciousness is lost). P a r t i a l s e i z u r e s – the discharge begins locally, and often remains localised. The symptoms depend on the brain region(s) involved Psychomotor epilepsy: involuntary muscle contractions, abnormal sensory experiences or autonomic discharge, or effects on mood and behaviour. In the form that is often associated with a focus in the temporal lobe, the attack may consist of stereotyped movement such as dressing or walking or hair-combing Jacksonian epilepsy: consists of repetitive jerking of a particular muscle group, which spreads and may involve much of the body within 2 minutes before dying out. The patient loses voluntary control of the affected parts of the body but does not necessarily

5. Types of epilepsy G e n e r a l i s e d s e i z u r e s involve the whole brain. Immediate loss of consciousness is characteristic of generalised seizures. Two common forms are: • Tonic- clonic seizures - grand mal - consists of an initial strong contraction of the whole musculature, causing a rigid extensor spasm. Respiration stops and defaecation, micturation and salivation often occur. This tonic phase lasts for about 1 min and is followed by a series of violent, synchronous jerks, which usually dies out in 2-4 min. The patient gradually recovers, felling ill and confused. Injury may occur during the convulsive episode • Absence seizures – petit mal – are much less dramatic but may occur more frequently. The patients abruptly ceases whatever he or she was doing, sometimes stopping speaking in mid-sentence, and stares vacantly for a few sec, with little or no motor disturbance.The patient is unaware of his or her surroundings and recovers abruptly with no after-effects • Status epilepticus – a life-threatening condition in which seizure activity is uninterrupted

6. Antiepileptic drugs With optimal drug therapy, epilepsy is controlled in about 75% of patients, but about 10% continue to have seizures at intervals of 1 month or less, which severaly disrupts their life and work M e c h a n i s m of a c t i o n: • enhancement of GABA action phenobarbital, benzodiazepines, vigabatrin, gabapentin • inhibition of sodium channel function (reduction of electrical excitability of cell membranes) phenytoin, carbamazepine, valproate, lamotrigine • inhibition of calcium channel function ethosuximide (T-type calcium channels),gabapentin (L-type calcium channels)

7. Antiepileptic drugsclinical use (tab.1)

8. Antiepileptic drugsclinical use Pharmacokinetics/pharmacodynamics • the range of Cpl over which antiepileptic drugs are effective without causing excessive adverse effects is quite narrow • Cpl is the only predictor of therapeutic effectiveness • large interindividual variabilityin both Cpl and patients´response • therapeutic effects are more related to Cpl (if compared to the given dose) TDM for effective and safe therapy

9. Antiepileptic drugsclinical use Phenytoin- widely used • well absorbed from the GIT, and about 80-90% of the plasma content is bound to albumin (salicylates and valproate inhibit this binding competitively) • metabolisedby CYP450, causes enzyme induction and thus increases the rate of metabolism of other drugs (warfarin) that share the same enzyme The metabolism shows the characteristic of saturation (the Css achieved when a patient is given a constant daily dose, varies disproportionately with the dose)

10. Antiepileptic drugsPhenytoin Adverse effects Type A (dose-related) vertigo, ataxia (low Cpl), confusion with intellectual deterioration, hyperplasia of the gums (disfiguring), hirsutism (androgen secretion), megaloblastic anemia (in deficiency of folic acid) Adverse effects Type B (not dose-related) quite common - allergy: rashes - idiosyncrasy: hepatitis Adverse effects Type D the increased incidence of fetal malformations in children born to epileptic mothers “fetal hydantoin syndrom“, particularly the occurrence of cleft palate (epoxide metabolite?)

11. Antiepileptic drugsCarbamazepine • well absorbed • a powerful inducer of hepatic microsomal enzymes---- accelerates biotransformation of many other drugs (phenytoin, warfarin) its combination with other antiepileptic drugs should be avoided • Adverse effects Type A (dose-related) low incidence drowsiness, dizziness, ataxia—more severe mental and motor disturbancies, water retention … to avoid it --treatment is usually started with a low dose • Adverse effects Type B (not dose-related) severe bone-marrow depression (very rare)

12. Antiepileptic drugsValproate • is effective in many kinds of epilepsy (see Tab.1) • free of adverse effects (low toxicity), absence of sedation (!) rare but serious: hepatotoxicity, teratogenicity (spina bifida and other neural tube defects), baldness Ethosuximide The main drug used to treat absence seizures with relatively few adverse effects (nauzea, anorexia)

13. Antiepileptic drugsPhenobarbital • is well absorbed, slowly eliminated • a powerful inducer of hepatic enzymes: lowers Cpl of several drugs (steroids, warfarin, oral contraceptives..) Adverse effects Type A (dose-related) sedation (!) - impairment of cognition and motor performance in overdose - respiratory and circulatory failure

14. Antiepileptic drugsBenzodiazepines Diazepam i.v. • is used to treat status epilepticus - in which seizures occur almost without a break • Advantage: very rapid action Clonazepam, clobazam (see tab.1) have some selective antiepileptic effects Sedation is the main adverse effect

15. Antiepileptic drugsNewer antiepileptic drugs Vigabatrin • is an irreversible inhibitor of the GABA-metabolising enzyme GABA transaminase increases the GABA content in the CNS a effectively enhances inhibitory transmission • is effectivein a substantial proportion of patients resistant to the established drugs • relatively free of adverse effects in a minority of patients occurrence of depression and psychotic disturbances

16. Antiepileptic drugsNewer antiepileptic drugs Lamotrigine was shown to have the broad therapeutic profile with no pharmacokinetic anomalies Gabapentin free of interaction, with limited efficacy when used on its own ---useful in combinations

17. Antiepileptic drugsmonotherapy or combination? At present, monotherapy is recommended

18. Antiepileptic drugswithdrawal can cause increased seizure frequency and severity. In general, barbiturates and benzodiazepines are the most difficult to discontinue. Weeks or months may be required, with very gradual dosage decrements, to accomplish their complete removal. Complete discontinuance is an especially difficult problem. If a patient is seizure-free for 3-4 years, gradual discontinuance is usually warranted.

19. Antiepileptic drugsandteratogenicity The potencial teratogenicity of antiepileptic drugs is contraversial and important. It is important because teratogenicity resulting from long-term drug treatment of million of people throughout the world may have a profound effect even if the effect occurs in only a small percentage of cases. Patients with severe epilepsy, in whom genetic factors than drug factors may be of greater importance in the occurrence of fetal malformations, are often receiving multiple antiepileptic drugs in high doses. In spite of these limitations, it appears that children born to mothers taking antiepileptic drugs have an increased risk, perhaps twofold, of congenital malformation.Phenytoin has been implicatedina specific sydrome called “fetal hydantoin syndrom“. A similar syndrome has been attributed both to phenobarbital and to carbamazepine.Valproate has also been implicated in a specific malformation- spina bifida.