Antiepileptic drugs prof.MUDr Jiřina Martínková, CSc 2006/2007. Antiepileptic drugs.
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prof.MUDr Jiřina Martínková, CSc
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
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.
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
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:
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:
phenobarbital, benzodiazepines, vigabatrin, gabapentin
(reduction of electrical excitability of cell membranes)
phenytoin, carbamazepine, valproate, lamotrigine
ethosuximide (T-type calcium channels),gabapentin (L-type calcium channels)
is quite narrow
TDM for effective and safe therapy
Phenytoin- widely used
The metabolism shows the characteristic of saturation
(the Css achieved when a patient is given a constant daily dose, varies disproportionately with the dose)
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?)
its combination with other antiepileptic drugs should be avoided
drowsiness, dizziness, ataxia—more severe mental and motor disturbancies, water retention …
to avoid it --treatment is usually started with a low dose
severe bone-marrow depression (very rare)
rare but serious: hepatotoxicity, teratogenicity (spina bifida and other neural tube defects), baldness
The main drug used to treat absence seizures with relatively few adverse effects (nauzea, anorexia)
Adverse effects Type A (dose-related)
sedation (!) - impairment of cognition and motor performance
in overdose - respiratory and circulatory failure
Clonazepam, clobazam (see tab.1)
have some selective antiepileptic effects
Sedation is the main adverse effect
increases the GABA content in the CNS a effectively enhances inhibitory transmission
in a minority of patients occurrence of depression and psychotic disturbances
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
At present, monotherapy is recommended
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.
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.