Title: Snmek 1
1 Antiepileptic drugs prof.MUDr Jirina
Martínková, CSc 2006/2007
2Antiepileptic drugs
- Epilepsy affects 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
3Antiepileptic 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.
4Types 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
5Types 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
6Antiepileptic 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)
7Antiepileptic drugsclinical use (tab.1)
8Antiepileptic 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 variability in both Cpl and
patientsresponse - therapeutic effects are more related to Cpl (if
compared to the given dose)
TDM for effective and safe therapy
9Antiepileptic 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) - metabolised by 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)
10Antiepileptic 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?) -
11Antiepileptic 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, ataxiamore 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)
12Antiepileptic 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)
13Antiepileptic 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
14Antiepileptic 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
15Antiepileptic 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 effective in 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
16Antiepileptic 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
17Antiepileptic drugsmonotherapy or combination?
- At present, monotherapy is recommended
18Antiepileptic 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. -
19Antiepileptic drugsand teratogenicity
- 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 implicated in a 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. -