Antiepileptic drugs
Epilepsy: -
A disorder of brain function that is characterized by periodic and unpredictable occurrence of
seizures, which is sudden, excessive, and synchronous discharge of population of cerebral neurons.
Seizures are thought to arise from brain cortex and not from other C.N.S. parts. The site of the
electrical discharge determines the symptoms that produced e.g. epileptic seizures may cause
convulsion if the motor cortex is involved.
Epileptic seizures(according to the cause ), either primary or secondary ;primary epilepsy when
there is no specific cause ,so called idiopathic or primary epilepsy may be due to genetic
abnormality of C.N.S.
Secondary epilepsy, secondary for other causes like meningitis, alteration of blood gases, blood PH,
electrolytes disturbances, or glucose availability
Other classification of epileptic seizures into:-
1-Partial (focal) seizures: -
They start locally in a certain site, it is divided into-
A) Simple partial seizures; they associated with preservation of consciousness.
B) Complex partial seizure; it is associated with loss of consciousness.
2-Generalized seizures
They involve both hemispheres of brain, they started locally, but spread rapidly producing electrical
discharge in both hemispheres, there is immediate loss of consciousness due to involvement
reticular formation system of brain; divided into:
A) Tonic- clonic seizures (Grand mal epilepsy).
B) Absence seizure (Petit mal epilepsy).
C) Myoclonic seizures; they are short episodes of muscle contraction that might occur for several
minutes.
D) Febrile seizures; associated with fever in children.
E) Status epileptics; (is life threatening condition in which seizure activity is uninterrupted).
Nature of epilepsy:-
The neurochemical basis of the abnormal discharge, it may be associated with enhanced excitatory
amino acid transmission, impaired inhibitory transmission, or abnormal electrical properties of the
affected cells.
Mechanism of drug action:-
1-Antiepileptic drugs act by inhibiting neuronal transmission by altering the movement of ions
across cell membrane through block sodium channels e.g. Carbamazepine, Phenytoin and
Lamotrigine.
2-calcium channels blockers e.g. Ethosuximide and Gabapentin.
3- Enhancing activity of gamma- amino butyric acid (GABA); the main inhibitory neurotransmitter of
the brain (GABA potentiators) e.g. Sodium valproate, Barbiturates, Benzodiazepines, Vigabatrin and
Gabapentin.
The GABA system can be enhanced by:
A) Binding directly to GABA- A receptors, (Benzodiazepines, Barbiturates)
B) Prevent presynaptic GABA uptake.( Nipecotic acid and its derivative Tiagabine (TGB).
C) Inhibiting the metabolism of GABA by GABA transaminase (Vigabatrin, Valproic acid)
4- Inhibiting excitatory neurotransmitters such as (glutamate, aspartate) e.g. Lamotrigine
Groups of antiepileptic drugs:
1:- Hydantoins:-
The most important drug is Phenytoin, act by
1- Stabilizes the neuronal membrane by decreasing the influx of sodium ions in neurons in the
resting stage or during depolarization. Consequently lead to limits seizures activity and reduces the
spread of seizures.
2-It reduces the influx of calcium during depolarization; therefor it suppresses repetitive firing of
neurons and inhibiting sequestration of calcium ions in the nerve terminals.
3 -At high concentration, it might enhance the activity of (GABA).
Pharmacokinetics of Phenytoin:
Well absorbed orally , it has a plasma protein binding activity ,so 90% of it will bound to albumin
and any simple change in the drug binding might cause major effect on the concentration of the
drug ,it is subjected to zero order kinetics ,so at low doses the half-life is about 6-24 hrs. While at
high doses, the half-life might increase to 60hrs.
Phenytoin is hydroxylated in the liver and this process becomes saturated at about the therapeutic
dose; therefore intake small dose and increase slowly at long intervals to obtain a proportional rise
in the plasma concentration, Excretion through the kidneys.
Phenytoin is a potent hepatic enzyme inducer, affecting its own metabolism and other drugs and
endogenous substances such as vitamin D and folate; this will result in:
A) Slight fall in the steady state of Phenytoin over the first few weeks.
B) It will enhance metabolism of other drugs including other antiepileptic drugs as well as Warfarin,
steroids, Thyroxin, and tricyclic antidepressant drugs
The level of Phenytoin is affected by inhibition of its metabolism either by competition for the
enzyme or by direct inhibition of the enzyme activity that can be produced by Sodium valproate,
cimetidine, INH, and some NSAIDs.
Therapeutic uses of Phenytoin:-
1) It is effective for both types of partial seizures (simple and complex)
2) Tonic –clonic seizures.
3) Status epileptics.
Phenytoin is not useful in case of absence seizure (Petit mal epilepsy) and myoclonus seizure.
Other clinical uses: cardiac arrhythmias; trigeminal neuralgia (if Carbamazepine is inappropriate
Side effects:-
1) Impairment of cognitive function and decrease ability to learn.
2) Other CNS side effects including; sedation, delirium, although it is not CNS depressant, but it
produces some degree of drowsiness and lethargy without progression to hypnosis, in high doses it
might produce acute cerebellar and vestibular disorders (ataxia and nystagmus).
3) It produces peripheral neuropathy.
4) Skin rashes (due to allergy).
5) Inhibition of collagen catabolism lead to gum hypertrophy and coarsening of facial features.
6) It may cause dupuytrens contracture.
7) Megaloblastic anemia due to decrease folic acid.
8) Osteomalacia due to decrease vitamin D
9) It may cause hirsutism (abnormal hair growth)
10) Pseudo lymphoma.
11) It may cause hyperglycemia and glycosuria.
12) Inhibition of ADH release.
13) Phenytoin like other antiepileptic drugs can cause cleft palate, cleft lips, congenital heart
diseases, slowed growth rate and mental deficiency in the offspring.
Fosphenytoin:-
It is a prodrug of phenytoin, it is safer and better tolerated than phenytoin and can be infused 3
times faster than I.V. phenytoin can, completely bioavailable after I.M. administration, indicated for
treatment of status epilepticus
2) Carbamazepine (Tegretol 200mg):-
It is structurally related to the tricyclic anti-depressant drugs (Imipramine), the most important
action is blockage of sodium ion channels, reducing membrane excitability.
P/K:-
It is absorbed slowly from intestine, it has high lipid solubility, so it is enters brain rapidly;
approximately 75%-85% of the drug is plasma protein bound; it induces hepatic enzymes, so its
half-life will fall from 35hrs.to 20 hrs. Over the first few weeks of drug therapy, its metabolism in
the liver is inhibited by Cimetidine and sodium valproate
CLINICAL USES:-
1-It is a drug of first choice in all partial seizures (simple and complex)
2-It is effective in tonic –clonic seizure
3-It is the drug of first choice in trigeminal neuralgia and other neuropathy like diabetic
neuropathy
Side effects of Carbamazepine:-
1- CNS symptoms (Dizziness, ataxia, headache)
2- Visual symptoms (diplopia, blurred vision)
3- GIT symptoms (nausea, vomiting)
4- It causes depression of bone marrow lead to aplastic anaemia with agranulocytosis and
thrombocytopenia
5- Elevation liver enzymes in 5-10 % of patients
6-Osteomalacia (enhance vitamin D metabolism) with folate deficiency
7- Reduce efficacy of contraceptive pills (enzyme induction)
8-Skin rash in 10% of patients
-
Sodium valproate or Valproic acid (Depakin 200mg, 500mg.):
This drug act by inhibition of the enzyme responsible for breakdown of GABA, ( GABA
transaminase) lead to potentiate of GABA, the main inhibitory neurotransmitter of brain
-
P/K:
1-it is taken orally and absorbed rapidly, 90% of it bound to plasma albumin, metabolized
extensively in the liver, it is enzyme inhibition, and it inhibits its own metabolism and metabolism of
other drugs like Phenytoin, Carbamazepine and Phenobarbitone .It displaces Phenytoin from
plasma protein binding and its metabolism is enhanced by induction of enzymes by other
antiepileptic drugs.
-
uses:
Clinical
1- It reduces the tonic-clonic seizures
2-It is effective against myoclonic seizures
3-It diminishes the absence attack
Adverse effects of Valproic acid
1- GIT irritation (nausea, vomiting and diarrhea)
2 – Weight gain (it increase the appetite)
3- It causes transient or temporary loss of hair with regrowth abnormally (curly with different color)
4- Coagulation disorders, this is due to inhibition of plate lets aggregation and thrombocytopenia.
5- Hepatic dysfunction (rare, but serious range from transient liver enzymes to liver failure)
-
Ethosuximide:
The main drug used to treat abscence seizures (petit mal epilepsy), act by blocking T- type calcium
channels
P/K: - It is well absorbed orally, not bound to plasma protein, half-life 55hrs. 25 % excreted
unchanged in urine and 75% is inactivated in the liver.
Side effects: -
1- It is irritant to stomach causes nausea and vomiting.
2- It might cause skin allergic reaction (Steven Johnson syndrome)
3- CNS symptoms include drowsiness, anxiety, lethargy, and agitation.
Barbiturates:-
a) Phenobarbital or Phenobarbitone (Luminal):-
It enhances the activity of GABA; In addition, block calcium channels presynaptic membrane and
decrease neurotransmitter release.
Clinical uses:-
1-It is the drug of first choice for treatment of febrile convulsion in children.
2- For simple partial seizures not used for complex partial seizures
3- Used for treatment of generalized tonic-clonic seizures and status epilepticus.
b) Primidone:-
A pro-drug metabolized to Phenobarbitone and has the same indications of Phenobarbitone; it is an
alternative drug in partial seizures and tonic clonic seizures.
Benzodiazepines
They enhance the action of GABA, include
1-Diazepam; used parenterally in treatment of status epilepticus (drug of choice); Phenytoin also
drug of choice in status epilepticus.
2-Clonazepam; most effective in myoclonic seizures and used in absence seizures (petit mal) and
status epilepticus.
GABA derivatives
1-Vigabatrin:-
It is act by inhibiting GABA transaminase leading to GABA accumulation used in treatment
generalized and partial seizures when other drugs are inadequate.
P/K
It is absorbed rapidly after oral ingestion with an oral bioavailability of 100%, it is not metabolized
and not induced hepatic enzymes, and it is excreted in urine with half- life (4-7hrs).
Associated with confusion, psychosis, and weight gain
2-Lamotrigin:-
It stabilizes presynaptic neuronal membrane by blockage of voltage dependent sodium channels
(similar to Phenytoin and Carbamazepine), also lead to decrease release of the excitatory amino
acids such as glutamate and aspartate.
It is effective in partial seizures and generalized tonic-clonic and absence seizures.
Rash is the main serious adverse effect especially in children
The reported low incidence of congenital malformation makes this drug one of the preferred
treatment during pregnancy
3- Gabapentin:-
It is an analogue of GABA, but does not appear to act through GABA pathway, with very little effect
on the liver
4- Topiramete:-
It is very potent anti-conversant that is structurally derived from fructose (monosaccharide) ,it act
by blockage of voltage sensitive sodium channels also increase GABA activity and blocks glutamate
receptors
P/K
1-Rapid absorption after oral administration
2-has a bioavailability close to 100%
3- Plasma protein binding is approximately 15%
4- 15% of it metabolized in liver by cytochrome P-450
5- 85% of drug is excreted unchanged in urine
5- Tiagabine (GABA reuptake inhibitor)
It cats by reversible inhibition of the GABA transporter-1(GAT-T),the compound that carry GABA
from the synaptic space into neurons and glial cells where it is metabolized ;this inhibition makes
increased amount of GABA in synaptic cleft and inhibit postsynaptic potential (IPSPs)