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Antiepileptics, acting predominantly as sodium-channel blockers

Antiepileptics are the drugs which suppress attacks of epilepsy or reduce their frequency and their severity.

Epilepsy can be defined as a recurrent paroxystic disorder of cerebral function. It is characterized by brutal and short attacks of impairment or loss of consciousness, motor activity, sensory phenomena or behavior misfits, isolated or combined symptoms, according to the various types of epilepsy.

The genesis of epilepsy is an increase of excitability of an area of the brain, due to an excessive depolarization, which can spreads to involve the whole brain. To avoid this abnormal depolarization, one increases cellular polarization, either by inhibiting sodium influx, or by inducing chloride influx.

Antiepileptic drugs like phenytoin, carbamazepine and lamotrigine inhibit the voltage-dependant sodium channels. They decrease the cellular excitability by reducing the penetration of sodium into neurones. They could moreover increase cellular polarization by increasing the sodium efflux by stimulation of Na + /K + -ATPase pump.

Others antiepileptic drugs like phenobarbital, progabide, vigabatrin, clonazepam, have a gabamimetic  effect and decrease excitability by inducing chloride influx into neurones without inhibiting the sodium influx. They are studied in the chapter GABA.

Valproic acid is an antiepileptic with a double mechanism of action: it decreases the influx of sodium and increases that of chloride by indirect gabamimetic effect.

Phenytoin

Phenytoin, by acting on the intracellular part of the voltage-dependant sodium channels, decreases the sodium influx into neurons and thus decreases excitability.

The antiepileptic activity of phenytoin was found during systematic research in animals: it suppresses the tonic phase but not the clonic phase elicited by an electric discharge and is not very active against the attacks caused by pentylenetetrazol.

Phenytoin was the first non sedative antiepileptic to be used in therapeutics.

It decreases the intensity of facial neuralgia and has an antiarrhythmic effect.

Concerning pharmacokinetics, the effective plasma concentrations of phenytoin for the treatment of the epilepsy ranges between 5 and 15 mg/L. Above 20 mg / L, it causes nystagmus, at 30 mg ataxia and at 40 mg lethargy. The high concentrations are not only ineffective against the attacks of epilepsies, but can worsen them.

Its digestive absorption is slow, variable from one individual to another and incomplete. Its protein binding is 90%. Its metabolism, primarily hepatic, is carried out by hydroxylation. Its plasma half-life increases with the dose. At 10 mg/L, its T1/2 is approximately 24 hours. With equal dosage, the plasma concentrations are higher in pregnant women.

Many drugs, when they are given to patients treated with phenytoin, can modify its plasma concentration: NSAID, cimetidine, disulfiram, chloramphenicol, miconazole, nifedipine and isoniazid tend to increase it, phenobarbital and carbamazepine as well as folic acid tend to decrease it.

Phenytoin, enzyme inducer, accelerates the catabolism of other drugs and of endogenous compounds: vitamin D (inducing osteomalacia), folic acid (inducing megaloblastic anemia), cortisol, oral contraceptives, anti-vitamin K and digoxin.

Phenytoin is effective in practically all types of epilepsy except absence and myoclonic seizures. It is taken by oral route in continuous treatment or given by injectable route as phenytoin or fosphenytoïne for status epilepticus or in prevention of postoperative or post-traumatic attacks and also to replace the oral route when this one is not possible.

Phenytoin can induce various adverse effects:

  • neurosensory: nystagmus, ataxia, dizziness, diplopia, overactivity, hyperreflexia, and at very high doses, mental confusion, hallucinations.
  • digestive: nausea, gastralgia, and a particular adverse effect, gingival hyperplasia .
  • endocrine: possible diuretic effect by decrease of secretion of the antidiuretic hormone, hyperglycemia perhaps by decrease of insulin secretion, hypocalcemia perhaps by exaggerated catabolism of vitamin D.
  • dermatological: severe cutaneous eruptions.
  • blood: leukopenia, thrombopenia or anemia are seldom observed.

In pregnant women, phenytoin increases the risk of malformations, in particular of the cleft palate, perhaps by deficiency in folic acid. This effect is observed in the human species and in animals. It is thus preferable not to prescribe phenytoin to pregnant women. Moreover, the treatment of the mother by phenytoin during pregnancy has been suspected to decrease the intelligence quotient of the child, effect not seen after treatment with carbamazepine.

Fosphenytoin is a water soluble phosphate of phenytoin, which is used by parenteral route (IM, IV). In the body fosphenytoin is hydrolyzed to phenytoin.

Notice

A dental paste containing phenytoin was marketed for the treatment of the parodontopathies.

Carbamazepine

The chemical structure of carbamazepine is closely related to that of the tricyclic antidepressants. Its effects resemble to those of phenytoin.  

Concerning pharmacokinetics, the effective plasma concentration of carbamazepine is 4 to 8 mg/L. Its digestive absorption is variable between individuals. It is transformed at the hepatic level into epoxide which is itself an active product. Its plasma half-life goes from 13 to 17 hours and that of its epoxide metabolite from 5 to 8 hours. It is an enzyme inducer able to accelerate the catabolism of certain drugs. Certain macrolides such as erythromycin inhibit the catabolism of carbamazepine whose plasma concentration rises.

Carbamazepine (Tegretol*) is indicated in the partial epilepsies, in particular the temporal or psychomotor epilepsies, and in generalized seizures. It is inactive in absence seizures.

It can be used for the treatment of facial neuralgia and bipolar disorder as an alternative to lithium when it is not well supported.

Carbamazepine, like lithium, is sometimes combined with an antidepressant in the treatment of resistant depressions.

Carbamazepine can have many adverse effects:

  • neurosensory: diplopia, blurred view, drowsiness, ataxia, dizziness
  • blood: leukopenia, thrombopenia requiring monitoring of the blood formula-count
  • cutaneous: pigmentation, rash and toxic bullous epidermal necrolysis.
  • hypersensivity: eosinophilia, arthralgia, hepatitis.
  • cardiac:arrhymthmias.
  • hyponatremia

Oxcarbazepine

Oxcarbazepine, (Trileptal*) chemically derived from carbamazepine, inhibits the voltage-dependant sodium channels and has antiepileptic properties. Its principal interest compared to carbamazepine is to have less drug interactions which exist nevertheless.

Lamotrigine

Lamotrigine, which has a triazine structure, is a voltage-gated sodium channel inhibitor. It is by this mechanism that it decreases aspartate and glutamate presynaptic release, which causes postsynaptic depolarization.

Lamotrigine (Lamictal*) is used for the treatment of epilepsies refractory to the usual treatment and of refractory bipolar disorder.

Its most frequent adverse effects are of neurosensory type (diplopia, dizziness) and sometimes exacerbation of epilepsy attacks. Severe cutaneous symptoms were exceptionally observed (Lyell syndrome, Stevens-Johnson syndrome).

The concomitant intake of lamotrigine and valproic acid can slow the metabolism of lamotrigine whose plasma concentration rises abnormally.

Valproic acid

Valproic acid, often called valproate, (Depakine*, Depakote*), inhibits the sodium influx into the cell by the voltage-dependant sodium channels and induces chloride influx by GABA-mimetic effect. By these two complementary mechanisms, it increases the polarization of the cell and decreases its excitability. Its GABA-mimetic effect prevails on its effect on the voltage-dependant sodium channels. It is effective in the majority of epilepsies and is very largely used. Valproate can be used instead of lithium - or combined with it- for the treatment of cyclic psychiatric disorders of manic-depressive type.

Valpromide, also called dipropylacetamide, is converted in the body primarily in valproic acid. Its activity in certain neuropsychiatric disorders was described many years ago; it is used in bipolar disorder.

Felbamate

Felbamate is a carbamate whose structure is closely related to that of meprobamate which has been largely used as anxiolytic since 1954. Felbamate, known since 1959, has antiepileptic properties and is used for the treatment of refractory partial seizures and of the Lennox-Gastaut syndrome refractory to other antiepileptics. The mechanism of action of felbamate is poorly understood; it is effective only at high-dose, 400 to 600 mg, which means that it does not have a high affinity for a given type of receptor. Several mechanisms of action were proposed, one of which is an inhibition of the voltage-dependant sodium channels.

Felbamate, (Toloxa*, Felbatol*), is a drug which has severe, even fatal, adverse effects, medullary aplasia, acute hepatic insufficiency and accidents of hypersensitizing from cutaneous symptom to shock. In addition, when it is used in parallel with others antiepileptic drugs, phenytoin, sodium valproate, it can modify their metabolism and it is necessary to control their plasma concentration. Its use thus is very limited and its prescription must be accompanied by clinical and biological monitoring (hematologic, hepatic).

Topiramate

Topiramate is a sulfamate (- SO 2 -NH 2 ) having an antiepileptic activity at a dose of 200 to 600 mg daily. It inhibits voltage-dependant sodium channels and non-NMDA glutamate receptors. Topiramate, (Topamax*, Epitomax*), is prescribed for the treatment of partial epilepsies, as an adjunct to other antiepileptics.

It inhibits carbonic anhydrase and increases the risk of formation of renal calculi. It can induce drowsiness and various neuropsychiatric disorders.

Use of antiepileptic drugs

Whatever the drug prescribed, as it is a treatment of very long duration, often life-long, the diagnosis of epilepsy and type of epilepsy must be clearly established before its prescription.

The initial treatment is based on only one antiepileptic (single-drug treatment) with dose adjustment.

In the event of failure of the one-drug treatment, it is necessary, either to replace the first drug by a second but by making them to overlap during a few days, or to add a second drug to the first. A certain number of studies show that dual-agent therapy can increase the efficacy of the treatment while reducing the adverse effects because, in this case, each of the two drugs can be used at lower dosage.

The brutal discontinuation of treatment with an effective antiepileptic induces a raised resumption of epilepsy attacks. If a discontinuation of treatment is decided, it must be performed gradually, under close monitoring, to avoid this risk.

Notice

Insecticides, pyrethrins, lindane also called hexachlorocyclohexane, DDT for dichlorodiphenyl-trichlorethane, increase the duration of opening of the voltage-dependant sodium channels and create a cellular depolarization. They give, in case of poisoning, seizures and heart rate disorders. Pyrethrins like permethrin are used under several proprietary names as drugs to treat lice scalp and scabies, in the form of powder, lotion or spray. They are also used as insect repellents by impregnation of clothes.

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