Sodium Channel Blocking Agents
Drugs sharing this mechanism include phenytoin (Di-lantin), carbamazepine (Tegretol), oxcarbazepine (Tri-leptal), topiramate (Topamax), valproic acid (Depakene), zonisamide (Zonegran), and lamotrigine (Lamictal). All of these agents have the capacity to block sustained high-frequency repetitive firing (SRF) of action poten-tials. This is accomplished by reducing the amplitude of sodium-dependent action potentials through an en-hancement of steady-state inactivation. The sodium channel exists in three main conformations: a resting (R) or activatable state, an open (0) or conducting state, and an inactive (I) or nonactivatable state. The anticonvul-sant drugs bind preferentially to the inactive form of the channel. Because it takes time for the bound drug to dis-sociate from the inactive channel, there is time depen-dence to the block. Since the fraction of inactive chan-nels is increased by membrane depolarization as well as by repetitive firing, the binding to the I state by antiepileptic drugs can produce voltage-, use-, and time-dependent block of sodium-dependent action potentials. This effect is similar to that of local anesthetic drugs and is shown in Figure 32.1.
These agents are discussed together because their pharmacological properties, clinical indications for the treatment of epilepsy, and presumed mechanisms of ac-tion are similar. They differ from each other in several ways, however, and one drug cannot routinely be sub-stituted for another. They differ primarily in their phar-macokinetic properties, their adverse reactions, and their interactions with other drugs. In addition to block-ing sodium channels, some possess other therapeutically relevant mechanisms of action as well.
Phenytoin is a valuable agent for the treatment of gen-eralized tonic–clonic seizures and for the treatment of partial seizures with complex symptoms. The establish-ment of phenytoin (at that time known as diphenylhy-dantoin) in 1938 as an effective treatment for epilepsy was more than simply the introduction of another drug for treatment of seizure disorders. Until that time the only drugs that had any beneficial effects in epilepsy were the bromides and barbiturates, both classes of compounds having marked CNS depressant properties.
The prevailing view among neurologists of that era was that epilepsy was the result of excessive electrical activity in the brain and it therefore seemed perfectly rea-sonable that CNS depressants would be effective in an-tagonizing the seizures. Consequently, many patients re-ceived high doses of barbiturates and spent much of their time sedated. Also, since CNS depression was con-sidered to be the mechanism of action of AEDs, the pharmaceutical firms were evaluating only compounds with profound CNS depressant properties as potential antiepileptic agents. It was, therefore, revolutionary when phenytoin was shown to be as effective as pheno-barbital in the treatment of epilepsy without any signif-icant CNS depressant activity. This revolutionized the search for new anticonvulsant drugs as well as immedi-ately improving the day-to-day functioning of epileptic patients.
An understanding of absorption, binding, metabo-lism, and excretion is more important for phenytoin than it is for most drugs. Following oral administration, phenytoin absorption is slow but usually complete, and it occurs primarily in the duodenum. Phenytoin is highly bound (about 90%) to plasma proteins, primarily plasma albumin. Since several other substances can also bind to albumin, phenytoin administration can displace (and be displaced by) such agents as thyroxine, tri-iodothyronine, valproic acid, sulfafurazole, and salicylic acid.
Phenytoin is one of very few drugs that displays zero-order (or saturation) kinetics in its metabolism. At low blood levels the rate of phenytoin metabolism is proportional to the drug’s blood 1evels (i.e., first-order kinetics). However, at the higher blood levels usually required to control seizures, the maximum capacity of drug-metabolizing enzymes is often exceeded (i.e., the enzyme is saturated), and further increases in the dose of phenytoin may lead to a disproportionate increase in the drug’s blood concentration. Since the plasma levels continue to increase in such a situation, steady-state lev-els are not attained, and toxicity may ensue. Calculation of half-life (t1/2) values for phenytoin often is meaning-less, since the apparent half-life varies with the drug blood level.
Acute adverse effects seen after phenytoin adminis-tration usually result from overdosage. They are gener-ally characterized by nystagmus, ataxia, vertigo, and diplopia (cerebellovestibular dysfunction). Higher doses lead to altered levels of consciousness and cogni-tive changes.
A variety of idiosyncratic reactions may be seen shortly after therapy has begun. Skin rashes, usually morbilliform in character, are most common. Exfoliative dermatitis or toxic epidermal necrolysis (Lyellís syndrome) has been observed but is infrequent. Other rashes occasionally have been reported, as have a variety of blood dyscrasias and hepatic necrosis.
The most common side effect in children receiving long-term therapy is gingival hyperplasia, or over-growth of the gums (occurs in up to 50% of patients). Although the condition is not serious, it is a cosmetic problem and can be very embarrassing to the patient. Hirsutism also is an annoying side effect of phenytoin, particularly in young females. Thickening of subcuta-neous tissue, coarsening of facial features, and enlarge-ment of lips and nose (hydantoin facies) are often seen in patients receiving long-term phenytoin therapy.
Peripheral neuropathy and chronic cerebellar degener-ation have been reported, but they are rare.
There is evidence that phenytoin is teratogenic in humans, but the mechanism is not clear. However, it is known that phenytoin can produce a folate deficiency, and folate deficiency is associated with teratogenesis.
Only a few well-documented drug combinations with phenytoin may necessitate dosage adjustment. Coadministration of the following drugs can result in elevations of plasma phenytoin levels in most patients: cimetidine, chloramphenicol, disulfiram, sulthiame, and isoniazid (in slow acetylators). Phenytoin often causes a decline in plasma carbamazepine levels if these two drugs are given concomitantly.
Ethotoin and mephenytoin are congeners of pheny-toin that are marketed as AEDs in the United States. They are not widely used.
Carbamazepine has become a major drug in the treat-ment of seizure disorders. It has high efficacy, is well tol-erated by most patients, and exhibits fewer long-term side effects than other drugs.
Oral absorption of carbamazepine is quite slow and often erratic. Its half-life is reported to vary from 12 to 60 hours in humans. The development of blood level as-says has markedly improved the success of therapy with this drug, since serum concentration is only partially dose related. Carbamazepine is metabolized in the liver, and there is evidence that its continued administration leads to hepatic enzyme induction. Carbamazepine-10,11-epoxide is a pharmacologically active metabolite with significant anticonvulsant effects of its own.
Carbamazepine is an effective agent for the treat-ment of partial seizures and generalized tonic–clonic seizures; its use is contraindicated in absence epilepsy. Carbamazepine is also useful in the treatment of trigeminal neuralgia and is an effective agent for the treatment of bipolar disorders .
Like most of the agents that block sodium channels, side effects associated with carbamazepine administra-tion involve the central nervous system (CNS). Drowsiness is the most common side effect, followed by nausea, headache, dizziness, incoordination, vertigo, and diplopia. These effects occur particularly when the drug is first taken, but tolerance often develops over a few weeks. There appears to be little risk of cognitive im-pairment with carbamazepine.
Carbamazepine causes a variety of rashes and other allergic reactions including fever, hepatosplenomegaly, and lymphadenopathy, but the incidence of serious hy-persensitivity reactions is rare. Systemic lupus erythe-matosus can occur, but discontinuation of the drug leads to eventual disappearance of the symptoms. Idiosyncratic hematological reactions to carbamazepine may occur, but serious blood dyscrasias are rare. Carbamazepine has been shown to exacerbate or pre-cipitate seizures in some patients, particularly those ex-hibiting generalized atypical absences.
While the number of side effects may be fairly large, most are not serious and can be managed. Severe ad-verse reactions occur less commonly than with pheny-toin and similar drugs. The overall incidence of toxicity seems to be fairly low at usual therapeutic doses.
Most of the drug interactions with carbamazepine are related to its effects on microsomal drug metabo-lism. Carbamazepine can induce its own metabolism (autoinduction) after prolonged administration, de-creasing its clearance rate, half-life, and serum concen-trations. The possibility of autoinduction requires the clinician to reevaluate the patient’s blood levels after a month of carbamazepine therapy. The autoinduction phenomenon is over in about a month.
Carbamazepine also can induce the enzymes that metabolize other anticonvulsant drugs, including phenytoin, primidone, phenobarbital, valproic acid, clonazepam, and ethosuximide, and metabolism of other drugs the patient may be taking. Similarly, other drugs may induce metabolism of carbamazepine; the end result is the same as for autoinduction, and the dose of carbamazepine must be readjusted. A common drug–drug interaction is between carbamazepine and the macrolide antibiotics erythromycin and trolean-domycin. After a few days of antibiotic therapy, symp-toms of carbamazepine toxicity develop; this is readily reversible if either the antibiotic or carbamazepine is discontinued.
Cimetidine, propoxyphene, and isoniazid also have been reported to inhibit metabolism of carbamazepine. It is essential to monitor blood levels and adjust the dose if necessary whenever additional drugs are given to patients taking carbamazepine.
Oxcarbazepine is chemically and pharmacologically closely related to carbamazepine, but it has much less capacity to induce drug-metabolizing enzymes. This property decreases the problems associated with drug interactions when oxcarbazepine is used in combination with other drugs. The clinical uses and adverse effect profile of oxcarbazepine appear to be similar to those of carbamazepine.
Lamotrigine has a broad spectrum of action and is ef-fective in generalized and partial epilepsies. Its primary mechanism of action appears to be blockage of voltage-dependent sodium channels, although its effectiveness against absence seizures indicates that additional mech-anisms may be active. Lamotrigine is almost completelyabsorbed from the gastrointestinal tract, and peak plasma levels are achieved in about 2 to 5 hours. The plasma half-life after a single dose is about 24 hours. Unlike most drugs, lamotrigine is metabolized primarily by glucuronidation. Therefore, it appears likely that lamotrigine will not induce or inhibit cytochrome P450 isozymes, in contrast to most AEDs.
Severe skin rashes appear to be the major concern with lamotrigine use. The incidence of rash is greater in children than in adults. Other adverse effects are similar to those of drugs with the same mechanism of action, such as cerebellovestibular changes leading to dizziness, diplopia, ataxia, and blurred vision. Disseminated in-travascular coagulation has been reported.
Topiramate is most useful in patients with generalized tonic–clonic seizures and those with partial complex seizures. Topiramate causes a higher incidence of CNS-related side effects (primarily cognitive slowing and confusion) than other AEDs. It does not appear to cause a significant incidence of rashes or other hyper-sensitivity reactions; however, a significantly higher in-cidence of kidney stones has been observed in persons receiving topiramate than in a similar untreated popu-lation.
Zonisamide has only recently been approved for use in the United States, although it has been available in Japan for several years. It is effective in partial complex and generalized tonic–clonic seizures and also appears to be beneficial in certain myoclonic seizures. It has a long half-life (about 60 hours) and requires about 2 weeks to achieve steady-state levels. It causes cere-bellovestibular side effects similar to those of most other AEDs sharing its mechanism of action. In addi-tion, it appears to cause an increased incidence of kid-ney stones.
Although it is marketed as both valproic acid (Depakene) and as sodium valproate (Depakote), it is the valproate ion that is absorbed from the gastroin-testinal tract and is the active form.
As with several other AEDs, it is difficult to ascribe a single mechanism of action to valproic acid. This com-pound has broad anticonvulsant activity, both in exper-imental studies and in the therapeutic management of human epilepsy. Valproic acid has been shown to block voltage-dependent sodium channels at therapeutically relevant concentrations. In several experimental stud-ies, valproate caused an increase in brain GABA; the mechanism was unclear.There is evidence that valproate may also inhibit T-calcium channels and that this may be important in its mechanism of action in patients with absence epilepsy.
Valproic acid is well absorbed from the gastroin-testinal tract and is highly bound (~90%) to plasma pro-tein, and most of the compound is therefore retained within the vascular compartment. Valproate rapidly en-ters the brain from the circulation; the subsequent de-cline in brain concentration parallels that in plasma, in-dicating equilibration between brain and capillary blood. A large number of metabolites have been identi-fied, but it is not known whether they play a role in the anticonvulsant effect of the parent drug. Valproic acid inhibits the metabolism of several drugs, including phe-nobarbital, primidone, carbamazepine, and phenytoin, leading to an increased blood level of these compounds. At high doses, valproic acid can inhibit its own metabo-lism. It can also displace phenytoin from binding sites on plasma proteins, with a resultant increase in un-bound phenytoin and increased phenytoin toxicity. In this instance, the dosage of phenytoin should be ad-justed as required. These examples reinforce the need to determine serum anticonvulsant levels in epileptic patients when polytherapy is employed.
Valproic acid has become a major AED against sev-eral seizure types. It is highly effective against absence seizures and myoclonic seizures. In addition, valproic acid can be used either alone or in combination with other drugs for the treatment of generalized tonic– clonic epilepsy and for partial seizures with complex symptoms.
The most serious adverse effect associated with val-proic acid is fatal hepatic failure. Fatal hepatotoxicity is most likely to occur in children under age 2 years, espe-cially in those with severe seizures who are given multi-ple anticonvulsant drug therapy. The hepatotoxicity is not dose related and is considered an idiosyncratic re-action; it can occur in individuals in other age groups, and therefore, valproic acid should not be administered to patients with hepatic disease or significant hepatic dysfunction or to those who are hypersensitive to it. Valproic acid administration has been linked to an in-creased incidence of neural tube defects in the fetus of mothers who received valproate during the first trimester of pregnancy. Patients taking valproate may develop clotting abnormalities.
Valproic acid causes hair loss in about 5% of pa-tients, but this effect is reversible. Transient gastroin-testinal effects are common, and some mild behavioral effects have been reported. Metabolic effects, including hyperglycemia, hyperglycinuria, and hyperammonemia, have been reported. An increase in body weight also has been noted. Valproic acid is not a CNS depressant, but its administration may lead to increased depression if it is used in combination with phenobarbital, primi-done, benzodiazepines, or other CNS depressant agents.
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