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Phenytoin

Phenytoin has been used for over 50 years. Thus, the characteristics and side-effects have been well elucidated. Its primary use is for treatment of partial epilepsy, including simple and complex partial seizures, as well as generalized tonic-clonic seizures, whether of primary or partial onset. Phenytoin can be initiated with a ‘loading dose’ of 13-20mg/kg, or with a starting dose of 3-5 mg/kg/day. Phenytoin was one of the first anti-epileptic drugs that became associated with a ‘therapeutic range’ (10-20 mg/1 in most laboratories), which represents serum concentrations most likely to produce a therapeutic effect without substantial dose-related side-effects. The phenytoin dose should be selected using therapeutic monitoring rather than a predetermined dose, such as 300 mg/day.

As the serum level increases, side-effects such as lethargy, ataxia, dysarthria, fatigue, diplopia, abnormal movements, mental confusion and cognitive changes may occur. This is particularly true at concentrations above 20 mg/1. However, the therapeutic range represents an average. A number of patients may remain seizure-free at serum concentrations below the range, or may tolerate levels substantially above the range. However, it is very important to understand the properties of phenytoin metabolism. As serum concentrations rise, particularly to levels above 15 mg/1, the metabolism of phenytoin slows substantially. This is called ‘zero order kinetics’. At levels below 15 mg/1, doubling the dose will lead to a doubling of serum concentration, and the half-life is 24 h.

As metabolism slows at higher concentrations, even a 50-mg change in dose can double the serum concentration, and the half-life increases to 48-70 h. Since the half-life is so prolonged, a steady state after dose adjustments may not occur for weeks, with serum levels slowly rising over this time. This can easily lead to serious phenytoin toxicity. Hospitalization due to phenytoin toxicity under these circumstances is not uncommon. Dosage adjustments must be made with great care, and levels should be repeated a month after any adjustment. In addition to dose-related toxicities, patients receiving phenytoin may experience side-effects that are relatively independent of dose. These include gingival hyperplasia, acne and hirsutism. Visits to the dentist every 6-12 months, accompanied by daily flossing, can help prevent gingival hypertrophy. There is now fairly substantial evidence that long-term phenytoin use can lead to reduced bone density and risk of fracture.

Obviously, this is a major issue for patients who fall with their seizures. All patients receiving phenytoin should receive supplemental calcium and vitamin D, and should be screened with bone densitometry. Allergic rash may occur. Although idiosyncratic side-effects are not common, they can occur, and patients should be advised of this possibility. These include Stevens-Johnson syndrome, aplastic anaemia, hepatic failure and a lupus-like syndrome. Monitoring of blood counts, liver function tests and electrolytes are warranted for the first 6-12 months of therapy. Drug interactions are relatively common, both with other epilepsy drugs and with drugs taken for other conditions. Interactions with other anti-epileptic drugs are listed in Because of phenytoin’s relatively long half-life, it can be administered only once or twice a day.

Carbamazepine

Carbamazepine has long been considered a first-line agent for simple partial, complex partial and generalized tonic-clonic seizures. Recently, many studies have compared the newer anti-epileptic drugs to carbamazepine as the ‘gold standard’ in patients with newly diagnosed epilepsy, and to date, none has been found to be more effective.

Table Pharmacokinetic impact of old anti-epileptic drugs (anti-epileptic drugs) on new anti-epileptic drugs. -I, levels decrease (faster clearance); T, levels increase (slower clearance)

Table Pharmacokinetic impact of new anti-epileptic drugs (anti-epileptic drugs) on old anti-epileptic drugs. -I, levels decrease (faster clearance); T, levels increase (slower clearance)

However, lamotrigine, topiramate and oxcarbazepine all caused fewer dropouts due to side-effects than carbamazepine. Of note, it is considered ‘narrow spectrum’, and may actually worsen generalized epilepsies, particularly those associated with absence or myoclonus. Initiation must be done with titration, to avoid appearance of dose-related side-effects. Dose selection should be done using clinical response and serum levels. Typically, a level of 8-12mgA will provide the best response, and few patients will tolerate serum concentrations above 15mg/l. Dose-related adverse effects include ataxia, drowsiness, vertigo, difficulty concentrating, diplopia and blurred vision.

Using sustained-release formulations of carbamazepine will reduce some of these side-effects by reducing peak serum concentrations. The other advantage is the ability to use twice-a-day dosing, rather than the three- to four-times-a-day dosing that would otherwise be necessary due to the short half-life of carbamazepine. Gastrointestinal symptoms such as nausea, vomiting, diarrhoea and constipation may also be seen. The other side-effects of carbamazepine are not necessarily linked to dose. These include more common, but less serious, effects such as leucopenia, hyponatraemia and rash as well as life-threatening but extremely rare idiosyncratic reactions such as Stevens-Johnson syndrome, aplastic anaemia and hepatic failure. Mild leucopenia can be disregarded. Rarely, more profound leucopenia (with leucocyte counts <2.5xl0⁹) may necessitate discontinuation of therapy.

Hyponatraemia does not necessitate discontinuation in all patients, as it can often be managed with water restriction. However, in some patients water restriction does not work, or too severely impacts lifestyle, and in these patients an alternative anti-epileptic drug should be sought. Because of the potential for all of the above issues, monitoring of liver function tests, white blood counts and electrolytes are necessary during the first 6-12 months of therapy, and yearly thereafter. The potential for carbamazepine to produce decreased bone density is under study. Of note, chronic carbamazepine use has been associated with some reduction in serum testosterone levels and increases in cholesterol levels.

The clinical implications of these changes are under study. As with phenytoin, carbamazepine is associated with many drug interactions affecting anti-epileptic drugs and other drugs. Because many drugs can inhibit or induce the metabolism of carbamazepine, and cause acute toxicity or reduced effect, it is a good idea to tell patients to inform their neurologist when starting any prescription drug. Carbamazepine, even in the extended-release formulations, is substantially less expensive than the newer anti-epileptic drugs.

Phenobarbital

Phenobarbital is the ‘grandfather of anti-epileptic drugs’. It has been available for over 100 years. It is effective for most seizure types and the fact that an intravenous (i.v.) formulation is available means it is often used for treatment of status epilepticus. In the modern era, it is rarely used as first-line therapy, as studies have demonstrated that it causes more dose-related side-effects, particularly sedation, than other options. Also, once started it is very difficult to withdraw without causing seizure exacerbation. Abrupt withdrawal is not recommended, and even slow withdrawal can lead to problems. The initial dose is 30-50 mg, which is best administered at bedtime.

Titration to optimal dose can be achieved over several weeks. Optimal effect is usually achieved at serum concentrations of 15-45 mg/1. Other dose-related side-effects include irritability, difficulty concentrating, memory loss, sedation, dysarthria and ataxia. Other reported adverse reactions include hyperactivity, mostly in children, and depression. As with phenytoin and carbamazepine, hypersensitivity syndrome, rash, hepatic failure and aplastic anaemia may occur. Since many patients who are currently on phenobarbital have been on it long term, an understanding of long-term side-effects is important. Some unique side-effects occur with long-term phenobarbital use, affecting the skin and connective tissue. These may include contractures, frozen shoulder and general pain. Drug interactions may occur with phenobarbital . It is the least expensive anti-epileptic drug, costing pennies a day, and its long half-life permits once-a-day dosing, which is important for potentially non-compliant patients.PhenytoinCarbamazepinePhenobarbital Primidone

Primidone

Primidone is no longer considered a first-line drug, and its use has diminished substantially. It is metabolized to a number of active metabolites, including phenobarbital and phenylethylmalonamide, although the parent compound is also active. When obtaining serum levels, therapeutic effect will be associated with both the parent primidone levels and phenobarbital levels. In the presence of enzyme-inducing drugs, primidone levels will go down, and phenobarbital levels will rise. Primidone causes all the problems seen with phenobarbital use, described above.

Valproate

Valproate has been available since the 1970s, but remains the first-line drug for many epilepsy syndromes, including juvenile myoclonic epilepsy and syndromes associated with absence seizures. Valproate may be the only effective agent for some patients. A recent large randomized open-label trial demonstrated superior efficacy compared with lamotrigine, and superior tolerability compared with topiramate, in adults and children with idiopathic generalized or unclassified epilepsy. Seizure control was maintained in the majority for 5 years.

In some countries, valproate is also used as first-line therapy for partial seizures. In a head-to-head study, valproate was as effective for generalized tonic-clonic convulsions as carbamazepine in patients with partial epilepsy, but was found to be less effective for complex partial seizures. However, in other studies, the efficacy was equivalent in all seizure types, when valproate was compared with phenytoin, carbamazepine or oxcarbazepine. Valproate is available in a variety of formulations, including sustained release, sprinkles and i.v.. With the availability of i.v., valproate has become more popular for treatment of status epilepticus. Typical initiation in outpatients is at a dose of 10—15mg/ kg/day, with subsequent increases of 5-10mg/kg/week as needed to control seizures. Serum levels between 50 and 100 mg/1 are typically therapeutic and well tolerated, but higher concentrations may be necessary in some patients.

Skin rashes are less common with valproate than with carbamazepine, phenytoin and lamotrigine, and therefore valproate is a reasonable choice for patients with a history of hypersensitivity. The main side-effects are Gastrointestinal upset, nausea, vomiting, tremor, weight gain and hair loss. Tremor and weight gain are dose related. Gastrointestinal upset can sometimes be avoided by using alternative formulations, such as sustained release or sprinkles. Elevated ammonia levels can be seen commonly, affecting 20-50% of patients. In some patients this is well tolerated and not problematic, while in others elevated ammonia can be associated with encephalopathy, triphasic waves and even coma. It is not recommended to monitor ammonia in asymptomatic patients.

However, if patients demonstrate encephalopathy, particularly in the presence of asteryxis and/or delta slowing on the electroencephalogram, it is reasonable to check for hyperammonaemia. Carnitine supplementation has been recommended to improve valproate-induced hyperammonaemia. Idiosyncratic side-effects include rare fatal hepatotoxicity. The incidence is 1 in 20 000 in adults on monotherapy, but much more common in polytherapy, in children under 10 years old, and even more so in children under 2 years old. Children who have seizures resulting from metabolic disorders may be at extremely high risk, and as a rule should not be treated with valproate. When children on polytherapy under the age of 2 are treated, the reported incidence is as high as 1 in 600-800.

The greatest risk is in the first 6 months of use, and clinical as well as blood monitoring is indicated during this time. Pancreatitis may also occur, which may have a frequency of up to 1 in 3000. The risk of pancreatitis does not diminish over time. Aplastic anaemia is rare, but thrombocytopenia and altered bleeding time are common. These are usually not clinically worrisome, and low platelet counts can usually be tolerated as they do not portend more significant blood dyscrasias. Some case reports note increased risk of bleeding during surgery in patients on valproate, whereas many others note no increase in bleeding. Recently, a number of studies have reported adverse fetal outcomes in offspring of women receiving valproate. Spina bifida is seen in up to 2% of children exposed to valproate before birth. This makes valproate a poor choice for women contemplating pregnancy. In some studies, valproate has also been associated with development of polycystic ovarian syndrome. This appears to be more prevalent when valproate is initiated in women under 40. Reports of menstrual cycle irregularities are common.

One property of valproate that must be kept in mind is that it is a hepatic metabolic inhibitor. This has a number of consequences, including a number of interactions with other anti-epileptic drugs as well as drugs of different classes. In addition, intrinsic substances such as oestrogen may be inhibited. Valproate is highly protein bound. It may displace phenytoin from binding sites, causing emergence of phenytoin toxicity in the absence of an increased plasma level.

Ethosuximide

Ethosuximide has a very narrow therapeutic indication, with use limited to patients with absence seizures. In most cases, it should be used as the sole agent only in patients who experience this seizure type in isolation, a condition seen primarily in childhood. Occasionally, in patients with primary generalized epilepsy with seizure types other than absence, addition of ethosuximide as an adjunctive medication may improve seizure control. Ethosuximide can be started at 500 mg/day, and titrated as tolerated, with weekly increments. Serum concentrations of 40-100 mg/1 are usually optimal. The most common side-effects noted with ethosuximide use include nausea and abdominal discomfort, drowsiness, anorexia and headache. In rare cases, behavioural changes may be seen, including psychosis. Blood dyscrasias have been reported. Drug-drug interactions are minimal.

Benzodiazepines

Available benzodiazepines for chronic use include clonazepam, clorazepate and clobezam. Most benzodiazepines are not good choices for long-term therapy and should not be used as first-line agents. Patients may develop tolerance to the therapeutic effects of many of the benzodiazepines. Seizures may initially be decreased, but as tolerance develops over time, seizures may recur, necessitating dosage increases to regain control. Among the available benzodiazepines, clobezam has been touted as having less propensity for tolerance development. The most common dose-related side-effects of this drug class include drowsiness, ataxia and behavioural problems. Clonazepam is particularly useful for myoclonus.

Clorazepate and clobezam may be used for both generalized and partial epilepsies. They tend to be used in patients with drug-resistant epilepsy. Starting dose for clonazepam is 0.5-1 mg twice daily, increasing as needed. Chlorazepate can be initiated at 7.5 mg twice daily or thrice daily. Clobezam can be started at 5mg twice daily and increased by 5-10 mg every 1-2 weeks to achieve the best seizure control without development of excessive sleepiness. Abrupt withdrawal from chronic benzodiazepines may precipitate status epilepticus. Even slow withdrawal may exacerbate seizures. Acute benzodiazepines such as diazepam, lorazepam and midazolam may be used as intermittent ‘rescue therapy’ in patients who experience seizure clusters or status epilepticus.

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Jennifer Bowles

Jennifer is a clinical pharmacologist. She helps doctors of all medical specialties choose medications. Jennifer consults about drug dosage, interactions, and side effects.