The Pharmaceutical Journal Vol 262 No 7038 p432-435
March 27, 1999 Continuing education

Epilepsy

(2) Treatment - the established drugs

By Theodora Michael, BPharm, MRPharmS

Other articles in the series
Epilepsy - the disease (PJ, February 27, 1999, pp297-300)
Epilepsy - new treatments (PJ, April 3, 1999, pp470-3)

A patient who has a single seizure and then fully recovers is not usually a candidate for drug treatment unless the seizure is associated with a definite disorder, such as a structural abnormality or a diagnostic EEG. In other patients, antiepileptic treatment is started in those who have had more than one attack in 12 months.
The type and severity of the seizures and the length of time between them also play a part in influencing the decision to treat. The patient has to be fully informed about the consequences of drug therapy, eg, with respect to possible adverse effects and the need for long-term treatment. Ideally, the diagnosis is made or confirmed by a specialist before starting therapy.
Between 70 and 80 per cent of patients with epilepsy can be managed successfully with a single antiepileptic agent.^1,2 The most suitable drug for the particular type of seizure is introduced slowly and then increased to a dose high enough to produce a therapeutic effect without inducing side effects that might reduce the patient's confidence.
The established antiepileptics, such as carbamazepine, phenytoin and sodium valproate, form the mainstay of treatment of epilepsy, along with the benzodiazepines and the barbiturates. Table 1 shows the first line drugs that are recommended.²
Carbamazepine, sodium valproate, phenytoin and phenobarbitone (and primidone) have been shown to be equally effective in reducing the frequency of partial seizures.^1,2 Carbamazepine and phenytoin are ineffective in the treatment of absence seizures and myoclonus. Myoclonus can actually be made worse by carbamazepine, gabapentin and lamotrigine, and absence seizures can be worsened by carbamazepine and gabapentin.

DRUG MONITORING
Poor compliance is the most common cause of treatment failure.³ Monitoring serum drug levels can be used to detect this. More often, therapeutic drug monitoring is used to optimise dosage.
Phenytoin levels are routinely monitored because of its narrow therapeutic range and non-linear kinetics. Carbamazepine, phenobarbitone and ethosuximide levels can be useful in certain cases where control is inadequate. The monitoring of serum levels of the other antiepileptic drugs is of limited clinical value.²

DRUG INTERACTIONS
One of the most important factors affecting drug serum levels is the effect of concomitant medication. Interactions between antiepileptic drugs or between antiepileptic drugs and other medication are complicated and well documented. They are usually caused by hepatic microsomal enzyme induction or inhibition and can be unpredictable. These interactions were discussed in a recent article in The Journal (March 6, p325) and will not be discussed further here.

EPILEPSY IN THE ELDERLY
Elderly patients are more likely to experience dose-related adverse effects because of their slower metabolism. Treatment principles are the same as for younger patients but particular attention should be paid to possible interactions with other medication. Drug regimes may also need to be simplified by using agents with long half-lives, such as phenytoin, to aid compliance in patients with memory problems.^2,3

Table1: SEIZURE TYPE AND DRUG SELECTION 2
Classification	First line drugs	Second line drugs
Partial (simple, complex, with or without secondary generalisation	Carbamazepine Sodium valproate	Clobazam Clonazepam Gabapentin Lamotrigine Phenytoin Tiagabine Topiramate Vigabatrin (Acetazolamide and phenobarbitone are possible alternatives)
Generalised absence	Sodium valproate	Clobazam Clonazepam Ethosuximide Lamotrigine
Generalised tonic-clonic	Sodium valproate	Carbamazepine Clobazam Gabapentin Lamotrigine Phenytoin Topiramate Vigabatrin (Acetazolamide, clonazepam and phenobarbitone are possible alternatives)
Myoclonic	Sodium valproate	Clobazam Clonazepam Ethosuximide Lamotrigine Piracetam

GENERIC PRESCRIBING
Generic prescribing in epilepsy remains controversial and expert recommendations vary. However, use of generics is acceptable in the majority of patients. A recent study which reported that generic "switching" can cause problems in some patients involved carbamazepine, phenytoin and sodium valproate.⁶ Almost 30 per cent of patients studied reported perceived problems (increased side effects or worsening of seizure frequency) with the "switch" and in one-third of these patients the GP agreed that there had been a problem. The study has been criticised for the fact that no control group was included to compare problems in patients with no change in drug brand. It is well understood that psychological factors can influence "switch-related" problems but in the vast majority of patients there is no problem with the use of generics.

ESTABLISHED ANTIEPILEPTIC DRUGS
Carbamazepine Carbamazepine has become one of the most widely used antiepileptics. It is thought to prevent the repetitive firing of action potentials in depolarised neurones by blocking sodium channels and prolonging the inactive state.^1,7,8
The drug is introduced gradually, starting at 100mg to 200mg at night and increased over a month to the optimum dose, usually in the range of 400mg to 1200mg per day. Adult daily doses can go beyond the manufacturer's recommended dose of 2,000mg.⁹ The dose is determined by the patient's response rather than the serum level and can be as high as 2,400mg per day.¹⁰ For high doses, the "retard" preparation is more useful, to prevent adverse effects associated with high peak concentrations.¹¹ This formulation is usually given twice daily. Suppositories are reserved for short-term use when no other route is available.
Adverse effects occur in up to one-third of patients but in only 5 per cent of cases will treatment need to be stopped.12 The most common adverse effects are dizziness, blurred vision, diplopia, headache and nausea. They are dose related. The drug has less effect on cognitive function than the barbiturates and phenytoin. Carbamazepine causes a rash in 5 to 10 per cent of patients.^1,12 Bone marrow depression, toxic hepatitis and Stevens-Johnson syndrome are rare but patients should be counselled on how to recognise symptoms of these conditions and to see their doctor immediately if they occur. Other adverse effects include arrhythmias, photosensitivity and dyskinesias. At high doses, hyponatraemia (because of the drug's antidiuretic hormone-like action) and neutropenia are common but they are usually mild and asymptomatic.
Carbamazepine is an enzyme inducer and not only causes drug interactions but also undergoes autoinduction whereby the half-life varies from 36 hours with a single dose to 16 to 24 hours after a month of treatment.^8,9
Doses should be reduced in severe liver disease to avoid accumulation and the drug should be used with caution in renal impairment.

Phenytoin During the past 15 years, trials have shown that phenytoin remains one of the most effective drugs for the treatment of partial and generalised tonic-clonic seizures.¹⁰ However, due to its unpredictable pharmacokinetics and its undesirable adverse effects in chronic use, it is not used as a first line drug.²
Phenytoin has a number of actions on neurones. It acts on voltage dependent sodium channels to prolong the inactive state, it reduces calcium entry into neurones which blocks neurotransmitter release and it enhances the action of the inhibitory neurotransmitter GABA.^7,9
Phenytoin is most useful in the treatment of status epilepticus where it rapidly penetrates brain neurones when given intravenously.¹⁰ Because of its long half life (average 22 hours⁹), a loading dose needs to be given; time to steady state is between two and four weeks. Phenytoin is also used in neurosurgery as prophylaxis and treatment of seizures.
The monitoring of phenytoin is complicated by non-linear kinetics, a narrow therapeutic range and by being highly protein bound. Small dose adjustments can produce large changes in serum concentration. The drug's metabolism varies between individuals and a standard adult dose of 300mg daily can be toxic or subtherapeutic in 50 per cent of patients.¹¹ Adult doses start at 200mg to 300mg daily, usually given as a single dose, and may go up to 500mg daily (or higher in exceptional cases) to reach the therapeutic range.⁹ Different oral formulations have differing bioavailabilities and, ideally, patients stabilised on one formulation should continue on it. Changes may need to be followed up with serum concentration monitoring.
Adverse effects are common in about 50 per cent of patients, with 10 per cent requiring drug withdrawal.¹³ Dose-related adverse effects include ataxia, nystagmus, lethargy, slurred speech and haematological disturbances that warrant frequent blood counts during treatment.
Long-term treatment causes gingival hyperplasia in many patients; this can be minimised by good dental hygiene.¹⁰ Hirsuitism and aggravation of acne are also seen in chronic use, making phenytoin less favourable than other antiepileptics. The drug can also cause megaloblastic anaemia and osteomalacia by interfering, respectively, with folic acid and vitamin D metabolism in chronic use.^9,10,13
Hypersensitivity reactions can manifest as skin rashes, blood dyscrasias, hepatic damage, fever and renal failure. Skin rashes are the most common of these and should always lead to discontinuation of treatment. In mild cases, the drug can be resumed after the rash has disappeared but must be discontinued if the reaction recurs. Phenytoin has been reported to cause more adverse effects on cognition than carbamazepine and sodium valproate.^2,10 Aggression, sedation, memory impairment and depression are some of the unwanted psychological effects commonly reported.2,9,14
Liver disease can lead to accumulation and doses need to be reduced to avoid toxicity.
Fosphenytoin is a pro-drug which is converted to phenytoin by hepatic alkaline phosphatase enzyme activity after injection.¹⁰ It is thought to cause less irritation at the injection site than phenytoin and can be given at a faster rate. The drug has recently been launched in the UK.

Sodium valproate Sodium valproate is effective in all types of epilepsy. It has multiple mechanisms of action. These include inhibiting GABA-degrading enzymes, stimulating the activity of enzymes that break down the excitatory neurotransmitter glutamic acid and limiting repetitive neuronal firing by blocking sodium channels.^1,7,10
Sodium valproate doses in adults start at 500mg to 600mg per day. The drug is an enzyme inhibitor and will possibly increase levels of other drugs.^9,15 There is usually no need to build up dose gradually with sodium valproate and the dose is titrated upwards, depending on the patient's response. The manufacturer of Epilim recommends a maximum dose of 2.5g per day9 but doses between 3g and 4g have been tolerated well in some patients.^11,13
The daily variation in serum concentration of sodium valproate is wide and routine monitoring is not useful, except in rare cases.
Common dose-related adverse effects are tremor, appetite stimulation leading to weight gain, thinning or loss of hair (rarely irreversible) and menstrual irregularities. Gastric irritation and nausea are common at the start of treatment, especially with the non-enteric coated preparations, but can be reduced by taking doses with or after food.⁹
Sedation is uncommon with sodium valproate monotherapy; it is more likely to be a problem in patients who are also taking other antiepileptics, such as the barbiturates.
Non-dose-related adverse effects, such as hepatotoxicity, are rare. Approximately 20 per cent of patients taking sodium valproate will have hyperammonaemia with no hepatic damage. It is usually asymptomatic but can cause confusion, nausea and vomiting in a few cases.¹
Fewer than 1 in 20,000 patients develop hepatotoxic effects, with most reports being in children, especially those below the age of three years and those with severe learning difficulties, many with co-existing metabolic disorders.^1,14 Hepatotoxicity mainly occurs in patients also taking other antiepileptic drugs and during the first six months of treatment, with the highest risk between two and 12 weeks.⁹
Other adverse effects include fatal pancreatitis and thrombocytopenia, usually in patients on high doses. Patients should be counselled on recognising the symptoms of these idiosyncratic reactions. In hepatic damage, these can vary from non-specific symptoms, such as tiredness, weakness and anorexia, to specific signs such as jaundice. Unexplained bruising or bleeding could be signs of thrombocytopenia.
Sodium valproate should be avoided in patients with liver disease because of its hepatotoxicity. In renal impairment the dose should be reduced, with drug level monitoring.

Contraception and pregnancy in patients with epilepsy Enzyme-inducing antiepileptic drugs increase the rate at which steroid hormones are metabolised.4 Women taking phenytoin, barbiturates, carbamazepine and topiramate require an oral contraceptive preparation that contains at least 50μg ethinyloestradiol. The current Family Planning Association advice is to "tricycle" with monophasic tablets by taking three packets without a break, followed by a short break of four days.5 There are risks of teratogenicity from any antiepileptic drug but 90 per cent of women with epilepsy will deliver healthy children. However, the risk of major malformations and minor anomalies is two to three times higher in infants of mothers who take antiepileptic drugs than in infants of mothers who do not.2 The lack of data with the newer antiepileptic drugs makes it difficult to determine the teratogenic risks associated with them. Medication is often reviewed before conception, with monotherapy being the aim to reduce the risks of foetal malformations. Folic acid supplementation is essential. Women who are taking carbamazepine or sodium valproate should take 5mg folic acid/day and others should take at least 0.4mg/day.2 Enzyme-inducing drugs can cause haemorrhagic disease of the newborn by causing a deficiency in vitamin K. Women taking such drugs should take vitamin K supplementation 20mg/day prophylactically in the last month of pregnancy and newborns should receive vitamin K injection. All antiepileptic drugs pass into the breast milk to varying degrees. Only carbamazepine and sodium valproate are in small enough concentrations not to pose a risk to the infant.5

Barbiturates The barbiturates, principally phenobarbitone, are the oldest antiepileptics still in use. Phenobarbitone is now reserved for patients who cannot tolerate other antiepileptics because of its potential neurological toxicity. However, in view of its low cost and general availability it is still widely used in developing countries.
These drugs act in a non-selective manner but the main mechanisms of action are reducing the action of glutamic acid and enhancing the action of GABAA at the receptor sites.^1,7,10
Oral adult doses of phenobarbitone range from 30mg to 240mg per day, increased gradually; the drug is given in a single daily dose.^1,10 Phenobarbitone is also a potent enzyme inducer. Its adverse effects include sedation and impairment in cognition, mood (especially depression) and behaviour. In children, it can have the opposite effect and cause hyperactivity, insomnia and aggression. Other effects include skin rashes, megaloblastic anaemia (caused by folic acid deficiency) and osteomalacia (caused by vitamin D deficiency). Vitamin K deficiency may also occur. Dupuytren's contracture and other connective tissue disorders have been reported.
Tolerance to adverse effects can develop, as can tolerance to the antiepileptic action.^1,13 Thus, the use of serum concentration monitoring is limited. Chronic use can cause physical dependence and abrupt withdrawal can lead to withdrawal seizures; reduction needs to occur over months.¹⁰
Phenobarbitone is an alternative to phenytoin in the treatment of status epilepticus; given intravenously, it is highly effective with a rapid onset and prolonged action. Thiopentone, another barbiturate generally used in anaesthesia, is also an effective agent in status epilepticus.¹⁶
Primidone and methylphenobarbitone are metabolised by the liver to form phenobarbitone (and other active metabolites in the case of primidone). Their efficacy and adverse effects are similar to phenobarbitone. Primidone actually has a higher incidence of adverse effects and is less well tolerated and there is little, if any, evidence to support its use over phenobarbitone.
Barbiturates accumulate in liver disease and in severe renal impairment and dose adjustment is needed to avoid neurotoxicity.

Benzodiazepines The benzodiazepines are potent antiepileptic drugs but are usually prescribed as adjuncts or add-on therapy.
Their site of action as anxiolytics and as antiepileptics is at the benzodiazepine-binding site of the GABAA receptor.^7,10
Diazepam is the first line treatment of status epilepticus, given either intravenously or rectally in doses of 5mg to 20mg. Lorazepam injection is an alternative.¹⁶ Both have little practical use in chronic treatment. If benzodiazepine treatment is not effective in status epilepticus, intravenous phenytoin or phenobarbitone would be given.
Clonazepam is mainly used as an adjunct for myoclonic seizures and also as an adjunct in other seizure types.^2,13 It is introduced gradually to limit sedation, with adult doses starting at 0.25mg to 0.5mg and increasing to 4mg daily, given in one or two doses. Higher doses, up to 8mg per day, can be used.⁹
Sedation is the most common adverse effect of clonazepam. Ataxia, lack of co-ordination, and behavioural and personality changes are also common. Few patients have a good response to the drug and tolerance, associated with worsening of all seizure types, is common. Discontinuation of the drug is associated with rebound insomnia, anxiety, tremor and psychosis as well as seizure exacerbation.¹⁰
Clobazam is less sedating than diazepam or clonazepam and is used as an adjunct in patients with poorly controlled epilepsy. Adult doses are usually in the range of 10mg to 20mg daily, but higher doses have been used. Tolerance, which is increased by high doses and decreased by intermittent therapy, develops within weeks or months in as many as 50 per cent of patients.¹⁰ Treatment in short courses as an adjunct in the treatment of seizure clusters has been beneficial in many patients, especially in the treatment of catamenial epilepsy, which is the exacerbation of seizures around menstruation.¹⁷
All benzodiazepines can precipitate coma in liver disease and are best avoided. Lower doses should be used in severe renal impairment.
Other benzodiazepines have also been used in epilepsy. Nitrazepam is effective in infantile spasms. Midazolam has been used in status epilepticus.

Ethosuximide Ethosuximide is only useful in the treatment of absence seizures and, sometimes, in myoclonic seizures. It reduces calcium conductance in the thalamic neurones which have been implicated in the pathophysiology of absence seizures.^1,7,10 Doses are increased slowly, starting at 250mg daily in children under six years and 500mg daily in older children and adults. Doses are increased every three to four days, usually to a maintenance dose of 2g to 3g daily in adults and children over six years.⁹ Introduction may be more gradual, increasing every two to four weeks, to limit adverse effects.¹ Serum concentration monitoring may be required at high doses as small increments in dose can result in large increases in serum concentration.
The most common adverse effects are gastric irritation, anorexia, abdominal pain, nausea and vomiting. Others include lethargy, dizziness, depression and headache, and inability to concentrate. Rarely, blood dyscrasias have been reported and can be fatal. They resolve on reduction of dose or on discontinuation. Patients should be advised to report signs of infection, such as sore throat or fever, so that blood counts can be carried out.

Other drugs Acetazolamide, a carbonic anhydrase inhibitor commonly used in glaucoma, has been used in the treatment of various seizure types. Its antiepileptic mechanism of action is not known. Doses of 250mg once to three times daily have been used to treat partial and primary generalised tonic-clonic seizures. It has also been used in catamenial epilepsy, starting eight to 10 days before menstruation and continued for up to 10 days.¹⁰
Paraldehyde, given rectally or less often intramuscularly, has been used in the treatment of status epilepticus where other measures have failed. The onset of action is rapid. Chlormethiazole infusion has also been used in status epilepticus.¹⁶

CONCLUSION
The established antiepileptics are effective for the majority of patients with epilepsy, either as monotherapy or in combination. However, an important minority of patients will fail to respond to the drugs or will suffer unacceptable side effects. For these patients, the recent development of several new antiepileptics has offered hope of seizure-free control with minimal adverse effects. These newer drugs will be discussed in the next article.

ACKNOWLEDGEMENTSI would like to thank Professor Simon Shorvon (professor in clinical neurology, Institute of Neurology, and consultant neurologist, National Hospital for Neurology and Neurosurgery) for his helpful comments.

Ms Michael is clinical pharmacist at the National Hospital for Neurology and Neurosurgery, Queen Square, London