Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 22) pdf

20 Epilepsy, parkinsonism and allied conditions SYNOPSIS • Antiepilepsy drugs: principles of management; withdrawal of therapy; pregnancy; teratogenic effects; epilepsy in children; status epilepticus • Individual drugs: carbamazepine, phenytoin, sodium valproate, lamotrigine, vigabatrin, gabapentin, clonazepam, topiramate, levetiracetam. • Parkinsonism Objectives of therapy Drug therapy; problems of long-term treatment • Other disorders of movement • Tetanus cortical neurons simultaneously (primary generalised seizure). Bromide (1857) was the first drug to be used for the treatment of epilepsy, but it is now obsolete. Phenobarbital, introduced in 1912, controlled patients resistant to bromides. The next success was the discovery in 1938 of phenytoin (a hydantoin) which is structurally related to the barbiturates. Since then many other drugs have been discovered, but phenytoin still remains a drug of choice in the treatment of major epilepsy. Over the past ten years there has been a dramatic increase in the number of new anticonvulsant drugs (vigabatrin, gabapentin, lamotrigine, topiramate, oxcarbazepine, levetira- cetam), but none has been shown to be superior to the major standard anticonvulsants (phenytoin, carbamazepine and sodium valproate). Antiepilepsy drugs Epilepsy affects 5-10 per 1000 of the general population. 1 It is due to sudden, excessive depolar- isation of some or all cerebral neurons. This may remain localised (focal seizure) or may spread to cause a secondary generalised seizure, or affect all 1 Some people with epilepsy make pilgrimages to Terni (Italy) to seek intercession from Saint Valentine to relieve their condition. There was more than one Saint Valentine and it is unclear if he was also the patron saint of lovers. MODE OF ACTION Antiepilepsy (anticonvulsant) drugs inhibit the neuronal discharge or its spread, and do so in one or more of three ways: 1. Reducing cell membrane permeability to ions, particularly the voltage-dependent sodium channels which are responsible for the inward current that generates an action potential. Cells that are firing repetitively at high frequency are blocked preferentially, which permits discrimination between epileptic and physiological activity. 2. Enhancing the activity of gamma-aminobutyric 413 20 EPILEPSY, PARKINSONISM AND ALLIED CONDITIONS acid (GABA) the principal inhibitory transmitter of the brain; the result is increased membrane permeability to chloride ion, which reduces cell excitability. 3. Inhibiting excitatory neurotransmitters, e.g. glutamate. CLASSIFICATION OF EPILEPSIES A generally accepted classification is given in Table 20.2 (p. 418), together with drugs of choice for the various seizure disorders. Principles of management These call for attention to nondrug as well as drug measures, as set out below: • Any causative factor must, of course, be treated, e.g. cerebral neoplasm. • Educate the patient about the disease, duration of treatment and need for compliance. • Avoid precipitating factors, e.g. alcohol, sleep deprivation, emotional stress. • Anticipate natural variation, e.g. fits may occur particularly or exclusively around periods in women (catamenial 2 epilepsy). • Give antiepilepsy drugs only if seizure type and frequency require it, i.e. more than one fit every 6-12 months. GENERAL GUIDETO ANTIEPILEPSY DRUG THERAPY The decision whether or not to initiate drug therapy after a single seizure remains controversial since approximately 25% of patients may not have another seizure. Some advocate treatment on the basis that early initiation may improve prognosis but the matter has not yet been resolved. 1. Therapy should start with a single well-tried and safe drug. The majority of patients (70%) can be controlled on one drug (monotherapy). 2. Anticonvulsant drug treatment should be 2 Greek katamenios, monthly appropriate to the type of seizure disorder. Although some drugs have a wide spectrum of action against different seizure types, some are more specific and may even aggravate certain seizure types. Carbamazepine is a drug of first choice for focal and secondary generalised epilepsy but aggravates myoclonic and absence seizures. Sodium valproate and lamotrigine have a wide spectrum of action and are active against both primary and secondary generalised epilepsy. 3. Choice of drug is also determined by the patient's age and sex. This is particularly true for women who prefer to avoid drugs associated with teratogenesis or that have adverse effects on their appearance, e.g. hirsutism from phenytoin. 4. If the attempt to control a patient's epilepsy by use of a single drug is unsuccessful, it should be withdrawn and replaced by a second line drug, though these are effective in only about 10% of patients. There is little evidence that three drugs are better than two, and not much that two are better than one. More drugs often mean more adverse effects. 5. Abrupt withdrawal. Effective therapy must never be stopped suddenly either by the doctor (carelessness) or by the patient (carelessness, intercurrent illness or ignorance), or status epilepticus may occur. But if rapid withdrawal is required by the occurrence of toxicity, a substantial dose of another antiepilepsy drug should be given at once. 6. In cases where fits are liable to occur at a particular time, e.g. the menstrual period, dosage should be adjusted to achieve maximal drug effect at that time or drug treatment can be confined to this time. For example, in catamenial epilepsy, clobazam can be useful given only at period time. Dosage and administration Generally drugs are best given as a single or twice daily dose to increase compliance. Many patients dislike taking medication to work or school and being seen to take it but, necessarily, drugs with short duration of action may require to be taken three or even four times a day. 414 PRINCIPLES OF MANAGEMENT 20 Regimens for initial dosing tend to vary with different drugs. In general, drugs are started in a small dose and increased at two-weekly intervals to the minimum effective dose. The patient's seizures are then monitored and further increases in dose only made if seizures continue. The time interval for dosage increases should therefore be sufficiently wide apart to allow changes in the seizure frequency due to changes in drug therapy to be accurately determined. These issues are particularly important for a doctor, e.g. in an emergency department, who has never seen the patient with a fit or series of fits. It is important then to consider the cause, whether it is noncompliance (which can be due to intercurrent disease), an inadequate drug regimen or an increase in the severity of the disease. MONITORING BLOOD CONCENTRATIONS OF ANTICONVULSANTS Many biochemistry laboratories no longer under- take routine measurement of the plasma concentra- tion for most anticonvulsant drugs because plasma concentrations are insufficiently stable to serve as a useful guide to change of dose. The exception is phenytoin, where a small increase in dose may lead to a disproportionate rise in the plasma drug concentration (see zero-order pharmacokinetics, p. 99) and plasma monitoring is essential. With other drugs the dose is increased to the maximum tolerated level and, if seizures continue, it is replaced by another. DRUG WITHDRAWAL After a period of at least 2-3 years free from seizures, withdrawal of antiepilepsy drug therapy can be considered. The prognosis of a seizure dis- order is determined by a number of factors. Some are known to remit spontaneously e.g. benign rolandic epilepsy and petit mal, whereas others never remit e.g. juvenile myoclonic epilepsy. In many types of epilepsy the outlook is less certain and only general indicators are available. The following factors can be important: • The type of seizure disorder — major seizures are more easily controlled. • The time to remission — early remission carries a better outlook. • The number of drugs required to induce remission — rapid remission on a single drug is a favourable indicator for successful withdrawal. • The presence of an underlying lesion — control is often difficult. • The presence of an associated neurological deficit or learning difficulty — control is often difficult. In general, if a patient with a major epilepsy has no neurological deficit or structural lesion and is of normal intelligence, there is a reasonable chance of continued remission, particularly if this is rapidly achieved with a single drug. In general, in adult epilepsy, discontinuing the antiepilepsy drug is asso- ciated with about 20% relapse during withdrawal and a further 20% relapse over the following 5 years; after this period relapse is unusual. It is generally recommended that the antiepilepsy drug be withdrawn over a period of 6 months. If a fit occurs during this time, full therapy must be resumed again until the patient has been free from seizures for a further 2-3 years. DRIVING REGULATIONS AND EPILEPSY The UK allows patients to drive a car (but not a truck or bus) if they have not had a daytime fit for 1 year (or after 3 years if they continue to be subject to fits only whilst asleep). Any fit that occurs during or after drug withdrawal incurs loss of the driving licence for a year. Because losing the right to drive is perceived to be a significant social disability, most patients prefer to remain on medication. PREGNANCY AND EPILEPSY Pregnancy can affect seizure disorder which worsens in about a third, improves in a third, and remains unchanged in the remainder. Ideally, patients should have their seizure disorder properly investigated and treated before pregnancy with the best control achieved on the lowest dose of the least teratogenic drug. Major seizures are harmful to the developing fetus because of the possibility of anoxia and meta- bolic disorder. Minor seizures are probably harm- less and therefore need not be eradicated. Patients 415 20 EPILEPSY, PARKINSONISM AND ALLIED CONDITIONS should be advised of the necessity of taking folic acid supplements, since some antiepilepsy drugs affect folic acid metabolism and folic acid deficiency is a risk factor for neural tube defects. Hepatic enzyme inducing antiepilepsy drugs lower the mother's concentration of vitamin K, which can aggravate any postpartum haemorrhage. Pregnant mothers should therefore be given an oral vitamin K for the last two weeks of pregnancy. Pharmacokinetics in pregnancy The total plasma concentration of drug falls, especially towards the end of pregnancy, due to haemodilution, but the therapeutically important free (unbound) fraction in plasma is less affected. In practice, the patient's clinical state is observed closely and the dose of drug is increased if seizures occur more often than expected. Hepatic drug metabolism tends to increase during pregnancy. After delivery, the pharmacokinetics revert to the prepregnancy state over a few days. Breast feeding Antiepilepsy drugs pass into breast milk (see p. 116), phenobarbital, primidone and ethosuximide in significant quantities, phenytoin and sodium valproate less so. There is a risk that the baby will become sedated or suckle poorly but, provided a watch is maintained for these effects, the balance of advantage favours breast feeding whilst taking antiepilepsy drugs. Teratogenic effects Children of mothers taking antiepilepsy drugs have an approximately 2-3 x increased frequency of malformations at birth. In a case-control study of pregnant women, the frequency of malformation was 20.6% in infants whose mothers took one anticonvulsant drug and 28.0% with two or more such drugs, compared to 8.5% in matched controls. 3 Infants of mothers who gave a history of epilepsy but did not take antiepilepsy drugs did not have a higher frequency than the controls, indicating that malformations are largely due to the antiepilepsy 3 Holmes LB et al 2001 New England Journal of Medicine 344:1132-1138. drugs themselves (rather than to factors related to the mother or her epilepsy). The features of what has collectively become known as anticonvulsant embryopathy comprise: major malformations (often cardiac), microcephaly, growth retardation, and hypoplasia of the midface and fingers. The frequency of most malformations was increased in infants exposed to phenytoin alone or phenobarbital alone. Carbamazepine was asso- ciated with major malformations, microcephaly and growth retardation but not hypoplasia of the mid- face and fingers. In general, the major malforma- tions were not distinct from those occurring among infants whose mothers had not taken antiepilepsy drugs, with two exceptions: marked hypoplasia of the nails and stiff joints were strongly associated with phenytoin with or without phenobarbitone, and lumbosacral spina bifida was commoner in infants exposed to carbamazepine or sodium valproate. With current information, carbamazepine seems to be the safest drug for use during pregnancy. Data on lamotrigine (more recently introduced) are increasing but it has not been shown to be strongly associated with malformations. When counselling whether or not to treat, and with which drug, factors such as the severity and type of seizure disorder also need to be taken in to account since control of major seizures is of fundamental importance. EPILEPSY AND ORAL CONTRACEPTIVES Some antiepilepsy drugs (carbamazepine, phenytoin, barbituates, topiramate, oxcarbazepine) induce steroid metabolising enzymes and can cause hormonal contraception to fail. Patients who are taking these drugs need a higher dose of oestrogen (least 50 micrograms/day) if they wish to continue on the pill, although this does not guarantee complete protection from pregnancy with the asso- ciated risks to the fetus. Lamotrigine and sodium valproate are not enzyme inducers and their use is not reason to alter the dose of oral contraceptive. EPILEPSY IN CHILDREN Fits in children are treated as in adults, but children 416 PHARMACOLOGY OF INDIVIDUAL DRUGS 20 may respond differently and become irritable, e.g. with sodium valproate or phenobarbitone. Whether antiepilepsy drugs interfere with later mental and physical development remains uncertain, and it is unwise to assume they do not. The sensible course is to control the epilepsy with monotherapy in minimal doses and with special attention to preci- pitating factors, and to attempt drug withdrawal when it is deemed safe (see above). When a child has, febrile convulsions the decision to embark on continuous prophylaxis is serious for the child, and depends on an assessment of risk factors, e.g. age, nature and duration of the fits. Most children who have febrile convulsions do not develop epilepsy. Prolonged drug therapy, e.g. with phenytoin or phenobarbitone, has been shown to interfere with cognitive 4 development, the effect persisting for months after the drug is withdrawn. Parents may be supplied with a specially formu- lated solution of diazepam for rectal administration (absorption from a suppository is too slow) for easy and early administration, and advised on managing fever, e.g. use paracetamol at the first hint of fever, and tepid sponging. STATUS EPILEPTICUS Status epilepticus is a medical emergency. Loraze- pam i.v. is now the preferred initial choice. Clona- zepam is an alternative. Diazepam i.v. was widely used as the first line drug, but it is more likely to cause hypotension and respiratory depression, and its antiepilepsy effect wears off after about 20 minutes, so that phenytoin i.v must also be given at the same time to suppress further fitting (with ECG and blood pressure monitoring, since cardiac arrhythmias and further hypotension may result). For this reason some consider phenobarbitone to be safer. If resuscitation facilities are not immediately available, diazepam can be given by rectal solution. Midazolam (nasally) may be preferred in institu- tions, e.g. mental hospitals, rather than diazepam rectally because patient and carer compliance are better. Clomethiazole is often given in status epilepticus since it is easy to administer, but it has no prolonged anticonvulsant effect and is prone TABLE 20.1 Treatment of status epilepticus in adults Early status Lorazepam 4 mg i.v.; repeat once after 10 minutes if necessary or Clonazepam I mg i.v. over 30 seconds, repeat if necessary or Diazepam 10-20 mg over 2-4 min; repeat once after 30 minutes if necessary. Established status Phenytoin 15-18 mg/kg i.v. at a rate of 50 mg/minute and/or Phenobarbitone 10-20 mg/kg i.v. at a rate of 100 mg/minute or Refractory status Thiopental or Propofol or Midazolam with full intensive care support to cause respiratory depression and hypotension. Details of further management appear in Table 20.1. Once the emergency is over, exploration of the reason for the episode and reinstitution of normal therapy are essential. Magnesium sulphate may be better than phenytoin for the treatment of the seizure disorder of eclampsia (see also p. 493). 5 Paraldehyde is now rarely used. It smells and tastes unpleasant and is partly excreted unchanged via the lungs (75% is metabolised; t 1 / 2 5 h); it is an irritant (avoid in peptic ulcer) and causes painful muscle necrosis when injected i.m. It dissolves plastic syringes. Pharmacology of individual drugs The drugs used in the treatment of epilepsy are given in Table 20.2. CARBAMAZEPINE Carbamazepine (Tegretol) has a range of actions, of which the most important probably is blockade of voltage-dependent sodium ion channels, reducing membrane excitability. Activities associated with thinking, learning and memory. 5 Eclampsia Trial Collaborative Group 1995 Lancet 345: 1455-1463. 417 20 EPILEPSY, PARKINSONISM AND ALLIED CONDITIONS TABLE 20.2 Drugs of choice for the treatment of epilepsy Seizure disorder Generalised seizures Primary generalised tonic-clonic (grand mal) Absence (petit mal) Atypical absence, myotonic, atonic Myoclonic Partial and/or secondary generalised seizures Drug Drugs of choice Sodium valproate Lamotrigine Alternatives Clonazepam To pi ram ate Carbamazepine (b) Phenytoin Drugs of choice Ethosuximide Sodium valproate Alternatives Clonazepam Lamotrigine Drugs of choice Sodium valproate Clonazepam Lamotrigine (c) Phenytoin Ethosuximide Phenobarbital Drug of choice Sodium valproate (d) Clonazepam Alternatives Lamotrigine Drugs of choice Carbamazepine Sodium valproate Alternatives Phenytoin Lamotrigine Gabapentin Vigabatrin (e) Topiramate Oxcarbazepine Levetiracetam Usual daily oral dose Adult Child 1-2 g (a) 2-6 mg 200-400 mg 0.8- 1.2 g 200-400 mg 1-1.5 g (as above) (as above) (a) (as above) (as above) (a) (as above) (as above) 60-90 mg (as above) (as above) (a) (as above) (as above) (as above) (a) 0.9- 1.2 g 2-3 g (as above) 0.6-2.4 g 1-3 g 1 5-40 mg/kg (a) < 1 y 0.5-1 mg 1 -5 y 1 -3 mg 5-12 y 3-6 mg 5-9 mg/kg (2-16 y) < 1 y 100-200 mg l-5y 200-400 mg 5-10 y 400-600 mg 10-15 y 0.6-1 g 4-8 mg/kg >6yl-l.5g (as above) (as above) (a) (as above) (as above) (a) (as above) (as above) 5-8 mg/kg (as above) (as above) (as above) (as above) (as above) (a) 0.9 g (26-36 kg b.wt.) 1.2 g (37-50 kg b.wt.) 0.5-1 g (10-15 kg b.wt.) 1-1.5 g (15-30 kg b.wt.) 1.5-3 g (30-50 kg b.wt.) 2-3 g (> 50 kg b. wt.) (as above) (a) Varies with mono- or adjunctive therapy; see manufacturer's recommendations. (b) Avoid if major seizures are accompanied by absence seizures or myoclonic jerks. (c) Lamotrigine may be effective, particularly if used with sodium valproate. (d) Alone or in combination with clonazepam, which may be synergistic. (e) In adults, used as a last resort; in children, used for infantile spasms (West's syndrome). Regular visual field monitoring is mandatory. 418 PHARMACOLOGY OF INDIVIDUAL DRUGS 20 Pharmacokinetics. Carbamazepine is extensively metabolised; one of the main products, an epoxide (a chemically reactive form), has anticonvulsant activity similar to that of the parent drug but may also cause some of its adverse effects. The t 1 / 2 of carbamazepine falls from 35 h to 20 h over the first few weeks of therapy due to induction of hepatic enzymes that metabolise it as well as other drugs, including corticosteroids (adrenal and contracep- tive), theophylline and warfarin. Cimetidine and valproate inhibit its metabolism. There are complex interactions with other antiepilepsy drugs, which constitute a reason for monodrug therapy. Standard tablets are taken twice a day, but with higher doses a three or four times a day regimen may be necessary. Rectal and liquid formulations are available, but there is no i.v. preparation. Uses. Carbamazepine is used for secondary gen- eralised and partial seizures, and primary genera- lised seizures. Because another antiepilepsy drug (phenytoin) was sometimes beneficial in trigeminal neuralgia, carbamazepine was tried in this con- dition, for which it is now the drug of choice Adverse effects include CNS symptoms (revers- ible blurring of vision, diplopia, dizziness and ataxia) and depression of cardiac AV conduction. Alimentary symptoms, skin rashes, blood disorders and liver and kidney dysfunction also occur. Osteo- malacia by enhanced metabolism of vitamin D (enzyme induction) occurs over years; so also does folate deficiency. Enzyme induction reduces the efficacy of combined and progestogen-only contra- ceptives. Carbamazepine impairs cognitive function less than phenytoin. Oxcarbazepine, like its analogue carbamazepine, acts by blocking voltage-sensitive sodium channels. It is rapidly and extensively metabolised in the liver; the t 1 / 2 of the parent drug is 2 h but that of its principal metabolite (which also has therapeutic activity) is 11 h. Unlike carbamazepine, it does not form an epoxide which may explain why oxcarba- zepine has fewer unwanted effects. Oxcarbazepine is a selective inducer of a cytochrome isoenzyme that metabolises the oral contraceptive and a 50 microgram oestrogen preparation is necessary for contraception. It does not induce hepatic enzymes in general. Oxcarbazepine is as effective as carbamazepine, sodium valproate and phenytoin in the treatment of partial and secondary generalised seizures, for which it is used either as monotherapy or add on therapy. The most common chronic adverse effect is hyponatraemia, but this is usually mild, asympto- matic and of no clinical significance. Routine serum monitoring of the plasma sodium is indicated only where there is special risk, e.g. patients taking diuretics or the elderly. PHENYTOIN Phenytoin (diphenylhydantoin, Epanutin, Dilantin) alters ionic fluxes but principally the voltage- dependent sodium ion channels in the neuronal membrane; this action is described as membrane stabilising, and discourages the spread (rather than the initiation) of seizure discharges. Pharmacokinetics. Phenytoin provides a good example of the application of pharmacokinetics for successful prescribing. The important aspects are: • Saturation (zero-order) kinetics • Hepatic enzyme induction and enzyme inhibition • Opportunities for clinically important unwanted interactions are extensive. Saturation kinetics. Phenytoin is extensively hyd- roxylated in the liver and this process becomes saturated at about the doses needed for therapeutic effect. Thus phenytoin at low doses exhibits first- order kinetics but saturation or zero-order kinetics develop as the therapeutic plasma concentration range (10-20 mg/1) is approached, i.e. the dose increments of equal size produce disproportional rise in steady-state plasma concentration. A clinically meaningful single half-life can be quoted where a drug is subject only to first-order kinetics. At low doses, giving subtherapeutic plasma concentrations, the t l / 2 of phenytoin is 6-24 h. But at doses giving therapeutic plasma concentrations, when metabolism is becoming saturated, elimina- tion of the drug is relatively slower. This has signi- 419 20 EPILEPSY, PARKINSONISM AND ALLIED CONDITIONS ficant implications for patient care, e.g. the time taken to reach a steady-state plasma concentration after a dose increment (about 5 x t 1 / 2 ) is 2-3 days at low dose and about 2 weeks at high doses. Thus dose increments should become smaller as the dose increases (which is why there is a 25-mg capsule). Plainly, monitoring serial plasma concentration measurement will help. Enzyme induction and inhibition. Phenytoin is a potent inducer of hepatic metabolising enzymes affecting itself, other drugs and dietary and endo- genous substances (including vitamin D and folate). The consequences of this are: a slight fall of steady state phenytoin level over the first few weeks of therapy, though this may not be noticeable if dose increments are being given; enhanced metabolism of other drugs, e.g. carbamazepine, warfarin, steroids (adrenal and gonadal), thyroxine, tricyclic anti- depressants, doxycycline. Naturally this can also work in reverse, and other enzyme inducers, e.g. rifampicin, ethanol, may lower phenytoin concen- trations when there is capacity for increase in enzyme induction. Drugs that inhibit phenytoin metabolism (causing its plasma concentration to rise) include: sodium valproate, cimetidine, co-trimoxazole, isoniazid, chloramphenicol, some NSAIDs, disulfiram. There is a considerable body of mediocre and contra- dictory data, the lesson of which is that possible interaction should be borne in mind wherever other drugs are prescribed to a patient taking phenytoin. Phenytoin is 90% bound to plasma albumin so that quite small changes in binding, e.g. a drop to 80%, will result in a higher concentration of free, active, drug. Since free drug is also available to be metabolised, the effect of such changes is probably short-lived. Phenytoin orally is well absorbed but there have been pharmaceutical bioavailability problems in relation to the nature of the diluent in the capsule; patients should always use the same formulation. Phenytoin should not be given i.m. since it precipitates and is poorly absorbed. It may be diluted and given by i.v. infusion over 1 hour but care should be taken to follow the manufacturer's instructions including the use of an in-line filter, because phenytoin may also precipitate in infusion fluids, particularly dextrose. Uses. Phenytoin is used to prevent all types of partial epilepsy, whether or not the seizures there- after become generalised, and to treat generalised seizures and status epiepticus. It is not used for absence attacks. Other uses. The membrane-stabilising effect of phenytoin has been used in cardiac arrhythmias and, rarely, in cases of resistant pain, e.g. trigeminal neuralgia. Adverse effects of phenytoin, many of which can be very slow to develop, include impairment of cognitive function, which has led many physicians to prefer carbamazepine and valproate. Other nervous system effects range from sedation to deli- rium to acute cerebellar disorder to convulsions. Peripheral neuropathy also occurs. Cutaneous reactions include rashes (dose related), coarsening of facial features and hirsutism. Gum hyperplasia (due to inhibition of collagen catabolism) may develop and is more marked in children and when there is poor gum hygiene. Other effects include Dupuytren's contracture and pseudolymphoma. Some degree of macrocyto- sis is common but anaemia probably occurs only when dietary folate is inadequate. This responds to folate supplement (the requirement for folate is increased, as it is a cofactor in some hydroxylation reactions that are accelerated by enzyme induction by phenytoin). Osteomalacia due to increased meta- bolism of vitamin D occurs after years of therapy. Overdose (causing cerebellar symptoms and signs, coma, apnoea) is treated according to general principles. The patient may remain unconscious for a long time because of saturation kinetics, but will recover if respiration and circulation are sustained. Fosphenytoin, a prodrug of phenytoin, is soluble in water, easier and safer to administer; its conver- tion in the blood to phenytoin is rapid and it may be used as an alternative to phenytoin for status epilepticus (Table 20.1). SODIUM VALPROATE Sodium valproate (valproic acid) (Epilim) acts by inhibiting GABA transaminase, the enzyme responsible for the breakdown of the inhibitory 420 PHARMACOLOGY OF INDIVIDUAL DRUGS 20 neurotransmitter, GABA, so increasing its concen- tration at GABA receptors. Sodium valproate is extensively metabolised in the liver and has a t 1 / 2 of 13 h. It is 90% bound to plasma albumin. Sodium valproate is a nonspecific inhibitor of metabolism, and indeed inhibits its own metabolism, and that of lamotrigine, phenobarbitone, phenytoin and carbamazepine. Sodium valproate does not induce drug metabolising enzymes but its metabolism is enhanced by induction due to other drugs, including antiepileptics. Sodium valproate is effective for a wide range of seizure disorders, including generalised and partial epilepsy, and the prophylaxis of febrile convulsions and post-traumatic epilepsy. Adverse effects can be troublesome. The main ones of concern, particularly to women, are weight gain, teratogenicity (see p. 416), polycystic ovary syndrome, and loss of hair which grows back curly. 6 Nausea may be a problem. Some patients exhibit a rise in liver enzymes which is usually transient and without sinister import, but they should be closely monitored until the biochemical tests return to normal as, rarely, liver failure occurs (risk maximal at 2-12 weeks); this is often indicated by anorexia, malaise and a recurrence of seizures. Other reactions include pancreatitis, and coagulation disorder due to inhibition of platelet aggregation (coagulation should be assessed before surgery). Ketone metabolites may cause confusion in uring testing in diabetes. Metabolic inhibition by valproate prolongs the action of co-administered antiepilepsy drugs (see above). The effect is significant and the dose of lamotrigine, for example, should be halved in patients who are also taking sodium valproate. BARBITURATES Antiepilepsy members include phenobarbital (pheno- barbitone) (t l / 2 100 h), methylphenobarbital and primidone (Mysoline), which is largely metabolised to phenobarbital, i.e. it is a prodrug. They are still used for generalised seizures; sedation is usual. CLONAZEPAM Clonazepam (Rivotril) (t 1 / 2 25 h) is a benzodiazepine used as a second line drug for treatment of primary generalised epilepsy and for status epilepticus (see Table 20.1). Vigabatrin (Sabril) (t 1 / 2 6 h) is structurally related to the inhibitory CNS neurotransmitter GABA and it acts by irreversibly inhibiting GABA-transaminase so that GABA accumulates. GABA-transaminase is resynthesised over 6 days. Vigabatrin is not meta- bolised and does not induce hepatic drug meta- bolising enzymes. Vigabatrin is effective in partial, secondary generalised seizures which are not satisfactorily controlled by other anticonvulsants, and in infantile spasms, as monotherapy. It worsens absence and myoclonic seizures Unwanted effects from drugs sometimes become apparant only following prolonged use, and viga- batrin is a case in point. Vigabatrin had been licenced for a number of years, before it was found to cause visual field constriction in up to 40% of patients, an effect that is insidious and leads to irreversible tunnel vision. 7 Its discovery emphasises the value of postmarketing drug surveillance programmes. 8 Vigabatrin is now indicated only for patients with the specific seizure disorders responsive to the drug (above), and no other. Patients should undergo visual field monitoring at six-monthly intervals whilst taking the drug. Other adverse effects on the CNS are similar to those of antiepilepsy drugs in general but include confusion and psychosis. Increase in weight also occurs in up to 40% of patients during the first 6 months of treatment. Lamotrigine acts to stabilise presynaptic neuronal membranes by blocking voltage-dependent sodium channels (a property it shares with carbamazepine and phenytoin) and it reduces the release of excita- tory amino acids, such as glutamate and aspartate. The t 1 / 2 of 24 h allows for a single daily dose. 6 'We thought the change might be welcomed by the patients, but one girl prefered her hair to be long and straight, and one boy was mortified by his curls and insisted on a short hair cut.' Jeavons P M 1977 Lancet 1: 359. 7 Eke T, Talbot J F et al. 1997 British Medical Journal 314: 180-181. 8 Wilton L V, Stephens M D B, Mann R D 1999 British Medical Journal 319:1165-1166. 421 20 EPILEPSY, PARKINSONISM AND ALLIED CONDITIONS Lamotrigine is effective as monotherapy and adjunctive therapy for partial and primary and secondarily generalised tonic-clonic seizures. It is generally well tolerated but may cause serious adverse effects on the skin, including Stevens- Johnson syndrome and toxic epidermal necrolysis (fatally, on rare occasions). The risk of cutaneous effects can be lessened if treatment is begun with a low dose and is escalated slowly. Concomitant use of valproate, which inhibits the metabolism and thus the inactivation of lamotrigine, adds to the hazard. Carbamazepine, phenytoin or primidone accelerate the metabolic breakdown of lamotrigine which must be given in higher dose when combined. Gabapentin is an analogue of GABA that is sufficiently lipid soluble to cross the blood-brain barrier but its mode of action is uncertain. It is excreted unchanged and, unlike other antiepilepsy agents, does not induce or inhibit hepatic meta- bolism of other drugs. Gabapentin is effective only for partial seizures and secondary generalised epilepsy (not absence or myoclonic epilepsy), in combination with established agents. It is also used for neuropathic pain. Gaba- pentin may cause somnolence, unsteadiness, dizz- iness and fatigue. Topiramate possesses a range of actions that include blockade of voltage-sensitive sodium channels, enhancement of GABA activity and possibly weak blockade of glutamate receptors. The t 1 / 2 of 21 h allows once daily dosing; it is excreted in the urine mainly as unchanged drug. Topiramate is used as adjunctive treatment for partial seizures, with or without secondary general- isation. It use is limited by its unwanted effects, particularly sedation, naming difficulty and weight loss. Acute myopia and raised intraocular pressure may occur. Levetiracetam acts in a manner different to other antiepilepsy drugs. It has a potentially broad spec- trum of use but is currently indicated for adjunctive treatment in partial seizures with or without secondary generalisation. It is rapidly and com- pletely absorbed after oral administration, and is effective with twice-daily dosing. Its therapeutic index appears to be high and the commonest of the adverse effects are asthenia, dizziness and drowsiness. Succinimides. Ethosuximide (Zarontin) (t 1 / 2 55 h) differs from other antiepilepsy drugs in that it blocks a particular type of calcium channel that is active in absence seizures (petit mal), and it is used specifically for this condition. Adverse effects include gastric upset, CNS effects and allergic reactions including eosinophilia and other blood disorders, and lupus erythematosus. Parkinsonism A NOTE ON PATHOPHYSIOLOGY Parkinson's disease 9 affects about 1 in 200 of the elderly population. In broad terms, it is caused by degeneration of the substantia nigra 10 in the mid- brain, and consequent loss of dopamine-containing neurons in the nigrostriatal pathway (see Fig. 19.3, p. 382). There is no known cure but drug treatment can, if properly managed, dramatically improve quality of life in this progressive disease. Two balanced systems are important in the extrapyramidal control of motor activity at the level of the corpus striatum and substantia nigra: in one the neurotransmitter is acetylcholine; in the other it is a dopamine. In Parkinson's disease there is degen- erative loss of nigrostriatal dopaminergic neurons and the symptoms and signs of the disease are due to dopamine depletion. Certain drugs also produce the features of Parkinson's disease (see below) and the general term 'parkinsonism' is used to cover both the disease and the drug-induced states. The symptom triad of the disease is bradykinesia, rigidity and tremor. Patients who have received levodopa for a long time may exhibit the 'on-off' phenomenon in which, abruptly and distressingly, dyskinesia (the 'on' phase) alternates with hypokinesia (the 'off phase). One sufferer, a physician, wrote about his condition: 9 James Parkinson (1755-1824), physician; he described paralysis agitans in 1817. 10 Substantia nigra is (Latin) black substance. A coronal section at this point in the brain shows the distinctive black areas, visible with the naked eye in the normal brain, but absent from the brains of patients with Parkinson's disease. 422 [...]... can be an advantage in patients who develop end-of-dose deterioration with levodopa Dosing should start very low (1-1.25 mg p.o at night), increasing at approximately weekly intervals and according to clinical response Nausea and vomiting are the commonest adverse effects; these may respond to domperidone but tend to become less marked as treatment continues Postural hypotension may cause dizziness... held that this action might be protective of dopaminergic neurons and so allow later initiation of therapy with levodopa It became one of the most widely prescribed drugs for Parkinson's disease Later clinical trials, however, failed to confirm these effects and indeed, combined treatment with levodopa and selegiline was associated with excess mortality;13 many patients discontinued selegiline without... activity relates closely to this action, which notably involves the D2-receptor, the principal target in Parkinson's disease It comes as no surprise, therefore, that these drugs can induce a state whose clinical features are very similar to those of idiopathic Parkinson's disease The piperazine phenothiazines, e.g trifluoperazine, and the butyrophenones, e.g haloperidol, are most commonly involved In... absorbed from food so that it accumulates in the liver, brain, cornea and kidneys Chelating copper in the gut with penicillamine (p 293) or trientine can establish a negative copper balance (with some clinical improvement if treatment is started early) The patients may also develop cirrhosis, and the best treatment for both may be orthotopic liver transplantation Chorea of any cause may be alleviated... trials, it is the first treatment to show a reduction in the number of relapses Interferon beta may also have a modest effect in delaying disability by 12-18 months in relapsing/remitting disease In a clinical trial 372 patients with relapsing-remitting disease, able to walk 100 metres without aid or rest, were randomised to receive 8 million IU or 1.6 million IU of interferon beta or placebo by s.c . fraction in plasma is less affected. In practice, the patient's clinical state is observed closely and the dose of drug is increased . CHILDREN Fits in children are treated as in adults, but children 416 PHARMACOLOGY OF INDIVIDUAL DRUGS 20 may respond differently and become