CLINICAL PHARMACOLOGY 2003 (PART 22)

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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...

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20 Epilepsy, parkinsonism and allied conditions SYNOPSIS cortical neurons simultaneously (primary generalised seizure). • Antiepilepsy drugs: principles of Bromide (1857) was the first drug to be used for management; withdrawal of therapy; the treatment of epilepsy, but it is now obsolete. pregnancy; teratogenic effects; epilepsy in Phenobarbital, introduced in 1912, controlled children; status epilepticus patients resistant to bromides. The next success was • Individual drugs: carbamazepine, phenytoin, the discovery in 1938 of phenytoin (a hydantoin) sodium valproate, lamotrigine, vigabatrin, which is structurally related to the barbiturates. gabapentin, clonazepam, topiramate, Since then many other drugs have been discovered, levetiracetam. but phenytoin still remains a drug of choice in the • Parkinsonism treatment of major epilepsy. Over the past ten years Objectives of therapy there has been a dramatic increase in the number of Drug therapy; problems of long-term new anticonvulsant drugs (vigabatrin, gabapentin, treatment lamotrigine, topiramate, oxcarbazepine, levetira- • Other disorders of movement cetam), but none has been shown to be superior • Tetanus to the major standard anticonvulsants (phenytoin, carbamazepine and sodium valproate). MODE OF ACTION Antiepilepsy drugs Antiepilepsy (anticonvulsant) drugs inhibit the neuronal discharge or its spread, and do so in one Epilepsy affects 5-10 per 1000 of the general or more of three ways: population.1 It is due to sudden, excessive depolar- 1. Reducing cell membrane permeability to ions, isation of some or all cerebral neurons. This may particularly the voltage-dependent sodium remain localised (focal seizure) or may spread to channels which are responsible for the inward cause a secondary generalised seizure, or affect all current that generates an action potential. Cells that are firing repetitively at high frequency are 1 blocked preferentially, which permits Some people with epilepsy make pilgrimages to Terni (Italy) to seek intercession from Saint Valentine to relieve discrimination between epileptic and their condition. There was more than one Saint Valentine and physiological activity. it is unclear if he was also the patron saint of lovers. 2. Enhancing the activity of gamma-aminobutyric 413
20 EPILEPSY, PARKINSONISM AND ALLIED CONDITIONS acid (GABA) the principal inhibitory transmitter appropriate to the type of seizure disorder. of the brain; the result is increased membrane Although some drugs have a wide spectrum of permeability to chloride ion, which reduces cell action against different seizure types, some are excitability. more specific and may even aggravate certain 3. Inhibiting excitatory neurotransmitters, e.g. seizure types. Carbamazepine is a drug of first glutamate. choice for focal and secondary generalised epilepsy but aggravates myoclonic and absence seizures. Sodium valproate and lamotrigine CLASSIFICATION OF EPILEPSIES have a wide spectrum of action and are active A generally accepted classification is given in Table against both primary and secondary generalised 20.2 (p. 418), together with drugs of choice for the epilepsy. various seizure disorders. 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 Principles of management on their appearance, e.g. hirsutism from phenytoin. These call for attention to nondrug as well as drug 4. If the attempt to control a patient's epilepsy by measures, as set out below: use of a single drug is unsuccessful, it should be withdrawn and replaced by a second line drug, • Any causative factor must, of course, be treated, though these are effective in only about 10% of e.g. cerebral neoplasm. patients. There is little evidence that three drugs • Educate the patient about the disease, duration are better than two, and not much that two are of treatment and need for compliance. better than one. More drugs often mean more • Avoid precipitating factors, e.g. alcohol, sleep adverse effects. deprivation, emotional stress. 5. Abrupt withdrawal. Effective therapy must never • Anticipate natural variation, e.g. fits may occur be stopped suddenly either by the doctor particularly or exclusively around periods in (carelessness) or by the patient (carelessness, women (catamenial2 epilepsy). intercurrent illness or ignorance), or status • Give antiepilepsy drugs only if seizure type and epilepticus may occur. But if rapid withdrawal frequency require it, i.e. more than one fit every is required by the occurrence of toxicity, a 6-12 months. substantial dose of another antiepilepsy drug should be given at once. GENERAL GUIDETO ANTIEPILEPSY 6. In cases where fits are liable to occur at a DRUG THERAPY particular time, e.g. the menstrual period, dosage should be adjusted to achieve maximal The decision whether or not to initiate drug therapy drug effect at that time or drug treatment can be after a single seizure remains controversial since confined to this time. For example, in catamenial approximately 25% of patients may not have epilepsy, clobazam can be useful given only at another seizure. Some advocate treatment on the period time. basis that early initiation may improve prognosis but the matter has not yet been resolved. Dosage and administration 1. Therapy should start with a single well-tried and safe drug. The majority of patients (70%) can be Generally drugs are best given as a single or twice controlled on one drug (monotherapy). daily dose to increase compliance. Many patients 2. Anticonvulsant drug treatment should be 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 2 Greek katamenios, monthly three or even four times a day. 414
PRINCIPLES OF MANAGEMENT 20 Regimens for initial dosing tend to vary with • The time to remission — early remission carries a different drugs. In general, drugs are started in a better outlook. small dose and increased at two-weekly intervals to • The number of drugs required to induce the minimum effective dose. The patient's seizures remission — rapid remission on a single drug is are then monitored and further increases in dose a favourable indicator for successful withdrawal. only made if seizures continue. The time interval • The presence of an underlying lesion — control is for dosage increases should therefore be sufficiently often difficult. wide apart to allow changes in the seizure frequency • The presence of an associated neurological deficit due to changes in drug therapy to be accurately or learning difficulty — control is often difficult. determined. These issues are particularly important In general, if a patient with a major epilepsy has for a doctor, e.g. in an emergency department, who no neurological deficit or structural lesion and is of has never seen the patient with a fit or series of fits. normal intelligence, there is a reasonable chance of It is important then to consider the cause, whether it continued remission, particularly if this is rapidly is noncompliance (which can be due to intercurrent achieved with a single drug. In general, in adult disease), an inadequate drug regimen or an increase epilepsy, discontinuing the antiepilepsy drug is asso- in the severity of the disease. ciated with about 20% relapse during withdrawal and a further 20% relapse over the following 5 MONITORING BLOOD years; after this period relapse is unusual. It is CONCENTRATIONS OF generally recommended that the antiepilepsy drug ANTICONVULSANTS be withdrawn over a period of 6 months. If a fit occurs during this time, full therapy must be Many biochemistry laboratories no longer under- resumed again until the patient has been free from take routine measurement of the plasma concentra- seizures for a further 2-3 years. tion for most anticonvulsant drugs because plasma concentrations are insufficiently stable to serve as a useful guide to change of dose. The exception is DRIVING REGULATIONS AND phenytoin, where a small increase in dose may lead EPILEPSY to a disproportionate rise in the plasma drug The UK allows patients to drive a car (but not a concentration (see zero-order pharmacokinetics, truck or bus) if they have not had a daytime fit for p. 99) and plasma monitoring is essential. With 1 year (or after 3 years if they continue to be subject other drugs the dose is increased to the maximum to fits only whilst asleep). Any fit that occurs during tolerated level and, if seizures continue, it is or after drug withdrawal incurs loss of the driving replaced by another. licence for a year. Because losing the right to drive is perceived to be a significant social disability, most DRUG WITHDRAWAL patients prefer to remain on medication. After a period of at least 2-3 years free from seizures, withdrawal of antiepilepsy drug therapy PREGNANCY AND EPILEPSY can be considered. The prognosis of a seizure dis- Pregnancy can affect seizure disorder which worsens order is determined by a number of factors. Some in about a third, improves in a third, and remains are known to remit spontaneously e.g. benign unchanged in the remainder. Ideally, patients should rolandic epilepsy and petit mal, whereas others have their seizure disorder properly investigated never remit e.g. juvenile myoclonic epilepsy. In and treated before pregnancy with the best control many types of epilepsy the outlook is less certain achieved on the lowest dose of the least teratogenic and only general indicators are available. The drug. Major seizures are harmful to the developing following factors can be important: fetus because of the possibility of anoxia and meta- • The type of seizure disorder — major seizures are bolic disorder. Minor seizures are probably harm- more easily controlled. less and therefore need not be eradicated. Patients 415
20 EPILEPSY, PARKINSONISM AND ALLIED CONDITIONS should be advised of the necessity of taking folic drugs themselves (rather than to factors related to acid supplements, since some antiepilepsy drugs the mother or her epilepsy). affect folic acid metabolism and folic acid deficiency The features of what has collectively become is a risk factor for neural tube defects. Hepatic known as anticonvulsant embryopathy comprise: enzyme inducing antiepilepsy drugs lower the major malformations (often cardiac), microcephaly, mother's concentration of vitamin K, which can growth retardation, and hypoplasia of the midface aggravate any postpartum haemorrhage. Pregnant and fingers. The frequency of most malformations mothers should therefore be given an oral vitamin was increased in infants exposed to phenytoin alone K for the last two weeks of pregnancy. or phenobarbital alone. Carbamazepine was asso- ciated with major malformations, microcephaly and growth retardation but not hypoplasia of the mid- Pharmacokinetics in pregnancy face and fingers. In general, the major malforma- The total plasma concentration of drug falls, tions were not distinct from those occurring among especially towards the end of pregnancy, due to infants whose mothers had not taken antiepilepsy haemodilution, but the therapeutically important free drugs, with two exceptions: marked hypoplasia of (unbound) fraction in plasma is less affected. In the nails and stiff joints were strongly associated practice, the patient's clinical state is observed with phenytoin with or without phenobarbitone, closely and the dose of drug is increased if seizures and lumbosacral spina bifida was commoner in occur more often than expected. Hepatic drug infants exposed to carbamazepine or sodium metabolism tends to increase during pregnancy. valproate. After delivery, the pharmacokinetics revert to the With current information, carbamazepine seems to prepregnancy state over a few days. be the safest drug for use during pregnancy. Data on lamotrigine (more recently introduced) are Breast feeding increasing but it has not been shown to be strongly associated with malformations. Antiepilepsy drugs pass into breast milk (see p. 116), When counselling whether or not to treat, and phenobarbital, primidone and ethosuximide in with which drug, factors such as the severity and significant quantities, phenytoin and sodium type of seizure disorder also need to be taken in valproate less so. There is a risk that the baby will to account since control of major seizures is of become sedated or suckle poorly but, provided a fundamental importance. watch is maintained for these effects, the balance of advantage favours breast feeding whilst taking antiepilepsy drugs. EPILEPSY AND ORAL CONTRACEPTIVES Teratogenic effects Some antiepilepsy drugs (carbamazepine, phenytoin, Children of mothers taking antiepilepsy drugs barbituates, topiramate, oxcarbazepine) induce have an approximately 2-3 x increased frequency steroid metabolising enzymes and can cause of malformations at birth. In a case-control study of hormonal contraception to fail. Patients who are pregnant women, the frequency of malformation taking these drugs need a higher dose of oestrogen was 20.6% in infants whose mothers took one (least 50 micrograms/day) if they wish to continue anticonvulsant drug and 28.0% with two or more on the pill, although this does not guarantee such drugs, compared to 8.5% in matched controls.3 complete protection from pregnancy with the asso- Infants of mothers who gave a history of epilepsy ciated risks to the fetus. Lamotrigine and sodium but did not take antiepilepsy drugs did not have a valproate are not enzyme inducers and their use is higher frequency than the controls, indicating that not reason to alter the dose of oral contraceptive. malformations are largely due to the antiepilepsy 3 EPILEPSY IN CHILDREN Holmes LB et al 2001 New England Journal of Medicine 344:1132-1138. Fits in children are treated as in adults, but children 416
PHARMACOLOGY OF INDIVIDUAL DRUGS 20 may respond differently and become irritable, e.g. TABLE 20.1 Treatment of status epilepticus in adults with sodium valproate or phenobarbitone. Whether Early status Lorazepam 4 mg i.v.; repeat once after antiepilepsy drugs interfere with later mental and 10 minutes if necessary or physical development remains uncertain, and it is Clonazepam I mg i.v. over 30 seconds, unwise to assume they do not. The sensible course repeat if necessary or Diazepam 10-20 mg over 2-4 min; is to control the epilepsy with monotherapy in repeat once after 30 minutes if minimal doses and with special attention to preci- necessary. pitating factors, and to attempt drug withdrawal Established status Phenytoin 15-18 mg/kg i.v. at a rate of when it is deemed safe (see above). 50 mg/minute and/or Phenobarbitone 10-20 mg/kg i.v. at a When a child has, febrile convulsions the decision rate of 100 mg/minute or to embark on continuous prophylaxis is serious for Refractory status Thiopental or the child, and depends on an assessment of risk Propofol or factors, e.g. age, nature and duration of the fits. Midazolam with full intensive care Most children who have febrile convulsions do not support develop epilepsy. Prolonged drug therapy, e.g. with phenytoin or phenobarbitone, has been shown to to cause respiratory depression and hypotension. interfere with cognitive4 development, the effect Details of further management appear in Table 20.1. persisting for months after the drug is withdrawn. Once the emergency is over, exploration of the Parents may be supplied with a specially formu- reason for the episode and reinstitution of normal lated solution of diazepam for rectal administration therapy are essential. Magnesium sulphate may be (absorption from a suppository is too slow) for easy better than phenytoin for the treatment of the and early administration, and advised on managing seizure disorder of eclampsia (see also p. 493).5 fever, e.g. use paracetamol at the first hint of fever, Paraldehyde is now rarely used. It smells and and tepid sponging. tastes unpleasant and is partly excreted unchanged via the lungs (75% is metabolised; t1/2 5 h); it is an STATUS EPILEPTICUS irritant (avoid in peptic ulcer) and causes painful muscle necrosis when injected i.m. It dissolves Status epilepticus is a medical emergency. Loraze- plastic syringes. 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 Pharmacology of minutes, so that phenytoin i.v must also be given at individual drugs the same time to suppress further fitting (with ECG and blood pressure monitoring, since cardiac The drugs used in the treatment of epilepsy are arrhythmias and further hypotension may result). given in Table 20.2. For this reason some consider phenobarbitone to be safer. If resuscitation facilities are not immediately available, diazepam can be given by rectal solution. CARBAMAZEPINE Midazolam (nasally) may be preferred in institu- tions, e.g. mental hospitals, rather than diazepam Carbamazepine (Tegretol) has a range of actions, of rectally because patient and carer compliance are which the most important probably is blockade of better. Clomethiazole is often given in status voltage-dependent sodium ion channels, reducing epilepticus since it is easy to administer, but it has membrane excitability. no prolonged anticonvulsant effect and is prone 5 Eclampsia Trial Collaborative Group 1995 Lancet 345: Activities associated with thinking, learning and memory. 1455-1463. 417
20 EPILEPSY, PARKINSONISM AND ALLIED CONDITIONS TABLE 20.2 Drugs of choice for the treatment of epilepsy Seizure disorder Drug Usual daily oral dose Adult Child Generalised seizures Primary generalised tonic-clonic (grand mal) Drugs of choice Sodium valproate 1-2 g 1 5-40 mg/kg Lamotrigine (a) (a) Alternatives Clonazepam 2-6 mg < 1y 0.5-1 mg 1 -5 y 1 -3 mg 5-12 y 3-6 mg To pi ram ate 200-400 mg 5-9 mg/kg (2-16 y) Carbamazepine (b) 0.8- 1.2 g < 1y 100-200 mg l-5y 200-400 mg 5-10 y 400-600 mg 10-15 y 0.6-1 g Phenytoin 200-400 mg 4-8 mg/kg Absence (petit mal) Drugs of choice Ethosuximide 1-1.5 g >6yl-l.5g Sodium valproate (as above) (as above) Alternatives Clonazepam (as above) (as above) Lamotrigine (a) (a) Atypical absence, myotonic, atonic Drugs of choice Sodium valproate (as above) (as above) Clonazepam (as above) (as above) Lamotrigine (c) (a) (a) Phenytoin (as above) (as above) Ethosuximide (as above) (as above) Phenobarbital 60-90 mg 5-8 mg/kg Myoclonic Drug of choice Sodium valproate (d) (as above) (as above) Clonazepam (as above) (as above) Alternatives Lamotrigine (a) Partial and/or secondary generalised seizures Drugs of choice Carbamazepine (as above) (as above) Sodium valproate (as above) (as above) Alternatives Phenytoin (as above) (as above) Lamotrigine (a) (a) Gabapentin 0.9- 1.2 g 0.9 g (26-36 kg b.wt.) 1.2 g (37-50 kg b.wt.) Vigabatrin (e) 2-3 g 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.) Topiramate (as above) (as above) Oxcarbazepine 0.6-2.4 g Levetiracetam 1-3 g (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 contraception. It does not induce hepatic enzymes metabolised; one of the main products, an epoxide in general. (a chemically reactive form), has anticonvulsant Oxcarbazepine is as effective as carbamazepine, activity similar to that of the parent drug but may sodium valproate and phenytoin in the treatment also cause some of its adverse effects. The t1/2 of of partial and secondary generalised seizures, for carbamazepine falls from 35 h to 20 h over the first which it is used either as monotherapy or add on few weeks of therapy due to induction of hepatic therapy. enzymes that metabolise it as well as other drugs, The most common chronic adverse effect is including corticosteroids (adrenal and contracep- hyponatraemia, but this is usually mild, asympto- tive), theophylline and warfarin. Cimetidine and matic and of no clinical significance. Routine serum valproate inhibit its metabolism. There are complex monitoring of the plasma sodium is indicated interactions with other antiepilepsy drugs, which only where there is special risk, e.g. patients taking constitute a reason for monodrug therapy. diuretics or the elderly. 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 PHENYTOIN are available, but there is no i.v. preparation. Phenytoin (diphenylhydantoin, Epanutin, Dilantin) alters ionic fluxes but principally the voltage- Uses. Carbamazepine is used for secondary gen- dependent sodium ion channels in the neuronal eralised and partial seizures, and primary genera- membrane; this action is described as membrane lised seizures. Because another antiepilepsy drug stabilising, and discourages the spread (rather than (phenytoin) was sometimes beneficial in trigeminal the initiation) of seizure discharges. neuralgia, carbamazepine was tried in this con- dition, for which it is now the drug of choice Pharmacokinetics. Phenytoin provides a good example of the application of pharmacokinetics for Adverse effects include CNS symptoms (revers- successful prescribing. The important aspects are: ible blurring of vision, diplopia, dizziness and • Saturation (zero-order) kinetics ataxia) and depression of cardiac AV conduction. • Hepatic enzyme induction and enzyme Alimentary symptoms, skin rashes, blood disorders inhibition and liver and kidney dysfunction also occur. Osteo- • Opportunities for clinically important unwanted malacia by enhanced metabolism of vitamin D interactions are extensive. (enzyme induction) occurs over years; so also does folate deficiency. Enzyme induction reduces the Saturation kinetics. Phenytoin is extensively hyd- efficacy of combined and progestogen-only contra- roxylated in the liver and this process becomes ceptives. Carbamazepine impairs cognitive function saturated at about the doses needed for therapeutic less than phenytoin. effect. Thus phenytoin at low doses exhibits first- order kinetics but saturation or zero-order kinetics Oxcarbazepine, like its analogue carbamazepine, develop as the therapeutic plasma concentration acts by blocking voltage-sensitive sodium channels. range (10-20 mg/1) is approached, i.e. the dose It is rapidly and extensively metabolised in the increments of equal size produce disproportional rise liver; the t1/2 of the parent drug is 2 h but that of its in steady-state plasma concentration. principal metabolite (which also has therapeutic A clinically meaningful single half-life can be activity) is 11 h. Unlike carbamazepine, it does not quoted where a drug is subject only to first-order form an epoxide which may explain why oxcarba- kinetics. At low doses, giving subtherapeutic plasma zepine has fewer unwanted effects. Oxcarbazepine concentrations, the tl/2 of phenytoin is 6-24 h. But at is a selective inducer of a cytochrome isoenzyme doses giving therapeutic plasma concentrations, that metabolises the oral contraceptive and a 50 when metabolism is becoming saturated, elimina- microgram oestrogen preparation is necessary for 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 Uses. Phenytoin is used to prevent all types of taken to reach a steady-state plasma concentration partial epilepsy, whether or not the seizures there- after a dose increment (about 5 x t1/2) is 2-3 days at after become generalised, and to treat generalised low dose and about 2 weeks at high doses. Thus seizures and status epiepticus. It is not used for dose increments should become smaller as the dose absence attacks. increases (which is why there is a 25-mg capsule). Plainly, monitoring serial plasma concentration Other uses. The membrane-stabilising effect of measurement will help. phenytoin has been used in cardiac arrhythmias and, rarely, in cases of resistant pain, e.g. trigeminal Enzyme induction and inhibition. Phenytoin is a neuralgia. potent inducer of hepatic metabolising enzymes affecting itself, other drugs and dietary and endo- Adverse effects of phenytoin, many of which can genous substances (including vitamin D and folate). be very slow to develop, include impairment of The consequences of this are: a slight fall of steady cognitive function, which has led many physicians state phenytoin level over the first few weeks of to prefer carbamazepine and valproate. Other therapy, though this may not be noticeable if dose nervous system effects range from sedation to deli- increments are being given; enhanced metabolism rium to acute cerebellar disorder to convulsions. of other drugs, e.g. carbamazepine, warfarin, steroids Peripheral neuropathy also occurs. Cutaneous (adrenal and gonadal), thyroxine, tricyclic anti- reactions include rashes (dose related), coarsening depressants, doxycycline. Naturally this can also of facial features and hirsutism. Gum hyperplasia work in reverse, and other enzyme inducers, e.g. (due to inhibition of collagen catabolism) may rifampicin, ethanol, may lower phenytoin concen- develop and is more marked in children and when trations when there is capacity for increase in there is poor gum hygiene. enzyme induction. Other effects include Dupuytren's contracture Drugs that inhibit phenytoin metabolism (causing and pseudolymphoma. Some degree of macrocyto- its plasma concentration to rise) include: sodium sis is common but anaemia probably occurs only valproate, cimetidine, co-trimoxazole, isoniazid, when dietary folate is inadequate. This responds to chloramphenicol, some NSAIDs, disulfiram. There folate supplement (the requirement for folate is is a considerable body of mediocre and contra- increased, as it is a cofactor in some hydroxylation dictory data, the lesson of which is that possible reactions that are accelerated by enzyme induction interaction should be borne in mind wherever by phenytoin). Osteomalacia due to increased meta- other drugs are prescribed to a patient taking bolism of vitamin D occurs after years of therapy. phenytoin. Overdose (causing cerebellar symptoms and Phenytoin is 90% bound to plasma albumin so signs, coma, apnoea) is treated according to general that quite small changes in binding, e.g. a drop to principles. The patient may remain unconscious for 80%, will result in a higher concentration of free, a long time because of saturation kinetics, but will active, drug. Since free drug is also available to be recover if respiration and circulation are sustained. metabolised, the effect of such changes is probably short-lived. Phenytoin orally is well absorbed but Fosphenytoin, a prodrug of phenytoin, is soluble there have been pharmaceutical bioavailability in water, easier and safer to administer; its conver- problems in relation to the nature of the diluent in tion in the blood to phenytoin is rapid and it may be the capsule; patients should always use the same used as an alternative to phenytoin for status formulation. Phenytoin should not be given i.m. epilepticus (Table 20.1). since it precipitates and is poorly absorbed. It may be diluted and given by i.v. infusion over 1 hour but SODIUM VALPROATE care should be taken to follow the manufacturer's instructions including the use of an in-line filter, Sodium valproate (valproic acid) (Epilim) acts because phenytoin may also precipitate in infusion by inhibiting GABA transaminase, the enzyme fluids, particularly dextrose. responsible for the breakdown of the inhibitory 420
PHARMACOLOGY OF INDIVIDUAL DRUGS 20 neurotransmitter, GABA, so increasing its concen- CLONAZEPAM tration at GABA receptors. Clonazepam (Rivotril) (t1/2 25 h) is a benzodiazepine Sodium valproate is extensively metabolised in used as a second line drug for treatment of primary the liver and has a t1/2 of 13 h. It is 90% bound to generalised epilepsy and for status epilepticus (see plasma albumin. Sodium valproate is a nonspecific Table 20.1). inhibitor of metabolism, and indeed inhibits its own metabolism, and that of lamotrigine, phenobarbitone, phenytoin and carbamazepine. Sodium valproate Vigabatrin (Sabril) (t1/2 6 h) is structurally related to does not induce drug metabolising enzymes but its the inhibitory CNS neurotransmitter GABA and it metabolism is enhanced by induction due to other acts by irreversibly inhibiting GABA-transaminase drugs, including antiepileptics. so that GABA accumulates. GABA-transaminase is Sodium valproate is effective for a wide range of resynthesised over 6 days. Vigabatrin is not meta- seizure disorders, including generalised and partial bolised and does not induce hepatic drug meta- epilepsy, and the prophylaxis of febrile convulsions bolising enzymes. and post-traumatic epilepsy. Vigabatrin is effective in partial, secondary generalised seizures which are not satisfactorily Adverse effects can be troublesome. The main controlled by other anticonvulsants, and in infantile ones of concern, particularly to women, are weight spasms, as monotherapy. It worsens absence and gain, teratogenicity (see p. 416), polycystic ovary myoclonic seizures syndrome, and loss of hair which grows back curly.6 Unwanted effects from drugs sometimes become Nausea may be a problem. Some patients exhibit a apparant only following prolonged use, and viga- rise in liver enzymes which is usually transient and batrin is a case in point. Vigabatrin had been without sinister import, but they should be closely licenced for a number of years, before it was found monitored until the biochemical tests return to to cause visual field constriction in up to 40% of normal as, rarely, liver failure occurs (risk maximal patients, an effect that is insidious and leads to at 2-12 weeks); this is often indicated by anorexia, irreversible tunnel vision.7 Its discovery emphasises malaise and a recurrence of seizures. Other reactions the value of postmarketing drug surveillance include pancreatitis, and coagulation disorder due programmes.8 Vigabatrin is now indicated only to inhibition of platelet aggregation (coagulation for patients with the specific seizure disorders should be assessed before surgery). responsive to the drug (above), and no other. Ketone metabolites may cause confusion in Patients should undergo visual field monitoring at uring testing in diabetes. six-monthly intervals whilst taking the drug. Other Metabolic inhibition by valproate prolongs the adverse effects on the CNS are similar to those of action of co-administered antiepilepsy drugs (see antiepilepsy drugs in general but include confusion above). The effect is significant and the dose of and psychosis. Increase in weight also occurs in up lamotrigine, for example, should be halved in to 40% of patients during the first 6 months of patients who are also taking sodium valproate. treatment. BARBITURATES Lamotrigine acts to stabilise presynaptic neuronal Antiepilepsy members include phenobarbital (pheno- membranes by blocking voltage-dependent sodium barbitone) (tl/2 100 h), methylphenobarbital and channels (a property it shares with carbamazepine primidone (Mysoline), which is largely metabolised and phenytoin) and it reduces the release of excita- to phenobarbital, i.e. it is a prodrug. They are still tory amino acids, such as glutamate and aspartate. used for generalised seizures; sedation is usual. The t1/2 of 24 h allows for a single daily dose. 6 7 'We thought the change might be welcomed by the patients, Eke T, Talbot J F et al. 1997 British Medical Journal 314: but one girl prefered her hair to be long and straight, and one 180-181. 8 boy was mortified by his curls and insisted on a short hair Wilton L V, Stephens M D B, Mann R D 1999 British Medical cut.' Jeavons P M 1977 Lancet 1: 359. Journal 319:1165-1166. 421
20 EPILEPSY, PARKINSONISM AND ALLIED CONDITIONS Lamotrigine is effective as monotherapy and Succinimides. Ethosuximide (Zarontin) (t1/2 55 h) adjunctive therapy for partial and primary and differs from other antiepilepsy drugs in that it secondarily generalised tonic-clonic seizures. It is blocks a particular type of calcium channel that generally well tolerated but may cause serious is active in absence seizures (petit mal), and it is adverse effects on the skin, including Stevens- used specifically for this condition. Adverse effects Johnson syndrome and toxic epidermal necrolysis include gastric upset, CNS effects and allergic (fatally, on rare occasions). The risk of cutaneous reactions including eosinophilia and other blood effects can be lessened if treatment is begun with a disorders, and lupus erythematosus. 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 Parkinsonism accelerate the metabolic breakdown of lamotrigine which must be given in higher dose when combined. A NOTE ON PATHOPHYSIOLOGY Gabapentin is an analogue of GABA that is Parkinson's disease9 affects about 1 in 200 of the sufficiently lipid soluble to cross the blood-brain elderly population. In broad terms, it is caused by barrier but its mode of action is uncertain. It is degeneration of the substantia nigra10 in the mid- excreted unchanged and, unlike other antiepilepsy brain, and consequent loss of dopamine-containing agents, does not induce or inhibit hepatic meta- neurons in the nigrostriatal pathway (see Fig. 19.3, bolism of other drugs. p. 382). There is no known cure but drug treatment Gabapentin is effective only for partial seizures can, if properly managed, dramatically improve and secondary generalised epilepsy (not absence or quality of life in this progressive disease. myoclonic epilepsy), in combination with established Two balanced systems are important in the agents. It is also used for neuropathic pain. Gaba- extrapyramidal control of motor activity at the level pentin may cause somnolence, unsteadiness, dizz- of the corpus striatum and substantia nigra: in one iness and fatigue. the neurotransmitter is acetylcholine; in the other it is a dopamine. In Parkinson's disease there is degen- Topiramate possesses a range of actions that erative loss of nigrostriatal dopaminergic neurons include blockade of voltage-sensitive sodium and the symptoms and signs of the disease are due channels, enhancement of GABA activity and to dopamine depletion. possibly weak blockade of glutamate receptors. The Certain drugs also produce the features of t1/2 of 21 h allows once daily dosing; it is excreted in Parkinson's disease (see below) and the general the urine mainly as unchanged drug. term 'parkinsonism' is used to cover both the Topiramate is used as adjunctive treatment for disease and the drug-induced states. The symptom partial seizures, with or without secondary general- triad of the disease is bradykinesia, rigidity and isation. It use is limited by its unwanted effects, tremor. Patients who have received levodopa for a particularly sedation, naming difficulty and weight long time may exhibit the 'on-off' phenomenon in loss. Acute myopia and raised intraocular pressure which, abruptly and distressingly, dyskinesia (the may occur. 'on' phase) alternates with hypokinesia (the 'off phase). One sufferer, a physician, wrote about his Levetiracetam acts in a manner different to other condition: antiepilepsy drugs. It has a potentially broad spec- trum of use but is currently indicated for adjunctive treatment in partial seizures with or without 9 secondary generalisation. It is rapidly and com- James Parkinson (1755-1824), physician; he described paralysis agitans in 1817. pletely absorbed after oral administration, and is 10 Substantia nigra is (Latin) black substance. A coronal section effective with twice-daily dosing. Its therapeutic at this point in the brain shows the distinctive black areas, index appears to be high and the commonest of the visible with the naked eye in the normal brain, but absent adverse effects are asthenia, dizziness and drowsiness. from the brains of patients with Parkinson's disease. 422
DRUGS FOR PARKINSON'S DISEASE 20 'One of its most trying aspects is the extent to approach is most effective against tremor and which it interferes with the trivial events in daily rigidity, and less effective in the treatment of life. Nothing is easy in Parkinson's disease. There bradykinesia (including iatrogenic, caused by is no feature of any task that is not potentially out dopamine receptor antagonists). of control. A cuff-link refuses to find its way into a Both approaches are effective in therapy and tuxedo shirt, my wife is out of town, and I miss the may usefully be combined. It therefore comes as no annual dinner. I am unable to stuff change from a surprise that drugs which prolong the action of $5 bill into my wallet, and the patrons in line acetylcholine (anticholinesterases) or drugs which behind the cash register fume. Bow ties won't tie deplete dopamine stores (reserpine) or block dopa- and shoelaces won't lace. A cube of beef obstructs mine receptors (antipsychotics, e.g. chlorpromazine) the glottis. In Parkinson's disease one must expect will exacerbate the symptoms of parkinsonism or the unexpected ... About five years ago, my induce a parkinson-like state. disease began to close in on me, becoming more Other parts of the brain in which dopaminergic aggressive and difficult to handle. I had increasing systems are involved include the medulla (induc- discomfort from hyperkinesias. My voice was tion of vomiting), the hypothalamus (suppression almost inaudible, and periods when my feet felt of prolactin secretion) and certain paths to the frozen to the floor became commonplace. I lost the cerebral cortex. Different effects of dopaminergic advantage I had previously enjoyed of a drugs can be explained by activation of these comfortable margin between the effective dose and systems, namely emesis, suppression of lactation the dose with intolerable side effects. I had an "off" (mainly direct dopamine agonists) and occasionally spell... in a telephone booth.. .'11 psychotic illness. Classical antipsychotics (see p. 381) used to manage psychotic behaviour act by blockade of dopamine D2 receptors and, as is to be expected, they are also antinauseant, may sometimes cause Objectives of therapy galactorrhoea, and can induce parkinsonism. Drug- induced parkinsonism is alleviated by anti- The dopaminergic/cholinergic balance may be muscarinics, but not by levodopa or dopamine restored by the following mechanisms. agonists, because the antipsychotics block dopamine receptors by which these drugs act. Since many 1. Enhancement of dopaminergic activity by antipsychotics also have some antimuscarinic activity, drugs which may: those with greatest efficacy in this respect, e.g. (a) replenish neuronal dopamine by supplying thioridazine, are the least likely to cause parkinsonism. levodopa, which is its natural precursor; administration of dopamine itself is ineffective as it does not cross the blood-brain barrier (b) act as dopamine agonists (bromocriptine, Drugs for Parkinson's pergolide, cabergoline, apomorphine); disease (c) prolong the action of dopamine through selective inhibition of its metabolism DOPAMINERGIC DRUGS (selegiline). (d) release dopamine from stores and inhibit re- Levodopa and dopa-decarboxylase uptake (amantadine) or inhibitors 2. Reduction of cholinergic activity by antimuscarinic (anticholinergic12) drugs; this Levodopa ('dopa' stands for dihydroxyphenyl- alanine) is a natural amino acid precursor of 11 Saltzman E W 1996 Living with Parkinson's disease. New dopamine. The latter cannot be used because it is England Journal of Medicine 334:114-116. rapidly metabolised in the gut, blood and liver by 12 The term antimuscarinic is now preferred (see p. 435). monoamine oxidase and catechol-O-methyltrans- 423
20 EPILEPSY, PARKINSONISM AND ALLIED CONDITIONS ferase; even intravenously administered dopamine, Compliance is important. Abrupt discontinua- or dopamine formed in peripheral tissues, is tion of therapy leads to dramatic relapse. insufficiently lipid-soluble to penetrate the CNS. But levodopa is readily absorbed from the upper Adverse effects. Postural hypotension occurs. Nausea small intestine by active amino acid transport and may be a limiting factor if the dose is increased too has a t1/2 of 1.5h. It can traverse the blood-brain rapidly; it may be helped by cyclizine 50 mg taken barrier by a similar active transport, and within the 30 min before food or by domperidone (little of brain it is decarboxylated (by dopa decarboxylase) which enters the brain). Levodopa-induced dyskine- to the neurotransmitter dopamine. sias take the form of involuntary limb jerking or But a major disadvantage is that levodopa is also head, lip or tongue movements and constitute a extensively decarboxylated to dopamine in periph- major constraint on how the drug is used (see later). eral tissues so that only 1-5% of an oral dose of Mental changes may be seen: these include depres- levodopa reaches the brain. Thus large quantities of sion, which is common (best controlled with a levodopa would have to be given. These inhibit tricyclic antidepressant), dreams, and hallucina- gastric emptying, delivery to the absorption site is tions and delusions (clozapine may help). Agitation erratic and fluctuations in plasma concentration and confusion occur but it may be difficult to decide occur. The drug and its metabolites cause signifi- whether these are due to drug or to disease. In these cant adverse effects by peripheral actions, notably circumstances, the drugs most likely to be the cause nausea, but also cardiac arrhythmia and postural of a toxic confusional state (antimuscarinics and hypotension. This problem has been largely circum- direct dopamine agonists) are withdrawn. vented by the development of decarboxylase inhibi- tors, which do not enter the central nervous system, Interactions. With nonselective monoamine oxi- so that they prevent only the extracerebral meta- dase inhibitors (MAOI), the monoamine dopamine bolism of levodopa. The inhibitors are given in formed from levodopa is protected from destruc- combination with levodopa and there is a range of tion; it accumulates and also follows the normal formulations comprising a decarboxylase inhibitor path of conversion to noradrenaline (norepineph- with levodopa: rine), by dopamine 5-hydroxylase; severe hypertension results. The interaction with the selective MAO-B • co-careldopa (carbidopa + levodopa in inhibitor, selegiline, is possibly therapeutic (see proportions 12.5/50 mg, 10/100, 25/100, below). Tricyclic antidepressants are safe. Levodopa 25/250) (Sinemet) antagonises the effects of antipsychotics (dopamine • co-beneldopa (benserazide + levodopa in receptor blockers). Some antihypertensives enhance proportions 12.5 mg/50 mg, 25/100,50/200) hypotensive effects of levodopa. Metabolites of (Madopar). dopamine in the urine interfere with some tests for The combinations produce the same brain con- phaeochromocytoma, and in such patients it is best centrations as with levodopa alone, but only 25% of to measure the plasma catecholamines directly. the dose of levodopa is required, which smooths Dopa-decarboxylase is a pyridoxine-dependent the action of levodopa and reduces the incidence of enzyme and concomitant use of pyridoxine, e.g. in adverse effects, especially nausea, from about 80% self-medication with a multivitamin preparation, to less than 15%. can enhance peripheral conversion of levodopa to dopamine so that less is available to enter the CNS, and benefit is lost. This effect does not occur, of Dose management course, with the now usual levodopa-decarboxylase Levodopa alone and in combination (see above) is inhibitor combinations. introduced gradually and titrated according to response, the dose being altered every 2 weeks. The Dopamine agonists dose is increased to provide sufficient benefit for each individual patient, not to a standard dose since These mimic the effects of dopamine, the endo- this is very variable. genous agonist, which stimulates both the main 424
DRUGS FOR PARKINSON'S DISEASE 20 two types of dopamine receptor, DI and D2 (coupled 2-3 hours; it is also valuable for night-time problems respectively to adenylyl cyclase stimulation and due to lack of levodopa. Pmmipexole is a non-ergot inhibition). The D2-receptor is the principal target in dopamine D2-receptor agonist that is more effective Parkinson's disease; chronic Dl stimulation appears against tremor than the others. Ropinirole is a to potentiate the response to D2 stimulation despite direct D2-receptor agonist, which is also a non-ergot acutely having an inhibitory action on adenylyl derivate. There are insufficient data to allow an cyclase. The main problems with dopamine (i.e. the informed choice between these drugs. prodrug, levodopa) are its short t1/2 and, possibly, the consequences of delivering large amounts of Apomorphine is a derivative of morphine having substrate to an oxidative pathway, MAO (see below). structural similarities to dopamine; it is a full On the other hand, the problems of developing agonist at D1 and D2-receptors. Its main use is in synthetic alternatives are: young patients with severe motor fluctuations and dyskinesias (the 'on-off phenomenon, see above) • reproducing the right balance of Dl and D2 when it is given by s.c. injection or infusion for stimulation (dopamine itself is slightly D1 patients with levodopa resistant 'off. The rapid selective, in test systems, but its net effect in vivo onset of action by the s.c. route (self-administration is determined also by the relative amounts and can be taught) enables the 'off component to be locations of receptors — which differ in aborted without the patient waiting 45-60 minutes Parkinsonian patients from normal) to absorb another oral dose of levodopa. Apo- • avoiding the undesired effects of peripheral, morphine may need to be accompanied by an mainly gastric, D2-receptors antiemetic, e.g. domperidone (which does not cross • synthesising a full, not partial, agonist. the blood-brain barrier as does metoclopramide), to prevent its characteristic emetic action. Overdose Bromocriptine (a derivative of ergot) is a D2- causes respiratory depression; it is antagonised by receptor agonist, but also a weak a-adrenoreceptor naloxone. Apomorphine can induce penile erection antagonist. It is commonly used with levodopa. The (without causing sexual excitement) and it enhances drug is rapidly absorbed after administration by the penile response to visual erotic stimulation. mouth; the tl/2 is 5 h, so that its action is smoother than that of levodopa, which can be an advantage in patients who develop end-of-dose deterioration Inhibition of dopamine metabolism with levodopa. Dosing should start very low Monoamine oxidase (MAO) enzymes have an (1-1.25 mg p.o. at night), increasing at approx- important function in modulating the intraneuronal imately weekly intervals and according to clinical content of neurotransmitter. The enzymes exist in response. two principal forms, A and B, defined by specific Nausea and vomiting are the commonest adverse substrates some of which cannot be metabolised by effects; these may respond to domperidone but tend the other form (Table 20.3). The therapeutic to become less marked as treatment continues. importance of recognising these two forms arises Postural hypotension may cause dizziness or because they are to some extent present in different syncope. In high dose confusion, delusions or tissues, and the enzyme at these different locations hallucinations may occur and, after prolonged use, can be selectively inhibited by the individual pleural effusion and retroperitoneal fibrosis. inhibitors: moclobemide for MAO-A (used for depression, p. 379) and selegiline for MAO-B (Table Lisuride (tl/2 2 h) and pergolide (tl/2 6 h) are similar 20.3). to bromocriptine, though the latter also stimulates Dj-receptors. Cabergoline, also an ergot derivative, Selegiline is a selective, irreversible inhibitor of has a tl/2 of more than 80 h. This long duration MAO type B. The problem with nonselective MAO of action allows it to be used in a single daily (or inhibitors is that they prevent degradation of even twice weekly) dose, which is appreciated by dietary amines, especially tyramine, which is then patients who are often taking other drugs every able to act systemically as a sympathomimetic: the 425
20 EPILEPSY, PARKINSONISM AND ALLIED CONDITIONS TABLE 20.3 Isoforms of monoamine oxidase: MAO-A and MAO-B: an explanation The table shows the definition of the isoforms by their specific substrates, and then their selectivity (or nonselectivity) towards a number of other substrates and inhibitors. Determination of therapeutic and adverse effects is a function of selectivity of the inhibitor and the tissue location of the enzyme. Enzyme MAO-A MAO-A and B MAO-B Substrate Serotonin (see below) Noradrenaline (norepinephrine) (see below) Phenylethylamine Adrenaline (epinephrine) Dopamine Tyramine Inhibitors Moclobemide Tranylcypromine Selegiline Phenelzine Iproniazid Tissues Liver See MAO-A, Gut CNS (neurons) MAO-B CNS (glial cells) Sympathetic neurons Explanation: the specific substrate for MAO-A is serotonin, whilst for MAO-B it is the nonendogenous amine, phenylethylamine (present in many brands of chocolate). Noradrenaline, tyramine and dopamine can be metabolised by both isoforms of MAO. MAO-A is the major form in liver and in neurons (both CNS and peripheral sympathetic); MAO-B is the major form in gut, but is also present in the liver, lungs and glial cells of the CNS. hypertensive 'cheese reaction'. As will be apparent receive selegiline although the reason for this from Table 20.3, selegiline does not cause the cheese benefit is not clear. reaction, because MAO-A is still present in the liver to metabolise tyramine. MAO-A also metabolises Entacapone inhibits catechol-O-methyltransferase tyramine in the sympathetic nerve endings, so (COMT), one of the principal enzymes responsible providing a further line of protection (tyramine is for the metabolism of dopamine; the action of levo- an indirect acting amine which displaces noradre- dopa is thus prolonged. It is most effective for naline from the nerve endings). In the CNS selegiline patients with early end-of-dose deterioration, and protects dopamine from intraneuronal degradation. allows them to take levodopa at 3- or 4-hourly inter- It has no effect on synaptic cleft concentrations vals, giving a more predictable and useful response. of those amines like serotonin and noradrenaline, Entacapone is preferred to long-acting preparations which are normally potentiated by the MAOI of levodopa whose main disadvantage is their slow used in depression; therefore selegiline has no onset of action. It can increase the dyskinesias seen in antidepressant action. the late stages of Parkinson's disease. Selegiline was originally introduced in the belief that it would delay end-of-dose deterioration by Dopamine release prolonging the action of levodopa; subsequently it was held that this action might be protective of Amantadine antedates the discovery of dopamine dopaminergic neurons and so allow later initiation receptor subtypes, and its discovery as an anti- of therapy with levodopa. It became one of the most parkinsonian drug was an example of serendipity. It widely prescribed drugs for Parkinson's disease. is an antivirus drug which, given for influenza to a Later clinical trials, however, failed to confirm these parkinsonian patient, was noticed to be beneficial. effects and indeed, combined treatment with The two effects are probably unrelated. It appears to levodopa and selegiline was associated with excess act by increasing synthesis and release of dopa- mortality;13 many patients discontinued selegiline mine, and by diminishing neuronal reuptake. It also without worsening of their condition. A minority has slight antimuscarinic effect. The drug is much deteriorated acutely and they have continued to less effective than levodopa, whose action it will slightly enhance. It is more effective than the 13 Ben-Sholomo Y, Churchyard A, Head J, Hurwitz B, standard antimuscarinic drugs, with which it has Overstall P, Ockelford J, Lees A J 1998 British Medical Journal an additive effect. Amantadine is relatively free 316:1191-1196. from adverse effects, which, however, include ankle 426
TREATMENT OF PARKINSON'S DISEASE 20 oedema (probably a local effect on blood vessels), relief. No agent has yet been found to alter the postural hypotension, livedo reticularis and central progressive course of the disease. nervous system disturbances: insomnia, hallucina- tions and, rarely, fits. Initial treatment ANTIMUSCARINIC Treatment should begin only when it is judged (ANTICHOLINERGIC) DRUGS necessary in each individual case. For example, a (see also p. 441) young man with a physically demanding job will require treatment before an older retired person. Antimuscarinic drugs benefit parkinsonism by Two conflicting objectives have to be balanced: the blocking acetylcholine receptors in the central desire for satisfactory relief of current symptoms nervous system, thereby partially redressing the and the avoidance of adverse effects as a result of imbalance created by decreased dopaminergic long-continued treatment. There is debate as to activity. Their use originated when hyoscine was whether the treatment should commence with given to parkinsonian patients in an attempt to levodopa or a synthetic dopamine agonist. Levodopa reduce sialorrhoea by peripheral effect, and it then provides the biggest improvement in motor symp- became apparent that they had other beneficial toms but its use is associated with the development effects in this disease. Synthetic derivatives are dyskinesias, which are inevitable after some 5-10 now used orally. These include benzhexol (tri- years, and sometimes sooner. Dopamine agonists hexyphenidyl), orphenadrine, benzatropine, procy- have a much less powerful motor effect but are less clidine, biperiden. There is little to choose between likely to produce dyskinesias. Some neurologists these. Antimuscarinics produce modest improve- therefore prefer a dopamine agonist alone as the ments in tremor, rigidity, sialorrhoea, muscular initial choice. Unfortunately, only about 30% of stiffness and leg cramps, but little in bradykinesia, patients obtain a satisfactory motor response. An the most disabling symptom of Parkinson's disease. alternative, therefore, is to begin treatment with They are also effective i.m. or i.v. in acute drug- levodopa in low dose to get a good motor response, induced dystonias. and to add a dopamine agonist when the initial Unwanted effects include dry mouth, blurred benefit begins to wane. With either approach, it vision, constipation, urine retention, glaucoma, seems likely that the position after 5 years treat- hallucinations, memory defects, toxic confusional ment may well be the same, but that by starting states and psychoses (which should be dis- with levodopa the patient will have had the benefit tinguished from presenile dementia). of a earlier motor response. Antimuscarinic drugs are suitable only for younger patients predominantly troubled with tremor and rigidity. They do not benefit bradykinesia, the main Treatment of Parkinson's disabling symptom. The unwanted effects of acute disease angle glaucoma, retention of urine, constipation and psychiatric disturbance are general contraindi- The main features that require alleviation are tremor, cations to the use of antimuscarinics in the elderly. rigidity and bradykinesia. Amantadine or selegiline can delay the use of either levodopa or a synthetic dopamine agonist in General measures are important and include the the early stages of the disease if mild symptomatic encouragement of regular physical activity and benefit is required, but this approach is seldom specific help such as physiotherapy, speech therapy necessary. and occupational therapy. A typical course is that for about 2-4 years on treatment with levodopa or a dopamine agonist, the patient's disability and motor performance remains DRUG THERAPY near normal despite progression of the underlying Drugs play the most important role in symptom disease. After some 5 years, about 50% of patients 427
20 EPILEPSY, PARKINSONISM AND ALLIED CONDITIONS exhibit the problems of long-term treatment, namely, preferable gradually to reduce the antiparkinsonian dyskinesia and end-of-dose deterioration with the treatment, even at the expense of lessened mobility. 'on-off phenomenon. After 10 years virtually 100% of patients are affected. DRUG-INDUCED PARKINSONISM Dyskinesia comprises involuntary writhing move- ment of the face and limbs that may be biphasic The classical antipsychotic (see p. 380) drugs block (occurring at the start and end of motor response) dopamine receptors and their antipsychotic activity or develop at the time of the maximum plasma relates closely to this action, which notably involves levodopa concentration. They respond initially to the D2-receptor, the principal target in Parkinson's reducing the dose of levodopa but at the cost of disease. It comes as no surprise, therefore, that bradykinesia and as time passes there is progres- these drugs can induce a state whose clinical sively less scope to obtain benefit without unwanted features are very similar to those of idiopathic effects. Parkinson's disease. The piperazine phenothiazines, End-of-dose deterioration is managed by increasing e.g. trifluoperazine, and the butyrophenones, e.g. the frequency of dosing with levodopa (e.g. to 2-3- haloperidol, are most commonly involved. In one hourly), but this tends to result in the appearance, series14 of 95 new cases of parkinsonism referred or worsening of the dyskinesia. The motor response to a department of geriatric medicine, 51% were then becomes more brittle with abrupt swings associated with prescribed drugs and half of these between hyper- and hypomobility (the on-off required hospital admission. After withdrawal of phenomenon). Despite their unpredicatable nature the offending drug most cases resolved completely over the course of a single day, these changes are in in 7 weeks. But fact dose-related, an effect that becomes apparent One old lady who had received trifluoperazine only when the response is related to total medica- (for a minor fright and anxiety) for 5 weeks, took tion taken over a week. 36 weeks to recover from the drug-induced Various strategies have been devised to over- parkinsonism but never managed to get home come these problems. Controlled release preparations again. of levodopa tend to be associated with an inadequate initial response and disabling dyskinesia at the end of When drug-induced parkinsonism is troublesome, the dose. A more effective approach appears to be the an antimuscarinic drug, e.g. benzhexol, is use of a COMT inhibitor, e.g. entacapone, which can beneficial. Atypical antipsychotics provoke fewer sometimes allay early end-of-dose deterioration extrapyrimidal effects (see p. 387). without causing dyskinesia. This is now the main indication for its use. In any event, many patients with Parkinson's disease take at least two and sometimes more drugs at frequent intervals each day, Other movement an outcome that tends to rule their lives. Continuous subcutaneous infusion of apomorphine disorders can transform the quality of life of younger patients Essential tremor is often, and with justice, called with severe motor fluctuations and dyskinesia, but benign, but a few individuals may be incapacitated this may lead to neuropsychiatric effects. If drug by it. Alcohol, through a central action, helps about treatment fails in young non-demented patients, 50% of patients but is plainly unsuitable for long- stereotactic subthalamotomy or bilateral stereotactic term use and a nonselective 3-adrenoceptor blocker, subthalamic stimulation can be very successful with e.g. propranolol 120 mg/day, will benefit about only a small risk of surgical complications in 50%; clonazepam or primidone are sometimes experienced hands. Some 20% of patients with beneficial. Parkinson's disease, notable the older ones, develop impairment of memory and speech with a fluctuating confusional state and hallucinations. As these 14 symptoms are often aggravated by medication, it is Stephen P J, Williamson J 1984 Lancet 2:1082. 428
T E T A N US 20 Drug-induced dystonic reactions are seen: • as an acute reaction, often of the torsion type, Multiple sclerosis and occur following administration of dopamine receptor blocking antipsychotics, e.g. Drugs are used to alleviate chronic muscle spasm or haloperidol, and antiemetics, e.g. spasticity (see above) but until recently, there has metoclopramide. An antimuscarinic drug, e.g. been no disease-modifying treatment in this relapsing biperiden or benzatropine, given i.m. or i.v. and and remitting condition, where the placebo effect of repeated as necessary, provides relief most drugs can appear quite powerful. Although its • in some patients who are receiving levodopa for cause remains unknown, it is now held to be an Parkinson's disease autoimmune disorder. This has led to the testing of • in younger patients on long-term antipsychotic both old and new forms of drugs, which might modify treatment, who develop tardive dyskinesia (see the immune response, and release of cytokines. p. 387). Interferon beta is set to test the resilience of Hepatolenticular degeneration (Wilson's disease) patients, doctors, health economists and adminis- is caused by a genetic failure to eliminate copper trators. In placebo-controlled trials, it is the first absorbed from food so that it accumulates in the treatment to show a reduction in the number of liver, brain, cornea and kidneys. Chelating copper relapses. Interferon beta may also have a modest in the gut with penicillamine (p. 293) or trientine effect in delaying disability by 12-18 months in can establish a negative copper balance (with some relapsing/remitting disease. In a clinical trial 372 clinical improvement if treatment is started early). patients with relapsing-remitting disease, able to The patients may also develop cirrhosis, and the walk 100 metres without aid or rest, were randomised best treatment for both may be orthotopic liver to receive 8 million IU or 1.6 million IU of interferon transplantation. beta or placebo by s.c. injection on alternate days. Chorea of any cause may be alleviated by dopa- After 2 years there was a reduction in the relapse rate mine receptor blocking antipsychotics, and also by from 1.27 per year in the placebo group to 0.84 per tetrabenazine, which inhibits neuronal storage of year in the patients receiving the higher dose.15 dopamine and serotonin. Interferon beta is not indicated in patients with progressive forms of disease, or in severely disabled Involuntary muscle spasm: blepharospasm, hemi- patients. The high cost per patient treated in relation facial spasm, spasmodic torticollis, and indeed to the benefit gained has prevented widespread the spasm of chronic anal fissure, are treated with access to this drug. In the UK, only designated botulinum toxin. This irreversibly blocks release of neurologists can prescribe interferon beta. acetylcholine from cholinergic nerve endings and is injected locally. Its effect lasts about 3 months. Botulinum toxin is at least partially effective in up to 90% of patients with these conditions. Mild Motor-neuron disease dysphagia occurs in -30% of patients receiving injections into their neck for torticollis due to The cause of the progressive destruction of upper spread of the toxin in to the pharyngeal muscles. and lower motor neurons is unknown. The only drug available, riluzole, may act by inhibiting accu- Spasticity results from lesions at various sites within mulation of the neurotransmitter, glutamate. In 959 the central nervous system and spinal cord. Drugs patients, riluzole prolonged median survival time used include the GABA agonist baclofen, diazepam from 13 to 16 months, with no effect on motor and tizanidine (an 2-adrenoceptor agonist). function.16 It may cause neutropenia. Myotonia in which voluntary muscle fails to relax 15 The IFNB Multiple Sclerosis Study Group and the after contraction may be symptomatically benefitted University of British Columbia MS/MRI Analysis Group by drugs that increase muscle refractory period, e.g. 1995. Neurology 45:1277-1285 16 procainamide, phenytoin, quinidine. Lacomblez L et al 1996 Lancet 347: 1425-1431. 429
20 EPILEPSY, PARKINSONISM AND ALLIED CONDITIONS Severe cases of tetanus generally require admis- Tetanus sion to an intensive care unit for 3-5 weeks. Weight loss is universal in tetanus and these patients Objectives of management are to: require enteral nutrition. Other important measures include: close control of fluid balance, chest physio- • immediately neutralise with globulin any toxin therapy to prevent pneumonia, prophylaxis of that has not yet become attached irreversibly to thromboembolism and intensive nursing care to the central nervous system prevent pressure sores. • destroy tetanus bacteria by chemotherapy, thus stopping toxin production • control convulsions whilst maintaining respiratory and cardiovascular function, which GUIDETO FURTHER READING may be disordered by the toxin • prevent intercurrent infection (usually Brodie M J, French IA 2000 Management of epilepsy pulmonary) in adolescents and adults. Lancet 356: 323-328 • prevent electrolyte disturbances and maintain Browne T R, Holmes G L 2001 Epilepsy. New England nutrition. Journal of Medicine 344:1145-1151 Cook T M, Protheroe R T, Handel J M 2001 Tetanus: a review of the literature. British Journal of TREATMENT Anaesthesia 87: 477-487 Human tetanus immunoglobulin 150 units/kg Compston A, Coles A 2002 Multiple sclerosis. Lancet should be given intramuscularly at multiple sites to 359:1221-1231 neutralise unbound toxin. Where present, wounds Delanty N, Vaughn C J, French J A1998 Medical should be debrided. Metronidazole is an antibiotic causes of seizures. Lancet 532: 383-390 of choice for Clostridium tetani, but penicillin, Harten P N van, Hoek H W, Kahn R S 1999 Acute erythromycin, tetracycline, chloramphenicol and dystonia induced by drug treatment. British clindamycin are acceptable alternatives (see p. 211). Medical Journal 319: 623-626 Avoid unnecessary stimulation, which may Heafield M T E 2000 Managing status epilepticus. induce rigidity and spasms. The primary treatment British Medical Journal 320: 953-954 for spasms and rigidity is sedation with a benzo- Kapoor W N 2000 Syncope. New England Journal of diazepine, such as midazolam or diazepam. Addi- Medicine 343:1856-1862 tional sedation may be provided with propofol or a Kwan P, Brodie M J 2001 Neuropsychological effects of phenothiazine, usually chlorpromazine. In severe epilepsy and antiepileptic drugs. Lancet 357:216-222 disease prolonged spasms and respiratory dys- Martin J B 1999 Molecular basis of the function will necessitate tracheal intubation and neurodegenerative disorders. New England mechanical ventilation will be required. If the patient Journal of Medicine 340:1970-1980 has been intubated and sedation alone is inadequate Munchau A, Bhatia K P 2000 Uses of botulinum toxin to control spasms, a neuromuscular blocking drug, injection in medicine today. British Medical Journal e.g., intermittent doses of pancuronium or a 320:161-165 continuous infusion of atracurium, will be required. Polman C H, Uitdehaag B M J 2000 Drug treatment of Tetanus toxin often causes disturbances in auto- multiple sclerosis. British Medical Journal 2000: nomic control, resulting in sympathetic overactivity 490-494 and high plasma catecholamine concentrations. The Shaw P J 1999 Motor neuron disease. British Medical first-line treatment for autonomic dysfunction is by Journal 318:1118-1121 sedation with a benzodiazepine and opioid. Infu- Stephen L J, Brodie M J 2000 Epilepsy in elderly sion of the short-acting fi-blocker esmolol, or the people. Lancet 355:1441-1446 a2-adrenergic agonist clonidine, helps to control Schapira A H V 1999 Parkinson's disease. British episodes of hypertension. Intravenous magnesium Medical Journal 318: 311-314 sulphate is also used to reduce autonomic disturbance. 430