BRITISH MEDICAL JOURNAL 18 MARCH 1972 741

Today's Drugs Br Med J: first published as 10.1136/bmj.1.5802.741 on 18 March 1972. Downloaded from

Treatment for Parkinsonism, Other than Levodopa

British Medical Journal, 1972, 1, 741-742 them better than another and the choice of drugs is sufficiently large to allow many alternatives to be tried if The treatment of Parkinsonism with levodopa has recently necessary. In general, (50 mg three times a day) been reviewed in this series of articles.' It was emphasized is less toxic than benzhexol, and benztropine (2 mg at night) that, while levodopa was beneficial in some 60-70% of cases, has a more prolonged action. There is no convincing evi- there remained a group of patients for whom this drug was dence that any one drug is specially useful for any particular unhelpful. The present article reviews the various forms of clinical feature. Sometimes a favourable result is achieved treatment which are available other than levodopa. by a combination of two drugs. Further details of dose regimens with the numerous anticholinergic drugs have appeared in several reviews.""7 Anticholinergic Drugs

For the last century Parkinsonism has been treated with drugs ADVERSE EFFECTS which block certain actions (the muscarinic effects) of acetyl- choline. Charcot first advocated atropine2 and subsequently The common dose-limiting side effects of anticholinergic other belladonna alkaloids such as hyoscine were employed. drugs are those of parasympathetic blockade consequent on After the second world war synthetic agents with actions impaired muscarinic function. They include defective ocular resembling atropine were introduced. These were considered accommodation, dryness of the mouth, constipation, and re- to possess similar therapeutic properties with fewer unwanted tention of urine. Adverse reactions involving the central effects. There is now a wide choice of these drugs, such as nervous system may also occur; confusion and hallucinations benzhexol (), benztropine, orphenadrine, have been reported in some 30% of patients receiving ethopropazine, methixene, , cycrimine, chlor- benzhexol.' phenoxamine, and . Caution is desirable when stopping anticholinergic therapy, as sudden complete withdrawal of drugs may precipitate a

syndrome of severe rigidity and tremor. http://www.bmj.com/ PHARMACOLOGY The therapeutic action of these agents is thought to arise by blockade of the muscarinic actions of in the INDICATIONS central nervous svstem. There is evidence that acetylcholine Anticholinergic drugs are particularly useful in patients with is a synaptic neurotransmitter in the corpus striatum. In the Parkinsonism induced by administration of phenothiazines normal brain there is a balance between excitatory effects of such as chlorpromazine or butyrophenones such as halo-

acetylcholine (which are muscarinic) and the inhibitory in- peridol. Phenothiazines and butyrophenones block dopaminer- on 26 September 2021 by guest. Protected copyright. fluences of another striatal transmitter, dopamine. In Parkin- gic receptors and this effect is probably responsible for their sonism the dopaminergic system appears to be impaired, so production of Parkinsonism. In these circumstances little that the normal balance between acetylcholine and dopamine benefit can be achieved by increasing the levels of striatal is disturbed in the direction of cholinergic dominance. Drugs dopamine with levodopa. On theoretical grounds treatment which block the muscarinic action of acetylcholine tend to should be directed at restoring the balance between acetyl- restore the balance and so bring about a therapeutic effect. choline and dopamine by reducing cholinergic function. Practical experience has shown that anticholinergic agents are very useful in this context. Indeed, many psychiatrists as THERAPEUTIC USE prescribe anticholinergic drugs routine prophylaxis against Parkinsonism when treating psychotic patients with pheno- The beneficial actions of anticholinergic drugs are limited. thiazines or butyrophenones. The main clinical features to respond are rigidity and tremor. Acute extrapyramidal syndromes induced by drugs may The most disabling motor deficit in Parkinsonism is hypo- require parenteral administration of anticholinergic agents kinesia, which disrupts everyday activities such as washing, such as benztropine, 2 mg intravenously.' Treatment with dressing, walking, and eating. Unfortunately this motor dis- anticholinergic drugs is also indicated in patients with other order is seldom helped by anticholinergic agents. In reviewing forms of Parkinsonism who are not helped by levodopa, and the overall value of these drugs Esplin3 considered that a even patients doing well on levodopa may obtain benefit 30% improvement in 80% of patients was an optimistic from concomitant administration of anticholinergic agents'; estimate. apart from any other action their antiemetic effect is useful. Benzhexol is one of the most widely employed anticholiner- Patients with difficulty in micturition (for example, pro- gic drugs. A dose of 2 mg three times a day may be in- statism) should not be given anticholinergic drugs, and there creased by 2 mg per day every week until unwanted effects is a risk of raising the ocular tension in patients with glau- are encountered, when the intake should be reduced by some coma. Reading difficulties, due to cycloplegia or iridoplegia, 2-5 mg. Benefit may be achieved from doses as low as 1 mg may be counteracted by the prescription of appropriate lenses daily.' Some patients find one anticholinergic agent suits or the regular instillation of 1 % eserine eye drops. 742 BRITISH MEDICAL JOURNAL 18 MARCH 1972 Other Drugs Amantadine was developed as an antiviral agent for the treat- Antihistamines such as promethazine and diphenydramine ment of Asian influenza. In 1968 Schwab and his coworkers have been advocated for Parkinsonism, but they also possess Br Med J: first published as 10.1136/bmj.1.5802.741 on 18 March 1972. Downloaded from noticed a remission of neurological symptoms in a Parkin- antimuscarinic properties and there is no evidence that their sonian patient who had received amantadine for her in- antihistaminic actions are relevant to any therapeutic effects. fluenza. After this chance observation they treated 163 patients Many psychotropic drugs have been claimed to exert bene- with Parkinsonism and found that most experienced worth- ficial effects in Parkinsonism. These include monoamine while improvement. oxidase inhibitors, amphetamine, diazepam, imipramine, methylphenidate, and meprobamate. Other drugs which have been used include beta-adrenergic blockers and . There is no evidence that these drugs have any advantage PHARMACOLOGY AND THERAPEUTIC USE over other forms of therapy, and many have clear disad- Amantadine is readily absorbed and most is excreted un- vantages. They are not employed in the routine management changed in the urine.'1 The mechanism of its therapeutic of Parkinsonism. actions in Parkinsonism is not known, but there is some evidence that it acts by releasing dopamine from nerve endings.'2 Several controlled trials have now shown a therapeutic Other Forms of Therapy action of amantadine in Parkinsonism.13-5 All three major features of the Parkinsonian syndrome respond; hypokinesia, Stereotactic surgery has achieved good results for some rigidity, and tremor. Nevertheless, the extent of the clinical patients but a recent analysis of long-term benefits22 indicates improvement induced by amantadine is considerably less that the early enthusiasm for this procedure may not be en- than that achieved with levodopa. Comparative studies indi- tirely justified. Surgery is certainly being performed less cate that amantadine has 12-50% of the therapeutic potency frequently now. The advent of levodopa is no doubt related of levodopa.'6 17 Furthermore, the amelioration of symptoms to Cooper's report that 900 operations were performed by his may not be sustained. unit in 1967, and only 50 in 1970.3 Amantadine is a very easy drug to administer. The prob- Finally, physiotherapy and the encouragement by relatives lems of prolonged dose titration (necessary when prescribing and medical attendants undoubtedly help patients with levodopa) are not encountered. An initial intake of 100 mg chronic neurological disorders such as Parkinsonism. The a day should be increased after one week to 100 mg twice simplest of practical measures may also be useful, such as daily if adverse effects are not encountered. Higher doses replacing fly buttons by zips and shoes with laces by slip-on are not recommended by the manufacturers, though the shoes. optimum dose was found to be 100 mg thrice daily in a recent study.18 References ADVERSE EFFECTS 1 British Medical Journal, 1970, 4, 478, 541. 2 Ordenstein, L., M.D. Thesis. Paris, Martinet, 1867.

Several of the undesirable actions of amantadine resemble 3 Esplin, D. W., in The Pharmacological Basis of Therapeutics, ed. L. S. http://www.bmj.com/ of the alkaloids, such as atropine. Patients Goodman and A. Gilman. New York, Macmillan, 1965. those belladonna 4 Yahr, M. D., and Duvoisin, R. C., in Diseases of the Basal Ganglia, Hand- may complain of a dry mouth, defective near vision, and book of Clinical Neurology, Vol. 6, ed. P. J. Vinken and G. W. Bruyn. difficulties with micturition. Intermittent confusion, night- Amsterdam, North Holland Publishing Co., 1968. 6 Onuaguluchi, G., Parkinsonism, London, Butterworths, 1964. mares hallucinations, restlessness, palpitations, and giddi- 6 Schwab, R. S., and England, A. C., journal of Chronic Diseases, 1958, 8, ness have been reported. Myoclonic jerkings of the legs and 488. The movements resemble certain 7 England, A. C., and Schwab, R. S., New England Journal of Medicine, trunk may be experienced. 1961, 265, 785, 837. forms of dyskinesia which may be produced by levodopa. 8 Porteous, H. B., and Ross, D. N., British Medical Journal, 1956, 2, 138. ' Ayd, F. J., J7ournal of the American Medical Association, 1961, 175, 1054. Nausea and hypotension may also occur,19 while gross over- on 26 September 2021 by guest. Protected copyright. 10 Hughes, R. C., Polgar, J. G., Weightman, D., and Walton, J. N., British dosage may result in convulsions. Medical 7ournal, 1971, 2, 487. 11 Bleidner, W. E., Harmon, J. B., Hewes, W. E., Lynes, T. E., and Hermann, E. C., Journal of Pharmacology and Experimental Therapeutics, 1965, 150, 484. INDICATIONS 12 Stromberg, U., Svensson, T. H., and Waldeck, B., J7ournal of Phar- macy and Pharmacology, 1970, 22, 959. Parkes, J. D., Zilkha, K. J., Calver, D. M., and Knill-Jones, R. P., Lancet, As amantadine is so simple to prescribe its introduction has 1970, 1, 259. been followed by its rapid use for treating patients with 14 Fieschi, C., Nardini, M., Casacchia, M., Tedone, M. E., and Robotti, E., Lancet, 1970, 1, 945. Parkinsonism. The most disabled patients often respond 15Mann, D. C., Pearce, L. A., and Waterbury, L. D., Neurology, 1971, 21, best19 and as most people tolerate amantadine without diffi- 958. culty it is particularly useful when other drugs provoke 16 Fieschi, C., et al., Lancet, 1970, 2, 154. 17 Hunter, K. R., Stem, G. M., Laurence, D. R., and Armitage, P., Lancet, prominent adverse reactions. Nevertheless, drug-induced 1970,1, 1127. Parkinsonism has been found to be refactory to amantadine,20 18 Parkes, J. D., Zilkha, K. J., Marsden, P., Baxter, R. C. H., Knill-Jones, R. P., Lancet, 1970, 1, 1130. presumably for the same reasons that levodopa is ineffective. 19 Godwin-Austen, R. B., Frears, C. C., Bergmann, S., Parkes, J. D., and Some studies have failed to show a therapeutic action of Knill-Jones, R. P., Lancet, 1970, 2, 383. amantadine in patients already receiving levodopa.38 21 20 Parkes, J. D., Knill-Jones, R. P., Clements, P. J., Postgraduate Medical Journal, 1971, 47, 116. Caution is necessary when administering amantadine to 21 Hunter, K. R., Stem, G. M., Laurence, D. R., and Armitage, P., Lancet, epileptics or to patients receiving central stimulants such as 1970,2,566. 22 Hoehn, M. M., and Yahr, M. D., Neurology, 1967, 17, 427. amphetamine. It is also desirable to exercise care in ad- 22 Cooper, I. S., in Parkinson's Disease, ed. G. C. Cotzias, and F. H. McDow- ministering amantadine to patients with peptic ulceration. ell, New York, Medcom, 1971.