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Levodopa and Decarboxylase Inhibitors: A Review of their Clinical Pharmacology and Use in the Treatment of Parkinsonism

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Summary

Benserazide, (±)-DL-seryl-2-(2,3,4-trihydroxybenzyl)hydrazine, and carbidopa, (−)-L-α-hydrazino-3,4-dihydroxy-α-methylbenzenepropanoic acid, are inhibitors of extracerebral aromatic L-aminoacid decarboxylase (dopa decarboxylase). Combinations of benserazide and levodopa1 (1:4) or carbidopa and levodopa2 (1:10) are used in the treatment of Parkinson’s disease, both to treat new patients and as replacements for levodopa alone. Like levodopa, they appear to have little influence on the disease process, and their role in the long-term management of Parkinsonism is symptomatic and palliative.

In comparison with levodopa alone the advantages of levodopa-benserazide or levodopacarbidopa are several, but there is apparently little or no difference between the two combination drugs. Their major advantage is that they allow a marked reduction in levodopa dosage without compromising the therapeutic effect. Benserazide and carbidopa diminish the optimum dose of levodopa by about 70 to 80%. Therapeutic response is often seen within days with full benefit within weeks with the combination, as compared with the months associated with levodopa alone, such that the optimum result at 12 months with combination treatment is reached only at 24 months with levodopa. The more rapid induction of therapeutic benefit is due to an increase in the bioavailability of levodopa and is associated with a much reduced incidence and severity of gastro-intestinal side-effects, particularly nausea and vomiting, which limit the rate at which levodopa dosage can normally be increased. The reduced incidence of these side-effects probably results from reduced gastric irritation. Other side-effects, such as cardiac dysrhythmias and postural hypotension, may also be reduced in some patients on combination therapy as compared with levodopa alone.

Levodopa plus benserazide or carbidopa may be given to patients receiving amantadine, or anticholinergic or antihistaminic drugs. Unlike with levodopa alone, combination therapy can be given, without reduction in therapeutic effect, in conjunction with pyridoxine. It is possible to treat more Parkinsonian patients effectively with the combinations than with levodopa alone, especially those in whom optimum dosage of levodopa cannot be reached because of dose-limiting side-effects. Levodopa-tolerant patients show a response to combination therapy no greater than that seen with levodopa alone.

The incidence and severity of mental disturbances are similar with the combination drugs to those with levodopa alone. Abnormal involuntary movements, which are the major dose-limiting central side-effects in most patients on levodopa, appear earlier in the course of combination therapy, often by the first week, and may be more frequent. At 24 months there may be a progressive decrease in overall performance capacity in some patients, similar to that observed in patients treated with levodopa alone for 3 to 4 years, consisting of a decreased threshold for dyskinetic manifestations and an increase in the incidence of diurnal oscillations in performance (the ‘on-off’ effect). In the short-term, decarboxylase inhibitors may reduce the incidence and severity of the ‘on-off’ effect, possibly by smoothing out fluctuations in plasma levels of levodopa.

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  1. Australasian Drug Information Services, P.O. Box 34-030, Birkenhead, Auckland 10, New Zealand

    R. M. Pinder, R. N. Brogden, Phyllis R. Sawyer, T. M. Speight & G. S. Avery

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Manuscript reviewed by: A. Barbeau, Clinical Research Institute of Montreal, Montreal, Quebec, Canada; J.R. Bianchine, Department of Pharmacology, Ohio State University, Columbus, Ohio, USA; D.B. Calne, National Institute of Neurological and Communicative Disorders and Stroke, Bethesda, Maryland, USA; M.J. Eadie, Department of Medicine, Royal Brisbane Hospital, Herston, Queensland, Australia; G. Glasgow, Department of Neurology, Auckland Hospital, Auckland, New Zealand; J.W. Lance, Division of Neurology, The Prince Henry Hospital, Little Bay, NSW, Australia; F.H. McDowell, Department of Neurology, The New York Hospital, Cornell Medical Centre, New York, USA; C.D. Marsden, Institute of Psychiatry, Denmark Hill, London, England; P. Mearrick, School of Physiology and Pharmacology, University of New South Wales, Kensington, NSW, Australia; J.D. Parkes, King’s College Hospital, Denmark Hill, London, England; U.K. Rinne, Department of Neurology, University of Turku, Turku, Finland; D.N. Wade, School of Physiology and Pharmacology, University of New South Wales, Kensington, NSW, Australia; M.D. Yahr, Department of Neurology, Mount Sinai School of Medicine, New York, USA

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Pinder, R.M., Brogden, R.N., Sawyer, P.R. et al. Levodopa and Decarboxylase Inhibitors: A Review of their Clinical Pharmacology and Use in the Treatment of Parkinsonism. Drugs 11, 329–377 (1976). https://doi.org/10.2165/00003495-197611050-00001

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