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The Parkinson's-Reversing Breakthrough

Parkinson Disease Medications

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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 from Table 20.3, selegiline does not cause the cheese reaction, because MAO-A is still present in the liver to metabolise tyramine. MAO-A also metabolises tyramine in the sympathetic nerve endings, so providing a further line of protection (tyramine is an indirect acting amine which displaces noradrenaline from the nerve endings). In the CNS selegiline protects dopamine from intraneuronal degradation. It has no effect on synaptic cleft concentrations of those amines like serotonin and noradrenaline, which are normally potentiated by the MAOI used in depression; therefore selegiline has no antidepressant action.

Selegiline was originally introduced in the belief that it would delay end-of-dose deterioration by prolonging the action of levodopa; subsequently it was 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 worsening of their condition. A minority deteriorated acutely and they have continued to

13 Ben-Sholomo Y, Churchyard A, Head J, Hurwitz B, Overstall P, Ockelford J, Lees A J 1998 British Medical Journal 316:1191-1196.

receive selegiline although the reason for this benefit is not clear.

Entacapone inhibits catechol-O-methyltransferase (COMT), one of the principal enzymes responsible for the metabolism of dopamine; the action of levodopa is thus prolonged. It is most effective for patients with early end-of-dose deterioration, and allows them to take levodopa at 3- or 4-hourly intervals, giving a more predictable and useful response. Entacapone is preferred to long-acting preparations of levodopa whose main disadvantage is their slow onset of action. It can increase the dyskinesias seen in the late stages of Parkinson's disease.

Dopamine release

Amantadine antedates the discovery of dopamine receptor subtypes, and its discovery as an antiparkinsonian drug was an example of serendipity. It is an antivirus drug which, given for influenza to a parkinsonian patient, was noticed to be beneficial. The two effects are probably unrelated. It appears to act by increasing synthesis and release of dopamine, and by diminishing neuronal reuptake. It also has slight antimuscarinic effect. The drug is much less effective than levodopa, whose action it will slightly enhance. It is more effective than the standard antimuscarinic drugs, with which it has an additive effect. Amantadine is relatively free from adverse effects, which, however, include ankle oedema (probably a local effect on blood vessels), postural hypotension, livedo reticularis and central nervous system disturbances: insomnia, hallucinations and, rarely, fits.

ANTIMUSCARINIC (ANTICHOLINERGIC) DRUGS

Antimuscarinic drugs benefit parkinsonism by blocking acetylcholine receptors in the central nervous system, thereby partially redressing the imbalance created by decreased dopaminergic activity. Their use originated when hyoscine was given to parkinsonian patients in an attempt to reduce sialorrhoea by peripheral effect, and it then became apparent that they had other beneficial effects in this disease. Synthetic derivatives are now used orally. These include benzhexol (trihexyphenidyl), orphenadrine, benzatropine, procy-clidine, biperiden. There is little to choose between these. Antimuscarinics produce modest improvements in tremor, rigidity, sialorrhoea, muscular stiffness and leg cramps, but little in bradykinesia, the most disabling symptom of Parkinson's disease. They are also effective i.m. or i.v. in acute drug-induced dystonias.

Unwanted effects include dry mouth, blurred vision, constipation, urine retention, glaucoma, hallucinations, memory defects, toxic confusional states and psychoses (which should be distinguished from presenile dementia).

The main features that require alleviation are tremor, rigidity and bradykinesia.

General measures are important and include the encouragement of regular physical activity and specific help such as physiotherapy, speech therapy and occupational therapy.

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