Objectives of therapy

The dopaminergic/cholinergic balance may be restored by the following mechanisms.

1. Enhancement of dopaminergic activity by drugs which may:

(a) replenish neuronal dopamine by supplying 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, pergolide, cabergoline, apomorphine);

(c) prolong the action of dopamine through selective inhibition of its metabolism (selegiline).

(d) release dopamine from stores and inhibit reuptake (amantadine) or

2. Reduction of cholinergic activity by antimuscarinic (anticholinergic12) drugs; this

11 Saltzman E W 1996 Living with Parkinson's disease. New England Journal of Medicine 334:114-116.

12 The term antimuscarinic is now preferred (see p. 435).

approach is most effective against tremor and rigidity, and less effective in the treatment of bradykinesia (including iatrogenic, caused by dopamine receptor antagonists).

Both approaches are effective in therapy and may usefully be combined. It therefore comes as no surprise that drugs which prolong the action of acetylcholine (anticholinesterases) or drugs which deplete dopamine stores (reserpine) or block dopamine receptors (antipsychotics, e.g. chlorpromazine) will exacerbate the symptoms of parkinsonism or induce a parkinson-like state.

Other parts of the brain in which dopaminergic systems are involved include the medulla (induction of vomiting), the hypothalamus (suppression of prolactin secretion) and certain paths to the cerebral cortex. Different effects of dopaminergic drugs can be explained by activation of these systems, namely emesis, suppression of lactation (mainly direct dopamine agonists) and occasionally 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 galactorrhoea, and can induce parkinsonism. Drug-induced parkinsonism is alleviated by anti-muscarinics, but not by levodopa or dopamine agonists, because the antipsychotics block dopamine receptors by which these drugs act. Since many antipsychotics also have some antimuscarinic activity, those with greatest efficacy in this respect, e.g. thioridazine, are the least likely to cause parkinsonism.

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