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Antiparkinsonians

Parkinson's disease is caused by neuronal loss, particularly dopaminergic neurons of the substantia nigra, inducing a dopamine deficiency. To compensate for dopamine deficiency it is possible to increase its synthesis and its release and to reduce its catabolism. But this treatment is only supportive, it does cure the cause of the disease which continues its course.

Increased dopamine synthesis: L-DOPA

Levodopa, L-dopa, is the precursor of dopamine. It can be used alone but generally it is used in combination with an inhibitor of Dopa decarboxylase.

L-dopa alone

As dopamine does not penetrate into the brain, the first way to compensate its deficiency, is to use its precursor, L-dopa which penetrates by active transport into the brain where it is converted into dopamine. Increase of L-dopa supply compensates, at least transitorily, for deficiency of dopamine synthesis.

L-dopa is used preferentially to L-tyrosin because activity of tyrosin hydroxylase in brain of patients with Parkinson's disease would be insufficient to ensure transformation of L-tyrosin into L-dopa.

L-dopa improves successively and preferentially akinesia, rigidity, tremors (less improvement) and decreases apathy of patients with Parkinson's disease.

Adverse effects of L-Dopa are peripheral and central.

  1. peripheral:
    • very frequently hypotension, sometimes hypertension, tachycardia
    • digestive disorders: anorexia, nausea, vomiting, hepatic damage (rise of transaminases).
    • brown-black coloration of urines
    • central
      • face and neck abnormal involuntary movements, explained by hypersensivity of certain dopamine receptors
      • insomnia, agitation, sometimes delusion
      • “one-off” effects: variations of the effects during the day, generally representing an aggravation of the disease
      • hyperthermia.

Actually, only a low part of L-dopa administered penetrates into the brain. The greatest part, approximately 95%, is decarboxylated by L-dopa decarboxylase in peripheral tissues and is transformed into dopamine which does not penetrate into brain. Activity of L-Dopa decarboxylase is dependant on B6 vitamin whose intake increases inactivation of L-dopa in the periphery.

The importance of inactivation of L-Dopa led to develop inhibitors of peripheral L-dopa decarboxylase and to combine them with L-Dopa.

L-dopa combined with an inhibitor of L-dopa decarboxylase

Inhibitors of peripheral L-dopa decarboxylase are benserazide and carbidopa. They are administered in combination with L-dopa. In doses used, these inhibitors do not penetrate into the brain and, consequently, they inhibit peripheral decarboxylase but not cerebral decarboxylase. Thus, L-dopa is less inactivated peripherically, there is less peripheral dopamine, less peripheral secondary effects and more L-dopa penetrates into brain.

In practice, results are obtained more rapidly and with less dopamine peripheral adverse effects, but central adverse effects, such as abnormal movements (dyskinesia) and hallucinations, are not reduced.

Inhibitors of L-Dopa decarboxylase administered alone, i.e. without L-dopa, are without apparent beneficial or harmful effects.

Carbidopa and levodopa

PARCOPA* Orally disintegrating tablets

Increased release

Amantadine, used as antiviral in treatment of type A influenza, appeared to have antiparkinsonian properties. It acts by increasing dopamine release. It is however a minor antiparkinsonian, used only in mild forms of the disease or as an adjunct to other treatments. It is used in prophylaxis and treatment of virus A influenza. It adverse effects are: insomnia, nervousness, nausea, anorexia, hypotension, seldom psychotic reactions.

Amantadine

SYMMETREL* Tablets and Syrup

Catabolism inhibition: COMT and MAO inhibitors

The two enzymes which inactivate catecholamines are COMT and MAO. Their inhibition slows down catecholamines degradation.

COMT inhibitors

COMT catalyzes transfer of a methyl group on an oxygen atom of the catechol group; L-DOPA is thus converted into 3-O-methyldopa, inactive metabolite.

When combined to L-DOPA, a COMT inhibitor inhibits peripheral inactivation of L-DOPA and there is an increase of plasma L-DOPA level and a decrease of 3-O-methyldopa level which is in competition with L-DOPA for penetration into brain. Thus increase in plasma concentration of L-DOPA and decrease of that of 3-O-methyldopa facilitate the passage of L-DOPA into brain. Moreover, if the inhibitor of the COMT penetrates into the brain, it slows down inactivation of catecholamines, in particular that of dopamine, which reinforces and prolongs its effects.

The two principal COMT inhibitors are tolcapone and entacapone. Tolcapone , one of the first COMT inhibitors, was withdrawn from the market shortly after its introduction because of its hepatic toxicity. Entacapone, specific and reversible COMT inhibitor, has primarily peripheral effect and is used in the treatment of Parkinson's disease as an adjunct to the treatment by the combination L-DOPA. / inhibitor of dopa decarboxylase. Because of its mechanism of action, entacapone inhibits the catabolism of drugs and endogenous products involving a catechol function (i.e. two contiguous - OH groups on a benzene nucleus): dopamine, adrenaline, dobutamine, alpha-methyldopa. It potentiates the beneficial effects of L-DOPA, but also some of its adverse effects such as dyskinesia, digestive disorders. Entacapone can chelate iron in digestive tract and decrease its bioavailability, which contraindicates the simultaneous intake of iron and entacapone and explains possible anemia, as an adverse effect.

Entacapone

COMTAN* Tablets

Tolcapone

TASMAR* Tablets

Entacapone, carbidopa and levodopa

STALEVO* Tablets

MAO inhibitors, MAOI

By inhibiting monoamine oxidase, more specifically monoamine oxidase B, selegiline reduces the catabolism of endogenous dopamine and is used in the treatment of Parkinson's disease. Selegiline could, by its MAOI activity, reduce the transformation of certain compounds like MTPT into toxic metabolites.

MPTP, or 1-methyl-4-phenyl-tetrahydropyridine, whose metabolite is 1-methyl-4-phenyl-pyridinium called MPP+, is not a drug but a chemical compound which causes destruction of dopaminergic neurons in animal and in human beings. Selegiline, by inhibiting the transformation of the MPTP into MPP+, reduces its toxicity.

Selegiline is metabolized to L-amphetamine and L-metamphetamine and to corresponding hydroxylated derivatives.

Selegiline

ELDEPRYL* Capsules

The concomitant use of selegiline and L-dopa in the treatment of Parkinson's disease has been suspected to increase mortality.

Rasagiline is a new MAO-B inhibitor intended to treatment of Parkinson's disease.

The properties of other MAOI are studied in the chapter “Serotonin”.

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