COMT Inhibitors

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Chapter: Essential pharmacology : Antiparkinsonian Drugs

Two selective, potent and reversible COMT inhibitors Entacapone and Tolcapone have been introduced as adjuvants to levodopa-carbidopa for advanced PD.


COMT  INHIBITORS

 

Two selective, potent and reversible COMT inhibitors Entacapone and Tolcapone have been introduced as adjuvants to levodopa-carbidopa for advanced PD. When peripheral decarboxylation of levodopa is blocked by carbidopa/benserazide, it is mainly metabolized by COMT to 3Omethyldopa (see Fig. 31.2). Blockade of this pathway by entacapone/tolcapone prolongs the t½ of levodopa and allows a larger fraction of administered dose to cross to brain. Since COMT plays a role in the degradation of DA in brain as well, COMT inhibitors could preserve DA formed in the striatum and supplement the peripheral effect. However, entacapone acts only in the periphery (probably because of short duration of action ~2 hr). For tolcapone also, the central action is less important.

 

Both entacapone and tolcapone enhance and prolong the therapeutic effect of levodopa-carbidopa in advanced and fluctuating PD. They may be used to smoothen ‘wearing off’, increase ‘on’ time, decrease ‘off’ time, improve activities of daily living and allow levodopa dose to be reduced. They are not indicated in early PD cases. Entacapone: 200 mg with each dose of levodopa-carbidopa.

 

Tolcapone:  100–200 mg BD or TDS.

 

Worsening of levodopa adverse effects such as nausea, vomiting, dyskinesia, postural hypotension, hallucinations, etc. occurs often when a COMT inhibitor is added. However, this can be minimised by adjustment of levodopa dose. Other prominent side effect is diarrhoea in 10–18% patients (less with entacapone) and yellow-orange discolouration of urine. Because of reports of acute fatal hepatitis and rhabdomyolysis, tolcapone has been suspended in Europe and Canada, while in USA its use is allowed only in those not responding to entacapone. Entacapone is not hepatotoxic.

 

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