MECHANISM OF ACTION OF DOPAMINERGIC AGENTS IN PARKINSONS-DISEASE

As the substantia nigra degenerates in Parkinson's disease (PD), the n igrostriatal pathway is disrupted, reducing striatal dopamine and prod ucing PD symptoms. Although dopamine does not readily cross the blood- brain barrier, its precursor, levodopa, does. Levodopa is absorbed in the small bowel and is rapidly catabolized by aromatic-L-amino-acid de carboxylase (AADC) and catechol-O-methyltransferase (COMT). Because ga stric AADC and COMT degrade levodopa, the drug is given with inhibitor s of AADC (carbidopa or benserazide), and inhibitors of COMT will also enter clinical use. Although the exact site of decarboxylation of exo genous levodopa to dopamine in the brain is unknown, most striatal AAD C is located in nigrostriatal dopaminergic nerve terminals. Newly synt hesized dopamine is stored in the terminals and then released, stimula ting postsynaptic dopamine receptors and mediating the antiparkinsonia n action of levodopa. Dopamine agonists act directly on postsynaptic d opamine receptors, thus obviating the need for metabolic conversion, s torage, and release. How the actions of dopaminergic drugs produce sid e effects and how these side effects should be managed are discussed.