Drugs for the Treatment of Parkinsons Disease

Over the last 25 years, few topics in medicine, and none in neurology, sur- pass Parkinsons disease from the viewpOInt of progress in understanding me- chanisms and treating symptoms. Our entire concept of anatomy (the very ex- istence of a nigrostriatal pathway) and physiology (dopaminergic trans- mission) has undergrone a revolution as the result of studies on Parkinsons disease leading to (a) the recognition of dopamine depletion as a crucial bio- chemical feature, and (b) the ability to alleviate symptoms by replenishing dopamine with levodopa. From this background has emerged a subclassifica- tion of dopamine receptors into Dl and D2 types, together with the develop- ment and therapeutic application of synthetic molecules that function as agonists at dopamine receptors. The pharmacological interrelationship be- tween parkinsonism (inadequate dopamine) and chorea (excessive dopamine) has been elucidated because dopaminomimetic agents were found to alleviate parkinsonism and induce chorea, while dopamine blocking drugs induced parkinsonism and alleviated chorea. Pharmacokinetic manipulation of levo- dopa achieved by adding extracerebral decarboxylase inhibitors (carbidopa, benserazide) decreased certain side effects and resulted in efficacy being at- tained with lower dosage. Extracerebral dopamine receptor blockers have proved invaluable in decreasing the emesis of dopaminomimetics, because the dopaminoceptive chemoreceptor trigger zone is located outside the blood- brain barrier. Recently, novel routes of administration of antiparkinson drugs, such as subcutaneous infusion, have been explored in an attempt to achieve more evenly sustained blood concentrations of therapeutic agents.