ABSTRACT
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of brain stem neurons and dysregulation of downstream basal ganglia motor pathways. Understanding the pathophysiology has led to the development of treatments that improve the symptoms of PD. Early pathological studies identied the loss of pigmented neurons in the substantia nigra of the parkinsonian brain, accounting for the loss of dopamine, the main neurotransmitter in the nigrostriatal tract [1]. Although cardinal features of PD, such as tremor, bradykinesia, and rigidity, are attributed to loss of dopamine, there is growing recognition that not all motor symptoms are due to dopamine deciency and many nonmotor symptoms may be due to involvement of nondopaminergic pathways. As dopamine does not cross the blood-brain barrier, levodopa (LD), the metabolic precursor of dopamine,
Abbreviations ............................................................................................................................................................................ 865 Introduction ............................................................................................................................................................................... 865 Dopamine Receptors ................................................................................................................................................................. 866
Anatomy and Physiology ..................................................................................................................................................... 866 Effects of DAs on Receptors ................................................................................................................................................ 867
Clinical Pharmacology of Individual Dopamine Agonists ....................................................................................................... 867 Bromocriptine ...................................................................................................................................................................... 867 Pergolide .............................................................................................................................................................................. 868 Cabergoline .......................................................................................................................................................................... 868 Lisuride ................................................................................................................................................................................ 868 Pramipexole .......................................................................................................................................................................... 869 Ropinirole ............................................................................................................................................................................. 870 Piribedil ................................................................................................................................................................................ 871 Sumanirole ........................................................................................................................................................................... 871 Apomorphine........................................................................................................................................................................ 871 Rotigotine ............................................................................................................................................................................. 872 Other Dopamine Agonists .................................................................................................................................................... 872
Use in Early versus Late PD ..................................................................................................................................................... 873 Do Dopamine Agonists Have Disease-Modifying Effect? ....................................................................................................... 873 Comparisons between DAs and Switching ............................................................................................................................... 874
Adverse Effects of DAs ........................................................................................................................................................ 874 Titrating and Switching DAs ................................................................................................................................................ 875
Summary and Conclusion ......................................................................................................................................................... 875 References ................................................................................................................................................................................. 876
has been used to replenish the dopamine. Though profoundly effective in alleviating the typical symptoms of PD, LD is not an ideal therapy [2]. Conversion of LD is dependent on the presence of dopa decarboxylase, an enzyme that diminishes in concentration in the degenerating nigrostriatal tract [3]. Furthermore, LD has a short half-life, and the pulsatile, rather than tonic, supraphysiological levels of dopamine it generates nonspecically stimulate dopamine receptors, resulting in a variety of adverse effects including motor Ÿuctuations and dyskinesia. Finally, in vitro (but not in vivo) studies suggest that LD promotes formation of oxidative metabolites and other toxic effects leading to apoptosis in the nigrostriatal neurons [4-6].
