Parkinson Disease Agents

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Parkinson Disease Agents

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Abstract

Parkinson disease is a progressive neurological condition characterized by slowness and paucity of movement (bradykinesia), muscle rigidity, resting tremors, and disordered posture. The onset is typically in the 6th or 7th decade of life with slow progression to akinesia, severe tremors, physical disability and death within 10 to 25 years of initial symptoms. Parkinson disease is common and affects approximately 1% of Americans above the age of 60 years. The cause of Parkinson disease is unknown, but is marked by loss of dopamine-containing neurons in the substantia nigra pars compacta of the brainstem and loss of normal dopaminergic neurotransmission. Therapy of Parkinson disease continues to evolve and has resulted in improved quality of life and survival. The initial agents used for Parkinson disease were anticholinergic agents including trihexyphenidyl (Artane, Trihexy: 1949), benztropine (Cogentin: 1954), and biperiden (Akineton: 1959); their mechanism of action in Parkinsonism is not completely clear. With the increased understanding of the role of dopamine in the pathophysiology of Parkinsonism, agents that directly or indirectly affect dopaminergic transmission have been developed that have resulted in marked improvements in the management of symptoms of Parkinson disease. Levodopa (L-DOPA: 1970) is a metabolic precursor of dopamine and is the single most effective agent for Parkinson disease. It is usually combined with carbidopa (Sinemet: 1975), which increases the drug levels and half life of levodopa by inhibiting the amino acid decarboxylase that metabolizes levodopa peripherally. Dopaminergic receptor agonists are also beneficial in Parkinson disease and are often combined with levodopa/carbidopa. Dopamine receptor agonists currently available include bromocriptine (1978: Parlodel), pergolide (Permax: 1988), apomorphine (Apokyn: 2004) and more selective agonists for the D2 class of dopamine receptors - ropinirole (Requip: 1997), pramipexole (Mirapex: 1997) and rotigotine (Neupro which is formulated in a transdermal patch: 2007). More recently, inhibitors of catechol-O-methyltransferase (COMT) have been developed that block the major enzyme responsible for the metabolism of dopamine; these agents include tolcapone (Tasmar: 1998) and entacapone (Comtan: 2003). Dopamine is also metabolized by the monamine oxidases and selegiline (Atapryl: 2006) and rasagiline (Azilect: 2007) which are specific inhibitors of monamine oxidase (MAO) type B, and are used as an adjunctive therapy with levodopa in therapy of Parkinson disease. Amantadine (Symmetrel: 1987) also has activity in Parkinson disease, perhaps through stimulation of release of dopamine in the substantial nigra. It is discussed separately as an anti-influenza agent. Other agents used in the management of Parkinson disease are used to treat specific complications such as psychosis (pimavanserin: Nuplazid, 2016) and postural hypotension (droxidopa: Vectibix, 2014). Most of the drugs used to treat Parkinson disease have little potential for hepatotoxicity and are rare causes of clinically apparent acute liver injury, the exception being tolcapone. The full references on hepatotoxicity and safety of the drugs for Parkinson disease are given in the discussion of the individual agents listed below.

DrugBank Data that Cites this Article

Drugs: Trihexyphenidyl