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Describe the drugs used in Parkinson disease. Add a note on drug-induced parkinsonism.

Pharmacology · 2nd Professional — Para-Clinical

Basis of Treatment

Parkinson disease results from degeneration of dopaminergic neurons in the substantia nigra pars compacta, producing a relative excess of cholinergic activity in the striatum.

Symptoms appear when about 70 to 80% of neurons are lost
Treatment therefore aims to restore dopamine or reduce acetylcholine; none of the available drugs alters the underlying degeneration

Drugs Used

Class	Drugs	Notes
Levodopa with a peripheral decarboxylase inhibitor	Levodopa + carbidopa or benserazide	The most effective drug. Dopamine cannot cross the blood–brain barrier but levodopa can, by an amino acid carrier. Carbidopa does not cross, so it blocks only peripheral conversion — increasing brain delivery and greatly reducing nausea and hypotension
Dopamine agonists	Pramipexole, ropinirole, rotigotine; bromocriptine, cabergoline	Used early in younger patients to delay levodopa; cause impulse control disorders (gambling, hypersexuality, compulsive shopping) which must be asked about, and sudden sleep attacks
MAO-B inhibitors	Selegiline, rasagiline	Block central dopamine breakdown; mild benefit; useful as an adjunct
COMT inhibitors	Entacapone, tolcapone	Prolong levodopa action by blocking its peripheral methylation; reduce "wearing off"; tolcapone is hepatotoxic
Antimuscarinics	Trihexyphenidyl (benzhexol), benztropine	Chiefly for tremor and for drug-induced parkinsonism; avoided in the elderly because of confusion
Amantadine	—	Releases dopamine and blocks NMDA receptors; useful for levodopa-induced dyskinesia

CLINICAL PEARL

Levodopa is given with carbidopa because of where each acts. Given alone, over 95% of levodopa is decarboxylated in the periphery, causing nausea and hypotension while little reaches the brain. Carbidopa cannot cross the blood–brain barrier, so it blocks the peripheral enzyme only — allowing the dose to be cut by about three-quarters while improving the effect. It is the clearest example of exploiting a barrier to gain selectivity.

Long-term Problems with Levodopa

"wearing off" — the benefit of each dose becomes shorter as storage capacity is lost; managed by more frequent doses, a COMT inhibitor, a MAO-B inhibitor or a controlled-release preparation
"ON–off" phenomenon — abrupt unpredictable fluctuation between mobility and immobility, unrelated to dose timing
Dyskinesias — involuntary choreiform movements at peak dose; managed by reducing the dose, adding amantadine, or apomorphine and deep brain stimulation in advanced cases
Adverse effects — nausea and vomiting, postural hypotension, cardiac arrhythmia, and psychiatric effects including vivid dreams, hallucinations and psychosis
Interactions — pyridoxine increases peripheral decarboxylation and reduces the effect (though not when carbidopa is used); a high-protein meal competes for the amino acid carrier and reduces absorption; antipsychotics and metoclopramide antagonise it

Drug-induced Parkinsonism

Caused by — antipsychotics (typical more than atypical), metoclopramide and prochlorperazine, reserpine, methyldopa, tetrabenazine, and some calcium channel blockers (flunarizine, cinnarizine)
Distinguished from idiopathic disease by a symmetrical onset, a clear drug history, and improvement on withdrawal — though recovery may take months
Treated by stopping or reducing the offending drug, or switching to an atypical antipsychotic; an antimuscarinic is used if the drug cannot be stopped. levodopa is not used, as the receptors are blocked and it worsens psychosis
Metoclopramide-induced parkinsonism is common and frequently missed in India, where the drug is widely available and used for prolonged periods

Applied Aspects

Delay levodopa in younger patients where possible, since motor complications relate to duration of treatment; but do not withhold it from an older patient who needs function now
Never stop antiparkinsonian drugs abruptly — a syndrome resembling neuroleptic malignant syndrome may follow, and this includes patients kept nil by mouth for surgery, for whom an alternative route must be arranged
Ask specifically about impulse control disorders in anyone on a dopamine agonist; families report them long before patients do, and the consequences can be financially ruinous
Take levodopa 30 to 60 minutes before meals and separate it from high-protein food
Physiotherapy, speech therapy and attention to falls, constipation, depression and sleep matter as much as the drugs in maintaining function

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