Medication Choice in Parkinson's Disease

Parkinson's disease (PD) is a neurological pathologic condition with the prevalence about 1 of every 100 individuals older than 55 years old in US alone. Main manifestations are commonly come from motoric system: resting tremor, rigidity of movement, bradykinesia, and postural instability (causes gait abnormality). Pathology of this disease is due to loss of dopaminergic neurons of the substansia nigra of the brain. This loss of dopaminergic neurons cause emergence of neurologic deficits which depend on dopaminergic system. Relatively, acetylcholine/dopamine ratio will rise and this cause more profound of tremor in patients.

There are several classes of PD pharmacotherapy are available in market nowadays.

1. Dopamine prodrugs
Examples: Levodopa-carbidopa, levodopa-benserazide

This class is still the cornerstone of pharmacotherapy for PD, since it was discovered first in 1960s. Dopamine does not cross blood-brain barrier, but levodopa does; this makes levodopa become the main substance to be used for this therapeutic purpose. Because levodopa is usually desintegrated in peripheral tissue by decarboxylase enzyme, levodopa needs an peripheral decarboxylase inhibitor/PDI given altogether (such as benserazide or carbidopa). According to Greenacre (1976), there is no difference of effectivity between carbidopa (PDI used in US) and benserazide (PDI used in several other countries, such as Indonesia).
Levodopa and its PDI usually be given in fixed ratio combination, 4:1 (usually in fixed-dose combination tablet of 100 mg/25 mg; given 3 times a day; maximum of 8 tablets per day).
Problem with levodopa-PDI therapy: sometimes levodopa's net availability in the brain is dropped on certain times, and by that time the patients will show PD symptoms again. This is called off period, or wearing off phenomenon.

2. Dopamine agonists
Examples: Bromocriptine, apomorphine, pramipexole, ropinirole

Bromocriptine is an ergot-alkaloid dopamine agonist that stimulates dopamine D2 receptors, with partial selectivity on D1 receptor. Pramipexole has more selectivity to D3 receptor than D2 receptor, thus this medicine also has effect on patient's mood. Pramipexole has similar selectivity with ropinirole. Apomorphine has high affinity on D4 receptor and low affinity on other dopamine receptors. Adverse effects are about the same: nausea, headache, vomiting, dizziness, constipation. Compulsive disorder sometimes occur in treatment with pramipexole and ropinirole.
Dosage: Bromocriptine 1.25 mg twice daily, increase until maximum dose of 40 mg/day. Pramipexole 0.125 mg 3 times daily, maximum dosage of 1.5-4.5 mg/day in 3 divided doses. Ropinirole 0.25 mg 3 times daily, maximum dosage of 3-12 mg/day in 3 divided doses.

3. COMT inhibitors

Examples: tolcapone, entacapone

One problem that causes COMT-inhibitors are necessary is the same with MAO-B: wearing off phenomenon.
COMT, or catechol-o-methyltransferase enzyme, is a peripheral metabolizer of levodopa. Existence of this enzyme makes levodopa's availability in central nervous system is diminished. Inhibition of COMT will prevent the metabolism of levodopa into 3-O-methyldopa and prolongs levodopa's duration of action by 2-fold. This class of medicine must be given together with dopamine precursor in PD's pharmacotherapy. Currently there is a combination with triple PD pharmacotherapy in one preparation, contains levodopa, carbidopa, and entacapone.
Dosage: Tolcapone 100 mg 3 times daily, maximum of 600 mg/day. Effectiveness must be seen after 3 weeks of therapy, and if not, stop the treatment. Entacapone 200 mg 3 times dalily, maximum of 1600 mg/day. Be careful about liver function, because it has been reported that several patients developed fulminant hepatic failure. Other adverse effects: headache, diarrhea, and abdominal pain.

4. MAO-B inhibitors
Examples: Selegiline, rasagiline

MAO-B, or monoamine oxidase inhibitor; is an adjunctive therapy for PD, since they inhibit the breakdown of dopamine by MAO-B and increase net amount of dopamine in the brain. Some literature mentioned MAO-B inhibitors have neuroprotective effect, even though it is not really proven until today. As COMT inhibitor, this class of medicine
Dosage: Selegiline 5 mg twice daily, Rasagiline 0.5 mg once daily. Adverse effects: nausea, abdominal pain, insomnia, dry mouth.

5. Anticholinergic
Example: trihexyphenidyl

This is the oldest class of Parkinson's disease pharmacotherapy; first approved in 1949 by FDA. Trihexyphenidyl is now still used in several PD cases, especially in PD cases with tremor as the predominant symptom. This medicine is usually excreted in the urine, predominantly in unchanged form. Dosage 1 mg/day, incremented until maximum of 12-15 mg/day. Dose adjustment is needed when given together with levodopa-PDI. Adverse effects: nausea, dizziness, glaucoma, constipation, urinary retention.

6. NMDA inhibitors
Examples: memantine, amantadine

Amantadine, an old antiviral compound which prevents the release of viral nucleic acid into host cell; also possesses effect against dyskinesia in PD patients; possibly by acting as an antagonist of N-methyl-D-aspartate (NMDA) receptor. Dosage: 100-200 mg/day; divided into 2 doses. Monitoring of renal function is necessary.
Memantine is an uncompetitive antagonist of NMDA receptor. Glutamate activation, is actually believed to be contributional in Alzheimer's disease symptom; but this class of medicine has efect too against 5-HT3 receptor, low antagonism against acetylcholine receptor, and augmentation of dopamine release. Memantine has not been widely used as pharmacotherapy in PD; compared to its use in moderate-severe Alzheimer's dementia. Dosage: 5-10 mg per day.

Treatment choice:

1. Early phase: Dopamine precursors or dopamine agonists.
2. Moderate phase: Add COMT inhibitor or MAO-B inhibitor.
3. Severe phase: Use combination therapy with incremented doses for each components.

References
Clinical Drug Data 11th edition, 2010.
Greenacre JK et al. The Lancet 1976; 308: 381-84.
Hauser RA. Parkinson's Disease. URL: http://emedicine.medscape.com/article/1831191-overview [last updated June 20; 2011]
Zigmond MJ, Burke RE. Parkinson's Disease, in Davis KL et al (eds). Neuropsychopharmacology: The Fifth Generation of Progress, 2002: 1781-1793.