Pharmacology of Parkinson's Disease

## Pathophysiology

Parkinson's disease (PD) results from progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta. Loss of nigrostriatal dopamine disrupts the balance between the direct (movement-facilitating) and indirect (movement-inhibiting) basal ganglia pathways. Cardinal motor features are bradykinesia, rigidity, resting tremor, and postural instability. Symptoms appear after approximately 60-80% of dopaminergic neurons are lost.

## Levodopa (L-DOPA)

Levodopa remains the most effective symptomatic treatment. It is the metabolic precursor to dopamine and crosses the blood-brain barrier (dopamine itself cannot). Always co-administered with a peripheral AADC inhibitor (carbidopa or benserazide) to prevent peripheral conversion, reducing nausea and increasing CNS delivery.

**Motor complications** emerge after 5-10 years:
- **Wearing-off** -- effect duration shortens between doses
- **On-off fluctuations** -- unpredictable switches between mobility and immobility
- **Dyskinesias** -- involuntary choreoathetoid movements during peak-dose periods

## Dopamine Agonists

Pramipexole and ropinirole directly stimulate D2/D3 receptors. They have longer half-lives than levodopa and produce fewer dyskinesias but more psychiatric side effects (impulse control disorders, hallucinations). Rotigotine is available as a transdermal patch.

## MAO-B Inhibitors

Selegiline and rasagiline selectively inhibit MAO-B, the predominant MAO isoform in the striatum, reducing dopamine degradation. They provide mild symptomatic benefit as monotherapy or extend levodopa's effect. Safinamide adds sodium channel blockade to MAO-B inhibition.

## COMT Inhibitors

Entacapone and opicapone inhibit peripheral COMT, blocking the conversion of levodopa to 3-O-methyldopa. This increases levodopa bioavailability and reduces wearing-off. Stalevo is a combination of levodopa/carbidopa/entacapone.

## Other Agents

- **Amantadine** -- weak NMDA antagonist; reduces levodopa-induced dyskinesias
- **Anticholinergics** -- trihexyphenidyl, benztropine restore dopaminergic-cholinergic balance; primarily for tremor; limited by cognitive side effects in elderly
- **Istradefylline** -- adenosine A2A antagonist for off-episodes; reduces indirect pathway overactivity

## Key Takeaways

- Levodopa/carbidopa is the gold standard but causes motor complications with long-term use
- Dopamine agonists delay dyskinesias but carry impulse control disorder risk
- MAO-B and COMT inhibitors extend levodopa's effect by reducing dopamine metabolism
- No current therapy slows neurodegeneration; all treatments are symptomatic