Some General Points

SOME GENERAL POINTS

1. None of the above drugs alter the basic pathology of PD—the disease continues to progress. Drugs only provide symptomatic relief and give most patients an additional 3–6 years of happier and productive life.

Considering that oxidative metabolism of DA generates free radicals which may rather hasten degeneration of nigrostriatal neurones, it has been argued that levodopa therapy might accelerate progression of PD. There is no proof yet for such a happening, but nevertheless it may justify use of anticholinergics/selegiline or newer direct DA agonists in early/mild cases.

2. Initially, when disease is mild, only anticholinergics or selegiline may be sufficient. Monotherapy with newer DA agonists ropinirole or pramipexole is being increasingly employed for early cases. Selegiline may also be combined with levodopa during the deterioration phase of therapy to overcome ‘wearing off’ effect.

3. Combination of levodopa with a decarboxylase inhibitor is the standard therapy, and has replaced levodopa alone. Slow and careful initiation over 2–3 months, increasing the dose as tolerance to early side effects develops and then maintenance at this level with frequent evaluation gives the best results. Full benefit lasts for about 2–3 years, then starts declining.

4. Subsequently the duration of benefit from a levodopa dose progressively shortens—end of dose ‘wearing off’ effect is seen. Dyskinesias appear, mostly coinciding with the peak of levodopa action after each dose. Relief of parkinsonian symptoms gets linked to the production of dyskinesias. Still later (4–8 years) the ‘on-off’ phenomena and marked dyskinesias may become so prominent that the patient is as incapacitated with the drug as without it. However, withdrawal of levodopa may precipitate marked rigidity, hampering even respiratory excursions.

5. Combination of levodopa with decarboxylase inhibitor increases efficacy and reduces early but not late complications.

6. Levodopa alone is now used only in those patients who develop intolerable dyskinesias with a levodopa-decarboxylase inhibitor combination.

7. Amantadine may be used with levodopa for brief periods during exacerbations.

8. The direct DA agonists bromocriptine or ropinirole/pramipexole are commonly used to supplement levodopa in late cases to smoothen ‘on off’ phenomenon, to reduce levodopa dose and possibly limit dyskinesias.

9. In advanced cases, the COMT inhibitor entacapone may be added to levodopa-carbidopa to prolong its action and subdue ‘on off’ fluctuation. It can be given to patients receiving selegiline or DA agonists as well.

10. Withdrawal of levodopa for 4–21 days (drug holiday) to reestablish striatal sensitivity to DA by increasing dopaminergic receptor population has now been given up.