Antiparkinsonian Drugs

Parkinson’s disease is a progressive neurodegenerative disorder of extra pyramidal motor system effecting motor skills, speech and other functions. It is a disorder of basal nuclei function → caudate nucleus, putamen, globus pallidus.

→ Specific loss of dopaminergic neurons in nigrostriatal pathway → which is an essential link in the extrapyramidal motor system involved in fine motor control. Impaired fine control of movement exerted by basal nuclei.

- Excessive activity of the intrinsic cholinergic fibres of the striatum, unchecked by dopamine is likely to be implicated in tremor. The imbalance between the two systems is thought to be the main cause of PD.

None of these drugs halt the progression of the disease. They just improve symptoms.

Drug Mechanism of action Side effects1) Dopamine (DA)

Replacement Therapy

→ Levodopa (L-Dopa)

First line treatment → most effective therapy.

L-Dopa is inactive and must be converted by aromatic aminoacid decarboxylase [AAAD] to DA.

Problem: AAAD found in many tissues as a result: L-Dopa → DA converstion might happen in peripheral tissues diminishing DA

1) L-Dopa Dyskinesia:- Abnormal involuntary movement of limbs,

trunk and orofacial regions.- Following 2+ years of treatment.- Starts initially at high blood levels and

disappears at lower doses → but rigidity returns.

- Later on this becomes unrelated to blood levels and there may be no movement atall

bioavailability (DA cannot cross BBB) → this increases S/E and decreases effectiveness.

SOLUTION → Combine L-Dopa with AAAD inhibitor→ Carbidopa which:- Reduces peripheral conversion to

DA Increases brain entry at lower

doses Increased therapeutic effect Decreased peripheral side effects

80% patients show improvement after treatment with L-Dopa= L-dopa+carbidopa.

Decreased rigidity and decreased bradykinesia→ less tremor.

Gradually in about 3-5 years →1/3 retain benefit → 1/3 slowly loose benefit while the last 1/3 rapidly loose benefit.

unless dyskinesia.

2) Nausea, vomiting- Stimulation of DA receptors in CTZ

3) Mental disturbances- psychosis → stimulation of DA receptors in limbic regions/cortex.

4) Hypotension, cardiac arrhythmias.

5) End of dose akinesia → progressive shortening of L-Dopa action → use: more frequent smaller L-Dopa doses. →rapid fluctuation ‘on’ and ‘off’ statesi.

2) Dopamine Receptor Agonists

→ Bromocriptine→Ropinirole

- Possibility that continuing loss of DA nerve terminals limits long-term effect of L-Dopa → DA agonists DO NOT require intact DA neurones.

- Can be used instead of or along with L-dopa.

- Long half life- Early treatment: Delays use of L-

Dopa- Later treatment: For ‘on-off’

effects.- Efficacy less than L-Dopa

- Nausea, Vomiting- Reduced prolactin- Less dyskinesia than L-Dopa- Hypotension

3) MAO-B Inhibitors→ Selegiline

- MAO-B deaminates DA in humans.- Reduces DA breakdown- Potentiates L-Dopa- Small reduction in L-Dopa dosage

- Controversy over retardation of disease progression vs symptomatic treatment.

4) COMT- Inhibitors→ Entacapone

- COMT inactivates L-Dopa and DA.

- Selective COMT inhibitor reduces breakdown of L-Dopa and DA.

- Potentiates L-Dopa- Thus there can be a moderate

reduction in L-Dopa dosage.- Improves motor functions.

- Dyskinesia

i Which are rapid fluctuations between yskinesia and hypokinesis/rigidity.