Pharmacologic management of parkinsonism

Question 1

Levodopa, levodopa+carbidopa

Answer 1

• MOA
• crosses into CNS, converted to dopamine
• carbidoba prevents peripheral L-dopa depletion but doesn’t enter CNS
• Effects
• ameliorates all motor symptoms of parkinson’s
• significant peripheral dopaminergic effects
• Clinical
• Parkinson’s - most efficacious therapy but not always first choice due to development of disabling response fluctuations over time
• Kinetics, tox, int.
• oral, 6-8h effect
• tox: GI upset, arrythmias, dyskinesias, on-off and wearing-off phenomena, behavioural disturbances
• int: use with carbidopa greatly diminishes required dosage and is now standard, use with COMT or MAO-B inhibitors prolongs duration of effect

Question 2

Pramipexole

Answer 2

• MOA
• direct agonist at D₃ receptors, nonergot
• Effects
• reduces symptoms of parkinsonism, smooths out fluctuations in L-dopa response
• Clinical
• parkinson’s - initial therapy or in on-off phenomenon
• Kinetics, tox, int.
• oral, 8h effect
• tox: nausea, vomiting, postural hypotension, dyskinesias, confusion, impulse control disorders, sleepiness

Question 3

Bromocriptine

Answer 3

• MOA
• ergot derivative, potent agonist at D₂ receptors
• More toxic than pramipexole or ropinirole, now rarely used for this indication

Question 4

Rasagiline, selegiline

Answer 4

• MOA
• MAO-B inhibitor, higher doses also inhibit MAO-A
• Effects
• increases dopamine stores in neurons
• may have neuroprotective effects
• Clinical
• parkinson’s: adjunct to L-dopa, smoothens L-dopa response
• Kinetics, tox, int.
• oral
• tox & int: serotonin syndrome with meperidine, SSRIs, tricyclic antidep.
• Selegiline
• like rasagiline, adjunctive use with L-dopa, may be less potent than rasagiline

Question 5

Entacapone

Answer 5

• MOA
• inhibits COMT in periphery, does not enter CNS
• Effects
• reduces metabolism of L-dopa and prolongs its action
• Clinical
• parkinson’s
• Kinetics, tox, int.
• oral
• tox: increased L-dopa toxicity, nausea, dyskinesias, confusion

Question 6

Benztropine, biperiden

Answer 6

• MOA
• antagonist at M receptor in basal ganglia
• Effects
• reduces tremor and rigidity, little effect on bradykinesia
• Clinical
• parkinson’s
• Kinetics, tox, int.
• oral
• tox: typical antimuscarinic effects - sedation, mydriasis, urinary retention, constipation, confusion, xerostomia