Test 3 Flashcards
L-DOPA
Pro-drug with little or no intrinsic dopaminergic activity.
It is converted to dopamine by DOPA decarboxylase
Improves all of the cardinal motor symptoms of PD
Bradykinesia, resting tremor, muscular rigidity, gait & postural impairments
DOPA decarboxylase is widely distributed; high activity in the GI tract and other peripheral tissues, and in the CNS.
Absorbed mainly from small intestine
In brain, increases the pool of dopamine stored in the remaining nigrostriatal terminals
L-DOPA peripheral metabolism
Via COMT (catechol-O-methyltransferase)
Product is inactive
Via DOPA decarboxylase
Product is dopamine
Carbidopa
a peripheral inhibitor of DOPA decarboxylase - always administered with L-DOPA
Reduces the systemic conversion of L-DOPA to dopamine
Increases oral bioavailability of L-DOPA
As a result: More of a dose of L-DOPA reaches the brain
Reduction in peripheral adverse effects of L-DOPA, but can accentuate its central adverse effects.
L-DOPA loss of efficacy
Wearing-off” or “end-of-dose” effect
Typically appears after months to years of treatment
Mobility declines within a few hours after each dose
Need to adjust dosing regimen (schedule or dose)
“On-off” effect
Ususally appears later than wearing-off effect
Unpredictable, sudden periods of reduced mobility
Not correlated with dosing schedule
L-DOPA adverse effects
Peripheral
These are greatly reduced by carbidopa
Nausea and vomiting (tolerance may develop)
Postural hypotension (orthostatic changes)
Arrhythmias
CNS
Dyskinesias (choreoathetoid)
Psychiatric changes including anxiety, hallucinations, insomnia, somnolence, euphoria
Contraindications: psychosis, narrow angle glaucoma, malignant melanona
Direct DA agonists
Used as monotherapy early in disease progression, when symptoms are mild
Used as adjunct to L-DOPA + carbidopa
Allow reduction in L-DOPA dose
Smooth out fluctuations in the response to L-DOPA
Pramipexole and Ropinirole
Direct DA agonists Both are selective D2 receptor agonists (D2 >> D1) Similar adverse effects to L-DOPA, both peripheral: anorexia, N/A, bleeding peptic ulcers, orthostatic hypotension and central (more frequent and severe than L-DOPA): hallucinations, delusion, pathologic compulsive behavior, narcolepsy like sleep attacks.
Pramipexole
direct DA agonist
Excreted unchanged in urine
Pronounced somnolence in some individuals poses hazard
Ropinirole
direct DA agonist
Metabolized by CYP1A2
So are caffeine & warfarin, so risk of interaction with these common drugs
Apomorphine
direct DA agonist
Administered s.c.: used as a rescue drug during off periods with L-DOPA
A potent emetic (vomiting) - used with antiemetic - use of 5HT3 is contraindicated because of hypotension and loss of consciousness
Cardiovascular effects are potentially serious
Angina, orthostatic hypotension, syncope
CNS adverse effects
Most common are somnolence, hallucinations, confusion
Elimination is rapid (t1/2 ~40 min)
Excreted unchanged, mostly in urine
MAO-B Inhibitors
Can be used as monotherapy or add ons later in therapy
Reduce the degradation of dopamine by MAO in the brain and increase dopamine levels
May be neuroprotective
MAO-B metabolizes DA, but not NE or 5HT
irreversible inhibitors
Used as adjuncts to L-DOPA
Prolong the elevation of central DA
Reduce response fluctuations
Allow a reduction in L-DOPA dosing
Can interact with meperidine (an opioid analgesic)
Serotonin syndrome: Includes agitation and delirium, potentially progressing to hyperpyrexic coma and death
Due to MAO-A inhibition (“selective” does not mean specific)
Treatment includes supportive care, sedation with benzodiazepines, and serotonin antagonists
Selegiline
MAO-B inhibitor
Mainly used as adjunctive therapy
Metabolites include amphetamine & methamphetamine
Side effects include anxiety and insomnia, confusion
Transdermal patch and orally disintegrating tablets reduce formation of amphetamine and methamphetamine by evading first-pass metabolism
Clear loss of MAO-B selectivity at high doses
Risk of tyramine-related hypertensive crisis
Tyramine is substrate for MAO-A and to a lesser extent MAO-B
Risk of serotonin syndrome with SSRIs
Potential interaction with diertary tyramine, which can cause a hypertensive crisis
Rasagline
More selective for MAO-B inhibition compared to selegiline.
Effective monotherapy for early (mild) PD symptoms, also used with L-DOPA
No amphetamine metabolites.
Some evidence for neuroprotective effect
COMT inhibitors
In the periphery up-regulates in response to DOPA decarboxylase inhibition.
Limits the effectiveness of carbidopa as an adjunct to L-DOPA
As COMT activity increases, 3-O-methyldopa accumulates.
This metabolite competes with L-DOPA for carriers, including those in blood-brain barrier.
Approved only as adjunct to L-DOPA for response fluctuations
Entacapone
Inhibits COMT only in the periphery
Relatively short duration of action
Taken with every dose of L-DOPA
Central and peripheral effects similar to L-DOPA + carbidopa, except no evidence for hepatotoxicity as with tolcapone
Stalevo® = L-DOPA + carbidopa + entacapone
