Parkinson's Agents Flashcards
(36 cards)
MPP+ Pathway
MPPP was goal. Accidentally synthesized MPTP MAO-B converts it to MPP+ - Or to MPDP+, then to MPP+ Neurotoxin, similar to Paraquat (bi-methylated)
Levodopa key point
It is a prodrug that has to access the CNS to be converted to DA by AAAD.
Key feature of Carbidopa structure, and why:
The hydrazine group; allows AAAD inhibition, and prevents access to CNS.
Bromocriptine mechanism and t1/2
D2/D3 partial agonist.
t1/2 = 5hr.
Pramipexole key point
Minimally metabolized, and mostly excreted unchanged, so good for patients taking multiple drugs to avoid interactions.
Pramipexole mechanism and t1/2
D3 > D2 full agonist.
t1/2 = 8hr.
Ropinirole metabolism
CYP1A2:
N-despropyl-ropinirole
7-hydroxy-ropinirole
Both Inactive products.
Rotigotine key point
When taken orally, rapidly Glucuronidated.
So, formulated as transdermal patch (daily).
Rotigotine mechanism and t1/2
D3 Agonist
t1/2 = 5-7hr
Apomorphine key points
Given as a subQ injection only for advanced PD patients.
Short acting.
Apomorphine mechanism and t1/2
D4 agonist.
t1/4 = 40 minutes.
COMT Inhibitor SAR
Nitrocatechol with EWG at position 5.
COMT-I mechanism
EWG and nitro group deactivate the ring, preventing the methyl-transfer by COMT.
Tolcapone key points
Aromatic ketone associated with liver toxicity - requires monitoring.
More lipophilic than Entacapone, inhibits COMT centrally as well.
Entacapone key points
No liver toxicity like Tolcapone.
Mainly just a peripheral COMT-I.
Can lead to orange-brown urine in about 10% of patients; harmless.
Selegiline key points
Leads to R-methamphetamine and R-amphetamine metabolites.
- Can lead to SE’s.
- Can lead to positive drug tests.
Selegiline metabolism*
Two routes, both by P450’s:
- Removal of “Propargyl” group: R-Methamphetamine.
- Removal of N-methyl group: N-desmethylseligiline (active as an MAO-B-I as well)
- Both undergo opposite metabolism: R-Amphetamine
Rasagiline key points
No amphetamine metabolites.
More potent than Selegiline.
Rasagiline metabolism
Two routes, both by CYP 1A2:
- N-dealkylation
- Hydroxylation
(both inactive)
Amantadine key point
An antiviral that is structurally similar to Memantine, an NMDA antagonist used for Alzheimer’s disease.
Mildly helps bradykinesia, rigidity, and tremor.
6 Levodopa SE’s
1 - Gastrointestinal: D2 receptors in brain stem trigger nausea, vomiting, severe loss of appetite.
2 - Cardiovascular: D1 receptors on mesenteric, renal, and coronary beds trigger orthostatic hypotension. Also, low risk for arrhythmias due to B-1 activation.
3 - Dystonia: Painful prolonged contractions, usually in feet, and not very well understood.
4 - Dyskinesia: Related to timing and dosage of L-dopa; uncontrollable movements called Choreoathetosis. Usually tolerated as it also comes with mobility.
5 - On/Off Phenomenon: Unrelated to timing and dosage of L-dopa; indicates patient is becoming refractory to treatment. “Off” = freezing, “on” = marked dyskinesia.
6 - Behavioral: Depression, restlessness, anxiety, insomnia, confusion, hallucinations, vivid dreams/nightmares, personality or mood changes.
3 Characteristics of L-Dopa induced Dyskinesias
1 - Off period Dystonia.
2- Diphasic Dyskinesia: when levels are rising or falling; rigidity or dyskinesia in lower limbs.
3 - Peak Dose Dyskinesia: at peak level, chorea-form dyskinesia of the upper body (less disabling)
What to do about “end-of-dose” effects?
Increase L-Dopa, switch to CR, add DA, COMT-I, or MAO-B-I.
What to do about delayed-on or no-response?
Take on empty stomach, use ODT/IR form, avoid high-protein foods when taking medication, or better yet, just take it crushed up with a glass of water.
