Parkinson's Agents Flashcards
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.
What to do about “start hesitation” problems?
Increase L-Dopa, add MAO-B-I or DA, try physical therapy.
What to do about peak dose dyskinesia?
Smaller doses more frequently; add Amantidine.
What is Pimvanserin?
A new drug for PD psychosis.
Acts at Serotonin receptors.
Increased risk of death in PD patients… various reasons.
Problems with the Second Generation DA’s?
Impulse control issues.
Sleep attacks during daytime (Pramipexole mostly).
Major contributors to psychosis and hallucination SE’s?
Levodopa DA's COMT-I's Amantadine Anticholinergics - Benztropine
What to do if patient is suffering from drug-induced psychotic / hallucination SE’s?
Remove the adjunct therapies inward until you have solved the problem, or got to the point where the SE’s are worth it.
Major problem with Bromocriptine
Pulmonary fibrosis
Selegiline SE’s
Insomnia, confusion, and psychosis in elderly.
Rasagiline SE’s
Hypertensive crisis due to tyramine interaction more common than Selegiline, also has the impulse control issue.
COMT-I’s mostly useful for?
Motor-symptoms of PD.
Anticholinergics mostly used for?
Tremor.
Not for the elderly!
Anticholinergic Toxicity Mnemonic:
Blind as a bat. (blurred vision) Dry as a bone. (dry skin and urinary retention) Hot as a hare. (fever / hyperthermia) Red as a beet. (flushing) Mad as a hatter. (confusion)
