Parkinson's Agents

Question 1

MPP+ Pathway

Answer 1

MPPP was goal.
Accidentally synthesized MPTP
MAO-B converts it to MPP+
- Or to MPDP+, then to MPP+
Neurotoxin, similar to Paraquat (bi-methylated)

Question 2

Levodopa key point

Answer 2

It is a prodrug that has to access the CNS to be converted to DA by AAAD.

Question 3

Key feature of Carbidopa structure, and why:

Answer 3

The hydrazine group; allows AAAD inhibition, and prevents access to CNS.

Question 4

Bromocriptine mechanism and t1/2

Answer 4

D2/D3 partial agonist.

t1/2 = 5hr.

Question 5

Pramipexole key point

Answer 5

Minimally metabolized, and mostly excreted unchanged, so good for patients taking multiple drugs to avoid interactions.

Question 6

Pramipexole mechanism and t1/2

Answer 6

D3 > D2 full agonist.

t1/2 = 8hr.

Question 7

Ropinirole metabolism

Answer 7

CYP1A2:
N-despropyl-ropinirole
7-hydroxy-ropinirole
Both Inactive products.

Question 8

Rotigotine key point

Answer 8

When taken orally, rapidly Glucuronidated.

So, formulated as transdermal patch (daily).

Question 9

Rotigotine mechanism and t1/2

Answer 9

D3 Agonist

t1/2 = 5-7hr

Question 10

Apomorphine key points

Answer 10

Given as a subQ injection only for advanced PD patients.

Short acting.

Question 11

Apomorphine mechanism and t1/2

Answer 11

D4 agonist.

t1/4 = 40 minutes.

Question 12

COMT Inhibitor SAR

Answer 12

Nitrocatechol with EWG at position 5.

Question 13

COMT-I mechanism

Answer 13

EWG and nitro group deactivate the ring, preventing the methyl-transfer by COMT.

Question 14

Tolcapone key points

Answer 14

Aromatic ketone associated with liver toxicity - requires monitoring.
More lipophilic than Entacapone, inhibits COMT centrally as well.

Question 15

Entacapone key points

Answer 15

No liver toxicity like Tolcapone.
Mainly just a peripheral COMT-I.
Can lead to orange-brown urine in about 10% of patients; harmless.

Question 16

Selegiline key points

Answer 16

Leads to R-methamphetamine and R-amphetamine metabolites.

• Can lead to SE’s.
• Can lead to positive drug tests.

Question 17

Selegiline metabolism*

Answer 17

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

Question 18

Rasagiline key points

Answer 18

No amphetamine metabolites.

More potent than Selegiline.

Question 19

Rasagiline metabolism

Answer 19

Two routes, both by CYP 1A2:
- N-dealkylation
- Hydroxylation
(both inactive)

Question 20

Amantadine key point

Answer 20

An antiviral that is structurally similar to Memantine, an NMDA antagonist used for Alzheimer’s disease.
Mildly helps bradykinesia, rigidity, and tremor.

Question 21

6 Levodopa SE’s

Answer 21

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.

Question 22

3 Characteristics of L-Dopa induced Dyskinesias

Answer 22

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)

Question 23

What to do about “end-of-dose” effects?

Answer 23

Increase L-Dopa, switch to CR, add DA, COMT-I, or MAO-B-I.

Question 24

What to do about delayed-on or no-response?

Answer 24

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.

Question 25

What to do about “start hesitation” problems?

Answer 25

Increase L-Dopa, add MAO-B-I or DA, try physical therapy.

Question 26

What to do about peak dose dyskinesia?

Answer 26

Smaller doses more frequently; add Amantidine.

Question 27

What is Pimvanserin?

Answer 27

A new drug for PD psychosis.
Acts at Serotonin receptors.
Increased risk of death in PD patients… various reasons.

Question 28

Problems with the Second Generation DA’s?

Answer 28

Impulse control issues.

Sleep attacks during daytime (Pramipexole mostly).

Question 29

Major contributors to psychosis and hallucination SE’s?

Answer 29

Levodopa
DA's
COMT-I's
Amantadine
Anticholinergics - Benztropine

Question 30

What to do if patient is suffering from drug-induced psychotic / hallucination SE’s?

Answer 30

Remove the adjunct therapies inward until you have solved the problem, or got to the point where the SE’s are worth it.

Question 31

Major problem with Bromocriptine

Answer 31

Pulmonary fibrosis

Question 32

Selegiline SE’s

Answer 32

Insomnia, confusion, and psychosis in elderly.

Question 33

Rasagiline SE’s

Answer 33

Hypertensive crisis due to tyramine interaction more common than Selegiline, also has the impulse control issue.

Question 34

COMT-I’s mostly useful for?

Answer 34

Motor-symptoms of PD.

Question 35

Anticholinergics mostly used for?

Answer 35

Tremor.

Not for the elderly!

Question 36

Anticholinergic Toxicity Mnemonic:

Answer 36

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)