Parkinson's Drugs (Proteau)

Question 1

MPPP

Answer 1

Designer heroin

Elimination of propionate —> MPTP

Question 2

MPTP through MAO-B can form what?

Answer 2

MPP+ directly, or MPDP+ and then MPP+ (this process could include another enzyme)

Question 3

Which product of MPPP is a neurotoxin?

Answer 3

MPP+

Question 4

What herbicide is structurally similar to MPP+? What symptoms does it cause?

Answer 4

Paraquat. It causes PD-like symptoms.

Question 5

What does tyrosine hydroxylase do?

Answer 5

It adds a hydroxylase to tyrosine to form L-Dopa

Question 6

What does CMOT do to L-Dopa in the periphery?

Answer 6

It forms adds a methyl group to L-Dopa to form 3-methoxydopa

Question 7

What does COMT do to dopamine in the CNS?

Answer 7

It adds a methyl group to form 3-methoxytyramine

Question 8

What does AAAD do?

Answer 8

It removes the hydroxy group on L-Dopa to form dopamine.

Question 9

What does MAO and aldehyde dehydrogenase do in the CNS?

Answer 9

It removes the NH2 on dopamine and adds a carboxylic acid.

Question 10

What is the end product of dopamine after it has undergone both MAO and COMT metabolism?

Answer 10

Homovanillic Acid (HVA)

Question 11

What drugs are used to treat Parkinson’s disease?

Answer 11

Dopamine precursors (L-dopa)
Dopa decarboxylase inhibitors (carbidopa)
Dopamine agonists (bromocriptine pramipexole, ropinirole, rotigotine, apomorphine)
COMT inhibitors (tolcapone, entacapone)
MAO-B inhibitors (Selegiline, rasagiline)
Others (Amantadine)

Question 12

What drug is a prodrug to dopamine? How does it cross the CNS?

Answer 12

L-dopa, because dopamine cannot pass the BBB. it uses a transporter to cross the CNS.

Question 13

What is carbidopa?

Answer 13

A peripheral AAAD inhibitor (decarboxylase inhibitor). This inhibits dopamine from forming in the periphery, but does not inhibit transport of L-dopa into the CNS (and subsequent transformation into dopamine).

Question 14

What does the hydrazine (NHNH2) do in carbidopa?

Answer 14

It makes the drug a decarboxylase inhibitor and inhibits transport into the CNS.

Question 15

What are 3 benefits of dopamine agonists?

Answer 15

1) Don’t require activation in the neurons
2) Can be more selective
3) Can have longer duration

Question 16

What is the ergot-like agonist?

Answer 16

Bromocriptine

Question 17

What are some features of bromocriptine?

Answer 17

It is lipophilic enough to get through the BBB (even though it is huge)
It is an ergot alkaloid like LSD
It has a portion that looks like dopamine

Question 18

What type of agonist is bromocriptine?

Answer 18

D2/D3 partial agonist

Question 19

What is the half-life of bromocriptine?

Answer 19

5 hours

Question 20

Define oath, para, and meta:

Answer 20

Para - across from
Ortho - next to
Meta - in the middle between ortho and para

Question 21

What group of anti-PD drugs is the meta H-bond donor common to?

Answer 21

Common to dopamine agonists

Question 22

Pramipexole

• structure
• metabolism

Answer 22

Thiazole instead of benzene ring (bioisostere); so has meta-like H-bond donor
Minimal metabolism (bulk is excreted unchanged)

Question 23

What type of agonist is pramipexole?

Answer 23

D3>D2

Question 24

What is the half-life of pramipexole?

Answer 24

8 hours

Question 25

Ropinirole - Structure - Metabolism

Answer 25

Benzene-ring with meta H-bond donor Metabolism is mainly CYp 1A2 Metabolites are N-despropyl ropinirole and 7-hydroxy ropinirole (both inactive)

Question 26

What type of agonist is ropinirole?

Answer 26

D3>D2

Question 27

What is the half-life of ropinirole?

Answer 27

6 hours

Question 28

Rotigotine - Structure - Metabolism

Answer 28

Transdermal patch (once daily) Has hydroxyl group that is removed to active drug when taken orally Metabolized through glucuronidation rapidly when taken orally

Question 29

What type of agonist is rotigotine?

Answer 29

D3 agonist

Question 30

What is the half-life of rotigotine?

Answer 30

5-7 hours

Question 31

Apomorphine - Structure - Metabolism of similar drug - Dosage form

Answer 31

- Has two hydroxyl groups - Similar structure to morphine: when morphine is in presence of heat and HCl, it rearranges to apomorphine - Sub-Q injection

Question 32

What type of agonist is apomorphine?

Answer 32

D4 used in advanced Parkinson's

Question 33

What is the half-life of apomorphine?

Answer 33

40 minutes, short-acting

Question 34

Tolcapone - Structure - Metabolism

Answer 34

- Nitrocatechol - EWG and nitro group deactivate the ring, preventing transfer of the methyl group by COMT - Associated with liver toxicity because of aromatic keytone - More lipophilic than encapone: can also inhibit central COMT - Requires liver monitoring

Question 35

What structural features do COMT inhibitors share?

Answer 35

- Nitrocatechol (benzene ring with two OH groups and NO2) with an EWG at position 5 - EWG is usually =O

Question 36

Entacapone - Structure - Metabolism

Answer 36

- Nitrocatechol group with extended conjugation - Mainly peripheral inhibition of COMT, no liver toxicity - Colored metabolites in urine of 10% of patients (orange-brown), but are harmless.

Question 37

Selegiline - Structure - Metabolism

Answer 37

- Propargl group CH3N--=-H is critical for irreversible inhibition of MAO-B - Metabolized using P450 to methamphetamine and N-desmethyl selegiline ( also an MAO-B inhibitor) - Methamphetamine is R isomer, which has less psychoactive effects than S isomer, although test would be positive for that drug. - Both metabolized to R-amphetamine

Question 38

Rasagiline - Structure - Metabolism

Answer 38

- Propargl group is critical for irreversible MAo-B inhibition - No amphetamine metabolites - More potent than selegiline - Uses CYP 1A2 to perform either N-dealkylation or hydroxylation to create inactive products

Question 39

Amantadine | -Sturcture

Answer 39

- Structurally similar to amantadine (non-competitive NDMA receptor antagonist) - Also antiviral drug