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Integrated Drug Structure, Action, and Therapeutics > Parkinson's Drugs (Proteau) > Flashcards

Parkinson's Drugs (Proteau) Flashcards

1
Q

MPPP

A

Designer heroin

Elimination of propionate —> MPTP

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2
Q

MPTP through MAO-B can form what?

A

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

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3
Q

Which product of MPPP is a neurotoxin?

A

MPP+

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4
Q

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

A

Paraquat. It causes PD-like symptoms.

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5
Q

What does tyrosine hydroxylase do?

A

It adds a hydroxylase to tyrosine to form L-Dopa

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6
Q

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

A

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

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7
Q

What does COMT do to dopamine in the CNS?

A

It adds a methyl group to form 3-methoxytyramine

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8
Q

What does AAAD do?

A

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

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9
Q

What does MAO and aldehyde dehydrogenase do in the CNS?

A

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

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10
Q

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

A

Homovanillic Acid (HVA)

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11
Q

What drugs are used to treat Parkinson’s disease?

A

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)

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12
Q

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

A

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

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13
Q

What is carbidopa?

A

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).

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14
Q

What does the hydrazine (NHNH2) do in carbidopa?

A

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

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15
Q

What are 3 benefits of dopamine agonists?

A

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

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16
Q

What is the ergot-like agonist?

A

Bromocriptine

17
Q

What are some features of bromocriptine?

A

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

18
Q

What type of agonist is bromocriptine?

A

D2/D3 partial agonist

19
Q

What is the half-life of bromocriptine?

A

5 hours

20
Q

Define oath, para, and meta:

A

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

21
Q

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

A

Common to dopamine agonists

22
Q

Pramipexole

  • structure
  • metabolism
A 
Thiazole instead of benzene ring (bioisostere); so has meta-like H-bond donor
Minimal metabolism (bulk is excreted unchanged)
23
Q

What type of agonist is pramipexole?

A

D3>D2

24
Q

What is the half-life of pramipexole?

A

8 hours

25
Q

Ropinirole

  • Structure
  • Metabolism
A

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

26
Q

What type of agonist is ropinirole?

A

D3>D2

27
Q

What is the half-life of ropinirole?

A

6 hours

28
Q

Rotigotine

  • Structure
  • Metabolism
A

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

29
Q

What type of agonist is rotigotine?

A

D3 agonist

30
Q

What is the half-life of rotigotine?

A

5-7 hours

31
Q

Apomorphine

  • Structure
  • Metabolism of similar drug
  • Dosage form
A
  • Has two hydroxyl groups
  • Similar structure to morphine: when morphine is in presence of heat and HCl, it rearranges to apomorphine
  • Sub-Q injection
32
Q

What type of agonist is apomorphine?

A

D4 used in advanced Parkinson’s

33
Q

What is the half-life of apomorphine?

A

40 minutes, short-acting

34
Q

Tolcapone

  • Structure
  • Metabolism
A
  • 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
35
Q

What structural features do COMT inhibitors share?

A
  • Nitrocatechol (benzene ring with two OH groups and NO2) with an EWG at position 5
  • EWG is usually =O
36
Q

Entacapone

  • Structure
  • Metabolism
A
  • 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.
37
Q

Selegiline

  • Structure
  • Metabolism
A
  • 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
38
Q

Rasagiline

  • Structure
  • Metabolism
A
  • 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
39
Q

Amantadine

-Sturcture

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

Integrated Drug Structure, Action, and Therapeutics (20 decks)

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