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Integrated Drug Structure, Action, and Therapeutics > Antipsychotic Drugs > Flashcards

Antipsychotic Drugs Flashcards

1
Q

What was the first approved antipsychotic?

A

Chlorpromazine

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2
Q

Chlorpromazine

  • Structure
  • SE’s
A 
- Phenothiazine ring system - leads to photosensitivity
Similar to M1 antagonist SAR
- SE's: antimuscarinic - M1 antagonism
sedative: H1
hypotension: alpha-1
Also antihistamine properties
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3
Q

Phenothiazine SAR

A

1) EWG substitution at 2, increases potency. Necessary.
2) Substitutions @ 1 and 4 decrease antipsychotic activity (1 > 4)
3) Three carbon chain connecting nitrogens is required. 2 or 4 decreases activity.
4) Branching on the side chain decreases activity. Branching at the y-carbon (the most distal) is tolerated.
5) Basic nitrogen substituents - tertiary amines provide optimal activity. 2ndary have decreased activity. Significant increases in size from dimethylmino groups decrease activity. Piperidine/piperazine rings are allowed. Addition of length on N2 of piperazine ring may increase receptor binding forces.

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4
Q

Which form of a phenothiazine is required for passage through the BBB? At the receptor?

A

Tertiary amine is needed for BBB, but the protonated form is needed at the receptor.

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5
Q

What are the metabolites of chlorpromazine?

A

CPZ sulfoxide - inactive
Nor1-CPZ - weakly active 2ndary amine
CPZ propionic acid - inactive
7-hydroxy CPZ - 2D6 major, 1A2 minor. Weakly active. Glucuronidation and excretion

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6
Q

Fluphenazine HCl

- structure

A

Phenothiazine with propyl piperazine side chain
Triflouromethyl - more potent than chlorpromazine
Piperazine ring with polar group - contributes to reduced antimuscarinic effects

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7
Q

Fluphenazine decanoate

A

Prodrug. This is an ester (formed from the primary hydroxyl group) that stays at the site of depot injection; slowly released and hydrolyzed to active fluphenazine in 3-4 weeks.

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8
Q

Thioridazine

  • structure
  • metabolism
  • SE’s
A
  • Phenothiazine with alkyl piperidyl side chain
  • CYP 2D6 creates active sulfide metabolite at methyl group (0=S-Ch3)
  • Used as racemate, but R enantiomer has higher D2 receptor affinity
  • prolongs the QT interval. Not for use in 2D6 poor metabolizers.
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9
Q

Clozapine

  • type
  • structure
  • metabolism
A
  • Atypical antipsychotic, dibenzazepine (2 nitrogens)
  • 7-membered ring instead of 6 (more flexible, less planar)
  • Cl is EWG, trans-like to tertiary amine.
  • D4/D2 antagonist, 5HT2 antagonist (less EPS)
  • major 1A2, minor 3A4
  • forms active N-desmethyl metabolite which may contribute to overall activity
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10
Q

What is the risk with clozapine? What reason?

A

Risk of agranulocytosis: 3A4 changes this to a reactive nitrenium ion, which can react with GSH or protein nucleophiles to lead to toxicities. Monitoring is required with this drug.

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11
Q

What is the half-life of clozapine?

A

12 hours

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12
Q

Olanzapine

  • type
  • structure
  • metabolites
A
  • Atypical Antipsychotic
  • Dibenzazepine
  • No EWG, thiophene isostere
  • N-demethylation (1A2)
  • 10-N-glucuronide
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13
Q

What is the half-life of olanzapine?

A

30 hours (once daily dosing)

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14
Q

What is olanzapine pamoate? When is it used? How is it released?

A

It is a decarboxylate, so a pamoate anion is attached to one olanzapine.
It is a less water-soluble salt form, used in IM formulations.
Effective in 2-4 weeks, released slowly.

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15
Q

Loxapine

  • type
  • structure
  • metabolism
  • Atypical?
A
  • Dibenzooxazepine.
  • Inhalation powder
  • cis-like, Cl is EWG
  • 3A4 N-demethylation produces amoxapine (antidepressant drug). This is an active metabolite that blocks NE reuptake.
  • Not considered an atypical antipsychotic (still see EPS)
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16
Q

Quetiapine

  • type
  • structure
  • metabolism
A
  • dibenzothiazepine (sulfur substitution)
  • atypical antipsychotic
  • No EWG
  • Long ether chain with OH at the end - reduces antimuscarinic effects
  • 3A4 major metabolite is inactive sulfoxide, minor 3A4 metabolite is N-desalkyl quetiapine (active, but different pharmacological profile. Potent M1 receptor antagonist = antimuscarinic effects).
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17
Q

What is the half-life of quetiapine? It’s minor metabolite?

A

Drug = 7 hours and metabolite = 12 hours

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18
Q

What receptor type agonist/antagonist gives antimuscarinic effects?

A

M1 antagonist

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19
Q

What receptor type agonist/antagonist gives sedation?

A

H1 antagonism

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20
Q

What receptor type agonist/antagonist gives hypotension?

A

alpha-1

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21
Q

Asenapine

  • type
  • structure
  • metabolism
A
  • dibenzdihydrooxepine
  • Central ring is not aromatic
  • differs from dibenzazepines
  • used as racemate
  • major direct glucuronidation of the tertiary amine, minor N-methylation (1A2). Both inactive
22
Q

Why is there no M1 antagonism of asenapine?

A

Basic nitrogen is too close to the ring system (only 1 carbon away vs 2-4)

23
Q

What is the half-life of asenapine?

24
Q

What enzyme does asenapine inhibit?

A

It is a weak 2D6 inhibitor, so some interactions are observed.

25
Q

Haloperidol

  • structure
  • type
  • metabolism
A
  • Fluorobutyrophenone
  • F is EWG
  • High incidence of EPS (increased D2 affinity)
  • Low antimuscarinic activity (decreased M1 affinity)
  • Major 1) N-dealkylation (3A4/2D6) 2) Reduction of the ketone to 2ndary alcohol
  • minor route leads to potential neurotoxic metabolite HPP+
26
Q

What is the half-life of haloperidol?

A

14-37 hours

27
Q

What is the ester prodrug of haloperidol?

A

Haldol decanoate. Used for depot injections lasting up to 4 weeks.

28
Q

Risperidone

  • Type
  • Structure
  • Metabolism
A
  • Misc. heterocyclic compound
  • atypical antipsychotic
  • Benzisoxazole
  • CYP 2D6 major enzyme produces paliperidone (separate drug)
29
Q

What is the half-life of risperidone?

A

Actually it is a range: 3 hr EM, 20 hr PM

30
Q

Why is there a range of metabolism length for risperidone?

A

Because it uses 2D6, and people can be poor metabolizers or extensive metabolizers, or even other options.

31
Q

What is a theory for EPS causes with risperidone?

A

It uses 2D6, and maybe the EPS is caused when risperidone hangs around a long time in poor metabolizers.

32
Q

What is the difference between paliperidone Invega and Sustenna?

A

Invega is an oral form, and Sustenna is an ester prodrug for depot injections.

33
Q

Paliperidone

  • type
  • structure
  • metabolism
A
  • atypical antipsychotic
  • Benzoisoxazole, same as risperidone except with an OH group
  • no major route for 2D6 metabolism, 60% excreted unchanged
34
Q

What is the half-life of paliperidone?

35
Q

Iloperidone

  • type
  • structure
  • metabolism
A
  • misc heterocyclic compound
  • atypical antipsychotic
  • portion that is identical to risperidone
  • metabolism: 1) reduction of ketone “active” 2) 2D6 hydroxylation “active” 3) 3A4 O-demethylation “inactive”
36
Q

What is the half-life range for Iloperidone?

A

18 hours EM, 33 hours PM

37
Q

What should you do to the dose if you are taking strong 2D6/3A4 inhibitors?

A

Decrease the dose.

38
Q

Ziprasidone

  • type
  • structure
  • metabolism
A
  • misc heterocyclic compounds
  • atypical antipsychotic
  • three components are isosteres of risperidone
  • Metabolism: 1/3 goes through 3A4/1A2 sulfide and sulphone metabolites and N-dealkylation - inactive. 1) aldehyde dehydrogenase mediates N-S bond, and then 2) S-methylation forms another inactive product
39
Q

What is the half-life of ziprasidone?

40
Q

What effect does cimetidine have on ziprasidone?

A

None, surprisingly. Maybe it has other enzymes to assist. This is different than in the sedation drugs.

41
Q

Lurasidone

  • type
  • structure
  • metabolism
A
  • misc. heterocyclic compounds
  • atypical antipsychotic
  • right side same as ziprasidone
  • two chiral centers
  • metabolism: 3A4 major enzyme, 4 metabolites: sulfoxide (possibly active)/sulfone (inactive?), hydroxylation (active), N-dealkylation (inactive because it breaks the molecule in half).
42
Q

How is lurasidone formulated? Racemate or enantiomer?

A

A single enantiomer

43
Q

What is the half-life of lurasidone?

44
Q

Aripiprazole

  • type
  • structure
  • metabolism
A
  • Misc. heterocyclic compounds
  • D2 partial agonist
  • slightly longer spacer between structural elements
  • Also more flexible (possibly contributes to partial agonist features)
  • Metabolism: key enzymes are 3A4 and 2D6: dehydroaripiprazole (active, but less potent)
45
Q

What is the half-life of aripiprazole and dehydroaripiprazole?

A

Very long: Aripiprazole is 75 hours (EM) and 146 hours (PM). It is very lipophilic as well, which may contribute to long half-life.
Dehydroaripiprazole t1/2 = 94 hours

46
Q

Aripiprazole lauroxil

  • type
  • structure
  • metabolism
A
  • lipophilic prodrug for IM injections once monthly or once every 6 weeks
  • “lauro”xil = 12 carbons
  • ester hydrolysis cleaves ester to form alcohol, which spontaneously collapses to active aripiprazole (spitting out formaldehyde in the process).
47
Q

Brexpiprazole

  • type
  • structure
  • metabolism
A
  • misc. heterocyclic compounds
  • D2 partial agonist (also action at 5HT2 R’s)
  • Benzothiophene vs. dichlorobenzene in aripiprazole
  • Pretty new, no details on metabolism
  • 2D6 and 3A4
  • inactive metabolites
48
Q

What is the half-life of brexpiprazole?

49
Q

Cariprazine

  • type
  • structure
  • metabolism
A
  • misc. heterocyclic compounds
  • D3/D2 partial agonist
  • right side same as aripiprazole
  • Metabolism: 3A4 major, 2D6 minor: desmethyl and didesmethyl metabolites (both active and contribute to overall activity - approximately equipotent)
50
Q

What is the half-life of cariprazine? Didesmethyl metabolites?

A

2-4 days for cariprazine, and 1-3 weeks for didesmethyl metabolites.

51
Q

Pimavanserin

  • type
  • structure
  • metabolism
A
  • misc. heterocyclic compounds
  • piperidine, urea, F = EWG
  • To treat Parkinson’s associated psychosis (acts at 5HTs R’s)
  • CYP 3A4–> N-desmethyl metabolite (active)
  • approved April 2016
52
Q

What is the half-life of pimavanserin and it’s N-desmethyl metabolite?

A

57 hours and 200 hours (overall activity)

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

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