Antipsychotic Drugs Flashcards Preview

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

Flashcards in Antipsychotic Drugs Deck (52):
1

What was the first approved antipsychotic?

Chlorpromazine

2

Chlorpromazine
- Structure
- SE's

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

3

Phenothiazine SAR

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.

4

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

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

5

What are the metabolites of chlorpromazine?

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

6

Fluphenazine HCl
- structure

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

7

Fluphenazine decanoate

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.

8

Thioridazine
- structure
- metabolism
- SE's

-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.

9

Clozapine
- type
- structure
- metabolism

-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

10

What is the risk with clozapine? What reason?

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.

11

What is the half-life of clozapine?

12 hours

12

Olanzapine
- type
- structure
- metabolites

-Atypical Antipsychotic
- Dibenzazepine
- No EWG, thiophene isostere
- N-demethylation (1A2)
- 10-N-glucuronide

13

What is the half-life of olanzapine?

30 hours (once daily dosing)

14

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

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.

15

Loxapine
- type
- structure
- metabolism
- Atypical?

- 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)

16

Quetiapine
- type
- structure
- metabolism

- 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).

17

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

Drug = 7 hours and metabolite = 12 hours

18

What receptor type agonist/antagonist gives antimuscarinic effects?

M1 antagonist

19

What receptor type agonist/antagonist gives sedation?

H1 antagonism

20

What receptor type agonist/antagonist gives hypotension?

alpha-1

21

Asenapine
- type
- structure
- metabolism

- 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

Why is there no M1 antagonism of asenapine?

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

23

What is the half-life of asenapine?

24 hours

24

What enzyme does asenapine inhibit?

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

25

Haloperidol
- structure
- type
- metabolism

- 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

What is the half-life of haloperidol?

14-37 hours

27

What is the ester prodrug of haloperidol?

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

28

Risperidone
- Type
- Structure
- Metabolism

- Misc. heterocyclic compound
- atypical antipsychotic
- Benzisoxazole
- CYP 2D6 major enzyme produces paliperidone (separate drug)

29

What is the half-life of risperidone?

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

30

Why is there a range of metabolism length for risperidone?

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

31

What is a theory for EPS causes with risperidone?

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

32

What is the difference between paliperidone Invega and Sustenna?

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

33

Paliperidone
- type
- structure
- metabolism

- atypical antipsychotic
- Benzoisoxazole, same as risperidone except with an OH group
- no major route for 2D6 metabolism, 60% excreted unchanged

34

What is the half-life of paliperidone?

23 hours

35

Iloperidone
- type
- structure
- metabolism

- 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

What is the half-life range for Iloperidone?

18 hours EM, 33 hours PM

37

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

Decrease the dose.

38

Ziprasidone
- type
- structure
- metabolism

- 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

What is the half-life of ziprasidone?

7 hours

40

What effect does cimetidine have on ziprasidone?

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

41

Lurasidone
- type
- structure
- metabolism

- 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

How is lurasidone formulated? Racemate or enantiomer?

A single enantiomer

43

What is the half-life of lurasidone?

18 hours

44

Aripiprazole
- type
- structure
- metabolism

- 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

What is the half-life of aripiprazole and dehydroaripiprazole?

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

Aripiprazole lauroxil
- type
- structure
- metabolism

- 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

Brexpiprazole
- type
- structure
- metabolism

- 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

What is the half-life of brexpiprazole?

91 hours

49

Cariprazine
- type
- structure
- metabolism

- 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

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

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

51

Pimavanserin
- type
- structure
- metabolism

- 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

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

57 hours and 200 hours (overall activity)