Term
| Describe the structure of phenothiazines. |
|
Definition
Tricyclic ring
(2 benzene rings linked by N and S)
3C linker to N in a ring |
|
|
Term
| Where was clorpromazine developed from? |
|
Definition
Antihistamine phenothiazines.
Discovered from observed side effects. |
|
|
Term
| Describe the structure of thioxanthenes. |
|
Definition
Tricyclic ring
(2 benzenes linked by S)
Double bond in 3C linker to N
(MUST BE CIS) |
|
|
Term
| Describe the PK/PD of phenothiazines and metabolism. |
|
Definition
Rapid but VARIABLE absorption.
Highly bound; long T1/2
Sulfoxide metabolite = active.
Other metabolites: N-demethylation, hydroxylation, deamination, N-oxidation |
|
|
Term
| What is an example of a phenothiazine? |
|
Definition
Chlorpromazine.
Active metabolite: sulfoxide
And, thioridazine. |
|
|
Term
| Which enzymes does chlorpromazine inhibit? |
|
Definition
CYP2D6 & 2E1
Substrate of 1A2, 3A4, 2D6 |
|
|
Term
| T/F: Thioridazine and chlorpromazine have sedative and hypotensive effects. |
|
Definition
|
|
Term
| T/F: Trifluoperazine has many drug interactions. |
|
Definition
FALSE.
50% renal elimination
50% enterohepatic recycling |
|
|
Term
| Which typical antipsychotics have 2 tertiary amines? |
|
Definition
Prochlorperazine
Trifluoperazine
In a ring. Makes for better activity.
TriF is also good for van der waals. |
|
|
Term
| T/F. Thiothixene is an inhibitor of CYP2D6. |
|
Definition
TRUE
Remember: 1 S in a ring and 1 S in place of the Cl. Also a double bond and 2N ring. |
|
|
Term
| What CYP enzymes are associated with thiothixene? |
|
Definition
Substrate for CYP1A2
Inhibitor of CYP2D6 |
|
|
Term
| Describe the SAR of butyrophenones. |
|
Definition
Tertiary amino at 4C.
Para substituted F at 1 position
Keto group = REQUIRED
Lengthening of chain = DECREASED activity
Cyclization = conformationally restricted. |
|
|
Term
| What CYP enzymes does haloperidol inhibit? |
|
Definition
|
|
Term
| List the metabolites of haloperidol. |
|
Definition
Aromatization of the piperidine ring
Reduction of ketone
Mostly by CYP 3A4. |
|
|
Term
| T/F: Droperidol is a centrallya cting AchE inhibitor. |
|
Definition
TRUE.
Increases risk of EPS. |
|
|
Term
|
Definition
Haloperidol
Droperidol
Pimozide (sort of) |
|
|
Term
| T/F: Pimozide is an inhibitor for CYP3A4. |
|
Definition
False
CYP2D6
Metabolized by 3A4 and 1A2 |
|
|
Term
| Describe the structural similarities of some of the atypical antipsychotics. |
|
Definition
Aromatic rings linked by 7 membered ring.
Clozapine is similar to phenothiazine (ring expansion, S bioisostere)
Less EPS |
|
|
Term
| What is the D2 occupancy theory? |
|
Definition
| 65% must be occupied for an effect. |
|
|
Term
| Clozapine is atypical due to affinity for... |
|
Definition
D4
Quetiapine does not have affinity for D4. |
|
|
Term
| What ADE is associated with clozapine? |
|
Definition
|
|
Term
| Describe clozapine's metabolites. |
|
Definition
Des-methyl metabolite:
Agonism at D2, D3, M1
Active!!!
Inactive n-oxide metabolite. |
|
|
Term
| Olanzapine has stabilizing and antidepressant effects through... |
|
Definition
| 5HT2a blockage and increased DA and NE concentrations. |
|
|
Term
| What is olanzapine's major metabolite? |
|
Definition
N-glucuronide
Other metabolites: hydroxymethyl; N-oxide |
|
|
Term
| T/F: Quetiapine has active metabolites. |
|
Definition
TRUE
Major metabolite, sulfoxide, is not active.
7-OH and 7-OH,desalkyl are ACTIVE! |
|
|
Term
| Paliperidone is the metabolite of... |
|
Definition
Risperidone.
racemic mixture of 9-hydroxyrisperidone |
|
|
Term
| What are the major metabolites of ziprasidone? |
|
Definition
S-oxidation
N-dealkylation
Must have sulfide in it. Not just n-dealkylation alone.
They are not active
BITP |
|
|
Term
| Describe aripiprazole's PD profile. |
|
Definition
Different profile than others.
Agonist at 5HT1a --> helps with (-) sx
Partial agonist at D2 receptors |
|
|
Term
| What is the primary metabolite of aripiprazole? |
|
Definition
Dehydroaripiprazole (double bond in N ring)
Metabolized by CYP3A4 and 2D6
ACTIVE! |
|
|
