Antipsychotic drugs

Question 1

Antypsychotic drugs

• uses
• types
• MOA

Answer 1

For severe anxiety, agitated depression and schizophrenia.
Other actions: central antiemetic, prominent sedative effect, potentiation of general anaesthesia, potentiation of analgesia.

2 groups:
1. Typical/classical (older)
- strong tendency to produce extrapyramidal motor symptoms
- better for positive symptoms, little effect on negative, may even produce apathy and decrease initiative
- chlorpromazine (phenothiazine) -> potentiates respiratory depression of opiates, obstructive jaundice
- fluphenazine (phenothiazine)
- thioridazine (phenothiazine)
- haloperidol -> butyrophenone
- thiotixene -> thioxanthene
2. Atypical/newer
- produce fewer extrapyramidal effects
- more effective against negative symptoms
- decrease D2 activity, increase 5-HT2 activity
- olanzepine
- clozapine -> serious agranulocytosis in 1%
- risperidone
Risperidone and olanzepine may be as effective as clozapine and don’t cause agranulocytosis.

MOA:

• dopamine D2 R antagonists -> D2 and D3
• other Rs -> a1, H1, M, 5-HT -> changes effectiveness / side effects
• take days to show effects

Question 2

Schizophrenia

Answer 2

Disabling illness, affects aprox 1%

Positive symptoms:

• delusions hallucinations
• thought disorders
• alliviated w/ antipsychotics

Negative symptoms:

• social withdrawal
• emotional flattening
• decrease drive
• inability to feel pleasure

Question 3

Antipsychotic drugs

• AE
• PK

Answer 3

AE:
Neurological (extrapyramidal moto symptoms associated w/ D2 R antagonism in nigrostriatal pathway)
- rigidity
- mask-like face
- bradykinesia
- dystonias
- akathisia (mm restlessness)
- tardive dyskinesias
Atypical agents have low extrapyramidal effects
Neuroleptic malignant syndrome (rare but fatal effect of haloperidol, flupentixol / chlorpromazine)
Blockade of D2 R in mesolimbic pathway produces clinically useful actions, but may also lead to apathy, sedation, decrease initiative (not w/ new agents)
Non-neurological (blockade of dopaminergic tuberohypophyseal pathway -> increase prolactin secretion -> galactorrhea, amenorrhea, gynecomastia, infertility

PK:

• mots HL = 15-30h
• p.o. / i.m. injection
• doses individualized
• elderly need lower dosage
• several have been esterified w/ long chain FAs to yield depot formulations that are only slowly absorbed from i.m. site of injection -> fluphenazine decancate (effective up to 28 days)
• increase risk for extrapyramidal symptoms w/ depot forms
• binding to plasma proteins is high (> 90%)
• properidol -> very short-acting and can be used in psychiatric emergencies is also used in anaesthesia and PP