A/27. 1 st generation (“typical”) antipsychotic agents

Question 1

Drugs need to know in this topic

Answer 1

chlorpromazine

flupentixole

haloperidol

droperidol

Question 2

Psychosis – definition and proposed mechanisms

Answer 2

1. Psychosis is a collection of psychological symptoms resulting in a loss of contact with reality.
2. The DSM-5 characterizes disorders as psychotic or on the schizophrenia spectrum as disorders having either positive or negative symptoms:

• *Positive symptoms**
  1. Thought disorders
  2. Delusions
  3. Hallucinations
  4. Paranoia/Catatonia
  5. Disorganized speech
• *Negative symptoms**
  1. Amotivation
  2. Social withdrawal
  3. Flat affect (reduction in emotional expressiveness) Poverty of speech
  4. Anhedonia (inability to feel pleasure)

Question 3

Psychosis – proposed mechanisms

Answer 3

Dopamine hypothesis of psychosis: States that the unusual behaviour and experiences associated with psychosis can be fully or largely explained by changes in dopamine function in the brain

Serotonin (5-HT) hypothesis of psychosis: States that excessive serotonergic stimulation in the cerebral cortex is the basic cause of the disease

Dysregulation hypothesis of psychosis: Psychosis is a multifactorial condition, affected by multiple pathways and neurotransmitter interactions (GABA,
glutamate, 5-HT, dopamine)

Question 4

Clinical uses of antipsychotic agents

Answer 4

1. Treatment of schizophrenia and other psychotic disorders (ex. psychotic depression, schizoaffective disorder)
2. (typical agents have no effect on negative symptoms; atypical agents exert beneficial effects on both positive and negative symptoms)
3. Initial treatment of bipolar disorders (atypical agents only), usually in combination with Lithium
4. Management of toxic (acute) psychosis due to overdose by CNS stimulants
5. Tourette’s syndrome
6. Huntington’s disease
7. Potential role in the management of Alzheimer’s disease and Parkinson’s disease (atypical agents only)
8. Antiemetic activity (due to H1 blockade)

Question 5

Chlorpromazine

Answer 5

D2 Block (low potency)

D2 > 5-HT2A antagonists

acute psychoses

Corneal depositions (high dose)

Question 6

Haloperidol

Answer 6

D2 block (high potency)

most used 1st gen in acute treatment despite its high level of
EPS
high D2 affinity

Question 7

Droperidol

Answer 7

D2 block (high potency)

1. Anti-emetic use (with potent sedative
   effect)
2. Used in combination with fentanyl in
   neuroleptanalgesia
3. Potential use in general anesthesia
   regimens

Question 8

Flupentixol

Answer 8

D2 block (high potency)

Question 9

Pharmacokinetic properties

Answer 9

1. Good oral bioavailability
2. Parenteral preparations available for both rapid initiation of therapy and depot formulations
3. Long T1/2 – allows once daily dosing
4. Hepatic P450 metabolism
5. High lipid solubility – freely penetrate the CNS

Question 10

Adverse effects and toxicity

Answer 10

Mnemonics (STANCE)

Sedation and Sunlight sensitivity

Tardive dyskinesia (TD) : involuntary, repetitive movements, which may
include muscles of the lips, buccal muscles, and tongue.

Anticholinergic and agranulocytosis

Neuroleptic malignant syndrome(NMS): Thermo-regulation abnormalities

Cardiac arrhythmias

Extrapyramidal symptoms (EPS):drug-induced parkinsonism