Antipsychotics

Question 1

What do NMDA antagonists cause?

What reverses this?

Answer 1

Positive, neg, and cog sxs. Increased glycine promotes glutamate binding to NMDA receptors –> improvement in neg and cog sxs.

Question 2

What is the mechanism of LSD?

Answer 2

5HT2a partial agonist inhibits NMDA transmission.

Question 3

What transporter do ALL antipsychotics block? What other transporters are commonly blocked?

Answer 3

All reduce D2 mediated transmission. Most are also antagonists at alpha-1a, 5HT2a, and H1 receptors.

Question 4

5 extrapyramidal sxs and treatments

Answer 4

• Acute dystonia: spasms of tongue, face, neck, back muscles; TX: anticholinergics (trihexyphenidyl, diphenhydramine [benadryl])
• Akathisia: uncontrollable urge to be in motion; pacing, restlessness; TX: reduce dose; benzodiazepines, nonselective beta blockers, anticholinergics. Propranolol is DOC.
• Parkinsonism: bradykinesia, rigidity, tremor, shuffling gait; TX: reduce dose; anticholinergics
• Perioral tremor (“rabbit syndrome”): involuntary, fine, rhythmic motions of the mouth along a vertical plane; onset months-to-years; TX: anticholinergics (trihexyphenidyl, diphenhydramine)
• Tardive dyskinesia: worm-like twisting movements of tongue, mouth, and face; onset months-to-years; no reliable TX, often irreversible

Question 5

Neuroleptic Malignant Syndrome
Time course
Sxs
Tx
Differences from SS

Answer 5

• Usually occurs w/in 10 days
• Agitated delirium, progressing to lethargy, stupor, coma; patient appears dazed and disoriented; incoherent speech, becomes mute
• Extreme “lead pipe” rigidity, tremor
• Hyperthermia > 38 degrees C (up to 41)
• Autonomic instability – tachycardia, unstable BP, and diaphoresis
• Tx – DC antipsychotic immediately, give dantrolene (blocks Ca release from sarcoplasmic reticulum to prevent muscle contraction) and bromocriptine (DA agonist, reversing DA blockade)
• Differences from Serotonin Syndrome
• Time of onset is much faster for SS
• Increased bowel tone / sounds in SS (decreased in NMS)
• Hyperreflexia in SS (rigid in NMS)
• Pupils are dilated in SS (mydriasis; normal in NMS).

Question 6

Adverse effects of antipsychotics

Answer 6

• Anticholinergic effects (muscarinic blockade)
• Orthostatic hypotension (α1 blockade)
• Sedation (H1 blockade)
• Hyperprolactinemia (D2 blockade in pituitary) - DA decreases prolactin release. Blockade increases release.
• Seizures (less than 1%, but clozapine 3-5%)
• Sexual dysfunction
• Dermatoses, photosensitivity
• Cardiac dysrhythmias, QTc prolongation (hERG K+ channel blockade).
• Metabolic effects
• Weight gain
• Hyperlipidemia
• Insulin insensitivity, hyperglycemia
• Agranulocytosis: clozapine (2%) – mainly a decrease in neutrophils. Must measure ANC (absolute neutrophil count) every 2 weeks.

Question 7

Which drug is good for pxs who are resistant to other drugs?
What is the main side effect with this drug?

Answer 7

Clozapine

Risk of agranulocytosis.

Question 8

Drug window for antipsychotics

Answer 8

Require occupation of 60% of D2 receptors for antipsychotic effects to work. EPS begins at occupation of > 80% of D2 receptors.

Question 9

Chlorpromazine
Type
Mechanism
Adverse rxns
Precautions

Answer 9

Typical. 1st ever antipsychotic.
•Mechanism – D2 receptor antagonist. Strong anticholinergic / a1 receptor blocking effects. Effects are gradual, taking up to 6 months.
•Adverse rxns (see above)
•Precautions
• CNS: depression, coma, encephalopathy, head trauma, ethanol intoxication
• Labor

Question 10

Haloperidol
Type
Comparison to chlorpromazine
Mechanism
Adverse rxns
Precautions

Answer 10

Typical. 50x more potent than chlorpromazine. Less sedating but much greater EPS, possibly due to lower anticholinergic effects. Most common cause of EPS.
•Mechanism – D2 receptor antagonist
•May be injected once a month
•Adverse rxns (see above)
•Precautions – depression, coma, and encephalopathy

Question 11

What is the most common cause of EPS?

Answer 11

Haldol

Question 12

Aripiprazole
Brand name
Type
Use
Mechanism
Adverse rxns

Answer 12

Abilify
Atypical
•Use – antipsychotic and bipolar disorder
•Mechanism – binds to D2, D3, D4, 5-HT1A, 5-HT2A, 5-HT2C, 5-HT7, a1, and H1 receptors. Partial agonist at D2 and 5-HT1A sites
•Anxiolytic effects due to action on 5HT1a receptor
•Can be injected once a month
•Adverse rxns
• CNS – akathisia, sedation, restlessness, tremor
• GI: NV, constipation, weight gain
• Most atypicals cause elevations in blood glucose and decreased insulin sensitivity, but this is rare w/ aripiprazole.

Question 13

Quetiapine
Type
Use
Mechanism
Adverse rxns

Answer 13

Atypical
•Use – Antipsychotic and bipolar.
•Mechanism – antagonist or inverse agonist at D2, 5HT1a, 5HT2a, M1, a1, and H1 receptors.
•Adverse rxns
•	GI: xerostomia, constipation
•	CNS: drowsiness, agitation, dizziness
•	HYPERLIPIDEMIA
•	WEIGHT GAIN
•	Elevation in blood glucose, decreased insulin sensitivity, and unmasking diabetes

Question 14

Olanzapine
Type
Comparison to Quetiapine
Use
Mechanism
Adverse rxns

Answer 14

Atypical. More potent than quetiapine.
•Use – 1st line for psychosis. Also used for agitation, acute mania, and bipolar disorder.
•Mechanism – potent antagonist at D1-D4 receptors, 5-HT2A and 5-HT2C receptors, M1-M5 receptors, a1 receptors, and H1 receptors
•8X more potent at 5-HT2A receptors than D2 receptors
•May be injected once a month
•Adverse rxns
• CNS: drowsiness
• GI: xerostomia, elevated LFTs, weight gain
• Elevated blood glucose, decreased insulin sensitivity, and unmasking diabetes.

Question 15

Risperidone
Type
Use
Mechanism
Adverse rxns

Answer 15

Atypical.
•Use – Antipsychotic and bipolar.
•Mechanism – Antagonist or inverse agonist at D2, D4, 5-HT1A, 5-HT2A, 5-HT2C, a1, H1 receptors
•Adverse rxns
•	CNS: parkinsonism, akathisia
•	Rash
•	Weight gain
•	Elevated blood glucose, decreased insulin sensitivity, diabetes

Question 16

Main side effect of Ziprasidone

Answer 16

Very long QT prolongation (21 msec)

Question 17

Other indications for antipsychotics

Answer 17

• Delirium and dementia with psychotic features
• Disruptive behaviors associated with autism or mental retardation
• Emesis
• Acute mania
• Intractable hiccups
• Tourette’s syndrome, tics
• Adjuncts to uptake inhibitors for anxiety disorders or major depression