Antipsychotic drugs - French

Question 1

Name and describe 4 dopamine pathways.

Answer 1

1. Mesolimbic (VTA –> NAc)
2. Mesocortical (VTA –> frontal cortex)
3. Nigrostriatal (SN –> Striatum)
4. Tuberoinfundibular (Hypothalamic release of dopamine prevents prolactin release)

Question 2

Hyperactivity in the mesolimbic pathway accounts for what type of symptoms?

What category of drugs is useful for relieving these symptoms?

Answer 2

Positive symptoms (hallucinations, delusions)

Antipsychotic agents (via D2 dopamine receptor blockade)

Question 3

Hypoactivity in the mesocortical pathway accounts for what type of symptoms?

What category of drugs is useful for relieving these symptoms?

Answer 3

Negative symptoms (flattening, disordered speech, disordered thought)

atypical antipsychotic agents such as CLOZAPINE or olanzapine (via additional BLOCK of 5HT2A receptors)

Question 4

D2 receptor blockade often causes side effects related to the nigrostriatal and tuberoinfundibular pathways. What side effects stem from each?

Answer 4

Nigrostriatal–> extrapyramidal symptoms

Tuberoinfundibular–> blockade of dopamine receptors causes prolactin release. Leads to weight gain, hyperprolactinemia, and interferes with body temperature regulation (poikilothermia)

Question 5

LSD and other hallucinogens act as ____ agonists and activation of _____ receptors leads to the hallucinogenic effects.

Answer 5

serotonin; 5HT2A

Question 6

Activation of 5HT2A receptors on DA neurons in the PFC
will (INcrease or DECrease) DA release leading to (NEGative or POSitive) symptoms?

So would an antagonist or agonist be desired?

Answer 6

Decrease

Negative

Antagonist

Question 7

Activation of 5HT2A receptors on glutamate pyramidal cells in the PFC result in stimulation of DA neurons in VTA will (increase or decrease) DA release in the mesolimbic pathway leading to (positive or negative) symptoms?

Treat with antagonist or agonist?

Answer 7

Increase

Positive

Antagonist

Question 8

What is the glutamate hypothesis?

Account for both positive and negative symptoms.

Answer 8

HYPOfunction of NMDA receptors located on GABAergic interneurons in the PFC leads to decreased inhibitory tone, which INCREASES CORTICAL OUTPUT, resulting in:

1) increased mesolimbic DA release (+ symptoms)
2) decreased mesocortical DA release (- symptoms)

Question 9

“Typical” agents (1st generation) are characterized by what? What is the adverse affect?

Answer 9

Characterized by a high D2 / 5HT2A ratio corresponding to good D2 block and good efficacy against positive symptoms of schizophrenia. But this good D2 block is also associated with a high incidence of extrapyramidal toxicity.

Question 10

Name two typical agents. State their potency and the side effect fallout.

Answer 10

Haloperidol - High potency. Lower doses can be used with good efficacy, greater risk of extrapyramidal toxicity.

Chlorpromazine - Low potency. Higher doses required leads to antimuscarinic, α1-blockade, and antihistamine side effects.

Question 11

What explains the most significant pharmacologic effects of antipsychotic agents?

Answer 11

D2 blockade.

[BUT efficacy has been found in antipsychotic agents that block 5HT2 receptors without possessing potent blockade of D2 receptors]

Question 12

What characterizes “atypical” agents (2nd generation)?

Answer 12

Characterized by a low D2 / 5HT2A ratio corresponding to poor D2 block yet… good efficacy in schizophrenia

Mnemonic: (an “atypical” observation).

Good efficacy against NEGATIVE symptoms of schizophrenia.

Question 13

Name 3 atypical agents. [4 bonus]

Answer 13

Aripiprazole (Abilify)
Clozapine
Olanzapine

[Bonus: Quetiapine]

Question 14

Will antipsychotic agents cross the placenta? Will they distribute into breast milk?

Answer 14

Yes, and yes.

Question 15

As a general rule, what can guide selection of a typical vs atypical antipsychotic, with regard to control of positive/negative symptoms?

Answer 15

Both are effective at controlling positive symptoms.

Atypical are more effective at resolving negative symptoms.

Question 16

______ is effective in majority of schizophrenic patients that are refractory to other drugs. It should be reserved for this specific indication because of frequency of substantial increases in weight and lipids as well as a 1-2 % incidence of agranulocytosis.

Answer 16

Clozapine

Question 17

What is the side effect profile of Chlorprozamine?

Answer 17

1) Dry mouth, constipation ( Autonomic - Muscarinic blockade)
2) orthostatic hypotension (α1-adrenergic blockade)
3) Sedation (Muscarinic blockade, antihistamine activity)

Question 18

What is the main side effect of note for Haloperidol?

Answer 18

Considerable EPS profile

Question 19

What are two main side effects of Risperidone? (Atypical)

Answer 19

Extrapyramidal dysfunction, hypotension with high dose

Question 20

What are two main side effects of Olanzapine (Atypical)

Answer 20

EPS, lowering of seizure threshold.

Question 21

Your patient is concerned about feeling “sleepy” while taking antipsychotic meds. What two might you consider?

Answer 21

Aripiprazole

Risperidone

Question 22

Your patient is concerned about weight gain. What antipsychotic medications might you avoid prescribing?

What might you prescribe?

Answer 22

Olanzapine
Clozapine

Try aripiprazole.

Question 23

This drug is generic and inexpensive, but has many autonomic side effects.

Answer 23

Chlorpromazine

Question 24

This drug is generic, but causes severe extrapyramidal syndrome

Answer 24

Haloperidol

Question 25

This drug should be considered for treatment-resistant patients, and has few EPS side effects. However, it is associated with agranulocytosis or seizures in a small percent of patients.

Answer 25

Clozapine

Question 26

This drug has broad efficacy, with little or no EPS effects at low dose. At high doses the EPS profile increases, and patients may be at risk of hypotension.

Answer 26

Risperidone

Question 27

This drug is effective against both positive and negative symptoms, with little EPS dysfunction. However, it lowers the seizure threshold and can cause weight gain.

Answer 27

Olanzapine.

Question 28

This drug has a lower weight gain risk, longer half life, and has few known side effects.

Answer 28

Aripiprazole