1. Pharmacodynamics: How do antipsychotic medications work?
Sz Consult ECHO
April 10, 2018
Sara Dugan, Pharm.D., BCPP, BCPS

2. Objectives
To identify common pharmacologic targets of first and second generation antipsychotic medications
To describe proposed therapeutic actions of first and second generation antipsychotic medications
To compare adverse effect profiles of the first and second generation antipsychotic medications

3. Definition Pharmacodynamics
A branch of pharmacology dealing with the reactions between drugs and living systems
- Merriam-Webster dictionary
The branch of pharmacology concerned with the action of drugs on the physiology or pathology of the body
-dictionary.com ;

4. Chlorpromazine
Haloperidol
Fluphenazine
Perphenazine
Thioridazine
Thiothixene
Trifluoperazine
Molindone
Loxitane
Clozapine
Olanzapine
Quetiapine
Risperidone
Aripiprazole
Asenapine
Iloperidone
Paliperidone
Ziprasidone
Brexpiprazole
Cariprazine
Lurasidone

5. Chlorpromazine
Haloperidol
Fluphenazine
Perphenazine
Thioridazine
Thiothixene
Trifluoperazine
Molindone
Loxitane
Clozapine
Olanzapine
Quetiapine
Risperidone
Aripiprazole
Asenapine
Iloperidone
Paliperidone
Ziprasidone
Brexpiprazole
Cariprazine
Lurasidone

6. First Generation Antipsychotics (FGA)
Potency
Generic Name
Chlorpromazine Equivalents
Olanzapine 1 mg equivalent oral form defined daily dose
High
Haloperidol 2
0.8
Fluphenazine 1
Thiothixene 4 3
Trifluoperazine 5
Perphenazine 8
Loxapine 10
Thioridazine
100 30
Low
Chlorpromazine

7. Actions of FGAs FGA Therapeutic actions Adverse effect 1 D2
Dopamine (D2) blockade*
Adverse effect
Dopamine (D2) blockade
Movement disorders, prolactin elevation
Histamine (H1) receptor blockade
Sedation, weight gain
Muscarinic (M1) receptor blockade
Blurred vision, constipation, dry mouth, urinary retention
Noradrenergic (1) receptor blockade
Orthostatic hypotension H1 M1 1
FGA D2

8. Actions with DA blockade3 1 2 4
Dopamine (DA) tract
Action
Actions with DA blockade
1- Nigrostriatal
Regulates movement
Extrapyramidal Side Effects
2- Mesolimbic
Arousal, memory, motivational behavior, stimulus processing
Relief of psychotic symptoms
3- Mesocortical
Cognition, communication, response to stress, social function
Relief of psychotic symptoms, akathisia
4- Tuberoinfundibular
Regulates prolactin release
Elevated prolactin levels

9. FGAs: Side Effect Comparison
Medication
Sedation
EPS
Anticholinergic Effects
Orthostatic
Hypotension
Weight gain
chlorpromazine
HIGH
Low
thioridazine
Mod
loxapine
perphenazine
trifluoperazine
thiothixene
fluphenazine
haloperidol
Will vary slightly depending on source.

10. Chlorpromazine
Haloperidol
Fluphenazine
Perphenazine
Thioridazine
Thiothixene
Trifluoperazine
Molindone
Loxitane
Clozapine
Olanzapine
Quetiapine
Risperidone
Aripiprazole
Asenapine
Iloperidone
Paliperidone
Ziprasidone
Brexpiprazole
Cariprazine
Lurasidone

11. Second Generation Antipsychotics (SGA)
Generic Name
Olanzapine Equivalents 1mg oral form defined daily dose
Aripiprazole
1.5
Asenapine 2
Brexpiprazole
Cariprazine
Clozapine 30
Iloperidone
Lurasidone 6
Olanzapine 1
Paliperidone
0.6
Quetiapine 40
Risperidone
0.5
Ziprasidone 8
Leucht S, et al. Schiz Bull 2016;42(Suppl1):S90-S94.

12. Second Generation Antipsychotics
Receptor
Proposed Activity
Dopamine (D2) partial agonism vs. antagonism
Relief of psychosis
Extrapyramidal effects (EPS)
Prolactin elevation
Histamine (H1) antagonism
Sedation
Weight gain
Muscarinic (M1) antagonism
Blurred vision
Constipation
Dry mouth
Urinary retention
Noradrenergic (α1) antagonism
Orthostatic hypotension
Serotonergic (5HT2A) antagonism
Role with EPS?
Serotonergic (5HT2C) antagonism
Satiety blockade

13. Actions with DA blockade3 1 2 4
Dopamine (DA) tract
Action
Actions with DA blockade
1- Nigrostriatal
Regulates movement
Extrapyramidal Side Effects
2- Mesolimbic
Arousal, memory, motivational behavior, stimulus processing
Relief of psychotic symptoms
3- Mesocortical
Cognition, communication, response to stress, social function
Relief of psychotic symptoms, akathisia
4- Tuberoinfundibular
Regulates prolactin release
Elevated prolactin levels

14. 5HT2A Antagonists Blockade of 5HT 2A receptor Dopamine 5HT2A receptor
Dopaminergic neurons
Facilitates release of dopamine in nigrostriatal pathway
Interactions with other neurons
Glutamatergic neurons
Reduce activation
Diminish signaling of GABA receptors
Dopamine
5HT2A receptor
Dopaminergic Neuron
5HT2A antagonist

15. Side Effects of SGA Drug Weight Lipids Glucose Movement Disorders
Sedation
Anticholinergic
Clozapine
+++ + ++
Risperidone
Olanzapine
Quetiapine
Ziprasidone
Aripiprazole
Paliperidone
Asenapine
Iloperidone
Lurasidone
Brexpiprazole
Cariprazine

16. Tolerability and adherence
Summary
Adverse effects
Tolerability and adherence
Therapeutic effect
Antipsychotics work on a variety of neurotransmitters
Desired therapeutic effects often have to be balanced with adverse effect profile
Individual variability makes it continually challenging