Choosing An Antipsychotic
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Choosing an Antipsychotic REFRENCES
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Transcript of Choosing An Antipsychotic
Choosing an Antipsychotic
REFRENCES
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M, Essential Psychopharmacology (2000)
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
Goals:To quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Goals:To quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
Older and newer antipsychotics show, in general, approximately the same efficacy in countering symptoms of auditory and visual hallucinations, delusional thoughts, and incoherent speech.
Difference Between Low and High States
•The dissociation constant (K) of dopamine for the high-affinity state of the D2 receptor is between 1.7 and 1.8nM.
•The traditional antipsychotics generally have dissociation constants lower than 1.75 nM.
•Virtually all of the atypical antipsychotics have dissociation constants that are higher than 1.75 nM.
•Some antipsychotics with dissociation constants between 1.8 and 10 nM can exhibit dose-dependent extrapyramidal signs (EPS)
•Antipsychotics with dissociation constants higher than 20 nM (clozapine, quetiapine, remoxipride) are bound so loosely that they never elicit
Relevant Occupancy
When fewer than 60% of receptors are occupied (ie, when sub threshold doses are prescribed or when medication is not taken as prescribed), the symptoms of psychosis return
• Motor Side Effects
At 80% occupancy of D2, most people will begin to experience these adverse motor effects. (However, patients on the new atypical compound, aripiprazole, may not exhibit parkinsonism even with 90% occupation of D2 receptors.[8] This drug needs to be studied more thoroughly than has been possible thus far.
• Does 65% Occupancy Need to Be Maintained Full Time?
• How to Prevent Tardive Dyskinesia With First-Generation Drugs
How to Prevent the Negative Syndrome Secondary to Antipsychotic Treatment ?
• Treating Cardiac Patients or Those With a Family History of Cardiac Disease
• Treating Patients With a Family History of Osteoporosis
• Treating Patients With a Family History of Diabetes
• Treating Patients With Sexual Dysfunction
Differences among Antipsychotic Drugs
• All effective antipsychotic drugs block D2 receptors• Chlorpromazine and thioridazine
– block α1 adrenoceptors more potently than D2 receptors– block serotonin 5-HT2 receptors relatively strongly – affinity for D1 receptors is relatively weak
• Haloperidol – acts mainly on D2 receptors– some effect on 5-HT2 and α1 receptors – negligible effects on D1 receptors
• Pimozide and amisulpride†
– act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
• Clozapine – binds more to D4, 5-HT2, α1, and histamine H1
receptors than to either D2 or D1 receptors• Risperidone
– about equally potent in blocking D2 and 5-HT2 receptors
• Olanzapine– more potent as an antagonist of 5-HT2 receptors– lesser potency at D1, D2, and α1 receptors
• Quetiapine– lower-potency compound with relatively similar
antagonism of 5-HT2, D2, α1, and α2 receptors
Differences among Antipsychotic Drugs
• Clozapine, olanzapine and quetiapine– potent inhibitors of H1 histamine receptors– consistent with their sedative properties
• Aripiprazole– partial agonist effects at D2 and 5-HT1A
receptors
Conclusion
• In summary, conventional antipsychotic drugs bind tightly to the dopamine D2 receptors, thereby eliciting EPS, elevated prolactin, and tardive dyskinesia. The newer atypical antipsychotic drugs attach more loosely to the D2 receptors, thus resulting in less or no EPS, no elevation of prolactin, and no risk of tardive dyskinesia. Good clinical practice involves using both types of medication at different times, depending on the specific needs of the patient.
