primary dopamine deficiency D2 receptor blockad e increase in negative and secondary cognitive dopamine symptoms deficiency mesocortical pathway10-11 Stahl S M, Essential Psychopharmacology (2000
Mechanism of Action of Antipsychotic Drugs Dopaminergic Pathways Goals: Presynaptic Dopaminergic Neuron To quiet hyperactive DAneurons that mediatepsychosis Autoreceptor To trigger underactive DAneurons that mediate Antipsychotic drugnegative and cognitivesymptoms Postsynaptic receptor To preserve physiologicfunction in DA neurons thatregulate movement and Postsynaptic neuronprolactin secretion
Older and newer antipsychotics show, ingeneral, approximately the same efficacyin countering symptoms of auditory andvisual 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 dissociationconstants lower than 1.75 nM.•Virtually all of the atypical antipsychotics have dissociationconstants that are higher than 1.75 nM.•Some antipsychotics with dissociation constants between1.8 and 10 nM can exhibit dose-dependent extrapyramidalsigns (EPS)•Antipsychotics with dissociation constants higher than 20nM (clozapine, quetiapine, remoxipride) are bound soloosely that they never elicit
Relevant OccupancyWhen fewer than 60% of receptors are occupied (ie,when sub threshold doses are prescribed or whenmedication is not taken as prescribed), the symptoms ofpsychosis return
• Motor Side EffectsAt 80% occupancy of D2, most people will begin to experiencethese adverse motor effects. (However, patients on the newatypical compound, aripiprazole, may not exhibit parkinsonismeven with 90% occupation of D2 receptors. This drug needs tobe studied more thoroughly than has been possible thus far.
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.