1. Antipsychotics: pharmacodynamics
Domina Petric, MD

2. Dopaminergic systems I.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

3. Dopaminergic systems
Five dopaminergic systems or pathways are important for understanding schizophrenia and the mechanism of action of antipsychotic drugs:
mesolimbic-mesocortical pathway
nigrostriatal pathway
tuberoinfundibular system
medullary-periventricular pathway
incertohypothalamic pathway
Katzung, Masters, Trevor. Basic and clinical pharmacology.

4. Mesolimbic-mesocortical pathway
This is the pathway most closely related to behavior and psychosis.
The mesolimbic-mesocortical pathway projects from cell bodies in the ventral tegmentum in separate bundles of axons to the limbic system and neocortex.
Wikipedia.org
Mesocortical
Mesolimbic
Katzung, Masters, Trevor. Basic and clinical pharmacology.

5. Nigrostriatal pathway
Consists of neurons that project from the substantia nigra to the dorsal striatum.
Dorsal striatum includes the caudate and putamen.
The nigrostriatal pathway is involved in the coordination of voluntary movement.
Blockade of D2 receptors in this pathway is responsible for extrapyramidal symptoms (EPS).
Nigrostriatal pathway
Katzung, Masters, Trevor. Basic and clinical pharmacology.

6. Image source: Pinterest.com
EPS
Image source: Pinterest.com
Katzung, Masters, Trevor. Basic and clinical pharmacology.

7. Tuberoinfundibular system
The tuberoinfundibular system arises in the arcuate nuclei and periventricular neurons: releases dopamine into the pituitary portal circulation.
Dopamine released by these neurons physiologically inhibits prolactin secretion from the anterior pituitary.
Tuberoinfundibular system
Katzung, Masters, Trevor. Basic and clinical pharmacology.

8. Medullary-periventricular pathway
Consists of neurons in the motor nucleus of the vagus.
These projections are not well defined.
This system may be involved in eating behavior.
Eating behavior
Katzung, Masters, Trevor. Basic and clinical pharmacology.

9. Incertohypothalamic pathways
Forms connections from the medial zona incerta to the hypothalamus and the amygdala.
It appears to regulate the anticipatory motivational phase of copulatory behavior in rats.
Usdbiology.com
Katzung, Masters, Trevor. Basic and clinical pharmacology.

10. Dopamine pathways and systems
Mesolimbic-mesocortical
Tuberoinfundibular
Incertohypothalamic
Behavior, psychosis
Inhibition of prolactin (PRL) secretion from the anterior pituitary
Copulatory behavior in rats
Behavior
EPS
PRL
Food
Sex
Nigrostriatal
Medullary-periventricular
Coordination of voluntary movement
Eating behavior
Katzung, Masters, Trevor. Basic and clinical pharmacology.

11. Dopamine
Dopamine effects electrical activity in central synapses and production of the second messenger cAMP synthesized by adenylyl cyclase.
Dopamine-receptor antagonists, such as chlorpromazine, haloperidol and thiothixene, block the effect of dopamine to inhibit the activity of adenylyl cyclase in the mesolimbic system.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

12. Dopamine receptors and their effects
II.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

13. Dopamine receptors and their effects
Five dopamine receptors have been described.
Two separate families: the D1-like and D2-like receptor groups.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

14. Dopamine receptors and their effects
D1-like receptor group
The D1 receptor is coded by a gene on chromosome 5.
D1 receptor increases cAMP by GS-coupled activation of adenylyl cyclase.
It is located mainly in the putamen, nucleus accumbens, olfactory tubercle and cortex.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

15. Dopamine receptors and their effects
D1-like receptor group
D5 receptor is coded by a gene on chromosome 4.
It also increases cAMP.
It is found in the hippocampus and hypothalamus.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

16. Dopamine receptors and their effects
D1-like receptor group
The therapeutic potency of antipsychotic drugs does not correlate with their affinity for binding to the D1 receptor.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

17. Dopamine receptors and their effects
D2-like receptor group
The D2 receptor is coded on chromosome 11.
It decreases cAMP by Gi-coupled inhibition of adenylyl cyclase.
This receptor inhibits calcium channels, but opens potassium channels.
It is found both presynaptically and postsynaptically on neurons in the caudate-putamen, nucleus accumbens and olfactory tubercle.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

18. Dopamine receptors and their effects
D2-like receptor group
D3 receptor is coded by a gene on chromosome 11.
It also decreases cAMP.
It is located in the frontal cortex, medulla and midbrain.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

19. Dopamine receptors and their effects
D2-like receptor group
D4 receptors also decrease cAMP.
These receptors are concentrated in the cortex.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

20. D5 receptor increases cAMP: hippocampus, hypothalamus.
Dopamine receptors
D1 receptor
Increases cAMP: putamen, nucleus accumbens, olfactory tubercle and cortex.
D1-like
D2-like
D2 receptor
Dopamine
Decreases cAMP: caudate-putamen, nucleus accumbens, olfactory tubercle.
D3 receptor
Decreases cAMP: frontal cortex, medulla, midbrain.
D5 receptor increases cAMP: hippocampus, hypothalamus.
D4 receptor
Decreases cAMP: cortex.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

21. Dopamine receptors and their effects
The typical antipsychotic agents block D2 receptors stereoselectively for the most part.
Their binding affinity is very strongly correlated with clinical antipsychotic and extrapyramidal potency.
The typical antipsychotic drugs must be given in sufficient doses to achieve at least 60% occupancy of striatal D2 receptors.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

22. Dopamine receptors and their effects
Atypical antipsychotic drugs, such as clozapine and olanzapine, are effective at lower occupancy levels of 30-50%.
This is most likely because of their concurrent high occupancy of 5-HT2A receptors.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

23. Dopamine receptors and their effects
The typical antipsychotic drugs produce EPS when the occupancy of striatal D2 receptors reaches 80% or higher.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

24. Aripiprazole Aripiprazole causes very high occupancy of D2 receptors.
This drug does not cause EPS because it is a partial D2 receptor agonist.
Aripiprazole also gains therapeutic efficacy through its 5-HT2A antagonism and possibly 5-HT1A partial agonism.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

25. Differences among antipsychotics
III.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

26. Differences among antipsychotics
Chlorpromazine: α1=5-HT2A>D2>D1
Haloperidol: D2>α1>D4>5-HT2A>D1>H1
Clozapine: D4=α1>5-HT2A>D2=D1
Olanzapine: 5-HT2A>H1>D4>D2>α1>D1
Aripiprazole: D2=5-HT2A>D4>α1=H1>>D1
Quetiapine: H1>α1>M1,3>D2>5-HT2A
Katzung, Masters, Trevor. Basic and clinical pharmacology.

27. Adverse pharmacologic effects of antipsychotics
Type
Manifestations
Mechanism
Autonomic nervous system
Loss of accommodation, dry mouth, difficulty urinating, constipation
Muscarinic cholinoceptor blockade
Central nervous system
Parkinson´s syndrome, akathisia, dystonias
Dopamine-receptor blockade
Tardive dyskinesia
Supersensitivity of dopamine receptors
Toxic-confusional state
Muscarinic blockade
Endocrine system
Amenorrhea-galactorrhea, infertility, impotence
Dopamine-receptor blockade resulting in hyperprolactinemia
Other
Weight gain
Possibly combined H1 and 5-HT2 blockade
Katzung, Masters, Trevor. Basic and clinical pharmacology.

28. Psychological effects
IV.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

29. Psychological effects
Most antipsychotic drugs cause unpleasant subjective effects in nonpsychotic individuals.
People without psychiatric illness given antipsychotic drugs, even at low doses, experience impaired performance as judged by a number of psychomotor and psychometric tests.
Psychotic individuals may show improvement in their performance as the psychosis is alleviated.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

30. Psychological effects
Some individuals with schizophrenia and bipolar disorder experience marked improvement of cognition with antipsychotics, some do not.
Cognition should be assessed in all patients with schizophrenia.
A trial of an atypical agent should be considered, even if positive symptoms are well controlled by typical agents.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

31. Electroencephalographic effectsV.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

32. EEG effects
Antipsychotics produce shifts in the pattern of EEG frequencies, usually slowing them and increasing their synchronization.
The slowing (hypersynchrony) is cometimes focal or unilateral, which may lead to erroneous diagnostic interpretations.
Some of the neuroleptic agents lower the seizure threshold and induce EEG patterns typical of seizure disorders.
With careful dosage titration, most can be used safely in epileptic patients.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

33. Endocrine effects
VI.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

34. Endocrine effects
Older typical antipsychotics, as well as risperidone and paliperidone, produce elevations of prolactin.
Newer antipsychotics olanzapine, quetiapine and aripiprazole cause no or minimal increases of prolactin.
They have reduced risk of extrapyramidal system dysfunction and tardive dyskinesia: diminished D2 antagonism.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

35. Cardiovascular effects
VII.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

36. Cardiovascular effects
The low potency phenothiazines frequently cause orthostatic hypotension and tachycardia.
Mean arterial pressure, peripheral resistance and stroke volume are decreased.
These effects are predictable from the autonomic actions of these agents.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

37. Cardiovascular effects
Abnormal ECG have been recorded, especially with thioridazine.
Changes include prolongation of QT interval and abnormal configurations of the ST segment and T waves.
These changes are readily reversed by withdrawing the drug.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

38. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Literature
Katzung, Masters, Trevor. Basic and clinical pharmacology.
Wikipedia.org
Pinterest.com
Usdbiology.com
Katzung, Masters, Trevor. Basic and clinical pharmacology.