1. Department of Psychiatry University of Illinois at Chicago
PHARMACODYNAMICS OF
ANTIPSYCHOTICS
ANXIOLYTICS
AND
SEDATIVE-HYPNOTICS
Yogesh Dwivedi, Ph.D.
Associate Professor
Department of Psychiatry
University of Illinois at Chicago

2. Psychosis Symptoms Positive Symptoms Delusion Hallucination
Disorganized speech
Disorganized behavior
Agitation
Negative Symptoms
Passivity
Apathetic social withdrawal
Stereotyped thinking
Anhedonia (loss of joy)
Attentional impairment
Emotional withdrawal
Cognitive Symptoms
Impaired verbal fluency
Problems with serial learning
Problems with focusing attention
Concentration

3. Neurodevelopmental Hypothesis of Schizophrenia

4. Neurodegenerative Hypothesis of Schizophrenia
(progressive loss of neuronal functions during the course of disease)
Stages of Schizophrenia Over a Life Time
Asymptomatic
Negative
symptoms
Positive symptoms
Negative/cognitive
symptoms
% of Brain Functioning
Age (years)
Increased excitatory glutamatergic neurotransmission

5. NMDA type glutamate receptor is a ligand-gated Ca2+ ion channel
Binding of glutamate causes opening of the channel and thus excitatory neurotransmission

6. Dopamine Pathway Limbic cortex Anterior pituitary
a = nigrostriatal pathway
b = mesolimbic pathway: Increase in dopamine causes positive symptoms
of schizophrenia
c = mesocortical pathway: Deficit in dopamine causes negative and cognitive
symptoms of schizophrenia
d = tuberoinfundibular pathway

7. Key Dopamine Pathways Mesolimbic pathway Mesocortical pathway
Increased dopamine in this pathway is associated with positive symptoms of
schizophrenia
Mesocortical pathway
Deficit in dopamine in this pathway is associated with negative and cognitive symptoms
of schizophrenia
Nigrostriatal pathway
Part of extrapyramidal system and controls motor movement
Blockade of D2 receptors causes:
-- movement disorder such as Parkinson’s disease (rigidity, akinesia, dystonia)
-- hyperkinetic movement such as tardive dyskinesia
Tuberoinfundibular pathway
Normally neurons of this pathway are active and inhibit prolactin release
Blockade of D2 receptor increases prolactin release and causes:
-- galactorrhea
-- amenorrhea

8. Pharmacodynamics of Antipsychotics

9. Antipsychotics First generation Second generation Chlorpromazine
Acetaphenazine
Fluphenazine
Haloperidol
Trifluoperazine
Triflupromazine
Second generation
Clozapine
Risperidone
Olanzapine
Quetiapine
Ziprasidone

10. DOPAMINE SYMPTOMS
Positive
Negative
EPS
Increases prolactin
release

11. First Generation Antipsychotics
Blockade of D2 receptors in mesolimbic pathway, resulting in reduced
positive symptoms of schizophrenia
Blockade of D2 receptors in mesocortical pathway, which is already
deficient in schizophrenia, causes cognitive symptoms or worsen
negative symptoms
Blockade of D2 receptors in nigrostriatal pathway, produces EPS
such as motor abnormalities (parkinsonism), tardive dyskinesia
or hyperkinetic movement disorder
Blockade of D2 receptors in tuberoinfundibular pathway causes
hyperprolactinemia
side effects:
dry mouth, blurred vision,
drowsiness, weight gain, dizziness, low bp
cholinergic properties: EPS
Chlorpromazine
Stahl, 2002

12. Anticholinergic (M1) Drugs and EPS (Acetylcholine may cause EPS)2 3
Dopamine and acetylchilone has reciprocal relationship
Stronger anticholinergic agents cause fewer EPS

13. Second Generation Antipsychotics
5HT2A and D2 antagonists (SDAs)

14. Serotonin-Dopamine Interaction1

15. 3 2 Key: 5HT interact with 5HT2A receptors at postsynaptic level
both at DA cell bodies and at axon terminals and inhibits
the release of DA or
5HT2A antagonists cause more release of DA
The action of 5HT2A and D2 antagonism causes different effects
in different dopamine pathways

16. Key Dopamine Pathways Mesolimbic pathway Mesocortical pathway
More dopamine or hyperactivity on this pathway is associated with positive symptoms
of schizophrenia
Mesocortical pathway
Deficit in dopamine in this pathway is associated with negative and cognitive symptoms
Nigrostriatal pathway
Part of extrapyramidal system and controls motor movement
Blockade of D2 receptors causes:
-- deficiency in dopamine in this pathway and thus movement disorder such
as Parkinson’s disease
-- hyperkinetic movement such as tardive dyskinesia
Tuberoinfundibular pathway
Increased neuronal activity of this pathway inhibits prolactin release
Blockade of D2 receptor increases prolactin release and causes:
-- galactorrhea
-- amenorrhea

17. In mesolimbic pathway the action of D2 receptor blockade of
antipsychotics are more robust than 5HT2A antagonism. This may help
reducing positive symptoms

18. Key Dopamine Pathways Mesolimbic pathway Mesocortical pathway
Hyperactivity on this pathway is associated with positive symptoms of schizophrenia
Mesocortical pathway
Deficit in dopamine in this pathway is associated with negative and cognitive symptoms
of schizophrenia
Nigrostriatal pathway
Part of extrapyramidal system and controls motor movement
Blockade of D2 receptors causes:
-- deficiency in dopamine in this pathway and thus movement disorder such
as Parkinson’s disease
-- hyperkinetic movement such as tardive dyskinesia
Tuberoinfundibular pathway
Increased neuronal activity of this pathway inhibits prolactin release
Blockade of D2 receptor increases prolactin release and causes:
-- galactorrhea
-- amenorrhea

19. In mesocortical pathway, dopamine deficiency causes negative and
cognitive symptoms. In mesocortical pathway, there is more 5HT2A
receptors than D2 receptors. Thus 5HT antagonistic property is more
profound than D2 receptor blocking property. This may help improve
negative symptoms

20. Key Dopamine Pathways Mesolimbic pathway Mesocortical pathway
Hyperactivity on this pathway is associated with positive symptoms of schizophrenia
Mesocortical pathway
Deficit in dopamine in this pathway is associated with negative and cognitive symptoms
of schizophrenia
Nigrostriatal pathway
Part of extrapyramidal system and controls motor movement
Blockade of D2 receptors causes:
-- deficiency in dopamine in this pathway and thus movement disorder such
as Parkinson’s disease
-- hyperkinetic movement such as tardive dyskinesia
Tuberoinfundibular pathway
Increased neuronal activity of this pathway inhibits prolactin release
Blockade of D2 receptor increases prolactin release and causes:
-- galactorrhea
-- amenorrhea

21. In nigrostriatal pathway: 5HT2A antagonists bind to 5HT2A receptors and
block the release of 5HT and thus cause more DA to be released.
This may reduce EPS 1 2 3 4

22. Key Dopamine Pathways Mesolimbic pathway Mesocortical pathway
Hyperactivity on this pathway is associated with positive symptoms of schizophrenia
Mesocortical pathway
Deficit in dopamine in this pathway is associated with negative and cognitive symptoms
of schizophrenia
Nigrostriatal pathway
Part of extrapyramidal system and controls motor movement
Blockade of D2 receptors causes:
-- deficiency in dopamine in this pathway and thus movement disorder such
as Parkinson’s disease
-- hyperkinetic movement such as tardive dyskinesia
Tuberoinfundibular pathway
Increased neuronal activity of this pathway inhibits prolactin release
Blockade of D2 receptor increases prolactin release and causes:
-- galactorrhea
-- amenorrhea

23. In tuberoinfundibular pathway: D2 blockade causes release of prolactin,
whereas, blocking 5HT2A inhibits release of prolactin. Antagonistic
properties of antipsychotics cancel DA and 5HT2A action 1 2 3 4

24. Other Actions of Second Generation Antipsychotics
Clozapine:
Very few EPS
No prolactin release
Causes agranulocytosis
Weight gain
Seizures
Sedative
Risperidone:
EPS at high dose
Low TD
Less weight gain
Ziprasidone:
Very few EPS
No prolactin release
No weight gain
SRI and NRI, thus act as AD
and anxiolytic
Quetiapine:
No EPS
No prolactin release
Weight gain
Olanzapine:
No prolactin release
Nonsedative
Weight gain
Low level of TD
Stahl, 2002

25. Pharmacodynamics of Anxiolytics/
Sedative-Hypnotics

26. Ionotropic GABA Receptors
Benzodiazepine
GABA
a subunit
Channel pore
Barbiturates
Steroids
Pentamers
Inhibitory in action because the
associated channels are permeable to
negatively charged Cl- ions
Benzodiazepines are allosteric modulators
to GABA neurotransmission
Picrotoxin

27. Benzodiazepine Anxiolytics
Chlordiazepoxide
Diazepam
Oxazepam
Chlorazepate
Lorazepam
Prazepam
Halazepam
Flumazil
Alprazolam
Midazolam
(Agonists)

28. The Agonist Spectrum

29. Action of Agonist
A balance between open and close

30. Antagonist Acting Alone
A balance between open and close
No action

31. Antagonist Acting in Presence of Agonist

32. Action of Inverse Agonist
Complete blockade
A balance between open and close

33. Action of Antagonist in Presence of Inverse Agonist
Acts like agonist

34. Action of Partial Agonist
Partially opens the channel

35. Antagonist Acting in the Presence Partial Agonist

36. Action of Partial Inverse Agonist

37. BZD Receptor Activity Full Agonist Partial Antagonist Partial Inverse
Full Inverse
Anxiolytic
Sed-Hypnotic
Myorelaxant
Anticonvulsant
Amnestic
Dependency
No clinical
effect
Promnestic
(memory
enhancing)
Anxiogenic
Pro-
convulsant
Pro-convulsant

38. Serotonergic Anxiolytics (buspirone, gepirone,* tandospirone*)
Partial 5HT1A agonist
Cause upregulation of presynaptic somatodendritic 5HT1A receptors
(anxiolytic action) and postsynaptic 5HT1A receptors (nausea, dizziness)
As compared with benzodiazepines, lacks interaction with alcohol,
benzodiazepines, and thus cause no drug dependence, withdrawal
symptoms
Delayed effect like antidepressants
*under development/clinical trial

39. Noradrenergic Anxiolytics-I
neuronal firing, Anxiety
Cerebral cortex

40. Clonidine:
a2 receptor agonist
Binds to a2 presynaptic autoreceptors
Decreases firing and release of NE which may reduces anxiety

41. Noradrenergic Anxiolytics-II
Blocking the postsynaptic
b receptors reduces anxiety
Overactivity at postsynaptic
b receptors increase anxiety
Beta-blockers :
Antagonist to postsynaptic b adrenergic receptors
Decreases postsynaptic b receptor-mediated signaling

42. Cholecystokinin (CCK)* and CRF* Antagonists as Anxiolytics
Tetra-peptide CCK causes panic attacks
CCK antagonists are anxiolytic in panic disorder
Cortotropin-releasing factor is a neuropeptide which mediates
anxiety behavior. Antagonists to CRF are anxiolytics
*under development

43. Sedative-Hypnotics-I (Treatment for insomnia)
Benzodiazepines:
Rapid onset, short acting
triazolam
Delayed onset, intermediate acting
temazepam, estazolam
Rapid onset, long acting
flurazepam
quazepam
Nonbenzodiazepines:
Rapid-onset, short acting
Zaleplon
Zolpidem
Zopiclone
Act at benzodiazepine receptors
and increase the inhibitory action
of GABA
High doses required
Develop tolerance
Binds to omega-1 benzodizepine
receptors
Less cognitive, memory and motor
side effects
Shorter half life
No dependence, tolerance or
withdrawal symptoms

44. Sedative-Hypnotics II
Sedative antidepressants:
tricyclics (anticholinergic/antihistaminergic)
trazodone (5HT2A antagonist)
mirtazapine (5HT2A antagonist)
nefazodone (5HT2A antagonist)
Sedative antihistamines:
diphenylhydramine
doxylamine
hydroxyzine
Other sedative:
chloral hydrate
Natural products:
melatonin
Good choice with AD properties
Safe with other psychotropic drugs
which disrupts sleep, such as SSRIs
Short-term use
Causes dependency
Tolerance

45. Suggeted Readings
Stahl SM. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications.
Cambridge University Press, NY
Nestler EJ, Hyman SE, Malenka RC. Molecular Neuropharmacology:
A Foundation for Clinical Neuroscience. McGraw-Hill Publications
Squire LR, Bloom FE, McConnel SK, Roberts JL, Spizer NC, Zigmond MJ. Fundamental Neuroscience.
Academic Press
Dwivedi Y. ey al. Chronic Treatment of Psychoactive Drugs Modulates
Phosphoinositide-Specific Phospholipase C (PLC) Activity and mRNA and protein Expression of Selective
PLC 1 Isozyme in Rat Brain. Neuropharmacology, 43: , 2002
Dwivedi Y. et al. Effect of subchronic administration of antidepressants and anxiolytics on the
levels a subunits of G-proteins in rat brain J Neural Transm, 104:747, 1997