PHARMACODYNAMICS OF

ANTIPSYCHOTICS
ANXIOLYTICS
SEDATIVE-HYPNOTICS

Yogesh Dwivedi, Ph.D.

Assistant Professor of Psychiatry
and Pharmacology
Department of Psychiatry
University of Illinois at Chicago
Email: ydwivedi@psych.uic.edu

Pharmacodynamics of Antipsychotics

1
 Psychosis Symptoms
Positive Symptoms
•Delusion
•Hallucination
•Disorganized speech
•Disorganized behavior
•Agitation

Negative Symptoms
•Passivity
•Apathetic social withdrawal
•Stereotyped thinking
•Anhedonia
•Attentional impairment
•Emotional withdrawal

Cognitive Symptoms
•Impaired verbal fluency
•Problems with serial learning
•Problems with focusing attention
•Concentration

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

2
 Key Dopamine Pathways
Mesolimbic 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

Neurodevelopmental Abnormalities in Schizophrenia

3
 Stages of Schizophrenia Over a Life Time

Age

Increased excitatory glutamatergic neurotransmission

Antipsychotics

First generation

Chlorpromazine
Acetaphenazine
Fluphenazine
Haloperidol
Trifluoperazine
Triflupromazine

Second generation

•Clozapine
•Risperidone
•Olanzapine
•Quetiapine
•Ziprasidone

4
 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

Anticholinergic (M1) Drugs and EPS

(Acetylcholine may cause EPS)

2 3

Dopamine and acetylchilone has reciprocal relationship

Stronger anticholinergic agents cause fewer EPS

5
Second Generation Antipsychotics

5HT2A and D2 antagonists (SDAs)

Serotonin-Dopamine Interaction

6
 2 3

•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

Key Dopamine Pathways

Mesolimbic pathway
•More dopamine or hyperactivity on this pathway is associated with positive symptoms
of schizophrenia

Mesocortical pathway
Mesocortical pathway
••Deficit
Deficit in
in dopamine
dopamine in
in this
this pathway
pathway is
is associated
associated with
with negative
negative and
and cognitive
cognitive symptoms
symptoms
of
of schizophrenia
schizophrenia

Nigrostriatal pathway
Nigrostriatal pathway
••Part
Part of
of extrapyramidal
extrapyramidal system
system and
and controls
controls motor
motor movement
movement

••Blockade
Blockade of
of D2
D2 receptors
receptors causes:
causes:
--
-- deficiency
deficiency in
in dopamine
dopamine in
in this
this pathway
pathway and
and thus
thus movement
movement disord
disorder such
disorder such
as
as Parkinson’s
Parkinson’s disease
disease
--
-- hyperkinetic
hyperkinetic movement
movement such
such asas tardive
tardive dyskinesia
dyskinesia

uberoinfundibular pathway
Tuberoinfundibular
T pathway
••Increased
Increased neuronal
neuronal activity
activity of
of this
this pathway
pathway inhibits
inhibits prolactin
prolactin release
release

••Blockade
Blockade ofof D2
D2 receptor
receptor increases
increases prolactin
prolactin release
release and
and causes:
causes:
--
-- galactorrhea
galactorrhea
--
-- amenorrhea
amenorrhea

7
 Second Generation Antipsychotics

•In mesolimbic pathway the action of D2 receptor blockade of

antipsychotics are more robust than 5HT2A antagonism. This may help
reducing positive symptoms

Key Dopamine Pathways

Mesolimbic pathway
Mesolimbic pathway

••Hyperactivity
Hyperactivity on
on this
this pathway
pathway is
is associated
associated with
with positive
positive sympto
symptoms of
symptoms of schizophrenia
schizophrenia

Mesocortical pathway

•Deficit in dopamine in this pathway is associated with negative and cognitive symptoms
of schizophrenia

Nigrostriatal pathway
Nigrostriatal pathway

••Part
Part of
of extrapyramidal
extrapyramidal system
system and
and controls
controls motor
motor movement
movement

••Blockade
Blockade of
of D2
D2 receptors
receptors causes:
causes:
--
-- deficiency
deficiency in
in dopamine
dopamine in
in this
this pathway
pathway and
and thus
thus movement
movement disord
disorder such
disorder such
as
as Parkinson’s
Parkinson’s disease
disease
--
-- hyperkinetic
hyperkinetic movement
movement such
such asas tardive
tardive dyskinesia
dyskinesia

uberoinfundibular pathway
Tuberoinfundibular
T pathway

••Increased
Increased neuronal
neuronal activity
activity of
of this
this pathway
pathway inhibits
inhibits prolactin
prolactin release
release

••Blockade
Blockade ofof D2
D2 receptor
receptor increases
increases prolactin
prolactin release
release and
and causes:
causes:
--
-- galactorrhea
galactorrhea
--
-- amenorrhea
amenorrhea

8
•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 that D2 receptor blocking property. This may help improving
negative symptoms

Key Dopamine Pathways

Mesolimbic pathway
Mesolimbic pathway

••Hyperactivity
Hyperactivity on
on this
this pathway
pathway is
is associated
associated with
with positive
positive sympto
symptoms of
symptoms of schizophrenia
schizophrenia

Mesocortical pathway
Mesocortical pathway

••Deficit
Deficit in
in dopamine
dopamine in
in this
this pathway
pathway is
is associated
associated with
with negative
negative and
and cognitive
cognitive symptoms
symptoms
of
of schizophrenia
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

uberoinfundibular pathway
Tuberoinfundibular
T pathway

••Increased
Increased neuronal
neuronal activity
activity of
of this
this pathway
pathway inhibits
inhibits prolactin
prolactin release
release

••Blockade
Blockade ofof D2
D2 receptor
receptor increases
increases prolactin
prolactin release
release and
and causes:
causes:
--
-- galactorrhea
galactorrhea
--
-- amenorrhea
amenorrhea

9
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

Key Dopamine Pathways

Mesolimbic pathway
Mesolimbic pathway

••Hyperactivity
Hyperactivity on
on this
this pathway
pathway is
is associated
associated with
with positive
positive sympto
symptoms of
symptoms of schizophrenia
schizophrenia

Mesocortical pathway
Mesocortical pathway

••Deficit
Deficit in
in dopamine
dopamine in
in this
this pathway
pathway is
is associated
associated with
with negative
negative and
and cognitive
cognitive symptoms
symptoms
of
of schizophrenia
schizophrenia

Nigrostriatal pathway
Nigrostriatal pathway

••Part
Part of
of extrapyramidal
extrapyramidal system
system and
and controls
controls motor
motor movement
movement

••Blockade
Blockade of
of D2
D2 receptors
receptors causes:
causes:
--
-- deficiency
deficiency in
in dopamine
dopamine in
in this
this pathway
pathway and
and thus
thus movement
movement disord
disorder such
disorder such
as
as Parkinson’s
Parkinson’s disease
disease
--
-- hyperkinetic
hyperkinetic movement
movement such
such asas tardive
tardive dyskinesia
dyskinesia

Tuberoinfundibular pathway

•Increased neuronal activity of this pathway inhibits prolactin release

•Blockade of D2 receptor increases prolactin release and causes:

-- galactorrhea
-- amenorrhea

10
•In tuberoinfundibular pathway: DA blocks the release of prolactin,
whereas, 5HT2A causes release of prolactin. Antagonistic properties
of antipsychotics cancel DA and 5HT2A action on prolactin release

1 2

3 4

Other Actions of Second Generation Antipsychotics

Clozapine: Risperidone:
•Very few EPS •EPS at high dose
•No prolactin release •Low TD
•Causes agranulocytosis •Less weight gain
•Weight gain
•Seizures
•Sedative

Ziprasidone: Quetiapine: Olanzapine:

•Very few EPS •No EPS •No prolactin release
•No prolactin release •No prolactin release •Nonsedative
•No weight gain •Weight gain •Weight gain
•SRI and NRI, thus act as AD •Low level of TD
and anxiolytic
Stahl, 2002

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 Pharmacodynamics of Anxiolytics/
Sedative-Hypnotics

Ionotropic GABA Receptors

Benzodiazepine
GABA

α subunit

Channel pore

Barbiturates

Steroids

•Pentamers
Picrotoxin
•Inhibitory in action because the
associated channels are permeable to
negatively charged Cl- ions
•Benzodiazepines are allosteric modulators
to GABA neurotransmission

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Benzodiazepine Anxiolytics

Chlordiazepoxide
Diazepam
Oxazepam
Chlorazepate
Lorazepam
Prazepam
Halazepam
Flumazil
Alprazolam
Midazolam

The Agonist Spectrum

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 Action of Agonist

A balance between open and close

Antagonist Acting Alone

A balance between open and close No action

14
 Antagonist Acting in Presence of
Agonist

Action of Inverse Agonist

A balance between open and close Complete blockade

15
Action of Antagonist in Presence of
Inverse Agonist

Acts like agonist

Action of Partial Agonist

Partially opens the channel

16
Antagonist Acting in the Presence
Partial Agonist

Action of Partial Inverse Agonist

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 BZD Receptor Activity

Full Agonist Partial Partial Inverse Full Inverse

Agonist Antagonist Agonist Agonist
Anxiolytic Anxiolytic No clinical Promnestic Promnestic
Sed-Hypnotic effect (memory Anxiogenic
Myorelaxant enhancing) Pro-convulsant
Anticonvulsant Anxiogenic
Amnestic Pro-convulsant
Dependency

Serotonergic Anxiolytics
(buspirone, gepirone,* tandospirone*)
•Depression/anxiety may be associated with less serotonin

•Partial 5HT1A agonist

•Cause upregulation of presynaptic somatodendritic 5HT1A autoreceptors

(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

•Act at postsynaptic signal transduction mechanisms, such as

Protein kinase A

*under development/clinical trial

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 Noradrenergic Anxiolytics-I

Cerebral cortex NE, neuronal firing, Anxiety

Clonidine:
•α2 receptor agonist
•Blocks α2 presynaptic autoreceptors
•Decreases firing and release of NE which may reduces anxiety

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 Noradrenergic Anxiolytics-II

Blocking the postsynaptic

Overactivity at postsynaptic β receptors reduces anxiety
β receptors increase anxiety

Beta-blockers :
•Antagonist to postsynaptic β adrenergic receptors
•Decreases postsynaptic β receptor-mediated signaling

Cholecystokinin (CCK)* and

CRF* Antagonists as Anxiolytics

•Tetrapeptide 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

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 Sedative-Hypnotics-I
(Treatment for Insomnia)
Benzodiazepines:
•Rapid onset, short acting •Act at benzodiazepine receptors
triazolam and increase the inhibitory action
•Delayed onset, intermediate acting of GABA
temazepam, estazolam •High doses required
•Rapid onset, long acting •Develop tolerance
flurazepam
quazepam
•Binds to omega-1 but not
Nonbenzodiazepines: to omega-2 benzodizepine receptors
•Rapid-onset, short acting •Less cognitive, memory and motor
Zaleplon side effects
Zolpidem •Shorter half life
Zopiclone •No dependence, tolerance or
withdrawal symptoms

Sedative-Hypnotics II
Sedative antidepressants:
tricyclics Good choice with AD properties
(anticholinergic/antihistaminergic)
trazodone (5HT2A antagonist)
Safe with other psychotropic drugs
mirtazapine (5HT2A antagonist)
which disrupts sleep, such as SSRIs
nefazodone (5HT2A antagonist)

Sedative antihistamines:
diphenylhydramine
doxylamine
hydroxyzine
Short-term use
Other sedative:
Causes dependency
chloral hydrate
Tolerance
Natural products:
melatonin

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 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 β1 Isozyme in Rat Brain. Neuropharmacology, 43:1269-1279, 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

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