ANTIPSYCOTIC

PHARMACOLOGY

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 Psychosis
Psychosis is a thought disorder characterized
by disturbances of reality and perception,
impaired cognitive functioning, and
inappropriate or diminished affect (mood).

Psychosis denotes many mental disorders.

Schizophrenia is a particular kind of psychosis

characterized mainly by a clear sensorium but a
November 4, 2017 marked thinking disturbance. 2
 Psychosis Producing Drugs

1) Levodopa
2) CNS stimulants
a) Cocaine
b) Amphetamines
c) Khat, cathinone, methcathinone
3) Apomorphine
4) Phencyclidine

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 Schizophrenia

Pathogenesis is unknown.
Onset of schizophrenia is in the late teens early
twenties.
Genetic predisposition -- Familial incidence.
Multiple genes are involved.

Afflicts 1% of the population worldwide.

May or may not be present with anatomical
changes.
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 Schizophrenia
It is a thought disorder.
The disorder is characterized by a divorcement
from reality in the mind of the person
(psychosis).
It may involved visual and auditory
hallucinations, delusions, intense suspicion,
feelings of persecution or control by external
forces (paranoia), depersonalization, and there is
attachment of excessive personal significance to
daily events, called ideas of reference.
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 Schizophrenia

Positive Symptoms.
Hallucinations, delusions, paranoia, ideas of reference.

Negative Symptoms.
Apathy, social withdrawal, anhedonia, emotional blunting,
cognitive deficits, extreme inattentiveness or lack of
motivation to interact with the environment.
These symptoms are progressive and non-responsive to medication.

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 Etiology of Schizophrenia

Idiopathic

Biological Correlates
1) Genetic Factors
2) Neurodevelopmental abnormalities.
3) Environmental stressors.
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 Etiology of Schizophrenia

Schizophrenia is not characterized by any

reproducible neurochemical abnormality.
However, structural and functional
abnormalities have been observed in the
brains of schizophrenic patients:
Enlarge cerebral ventricles.
1) Atrophy of cortical layers.
2) Reduced volume of the basal ganglia.
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Dopamine Theory of Schizophrenia

Many lines of evidence point to the

aberrant increased activity of the
dopaminergic system as being critical in
the symptomatology of schizophrenia.

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 Dopamine Theory of Schizophrenia
Dopamine Correlates:
Antipsychotics reduce dopamine synaptic activity.
These drugs produce Parkinson-like symptoms.
Drugs that increase DA in the limbic system cause
psychosis.
Drugs that reduce DA in the limbic system
(postsynaptic D2 antagonists) reduce psychosis.
Increased DA receptor density (Post-mortem, PET).
Changes in amount of homovanillic acid (HVA), a
DA metabolite, in plasma, urine, and CSF.
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 Pharmacodynamics

Anatomic Correlates of Schizophrenia...

Areas Associated with Mood and Thought Processes:

Frontal cortex DA
Amygdala DA
Hippocampus DA
Nucleus accumbens DA
Limbic Cortex DA
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 Dopamine Theory of Schizophrenia

Evidence against the hypothesis

Antipsychotics are only partially effective in
most (70%) and ineffective for some patients.
Phencyclidine, an NMDA receptor antagonist,
produces more schizophrenia-like symptoms in
non-schizophrenic subjects than DA agonists.
Atypical antipsychotics have low affinity for
D2 receptors.
Focus is broader now and research is geared to
produce drugs with less extrapyramidal effects.
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 Dopamine System
There are four major pathways for the
dopaminergic system in the brain:

I. The Nigro-Stiatal Pathway.

II. The Mesolimbic Pathway.
III. The Mesocortical Pathway.
IV. The Tuberoinfundibular Pathway.

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 THE DOPAMINERGIC SYSTEM

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 Catecholamines
Tyrosine
Tyrosine hydroxylase
L-Dopa
Dopa decarboxylase
Dopamine (DA)
Dopamine hydroxylase
Norepinephrine (NE)
(Noradrenaline) Phenylethanolamine-
-N-methyltransferase
Epinephrine (EPI)
(Adrenaline)
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 Tyrosine
Dopamine Synapse
Tyrosine

L-DOPA

DA

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 Dopamine System
DOPAMINE RECEPTORS

There are at least five subtypes of receptors:

Receptor
D1 (Adenylat Cyclase Stimulation)
D2 (Adenylat Cyclase Inhibition)
D3 ~ D2
D4 ~ D2
D5 ~ D1
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 Dopamine ~ the production of cyclic AMP
Using the close-up view, explain what happens when dopamine

binds to its receptor. When dopamine binds to its receptor,

another protein called a G-protein (in pink) moves up close to

the dopamine receptor. The G-protein signals an enzyme to

produce cyclic adenosine monophosphate (cAMP) molecules

(in green) inside the cell. [Sometimes the signal can decrease

production of cAMP, depending on the kind of dopamine receptor

and G-protein present.] Point to the dopamine receptor-G-protein

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 Dopamine System
DOPAMINE RECEPTORS

Receptor 2o Messenger System

D1 cAMP
D2 cAMP,K+ ch.,Ca2+ch.
D3 cAMP,K+ ch.,Ca2+ch.
D4 cAMP
D5 cAMP
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Dopamine Reuptake System

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 Antipsychotic treatments

SCHIZOPHRENIA IS FOR LIFE

There is no remission

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 Antipsychotic treatments
Schizophrenia has been around perhaps, since the
beginning of humankind, however, it was not until
the last century that it was established as a separate
entity amongst other mental disorders.
Many treatments have been devise:
Hydrotherapy:
The pouring of cold water in a stream, from a height of
at least four feet onto the forehead, is one of the most
certain means of subsiding violent, maniacal excitement
that we have ever seen tried... wrote an anonymous
physician in the early 1800s.

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 Antipsychotic treatments
Lobotomies (Egaz Moniz received the Nobel Prize).

In 1940s Phenothiazenes were isolated and were

used as pre-anesthetic medication, but quickly were
adopted by psychiatrists to calm down their mental
patients.

In 1955, chlorpromazine was developed as an

antihistaminic agent by Rhne-Pauline Laboratories
in France. In-patients at Mental Hospitals dropped
by 1/3.
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 Antipsychotics treatment
Antipsychotics/Neuroleptics
Antipsychotics are the drugs currently used in
the prevention of psychosis.
They have also been termed neuroleptics,
because they suppress motor activity and
emotionality.
** These drugs are not a cure **
Schizophrenics must be treated with
medications indefinitely, in as much as the
disease in lifelong and it is preferable to
prevent the psychotic episodes than to treat
them.
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 Antipsychotics/Neuroleptics

Although the antipsychotic/neuroleptics are drugs

used mainly in the treatment of schizophrenia,
they are also used in the treatment of other
psychoses associated with depression and
manic-depressive illness, and psychosis
associated with Alzheimers disease. These
conditions are life-long and disabling.

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 Antipsychotics/Neuroleptics

NON-compliance
is the major reason for relapse.

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 Antipsychotic/Neuroleptics

OLDER DRUGS / CLASSICAL

Three major groups :
1) Phenothiazines
2) Thioxanthines
3) Butyrophenones

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 Antipsychotics/Neuroleptics
Tyrosine
Dopamine Synapse
Old
Tyrosine
antiphsychotics
L-DOPA
/neuroleptics are D2
DA
dopamine
receptor
dopamine receptor
antagonist
antagonists.
Although they are
also effective
D2 antagonists at ACh,
5-HT, NE receptors.
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 Antipsychotics/Neuroleptics
It appears that the specific interaction of
antipsychotic drugs with D2 receptors is
important to their therapeutic action.

The affinities of most older classical

agents for the D2 receptors correlate with
their clinical potencies as antipsychotics.

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 Antipsychotic/Neuroleptics
Correlations between therapeutic potency and
affinity for binding D2 receptors.
[3H]Haloperidol binding

promazine
chlorpromazine
IC50 (mol/L)

clozapine
thiothixene

haloperidol

spiroperidole

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Clinical dose of drug [mg d-1]
 Antipsychotics/Neuroleptics
Both D1 and D2 receptors are found in high
concentrations in the striatum and the nucleus
accumbens.

Clozapine has a higher affinity for the D4 receptors

than for D2.

Recently it has been found that most antipsychotic

drugs may also bind D3 receptors (therefore, they
are non-selective).
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 Antipsychotics/Neuroleptics
Antipsychotics produce catalepsy (reduce motor
activity).
BLOCKADE OF DOPAMINE RECPTORS IN BASAL GANGLIA.

Antipsychotics reverse hyperkinetic behaviors

(increased locomotion and stereotyped behavior).
BLOCKADE OF DOPAMINE RECPTORS IN LIMBIC AREAS.

Antipsychotics prevent the dopamine inhibition of

prolactin release from pituitary.
BLOCKADE OF DOPAMINE RECEPTORS IN PITUITARY.
hyperprolactinemia
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 Pharmacokinetics
Absorption and Distribution
Most antipsychotics are readily but incompletely
absorbed.
Significant first-pass metabolism.
Bioavailability is 25-65%.
Most are highly lipid soluble.
Most are highly protein bound (92-98%).
High volumes of distribution (>7 L/Kg).
Slow elimination.
**Duration of action longer than expected, metabolites are present
and relapse occurs, weeks after discontinuation of drug.**
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 Pharmacokinetics

Metabolism
Most antipsychotics are almost completely
metabolized.
Most have active metabolites, although not
important in therapeutic effect, with one exception.
The metabolite of thioridazine, mesoridazine, is
more potent than the parent compound and
accounts for most of the therapeutic effect.

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 Pharmacokinetics

Excretion
Antipsychotics are almost completely metabolized
and thus, very little is eliminated unchanged.
Elimination half-lives are 10-24 hrs.

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 Antipsychotic/Neuroleptics

1) Phenothiazines
Aliphatic Piperidine Piperazine*
Chlorpromazine Thioridazine Fluphenazine
Trifluopromazine Piperacetazine Perfenazine
Mesoridazine Acetophenazine
Carphenazine
Prochlorperazine
Trifluoperazine

* Most likely to cause extrapyramidal effects.

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 Antipsychotic/Neuroleptics
Piperazine

Piperidine
Aliphatic
Effect

[Drug dose]
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 Antipsychotic/Neuroleptics

2) Thioxanthines
Thiothixene
Chlorprothixene

Closely related to phenothiazines

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 Antipsychotic/Neuroleptics

3) Butyrophenones
Haloperidol
Droperidol*

*Not marketed in the USA ~ Indonesia

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 Antipsychotic/Neuroleptics
Butyrophenone d.

Phenothiazine d.
Thioxanthene d.
Effect

[Drug dose]
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 Antipsychotics/Neuroleptics
Newer drugs have higher affinities for D1, 5-
HT or -AR receptors.

NE, GABA, Glycine and Glutamate have

also been implicated in schizophrenia.

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 Antipsychotics/Neuroleptics
The acute effects of antipsychotics do not explain why
their therapeutic effects are not evident until 4-8
weeks of treatment.

Blockade of D2 receptors

Short term/Compensatory effects:
Firing rate and activity of nigrostriatal and
mesolimbic DA neurons.
DA synthesis, DA metabolism, DA release
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 Antipsychotics/Neuroleptics
Presynaptic Effects
Blockade of D2 receptors

Compensatory Effects
Firing rate and activity of nigrostriatal and mesolimbic DA
neurons.
DA synthesis, DA metabolism, DA release.

Postsynaptic Effects
Depolarization Blockade
Inactivation of nigrostriatal and mesolimbic DA neurons.

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Receptor Supersensitivity
 Antipsychotic/Neuroleptics
Newer Drugs / Atypical
Pimozide
Molindone
Loxapine
Clozapine
Olanzapine
Qetiapine
Risperidone
Sertindole
Ziprasidone
Olindone
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 Antipsychotic/Neuroleptics
Clinical Ex. Py.
Drug Potency toxicity Sedation Hypote.
Chlorpromaz. Low Medium Medium High
Haloperidol High Very High Very High Low
Thiothixene High Medium Medium Medium
Clozapine Medium Very low Low Medium
Ziprasidone Medium Very Low Low Very low
Risperidone High Low Low Low
Olanzapine High Very Low Medium Very low
Sertindole High Very Low Very low Very Low
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 Antipsychotic/Neuroleptics

Chlorpromazine: 1 = 5-HT2 = D2 > D1 > M > 2

Haloperidol: D2 > D1 = D4 > 1 > 5-HT2 >H1>M = 2
Clozapine: D4 = 1 > 5-HT2 = M > D2 = D1 = 2 ; H1
Quetiapine: 5-HT2 = D2 = 1 = 2 ; H1
Risperidone: 5-HT2 >> 1 > H1 > D2 > 2 >> D1
Sertindole: 5-HT2 > D2 = 1
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 Antipsychotic/Neuroleptics
Clinical Problems with antipsychotic drugs
include:
1) Failure to control negative effect
2) Significant toxicity
a) Parkinson-like symptoms
b) Tardive Dyskinesia (10-30%)
c) Autonomic effects
d) Endocrine effects
e) Cardiac effects
3) Poor Concentration
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 The Nigro-Striatal Pathway
DA
neuron -
ACh
Striatum neuron
+
Substantia GABA
Nigra - neuron
-

GABA
- neuron
Inhibition
of
Motor Activity
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 Antipsychotic/Neuroleptics

Some antipsychotics have effects at

muscarinic acetylcholine receptors:

dry mouth
blurred vision
urinary retention
constipation
Clozapine, Chlorpromazine
Haloperidol, Thioridazine
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 Antipsychotic/Neuroleptics
Some antipsychotics have effects at
adrenergic receptors:
orthostatic hypotension
Chlorpromazine
Thioridazine

Some antipsychotics have effects at H1-

histaminergic receptors:
sedation
Risperidone
November 4, 2017 Haloperidol 50
 Antipsychotic/Neuroleptics

Blockade of D2 receptors in lactotrophs

in breast increase prolactin concentration
and may produce breast engorgement
and galactorrhea.

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 Antipsychotic/Neuroleptics

Neuroleptic Malignant Syndrome

Is a rare but serious side effect of neuroleptic

(antipsychotic) therapy that can be lethal. It
can arise at any time in the course of treatment
and shows no predilection for age, duration of
treatment, antipsychotic medication, or dose.

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 Antipsychotic/Neuroleptics
Neuroleptic Malignant Syndrome
Occurs in pts. hypersensitive to the Ex.Py. effects of
antipsychotics.
Due to excessively rapid blockade of postsynaptic
dopamine receptors.
The syndrome begins with marked muscle rigidity.
If sweating is impaired, a fever may ensue. The
stress leukocytosis and high fever associated with this
syndrome may be mistaken for an infection.
Autonomic instability with altered blood pressure and
heart rate is another midbrain manifestation.
Creatine kinase isozymes are usually elevated,
reflecting muscle damage.
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 Antipsychotic/Neuroleptics

Neuroleptic Malignant Syndrome

Treatment
Vigorous treatment with antiparkinsonian drugs is
recommended as soon as possible.
Muscle relaxants such as diazepam, dantrolene or
bromocriptine may be helpful.

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 Antipsychotic/Neuroleptics

Drug Interactions
Additive effects with sedatives.
Additive effects with anticholinergics.
Additive effects with antihistaminergics.
Additive effects with -AR blocking drugs.
Additive effects with drugs with quinidine-like
action (thioridazine).

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 REFERENCES
1. Katzung, B.G. (2001) Basic and Clinical
Pharmacology, Chapter 29, 8th Ed. Lange. 478-
497pp.
2. Kandell, E.R. and Schwartz, J.H. (1981).
Principles of Neuroscience. Elsvier/North
Holland. N.Y.
3. Wingard et al., (1991) Human Pharmacology.
Molecular to Clinical. Mosby Year Book.

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