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PHARMACOLOGY
31 January 2018 1
Psychosis
Psychosis is a thought disorder characterized
by disturbances of reality and perception,
impaired cognitive functioning, and
inappropriate or diminished affect (mood).
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.
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
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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
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:
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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)
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(Adrenaline) 15
Tyrosine
Dopamine Synapse
Tyrosine
L-DOPA
DA
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Dopamine System
• DOPAMINE RECEPTORS
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Antipsychotic treatments
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 1800’s.
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Antipsychotic treatments
Lobotomies (Egaz Moniz received the Nobel Prize).
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Antipsychotics/Neuroleptics
NON-compliance
is the major reason for relapse.
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Antipsychotic/Neuroleptics
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Antipsychotics/Neuroleptics
Tyrosine
Dopamine Synapse
• Old antiphsychotics
Tyrosine
/neuroleptics are D2
L-DOPA
dopamine receptor
DA dopamine
receptor
antagonists.
antagonist
Although they are
also effective
antagonists at ACh,
D2 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.
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Antipsychotic/Neuroleptics
Correlations between therapeutic potency and
affinity for binding D2 receptors.
promazine
chlorpromazine
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.
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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
Piperidine
Aliphatic
[Drug dose]
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Antipsychotic/Neuroleptics
2) Thioxanthines
Thiothixene
Chlorprothixene
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Antipsychotic/Neuroleptics
3) Butyrophenones
Haloperidol
Droperidol*
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Antipsychotic/Neuroleptics
Butyrophenone d.
Phenothiazine d.
Thioxanthene d.
[Drug dose]
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Antipsychotics/Neuroleptics
• Newer drugs have higher affinities for D1, 5-
HT or -AR receptors.
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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 43
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
GABA
- neuron
Inhibition
of
Motor Activity
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Antipsychotic/Neuroleptics
• 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
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Antipsychotic/Neuroleptics
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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
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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