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PSYCHOSIS
1) Levodopa
2) CNS stimulants
a) Cocaine
b) Amphetamines
c) Khat, cathinone, methcathinone
3) Apomorphine
4) Phencyclidine
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.
Etiology of Schizophrenia
Idiopathic
Biological Correlates
1) Genetic Factors
2) Neurodevelopmental abnormalities.
3) Environmental stressors.
Etiology of Schizophrenia
L-DOPA
DA
Dopamine System
• DOPAMINE RECEPTORS
There is no remission
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.
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.
Antipsychotic treatments
Lobotomies (Egaz Moniz received the Nobel Prize).
OLDER DRUGS
Three major groups :
1) Phenothiazines
2) Thioxanthines
3) Butyrophenones
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.
Antipsychotics/Neuroleptics
• It appears that the specific interaction of
antipsychotic drugs with D2 receptors is
important to their therapeutic action.
promazine
chlorpromazine
IC50 (mol/L)
clozapine
thiothixene
haloperidol
spiroperidole
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.
Pharmacokinetics
Excretion
• Antipsychotics are almost completely metabolized
and thus, very little is eliminated unchanged.
• Elimination half-lives are 10-24 hrs.
Antipsychotic/Neuroleptics
1) Phenothiazines
• Aliphatic Piperidine Piperazine*
Chlorpromazine Thioridazine Fluphenazine
Trifluopromazine Piperacetazine Perfenazine
Mesoridazine Acetophenazine
Carphenazine
Prochlorperazine
Trifluoperazine
* Most likely to cause extrapyramidal effects.
Antipsychotic/Neuroleptics
Piperazine
Piperidine
Aliphatic
Effect
[Drug dose]
Antipsychotic/Neuroleptics
2) Thioxanthines
Thiothixene
Chlorprothixene
3) Butyrophenones
Haloperidol
Droperidol*
[Drug dose]
Antipsychotics/Neuroleptics
• Newer drugs have higher affinities for D1, 5-
HT or -AR receptors.
Blockade of D2 receptors
Short term/Compensatory effects:
Firing rate and activity of nigrostriatal and
mesolimbic DA neurons.
DA synthesis, DA metabolism, DA release
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.
Receptor Supersensitivity
Antipsychotic/Neuroleptics
Newer Drugs
Pimozide
Molindone
Loxapine
Clozapine
Olanzapine
Qetiapine
Risperidone
Sertindole
Ziprasidone
Olindone
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
Antipsychotic/Neuroleptics
GABA
neuron
-
Inhibition
of
Motor Activity
Antipsychotic/Neuroleptics
• dry mouth
• blurred vision
• urinary retention
• constipation
Clozapine
Chlorpromazine
Thioridazine
Antipsychotic/Neuroleptics
Some antipsychotics have effects at
adrenergic receptors:
• orthostatic hypotension
Chlorpromazine
Thioridazine
Treatment
Vigorous treatment with antiparkinsonian drugs is
recommended as soon as possible.
Muscle relaxants such as diazepam, dantrolene or
bromocriptine may be helpful.
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).
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.