antipsychotics drug treatmen

DRUG TREATMENT OF PSYCHOSIS

Martha I. Dávila-García, Ph.D.Howard University

Department of PharmacologySpring 2002

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PsychosisPsychosis 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

marked thinking disturbance.



Psychosis Producing Drugs

1) Levodopa2) CNS stimulants

a) Cocaine b) Amphetaminesc) 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.

• Afflicts 1% of the population worldwide.• May or may not be present with anatomical

changes.



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”.



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.



Etiology of Schizophrenia

Idiopathic

Biological Correlates1) Genetic Factors2) Neurodevelopmental abnormalities.3) Environmental stressors.



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:

1) Enlarge cerebral ventricles.2) Atrophy of cortical layers.3) Reduced volume of the basal ganglia.



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.




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.



Pharmacodynamics

Anatomic Correlates of Schizophrenia...

Frontal cortexAmygdalaHippocampusNucleus accumbensLimbic Cortex

Areas Associated with Mood and Thought Processes:

DADADADADA




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.



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.



THE DOPAMINERGIC SYSTEM



CatecholaminesTyrosine

⇓ Tyrosine hydroxylase

L-Dopa⇓ Dopa decarboxylase

Dopamine (DA)⇓ Dopamine β hydroxylase

Norepinephrine (NE)(Noradrenaline) Phenylethanolamine-

⇓ -N-methyltransferase

Epinephrine (EPI)(Adrenaline)



Dopamine Synapse

DA

L-DOPA

TyrosineTyrosine



Dopamine System

• DOPAMINE RECEPTORS

There are at least five subtypes of receptors:ReceptorD1D2D3D4D5



Dopamine System

• DOPAMINE RECEPTORS

Receptor 2o Messenger SystemD1 ⇑cAMPD2 ⇓cAMP,⇑K+ ch.,⇓Ca2+ch.D3 ⇓cAMP,⇑K+ ch.,⇑Ca2+ch.D4 ⇓cAMPD5 ⇑cAMP



Dopamine Reuptake System



Antipsychotic treatments

SCHIZOPHRENIA IS FOR LIFE

There is no remission



Antipsychotic treatmentsSchizophrenia 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:

v 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 treatmentsv Lobotomies (Egaz Moniz received the Nobel Prize).

v In 1940’s Phenothiazenes were isolated and were used as pre-anesthetic medication, but quickly were adopted by psychiatrists to calm down their mental patients.

v In 1955, chlorpromazine was developed as an antihistaminic agent by Rhône-Pauline Laboratories in France. In-patients at Mental Hospitals dropped by 1/3.



Antipsychotics treatmentAntipsychotics/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.



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 Alzheimer’s disease. These conditions are life-long and disabling.




NON-compliance is the major reason for relapse.



Antipsychotic/Neuroleptics

Three major groups :1) Phenothiazines2) Thioxanthines

3) Butyrophenones

OLDER DRUGS




• Old antiphsychotics/neuroleptics are D2dopamine receptor antagonists. Although they are also effective antagonists at ACh, 5-HT, NE receptors.

Dopamine Synapse

DA

L-DOPA

TyrosineTyrosine

dopaminereceptorantagonist

D2




• 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.




Correlations between therapeutic potency and affinity for binding D2 receptors.

[3 H]H

alop

erid

olbi

ndin

gIC

50(m

ol/ L

)

Clinical dose of drug [mg d-1]

haloperidol

clozapinethiothixene

chlorpromazinepromazine

spiroperidole




• 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).




• 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.

è hyperprolactinemia



PharmacokineticsAbsorption 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.**



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.



Pharmacokinetics

Excretion

• Antipsychotics are almost completely metabolized and thus, very little is eliminated unchanged.

• Elimination half-lives are 10-24 hrs.




1) Phenothiazines

Chlorpromazine Thioridazine FluphenazineTrifluopromazine Piperacetazine Perfenazine

Mesoridazine AcetophenazineCarphenazineProchlorperazineTrifluoperazine

• Aliphatic Piperidine Piperazine*

* Most likely to cause extrapyramidal effects.




[Drug dose]

Effe

ctPiperazine

Aliphatic

Piperidine




2) ThioxanthinesThiothixeneChlorprothixene

Closely related to phenothiazines




3) ButyrophenonesHaloperidolDroperidol*

*Not marketed in the USA




[Drug dose]

Effe

ct

Phenothiazine d.

Thioxanthene d.

Butyrophenone d.




• Newer drugs have higher affinities for D1, 5-HT or α-AR receptors.

• NE, GABA, Glycine and Glutamate have also been implicated in schizophrenia.



Antipsychotics/NeurolepticsThe acute effects of antipsychotics do not explain why

their therapeutic effects are not evident until 4-8 weeks of treatment.

Blockade of D2 receptors

êShort term/Compensatory effects:⇑ Firing rate and activity of nigrostriatal and

mesolimbic DA neurons.⇑ DA synthesis, DA metabolism, DA release



Antipsychotics/NeurolepticsPresynaptic Effects

Blockade of D2 receptorsê

Compensatory Effects⇑ Firing rate and activity of nigrostriatal and mesolimbic DA

neurons.⇑ DA synthesis, DA metabolism, DA release.

Postsynaptic EffectsDepolarization Blockade

Inactivation of nigrostriatal and mesolimbic DA neurons.ê

Receptor Supersensitivity




PimozideMolindoneLoxapineClozapineOlanzapineQetiapine

RisperidoneSertindole

ZiprasidoneOlindone

Newer Drugs




Clinical Ex. Py.Drug Potency toxicity Sedation Hypote.

Chlorpromaz. Low Medium Medium HighHaloperidol High Very High Very High LowThiothixene High Medium Medium MediumClozapine Medium Very low Low MediumZiprasidone Medium Very Low Low Very lowRisperidone High Low Low LowOlanzapine High Very Low Medium Very lowSertindole High Very Low Very low Very Low




Chlorpromazine: α1 = 5-HT2 = D2 > D1 > M > α2

Haloperidol: D2 > D1 = D4 > α1 > 5-HT2 >H1>M = α2

Clozapine: D4 = α1 > 5-HT2 = M > D2 = D1 = α2 ; H1

Quetiapine: 5-HT2 = D2 = α1 = α2 ; H1

Risperidone: 5-HT2 >> α1 > H1 > D2 > α2 >> D1

Sertindole: 5-HT2 > D2 = α1




Clinical Problems with antipsychotic drugsinclude:

1) Failure to control negative effect2) Significant toxicity

a) Parkinson-like symptomsb) Tardive Dyskinesia (10-30%)c) Autonomic effectsd) Endocrine effectse) Cardiac effects

3) Poor Concentration



The Nigro-Striatal Pathway

Inhibitionof

Motor Activity

DAneuron ACh

neuron

GABAneuron

GABAneuron

SubstantiaNigra

+

-

-

-

-

Striatum




v Some antipsychotics have effects at muscarinic acetylcholine receptors:

• dry mouth• blurred vision• urinary retention• constipation

ClozapineChlorpromazineThioridazine




v Some antipsychotics have effects at α−adrenergic receptors:

• orthostatic hypotensionChlorpromazineThioridazine

v Some antipsychotics have effects at H1-histaminergic receptors:

• sedationRisperidoneHaloperidol




v Blockade of D2 receptors in lactotrophs in breast increase prolactin concentration and may produce breast engorgement and galactorrhea.




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.



Antipsychotic/NeurolepticsNeuroleptic 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.




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.




Drug Interactions• Additive effects with sedatives.• Additive effects with anticholinergics.• Additive effects with antihistaminergics.• Additive effects with α-AR blocking drugs.• Additive effects with drugs with quinidine-like

action (thioridazine).



REFERENCES1. 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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