Neuroleptics Medicine

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Antipsychotic drugs

Wesam R. Kadhum


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Nature of Psychosis & Schizophrenia

The term "psychosis" denotes a variety of mentaldisorders.

Schizophrenia is a particular kind of psychosischaracterized mainly by a clear sensorium but amarked thinking disturbance.

The pathogenesis of schizophrenia is unknown.

Largely as a result of research stimulated by thediscovery of antipsychotic drugs, a genetic

predisposition has been proposed as a necessary butnot always sufficient condition underlying psychoticdisorder.

This assumption has been supported by the observedfamilial incidence of schizophrenia.


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Schizophrenia

Schizophrenia is a particular type ofpsychosis that is, a mental disordercaused by some inherentdysfunction of the brain.

It is characterized by delusions,

hallucinations and thinking or speechdisturbances.

This mental disorder is a commonaffliction, occurring among aboutone percent of the population.

Schizophrenia has a strong geneticcomponent and probably reflectssome fundamental biochemicalabnormality, possibly a dysfunctionof the dopaminergic neurons.


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The Dopamine Hypothesis

The dopamine hypothesis for schizophrenia is the mostfully developed of several hypotheses and is the basisfor much of the rationale for drug therapy. Several linesof circumstantial evidence suggest that excessivedopaminergic activity plays a role in the disorder:

(1) Most antipsychotic drugs strongly blockpostsynaptic D2 receptors in the central nervoussystem, especially in the mesolimbic-frontal system.

(2) Drugs that increase dopaminergic activity, such as

levodopa (a precursor), amphetamines (releasers ofdopamine), or apomorphine (a direct dopaminereceptor agonist), either aggravate schizophrenia orproduce psychosis de novo in some patients.


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(3) Dopamine receptor density has been found,postmortem, to be increased in the brains of

schizophrenics who have not been treated withantipsychotic drugs.

(4) Positron emission tomography (PET) hasshown increased dopamine receptor density in

both treated and untreated schizophrenics whencompared with such scans of nonschizophrenicpersons.

(5) Successful treatment of schizophrenic patientshas been reported to change the amount ofhomovanillic acid (HVA), a metabolite ofdopamine, in the cerebrospinal fluid, plasma, andurine.


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Neuroleptic drugs

The neuroleptic drugs (also called antipsychotic drugs, or majortranquilizers) are used primarily to treat schizophrenia, but they arealso effective in other psychotic states, such as manic states withpsychotic symptoms such as grandiosity or paranoia andhallucinations, and delirium.

All currently available antipsychotic drugs that alleviate symptomsof schizophrenia decrease dopaminergic and/or serotonergicneurotransmission.

The traditional or typical neuroleptic drugs (also calledconventional or first-generation antipsychotics) are competitiveinhibitors at a variety of receptors, but their antipsychotic effects

reflect competitive blocking of dopamine receptors. These drugs vary in potency. For example, chlorpromazine is a low-

potency drug, and fluphenazine is a high-potency agent.


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Classification of

neuroleptic agents


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No one drug is clinically more effective than another. Incontrast, the newer antipsychotic drugs are referred toas atypical (or second-generation antipsychotics),

because they have fewer extrapyramidal adverseeffects than the older, traditional agents.

These drugs appear to owe their unique activity toblockade of both serotonin and dopamine (and,perhaps, other) receptors.

Current antipsychotic therapy commonly employs theuse of the atypical agents to minimize the risk ofdebilitating movement disorders associated with thetypical drugs that act primarily at the D2 dopaminereceptor.

All of the atypical antipsychotics exhibit an efficacythat is equivalent to, or occasionally exceeds, that ofthe typical neuroleptic agents.


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Neuroleptic drugs are not curative and do not

eliminate the fundamental and chronicthought disorder, but they often decrease the

intensity of hallucinations and delusions and

permit the person with schizophrenia to

function in a supportive environment.


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Mechanism of action

1. Dopamine receptor blockingactivity in the brain:

All of the older and most of

the newer neuroleptic drugsblock dopamine receptors inthe brain and the periphery.Five types of dopaminereceptors have been identified.

The neuroleptic drugs bind tothese receptors to varyingdegrees.


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Relative affinity of clozapine,

chlorpromazine, and

haloperidol at D1- and D2

dopaminergic receptors.


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2. Serotonin receptor blocking

activity in the brain:

Most of the newer atypical

agents appear to exert part

of their unique actionthrough inhibition of

serotonin receptors (5-HT),

particularly 5-HT2A receptors.


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Actions

The antipsychotic actions of neuroleptic drugsappear to reflect a blockade at dopamine and/orserotonin receptors.

However, many of these agents also blockcholinergic, adrenergic, and histaminergicreceptors. It is unknown what role, if any, theseactions have in alleviating the symptoms of

psychosis. The undesirable side effects of these agents,

however, are often a result of actions at theseother receptors.


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Antipsychotic actions: All of the neuroleptic drugscan reduce the hallucinations and delusions

associated with schizophrenia (the so-calledpositive symptoms) by blocking dopaminereceptors in the mesolimbic system of the brain.

The negative symptoms, such as blunted affect,

anhedonia, apathy, and impaired attention, aswell as cognitive impairment are not asresponsive to therapy, particularly with thetypical neuroleptics.

Many atypical agents, such as clozapineameliorate the negative symptoms to someextent.


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Extrapyramidal effects: Dystonias (sustainedcontraction of muscles leading to twistingdistorted postures), parkinson-like symptoms,akathisia (motor restlessness), and tardivedyskinesia (involuntary movements of thetongue, lips, neck, trunk, and limbs) occur withchronic treatment.

Blocking of dopamine receptors in thenigrostriatal pathway probably causes theseunwanted movement symptoms.

The atypical neuroleptics exhibit a lowerincidence of these symptoms.


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Antiemetic effects: With the exceptions of

aripiprazole and thioridazine, most of theneuroleptic drugs have antiemetic effects that

are mediated by blocking D2-dopaminergic

receptors of the chemoreceptor trigger zone

of the medulla.

[Note: The atypical antipsychotic drugs are not

used as antiemetics.]


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Antimuscarinic effects: Some of the

neuroleptics, particularly thioridazine,chlorpromazine, clozapine, and olanzapine,

produce anticholinergic effects, including

blurred vision, dry mouth (exception:

clozapine increase salivation), confusion, and

inhibition of gastrointestinal and urinary tract

smooth muscle, leading to constipation and

urinary retention.


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Other effects: Blockade of -adrenergic receptorscauses orthostatic hypotension and light-headedness.

The neuroleptics also alter temperature-regulatingmechanisms and can produce poikilothermia (bodytemperature varies with the environment).

In the pituitary, neuroleptics block D2 receptors,leading to an increase in prolactin release.

Atypical neuroleptics are less likely to produceprolactin elevations.

Sedation occurs with those drugs that are potentantagonists of the H1-histamine receptor, including

chlorpromazine, olanzapine, quetiapine, and clozapine.

Sexual dysfunction may also occur with theantipsychotics due to various receptor-bindingcharacteristics.


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Therapeutic uses:

1. Treatment of schizophrenia:

The traditional neuroleptics are most effective in treatingpositive symptoms of schizophrenia (delusions,hallucinations, thought processing, and agitation).

The newer agents with 5-HT2A receptor blocking activitymay be effective in many patients who are resistant to thetraditional agents, especially in treating the negativesymptoms of schizophrenia (social withdrawal, bluntedemotions, ambivalence, and reduced ability to relate to

people).[Note: Clozapine is reserved for the treatment ofindividuals who are unresponsive to other neuroleptics,because its use is associated with blood dyscrasias andother severe adverse effects].


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2. Prevention of severe nausea andvomiting:

With the exceptions ofaripiprazole andthioridazine, most of the neurolepticdrugs have antiemetic effects that aremediated by blocking D2-dopaminergicreceptors of the chemoreceptor trigger

zone of the medullaThe older neuroleptics (most commonlyprochlorperazine) are useful in thetreatment ofdrug-induced nausea.

[Note: Transdermal scopolamine is adrug of choice for treatment of motionsickness.]


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3. Other uses:

Neuroleptics are used in combination with narcoticanalgesics for treatment of chronic pain with severeanxiety.Chlorpromazine is used to treat intractable hiccups.

Promethazine is not a good antipsychotic drug;however, this agent is used in treating pruritus

because of its antihistaminic properties.Pimozide is primarily indicated for treatment of themotor and phonic tics ofTourette's disorder.

However, risperidone and haloperidol are alsocommonly prescribed for this tic disorder.

Also, risperidone is now approved for themanagement of disruptive behavior and irritabilitysecondary to autism.


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Adverse effects commonly

observed in individualstreated with neuroleptic

drugs.


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Cautions and contraindications:

All antipsychotics may lower the seizurethreshold, and chlorpromazine and clozapine arecontraindicated in patients with seizure

disorders. Therefore, the neuroleptics can also aggravate

preexisting epilepsy, and they should be usedwith caution in patients with epilepsy.

All of the atypical antipsychotics also carry thewarning of increased risk for mortality when usedin elderly patients with dementia-relatedbehavioral disturbances and psychosis.


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Rates of relapse among patients with schizophrenia after

maintenance therapy with either risperidone or haloperidol

Relapse: is a return of symptoms after a period of time when

no symptoms are present


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