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NEUROLEPTICS (ANTIPSYCHOTICS)

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ANTIPSYCHOTICS / NEUROLEPTICSNeuroleptic: synonym for antipsychotic drug.

Antipsychotics are the drugs currently used in the prevention of psychosis.

They have also been termed neuroleptics, because they suppress motor activity and emotionality.

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WHAT IS PSYCHOSIS……….????

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PSYCHOSIS

Psychosis (from the Greek , psyche, "mind/soul", and -osis, "abnormal condition or derangement") refers to an abnormal condition of the mind.

A syndrome of chronic disordered thinking and disturbed behavior (schizophrenia, mania, depression)

The most important types of psychosis are:

• Schizophrenia• Affective disorders (e.g. depression, mania)• Organic psychoses (mental disturbances caused by head

injury, alcoholism, or other kinds of organic disease).

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SCHIZOPHRENIA• A chronic mental disorder of a type

involving a breakdown in the relation between thought, emotion, and behaviour, leading to faulty perception, inappropriate actions and feelings, withdrawal from reality and personal relationships into fantasy and delusion, and a sense of mental fragmentation.

• The disorder is characterized by a divorcement from reality in the mind of the person (psychosis).

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SYMPTOMSPOSITIVE SYMPTOMS:

• Delusions

• Hallucinations

• Combativeness

• Insomnia

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SYMPTOMSNEGATIVE SYMPTOMS:

• Affective Flattening (blunt)

• Alogia

• Anhedonia

• Amotivation

• Apathy

• Asocial Behavior

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SYMPTOMSDISORGANIZED SYMPTOMS:

• Disorganized thought,speech,behavior.

• Poor Attention.

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TYPES OF SCHIZOPHRENIA• PARANOID : a person feels extremely suspicious (everyone

plotting against me), persecuted (opressed), grandiose ( great), or experiences a combination of these emotions.

• DISORGANIZED : a person is often incoherent but may not have delusions.

• CATATONIC : a person is withdrawn, mute, negative and often assumes very unusual postures ( motor symptoms).

• RESIDUAL : a person is no longer delusion or hallucinating (psychotic), but has no motivation or interest in life. These symptoms can be most devastating.

• UNDIFFERENTIATED : a person meet the criteria for schizophrenia but cant be classified as a particular type.

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SCHIZOPHRENIA

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DOPAMENERGIC SYSTEM:

There are four major pathways for the dopamenergic system in brain :I. The Nigro-Striatal

Pathway.

II. The Mesolimbic Pathway.

III. The Mesocortical Pathway.

IV. The Tuberoinfundibular Pathway.

ETIOLOGY

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THE DOPAMINE HYPOTHESIS

Schizophrenia results from excess activity of dopamine neurotransmission in Mesolimbic and Mesocortical Pathways because:

All antipsychotic drugs block dopamine receptors.

Stimulant drugs which act through dopamine can produce schizophrenic-like behaviors (eg.amphetamines).

Levodopa, a dopamine precursor, can exacerbate schizophrenic symptoms, or occasionally elicit them in non-schizophrenic patients.

Higher levels of dopamine receptors measured in brains of schizophrenics by PET.

Brain [DA] increases during psychotic episodes but not during remissions.

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THE DOPAMINE HYPOTHESIS

The role of dopamine in Schizophrenia is quite complex :

• Positive Symptoms are thought to be result of OVERACTIVITY in Mesolimbic pathway ( activating D2 receptors ).

• While, negative symptoms may result from a DECREASE ACTIVITY in Mesocortical pathway (D1 receptors).

• Nigrostriatal and Tuberoinfundibular pathways appear to be normal in Schizophrenia.

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GLUTAMATE HYPOTHESIS

Glutamate : excitatory Neurotransmitter

NMDA Receptors : Ionotropic Glutamate Receptors

It is observed that NMDA hypofunction on one hand

• Decrease DA in Mesocortical Pathway so Increase Negative Symptoms

And on the other hand

• Increase DA in Mesolimbic Pathway , hence, Increase Positive Symptoms.

• Evidence : NMDA rec Antagonists (Phencyclidine,ketamine) produce both Positive and Negative Psychotic Symptoms.

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SEROTONINE HYPOTHESIS• Many effective antipsychotic drugs, in addition to blocking

dopamine receptors, also act as 5-HT-receptor antagonists.

• Many 'atypical‘ antipsychotic drugs produce fewer extrapyramidal side effects than dopamine-selective compounds, as they also combine with 5-HT2A-receptors.

• Whether 5-HT2A-receptor blockade accounts directly for their antipsychotic effects, or merely reduces undesirable side effects associated with D2-receptor antagonists, remains controversial.

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CLASSIFICATION OF ANTIPSYCHOTIC DRUGS

Typical antipsychotics

• Phenothiazines • e.g. chlorpromazine,

fluphenazine, thioridazine

• Butyrophenones • e.g. haloperidol,

droperidol

• Thioxanthines• e.g. chlorprotixen,

thiothixene

Atypical antipsychotics

• Clozapine• Risperidone• Sulpiride• Sertindole• Seroquel• Olanzapine• Quetiapine.

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CLASSIFICATION

Distinction between ‘typical’ and ‘atypical’ groups is not clearly defined, but rests on:

• Incidence of extrapyramidal side-effects (less in ‘atypical’ group)

• Efficacy in treatment-resistant group of patients• Efficacy against negative symptoms.

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DRUG TARGETSDopamine receptors: D1, D2, D3, D4, D5

Serotonin receptors: 5-HT-1A, 2A, 3, 6, 7

Norepinephrine: -1 & -2

Muscarinic acetylcholine: mACh-1 & 4

Histamine: H-1 & 2

Dopamine, norepinephrine & serotonin transporters

NMDA-glutamate receptor

Haloperidol Clozapine Risperidone Olanzapine

Quetiapine Ziprasidone

5HT2A D2 D1 Alpha 1 Musc H1 5HT1A (agonist)

Casey 1994

Atypical Antipsychotics In Vivo Binding Affinities

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MECHANISM OF ACTION

• There are many type of DA-receptors (see upper).

• The antipsychotic drugs probably owe their therapeutic effects mainly to blockade of D2 receptors.

• The main groups, phenothiazines, thioxanthines and butyrophenones, show preference for D2 over D1 receptors; some newer agents (e.g. remoxipride) are highly selective for D2 receptors, whereas clozapine is relatively non-selective between D1 and D2, but has high affinity for D4.

• Most striatal neurons have D1 responses and most accumbens neurons have D2 responses.

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MECHANISM OF ACTION

• Daily treatment with neuroleptics for several weeks produces a reversible cessation of firing of midbrain DA neurons. These inactivated neurons are said to be in a state of “depolarization block”.

• The time antipsychotics take for the clinical response to be manifested is thought to correlate with this delayed induction of depolarization blockade of mesolimbic DA neurons.

• DA-ergic blockade in basal ganglia (nigrostristal pathway) appears to cause the extrapyramidal symptoms, while that in tubero-hypophyseal pathway induces endocrine disorders, and in central trigger zone - is responsible for antiemetic action.

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EFFECTS OF ANTIPSYCHOPTIC DRUGS1.Central Nervous System :• In a psychotic patients they reduce irrational behaviour, agitation and

aggressiveness and controls psychotic symptoms. Disturbed thought and behaviour are gradually normalised, anxiety is relieved. Hyperactivity, hallucinations and delusions are suppressed.

• All phenothiazines, thioxanthenes and butyrophenones have the same antipsychotic efficacy, but potency differs .

• Chlorpromazine, triflupromazine, thioridazine have low potency, produce more sedation and cause greater potentiation of hypnotics, opioids etc.

• The sedative effect is produced immediately while antipsychotic effect takes weeks to develop. Moreover, tolerance develops to the sedative but not to the antipsychotic effect.

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EFFECTS OF ANTIPSYCHOPTIC DRUGS• antiemetic effect : inhibit chemoreceptor trigger zone or directly

depress the medullary vomiting center.

• temperature-regulating effect : produce hypothermia

2. Autonomic Nervous System :

Neuroleptics have varying degrees of

• α--adrenergic blocking activity clorpromazine=triflupromazine>thioridazine> fluphenazine>haloperidol>trifluoperazine>clozapine>pimozide.

• anticholinergic property of neurolrptics is weak and may be graded as thiridazine>chlorpromazine>triflupromazine>trifluoperazine=haloperidol

• The phenothiazines have weak H1- antihistaminic and anti-5-HT action as well.

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EFFECTS OF ANTIPSYCHOPTIC DRUGS3.Local anaesthetic

• Chlorpromazine : potent a local anaesthetic.

• However, not used because of its irritant action.

4.Cerebrovascular system

• Produce hypotension (primarily postural) by α-adrenergic blocked.

• High doses of chlorpromazine : produce ECG changes – QT prolongation and suppression of T wave.

5.Endocrine system

• Increase prolactin : which may result in galactorrhea and gynecomastia. They reduce gonadotropin secretion but amenorrhea and infertility occur only occasionally.

• ACTH release in response to stress is diminish.

• Decreased release of ADH may result in an increase in urine volume.

TYPE MANIFESTATIONS MECHANISM

Autonomic nervous system

Dry mouth, loss of accommodation; difficulty urinating, constipation

Muscarinic blockade

Orthostatic hypotension, impotence, failure to ejaculate

Alpha adrenergic blockade

Central nervous system

Parkinson’s syndrome; akathisia, dystonia

Dopamine receptor blockade

Tardive dyskinesia Dopamine receptor supersensitivity

Toxic confusional state Muscarinic blockade

Endocrine system Galactorrhea; amenorrhea; infertility, impotence

Hyperprolactinemia secondary to dopamine receptor blockade

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UNWANTED EFFECTS1.”Extrapyramidal” reactions include

a) Parkinsonism : usually of mild degree responds to anticholinergic drugs or amantadine.

b) Akathisia : is a subjective sense of restlessness usually (inability to sit) accompanied by mild to moderate motor hyperactivity, usually responds to α-adrenergic receptor antagonists, anticholinergics, antihistamines or amantadine.

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UNWANTED EFFECTSAcute dystonia :

• Due to the blocked of DA-nergic nigrostriatal pathway.

• Reactions are involuntary movements (restlessness,muscle spasms, protruding tongue, fixed upward gaze, torticollis, etc.)

• Occur commonly in the first few weeks, often declining with time, and are reversible on stopping treatment.

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UNWANTED EFFECTS• Tardive dyskinesia :

• develops after months or years in 20-40% of patients treated with typical antipsychotic drugs

• Irreversible and highly disabling.

• Involuntary and excessive oral-facial movements but also of trunk n limbs.

• it is associated with a gradual increase in the number of D2 receptor in striatum (up-regulation), which is less marked with the atypical antipsychotic drugs.

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UNWANTED EFFECTS2.Endocrine effects

• DA released by neurons of the tuberoinfundibular pathway acts via D2 receptors as an inhibitor of prolactin.Thus blocking D2 receptors therefore increases the plasma prolactin concentration, resulting breast swelling, pain and lactation, which can occur in men as well as women.

3. Neuroleptic malignant syndrom :

• Rare but serious complication.

• It occurs in 1% to 2% of patients and is fatal in almost 10% of those affected.

• This is observed early in treatment and is characterized by a near complete collapse of the autonomic nervous system, causing, for example, fever, muscle rigidity, diaphoresis, mental confusion and cardiovascular instability.

• Immediate medical intervention with bromcriptine (DA agonist) and dantrolene is nessesary.

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UNWANTED EFFECTS4. Sedation:

• Tends to decrease with continued use. Antihistaminic (H1) property of phenothiazines contributes to their sedative and antiemetic properties.

5.Peripheral effects.

• Blocking muscarinic receptors : produce blurring of vision and increased intraocular pressure, dry mouth and eyes, constipation and urinary retention.

• Blocking α-adrenoreceptors : orthostatic hypotension.

• Weight gain is a common and troublesome side-effect, probably related to 5-HT antagonism.

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UNWANTED EFFECTS6.Idiosyncratic and hypersensitivity Reactions :

• Jaundice:

• with older phenothizines, such as chlorpromazine.

• usually mild,obstructive and reversible

• Leukopenia and agranulocytosis :

• rare, but potentially fatal, and occur in the first few weeks.

• The incidence of leukopenia (usually reversible) is higher (1-2%) with clozapine,provided the drug is stopped at the first sign of leukopenia or anemia, the effect is reversible.

• Olanzapine appears to be free of this disadvantage.

• Urticarial skin reactions are common but usually mild. Excessive sensitivity to ultraviolet light may also occur.

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CLINICAL USESBehavioural emergencies

(e.g. violent patients with a range of psychopathologies including mania, toxic delirium, schizophrenia and others):

• classic antipsychotic drugs (e.g. chlorpromazine, haloperidol) can rapidly control hyperactive psychotic states

• note that the intramuscular dose is lower than the oral dose of the same drug because of presystemic metabolism.

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CLINICAL USESSchizophrenia

• The major use of antipsychotic drugs is in the treatment of schizophrenia and other psychotic disorders .

• The traditional neuroleptics are most effective in treating positive symptoms of schizophrenia (delusions, hallucination and thought disorders).

• The newer agents with 5-HT blocking activity (e.g.sulpirid ) are effective in many patients resistant to the traditional agent, especially in treating negative symptoms of schizophrenia and depression.

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CLINCAL USES• Nausea and Vomiting :

• The neuroleptics (most commonly prochlor-perazine), are useful in treatment of drug induced nausea.

• Other uses :

• Neuroleptics are used in combination with narcotic analgetics for treatment of chronic pain with severe anxiety.

• Chlorpromazine is used to treat intractable hiccups.

• Droperidol is a component of neuroleptanesthesia.

• Prometathazine is not a good antipsychotic drug, but the agent is used in treating pruritus because of its antihistaminic properties.

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