Post on 20-Jun-2020
Neuroleptic drugs
(also called antischizophrenic drugs, antipsychotic drugs or
major tranquilizers)
Psychosis—severe mental disorder character. By
disordered though processes, inappropriate emotional
responses, bizarre behavior, agitation, aggressiveness,
hostility, social withdrawal, deterioration in occupational and
social functioning, hallucinations and paranoid delusions.
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).
Schizophrenia is a particular type of psychosis, that is, a mental disorder caused by some inherent dysfunction of the brain. It is characterized by delusions, hallucination (often in the form of voices), and thinking or speech disturbances.
Hallucinations—sensory perceptions of people or objects
that are not present. Unable to distinguish between
false perceptions and reality.
In schizophrenia or bipolar disorder, usually auditory; in
delirium, usually visual or tactile; in dementia usually
are visual.
Delusions are false beliefs that persist in absence of
reason or evidence. May believe others control their
thoughts, feelings or seek to harm them.
Psychosis may be acute or chronic.
When acute—may be confusion or delirium. Can be
precipitated by illness, drug effects or superimposed on
chronic dementias.
Positive symptoms: CNS stimulation, agitation, behavioral
disturbances, delusions, hallucinations, insomnia, and paranoia.
Negative symptoms: anhedonia, lack of motivation, blunted
affect, poor hygiene, poor social skills and social withdrawal.
Schizophrenia:
Symptoms
Etiology of Schizophrenia- Evidence indicates abnormal neurotransmission systems
in the dopaminergic, serotonergic, and glutaminergic
systems. Also, seems to be interplay between the systems
so one system may affect others.
- Imbalance in amount of neurotransmitters, most notably
dopamine. Overactivity accounts for the positive symptoms
of schizophrenia and underactivity in another part of the
brain may account for the negative symptoms.
- Glutamatergic dysfunction may be genetically linked as
well as causative in the cognitive impairments and negative
symptoms of this disorder.
Dopamine Receptor Subtypes• D1, D5: Gs coupled - increase cAMP
• D2, D3, D4: Gi coupled - decrease
cAMP
• D2 mediates much of „typical APD‟
therapeutic action and side effects
Classification of Antipsychotic drugs
– Typical antipsychotics
Phenothiazines (chlorpromazine, perphenazine,
fluphenazine, thioridazine et al)
Thioxanthenes (Thiothixene, flupenthixol, clopenthixol)
Butyrophenones (haloperidol, droperidol)
– Atypical antipsychotics (e.g. clozapine, risperidone,
sulpiride, olanzapine)
Mode of action
All of the neuroleptic drugs block dopamine receptors in the brain and in the periphery.
The neuroleptic drugs bind to receptors to varying degrees; however, the clinical efficacy of the traditional neuroleptic drugs correlates closely with their relative ability to block D2 receptors in the mesolimbic system.
Mode of action
The newer “atypical” agents appear to exert part of their unique action through inhibition of serotonin (5-HT) receptors.Thus, Clozapine has high affinity for D1 and D4, 5-HT2, M-cholinergic and α-adrenergic receptors, but it is also a dopamine D2-receptor antagonist. Another new agent, Risperidone, blocks 5-HT2 receptors to a greater extent than it does D2 receptors. Both of these drugs exhibit a low incidence of exrapyramidal side effects.
Atypical antipsychotics
Relative receptor-binding of atypical antipsychotics
Drug D1 D2 5-HT2 1 M1 H1
Clozapine ++ ++ +++ +++ +++ +
Risperidone - +++ +++ +++ - +
Olanzapine ++ ++ +++ ++ +++ ++
Quetiapine - + ++ +++ + +
Ziprasidone +/- ++ +++ ++ - +
Aripiprazole + +++ ++ ++ - +
Actions
The antipsychotic actions of neuroleptic drugs reflect blockade at dopamine and/ or serotonin receptors. However, many of these drugs block cholinergic, adrenergic, and histamine receptors, causing a variety of side effects.
Actions
1. Antipsychotic actions.This effect is differ in normal and psychotic individuals.In normal individuals neuroleptic drugs produce indifference to surroundings, psychomotor slowing, emotional quietening, reduction in initiative and tendency to go off to sleep from which the subject is easily arousable. This has been refered to as the «neuroleptic syndrome».In a psychotic individuals neuroleptic drugs reduse agitation and aggressiveness and controls psychotic symptomatology. Hyperactivity,hallucinations and delusions are supressed.
Actions
2. Extrapyramidal effects.
Neuroleptic drugs block dopamine receptors in the nigrostriatal pathway and may cause Parkinsonian symptoms, akathisia (motor restlessness), and tardive dyskinesia (inappropriate postures of the neck, trunk and limbs), which occur with chronic treatment.
Actions
3. Antiemetic effect.
Most of the neuroleptic drugs (with the exception of Thiordazine) block D2 dopaminergic receptors of the chemoreceptor trigger zone of the medulla and have antiemetic effects.
Actions
4. Antimuscarinic effects.
All of the neuroleptic drugs, particularly Thioridazine and Chlorpromazine, cause anticholinergic effects, including blurred vision, dry mouth, sedation, confusion, and inhibition of gastrointestinal and urinary smooth muscle, leading to constipation and urinary retention.
Actions
5. Other effects.The neuroleptic drugs produce orthostatic hypotension and lightheadedness, because they block α-adrenergic receptors. The reflex tachycardia may occur.The neuroleptic drugs alter temperature-regulating mechanisms and can produce poikilothermia (body temperature varies with the environment).In the pituitary, neuroleptics block D2receptors, leading to an increase in prolactin release, reduce gonadotropin secretion and decrease on release of ADH (this may result in an increase in urine volume).
Chlorpromazine is a more potent a local anestheticthan Procaine.
However, it is not used for this pupose because of its irritant action. Other have weaker membrane stabilizing action.
Neuroleptic drugs have no effect on muscle fibres or neuromuscular transmission. They reduce certain types of spasticity: the site of action being in the basal ganglia or medulla ablongata. Spinal reflexes are
not affected.
Therapeutic uses1. Treatment of schizophrenia.
The traditional neuroleptics are most effective in treating positive symptoms. The newer agents are effective in many patients resistant to the traditional agents, especially in treating negative symptoms of schizophrenia.
2. Other psycoses3. Prevention of severe nausea and vomiting.4. Neuroleptanalgesia (droperidol and fentanil)5. Malignant hyperthermia6. Hypertensive crisis (droperidol)7. Bipolar Affective Disorders8. Hiccups
Adverse effects
All neuroleptics may cause:
1) Drowsiness;
2) Confusion;
3) Postural hypotension, palpitation;
4) Amenorrhea, galactorrhea, infertility and impotence;
5) Dry mouth, blurring of vision, constipation, urinary retention 6) Parkinsonian effects (extrapyramidal disturbances).
Adverse effects
a) Parkinsonism with typical manifestations: rigidity, tremor, hypokinesia, mask like facies. It often responds to central anticholinergic drugs.
b) Acute muscular dystonias: bizarre muscles spasms, mostly involving linguo-facial muscles – grimacing, torticollis. It lasts one to few hours and then resolves spontaneously.
c) Tardive dyskinesia. It occurs late in the therapy, sometimes even after withdrawal of the neuroleptics: manifests as purposeless involuntary facial and limb movements.
Blockade Of D2 Receptors
D2
ANTAGONIST
Mesolimbic pathway
dramatic therapeutic action on positive
psychotic symptoms
Tuberoinfundibular pathway
hyperprolactinemia (lactation, infertility,
sexual dysfunction)
Nigrostriatal pathway
extrapyramidal side effects (EPS) and
tardive dyskinesia
Mesocortical pathway
enhanced negative and cognitive
psychotic symptoms
Diabetes
Lowered seizure threshold
Myocarditis
Neutropenia and other blood dyscrasias
Agitation and anxiety
Photosensitivity
Neuroleptic malignant syndrome (NMS)
Jaundice
Cerebral edema
Weight gain
Other side effects
Neuroleptic Malignant Syndrome
An idiosyncratic, life-threatening neurological disorder associated
with antipsychotic therapy
Idiosyncrasy: An unusual or unexpected sensitivity of an individual
to a particular food or drug. Idiosyncrasy is usually determined
genetically and it may be due to a biological deficiency (e.g. an
inability to metabolize a drug).
Clinical manifestations include:
Encephalopathy, Hyperpyrexia, delirium
Autonomic instability (vitals unstable)
Rigidity of muscles
Elevated creatine phosphokinase (CPK) due to
increased muscular activity and rhabdomyolysis
(destruction of muscle tissue)
Neuroleptic Malignant Syndrome
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