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CLASSIFICATION%20OF%20ANTIPSYCHOTIC%20DRUGS

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Title: CLASSIFICATION%20OF%20ANTIPSYCHOTIC%20DRUGS


1
  • CLASSIFICATION OF ANTIPSYCHOTIC DRUGS
  • More than 20 different antipsychotic drugs are
    available for clinical use, but with certain
    exceptions the differences between them are
    minor.
  • An important distinction is drawn between the
    main group, often referred to as classical or
    typical antipsychotic drugs atypical
    antipsychotic drugs
  • Atypical commonly refers to the diminished
    tendency of some newer compounds to cause
    unwanted motor side-effects. Their
    pharmacological profile somewhat different from
    that of classical pre-1980 drugs
    (phenothiazines, thioxanthines and
    butyrophenones).

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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. DA, the naturally
occurring agonist, interacts with D1 and D2
receptors, and both receptors are found in high
density in the corpus striatum and nucleus
accumbens. Most striatal neurons have D1
responses and most accumbens neurons have D2
responses.
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Fig.8
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Although D-receptor blockade occurs rapidly after
initial antipsychotic drug treatment, a
therapeutic response is not usually observed for
several weeks. The time it takes for the clinical
response to be manifested is thought to correlate
with the delayed induction of depolarization
blockade of mesolimbic DA neurons. Induction of
depolarization blockade also correlates with a
reversal of initial increase in the concentration
of DA metabolites in cerebrospinal fluid.
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10
  • EFFECTS OF ANTIPSYCHOPTIC DRUGS
  • 1.Central Nervous System
  • Effects of antipsychotic drugs differ in normal
    and psychotic individuals.
  • In normal individuals they produce indifference
    to surrounding, paucity of thought, psychomotor
    slowing, emotional quiet, reduction in initiative
    and tendency to go off to sleep. Spontaneous
    movements are minimized, but slurring of speech,
    ataxia or motor uncoordination does not occur.
    This has been referred to as the neuroleptic
    syndrome and is quite different from the
    sedative action of barbiturates and other
    similar drugs. The effects are appreciated as
    neutral and unpleasant by most normal
    individuals.

11
  • Catalepsy arises primarily from acute blockade of
    postsynaptic D2 receptors in basal ganglia.
  • Chlorpromazine lowers seizure threshold and can
    precipitate fits in untreated epileptics. The
    piperazine side chain compounds have a lower
    property for this action. The temperature control
    is knocked off at relatively higher doses
    rendering the individual poikilothermic body
    temperature falls if surrounding are cold. The
    medullary respiratory and other vital centers are
    not affected, except at high doses. It is very
    difficult to produce coma with these drugs.
    Neuroleptics, except thioridazine, have potent
    antiemetic action exerted through the central
    trigger zone. However, they are ineffective in
    motion sickness.

12
  • 3.Local anaesthetic
  • Chlorpromazine is as potent a local anaesthetic
    as procaine. However, it is not used for this
    purpose because of its irritant action. Others
    have weaker membrane stabilizing action.

13
  • 5.Skeletal muscle
  • Neuroleptics have no effects on muscle fibers or
    neuromuscular transmission. They reduce certain
    types of spasticity the site of action being in
    the basal ganglia or medulla oblongata. Spinal
    reflexes are not affected.

14
  • PHARMACOKINETICS
  • Most neuroleptic drugs are highly lipophilic,
    bind avidly to proteins, and tend to accumulate
    in highly perfused tissues. Oral absorption is
    often incomplete and erratic, whereas IM
    injection is more reliable. With repeated
    administration, variable accumulation occurs in
    body fat and possibly in brain myelin. Half-lives
    are generally long, and so a single daily dose is
    effective. An esterified derivate of fluphenazine
    requires dosing only once every few weeks. After
    long-term treatment and drug administration is
    stopped, therapeutic effects may outlast
    significant blood concentrations by days or
    weeks. This may result from tight binding of
    parent drug of active metabolites in the brain.

15
  • ANWANTED EFFECTS
  • Neuroleptic drugs are replete with side effects.
    Many side effects occur early during treatment
    and result from neuroleptic blockade of receptors
    in the central and peripheral nervous systems
    others appear later in the course of treatment
    (fig.12).
  • 1.Extrapyramidal reactions include
  • Parkinsonism, which can mimic idiopathic
    Parkinsons disease but is usually of mild
    degree. It responds to anticholinergic drugs or
    amantadine
  • Akatisia is a subjective sense of restlessness
    usually accompanied by wild to moderate motor
    hyperactivity. It is among the most common of
    side effects and usually responds to a-adrener
    gic receptor antagonists, anticholinergics,
    antihistamines or amantadine. Akathisia is
    sometimes misinterpreted as increased agitation,
    leading to increased neuroleptic dosing,
    resulting in greater akathisia.

16
  • 2.Endocrine effects
  • DA, released in the median eminence by
    neurons of the tuberohypophyseal pathway acts
    physiologically via D2 receptors as an inhibitor
    of prolactin secretion. The result of blocking D2
    receptors by antipsychotic drugs is therefore to
    increase the plasma prolactin concentration,
    resulting breast swelling, pain and lactation,
    which can occur in men as well as women. Other
    less pronounced endocrine changes including a
    decrease of growth hormone secretion, but these,
    unlike the prolactin response, are unimportant
    clinically.

17
  • 4. Sedation, which tends to decrease with
    continued use, occurs with many antypsychotic
    drugs. Antihistamine (H1) activity is a property
    of phenothiazines and contributes to their
    sedative and antiemetic properties, but not to
    their antipsychotic action.

18
  • 6.Various idiosyncratic and hypersensitivity
    reaction can occur, the most important being.
  • Jaundice, which occurs with older phenothizines,
    such as chlorpromazine. The jaundice is usually
    mild, and of obstructive origin it disappears
    quickly when the drug is stopped of substituded
    by an antipsychotic of different class.

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  • CLINICAL USE AND EFFICACY
  • Although the underlying cause of psychosis is
    unknown, treatment with neuroleptic drugs usually
    results in a specific improvement in psychotic
    sings and symptoms and does not simply cause
    sedation or reduce agitation. Modern
    antipsychotic drugs allow many schizophrenics to
    lead productive lives outside hospitals or less
    restrictive lives within hospitals.
    Unfortunately, for about half of patients with
    schizophrenia, classical neuroleptics are not
    completely effective in controlling positive
    symptoms. The progression of negative symptoms
    can lead to progressive deterioration. In
    schizophrenia, negative signs and symptoms are
    generally more resistant to antipsychotic drug
    therapy and are commonly the cause of chronic
    disability. It is likely that negative sings and
    symptoms have a pathophysiological description
    different from that of positive sings and
    symptoms and are associated more with decreased
    frontal lobe metabolic rate. In some patients,
    negative sings and symptoms way worsen with
    neutoleptoic treatment. The increased efficacy of
    clozapine compared to traditional neuroleptics
    derives primary from its greater efficacy in
    improving negative sings and symptoms.

21
  1. The major use of antipsychotic drugs is in the
    treatment of schizophrenia and other psychotic
    disorders . The neuroleptics are the only
    efficacious treatment for schizophrenia. Not all
    patients respond, and complete normalisation of
    behavior is seldom achieved. 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.

22
  • REFERENCES
  • Pharmacology, Fourth Edition, H.P.Rang, M.M.Dale,
    J.M.Ritter, CHURCHILL LIVINGSTONE, 2001.
  • Human Pharmacology, Molecular to Clinical, Third
    Edition, T.Brody, J.Larner, K.Minneman, Mosby,
    1998 by Mosby-Year Book,Inc.
  • Basic Clinical Pharmacology. A LANGE medical
    book. 8 EDITION, B.G.Katzung, 2001, McGraw-Hill
    Comp.
  • Lippincotts Illustrated Reviews Pharmacology,
    2nd Edition, M.J.Mycek, R.A.Harvey P.C.Champe,
    LIPPINCOTT WILLIAMS WILKINS, 2000.
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