CLASSIFICATION OF ANTIPSYCHOTIC DRUGS

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• 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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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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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.

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• 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.