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CLASSIFICATION OF
ANTIPSYCHOTIC DRUGS
http://www.bibalex.org/supercourse/SupercoursePPT/5011-6001/6011.ppt
Akhmad Edy Purwoko
Pharmacology Dept.
Medical Faculty MUY
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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 -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
1.Pharmacology, Fourth Edition, H.P.Rang,
M.M.Dale, J.M.Ritter, CHURCHILL
LIVINGSTONE, 2001.
2.Human Pharmacology, Molecular to
Clinical, Third Edition, T.Brody, J.Larner,
K.Minneman, Mosby, 1998 by Mosby-Year
Book,Inc.
3.Basic & Clinical Pharmacology. A LANGE
medical book. 8 EDITION, B.G.Katzung,
2001, McGraw-Hill Comp.
4.Lippincotts Illustrated Reviews:
Pharmacology, 2nd Edition, M.J.Mycek,
R.A.Harvey & P.C.Champe, LIPPINCOTT
WILLIAMS & WILKINS, 2000.
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