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The introduction in the mid-1950s of chlorpromazinecan truly be said to have revolutionized
the practice of psychiatry. Prior to that time no regularly efficacious treatment was available
for the most common psychotic disorders. Discovery of the neuroleptics made possible the
release to their homes and to their communities of many thousands of patients who previously
faced the prospect of lifetime institutionalization.
          There is a tendency among students of medicine to regard psychotherapeutic drugs in general and
neuroleptics in particular, as the province of psychiatry. In fact, surveys have indicated that two thirds of all
prescriptions for antidepressants and neuroleptics are written by physicians other than psychiatrics. It is therefore
essential that all physicians have a working general knowledge of the indications, adverse effects, and drug
interactions of the neuroleptics.
        P s y c h o s i s is the condition most often treated with neuroleptics. The most
common forms of psychosis for which neuroleptics are indicated are the schizophrenic
disorders. These are characterized by chronicity, impaired function and disturbances of
thinking and affect.
The American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders
third edition provides the following criteria for the use of neuroleptics:
 One or more psychotic symptoms such as delusions, hallucinations, illogical thinking, or
    disorganized behaviour
 Deterioration from a previous level of functioning
 Continuous signs of the illness for at least 6 months
 tendency toward onset before age 45
 smptoms not due to affective disorders
 symptoms not due to organic mental disorders or mental retardation.

    The dopamine hypothesis of schizophrenia states that hyperactivity in dopaminergic systems causes the
    signs and symptoms characteristic of the disease. Primary support for the hypothesis comes from the
    observation that all clinically effective antipsychotic drugs block one or another aspect of dopamine
    function. Further evidence is provided by the fact that chronic treatment with amphetamine, a drug believed
    to interact with dopaminergic systems, causes a syndrome that closely resembles paranoid schizophrenia .

    The majority of antipsychotics block dopamine receptors (D1 and D2) in the forebrain.
This blockade is though to participate mainly in antipsychotic effects. Blockade of D2
receptors, however, appears also in the striatum and induces unwanted extrapyramidal effects
(Fig. 1). Moreover, repeated administration causes an increase in D2 receptors sensitivity due
to an increase in abundance of these receptors. This appears to underlie both tolerance to
antipsychotic effects and the tardive dyskinesias that are caused by prolonged use of most
    Although psychosis is the primary indication for use of neuroleptics, they are widely
prescribed as well for a variety of abberant behaviors of nonspecific origin including
a g g r e s s i o n, h o s t i l i t y, and s e l f - d e s t r u c t i v e behavior.

Neuroleptics have also antiemetic properties.
Nausea and vomiting are profoundly influenced by dopamine-sensitive receptors of a
medullary center called the chemoreceptor trigger zone (CRT). The antiemetic properties of
neuroleptics are believed to arise from dopaminergic blockagde of CRT. Thus, neuroleptics,
especially chlorpromazine and prochlorperazine, often are used to control nausea and emesis
in a variety of disease states as well as that associated with cancer chemotherapy.
Adverse effects
Extrapyramidal motor systém (EPMS)
Neuroleptics are believed to act as antagonists of dopaminergic components of the EPMS.
The functional consequences of neuroleptic-induced disturbance of the EPMS may be divided
into four distinct syndromes: parkinsonian syndrome, acute dystonia, akathisia, and tardive
dyskinesia. The first three occur soon after initiation of neuroleptic therapy and usually are
amenable to treatment. These early-onset extrapyramidal disturbances are thought to be due to
the direct effects of dopaminergic blockade in the striatum as mentioned above.
Parkinsonian syndrome (PS) that is characterized by tremors and rigidity of skeletal muscles,
especially of the upper limbs. Akinesia, a state of decreased motor activity, is often a major
sign of the PS. Anticholinergic antiparkinsonian drugs are of value in treating the
neuroleptic-induced condition.
Acute dystonia may appear shortly after initiation of neuroleptic therapy. Hypertonicity of the
muscles of the neck and back may progress to opisthotonos. Difficulty in swallowing and
spasms of the muscles of tongue, and eyes may occur. At the first appearance of dystonia,
administration of the neuroleptic should be stopped and the patient reassured as to the
essentially benign nature of the condition. Especially severe cases may require the parenteral
administration of an anticholinergic antiparkinsonian agent.
Akathisia . The literal meaning of this term is „without sitting“. It refers particularly to motor
restlessness and a desire on the part of patient to be in constant motion. It is resonable to
conclude that this syndrome may contribute to noncompliance by some patients. Reduction
of dosage may be of value.
Tardive dyskinesia. As is implied by its name, tardive dyskinesia has a delayed onset,
sometimes becoming apparent only after years of treatment. Among the most prominent signs
are athetoid or, choreiform movements of voluntary muscles. Usually the face and mouth are
involved causing repetitive sucking, chewing and lip smacking, the togue may be injured.
Most important is the apparent irreversibility of the condition. It responed poorly if at all to
antiparkinsonian agents and may worsen rather than improve with discontinuation of
neuroleptic treatment. Tardive dyskinesia has many of the features of a supersensitivity
phenomenon (compensatory increase in dopamine release and/or increased sensitivity of
selective receptors).

Neuroleptic malignant syndrome
An unusual and sometimes fatal reaction to antipsychotic drugs that combines features of
disordered temperature regulation and extrapyramidal reactions is called the neuroleptic
malignant syndrome (NMS). About 10% of patients with NMS die. The hallmarks of NMS
are hyperthermia and rigidity, presumably of extrapyramidal origin. In addition, delirium and
increased blood pressure ofter occur. Treatment is uncertain but should include termination of
all neuroleptics and use of general supportive measures including body cooling and
rehydration as needed. NMS is believed to be caused by inhibition of dopaminergic receptors
in the hypothalamus (disorder of temperature regulation), in EPMS (rigidity), and increased
intracellular calcium. Among those claimed to have some beneficial effects are bromocriptine
(stimulates dopaminergic receptor), and dantrolene (an intracelullar Ca2+ antagonist).

in general, neuroleptics depress activity in the central nervous system. The resulting
drowsiness and sedation are sometimes useful in agited patients but more often are regarded
as undesired properties. This is especially true during maintenance therapy.
There appears to be no relationship between the degree of sedation produced and the actual
antipsychotic effects. Although multiple mechanisms are probably involved, activity of
neuroleptics at histaminergic and cholinergic receptors in the CNS seems a likely factor.
The depressant effects of antipsychotic drugs are at least additive with those of ethanol,
barbiturates, opiates, and other depressants of CNS activity. Appropriate adjustement in
dosage should be made when neuroleptics are combined with such drugs.

Neuroleptics decrease the convulsive threshold and may precipitate seizures in persons with
pre-existing CNS pathology. Potentiation of the depressant effects of barbiturates does not
extend their anticonvulsant properties. For this reason, doses of barbiturates and other
antiepileptic agents should not be reduced routinely on initiation of antipsychotic drug
therapy. Furthermore, neuroleptics are contraindicated in the treatment of conditions such as
ethanol and barbiturates withdrawal.

Cardiovacular system:
 Antimuscarinic effects may results in tachycardia while direct action on myocardium can
    cause prolongation of the QT interval and a widening of the QRS complex.
 In the periphery, neuroleptics appear to be selectively active at α-adrenergic receptors,
    and epinephrine reversal may occur. This is a phenomenon in which doses of epinephrine
    that usually produce pressor effects result in hypotension owing to unopposed stimulation
    of β- adrenergic receptors. The pressor agent of choice in neuroleptic-induced hypotenion
    is norepinephrine.
Those physicians who prescribe neuroleptics must také into account possible untoward effects
on the myocardium particularly in those patients with pre-existing coronary atherosclerosis or
disturbances in cardiac rhythm.

Temperature regulation
Neuroleptics serve to loosen in general the homeostatic mechanisms that normally maintain
body temperature. Disordered temperature regulation is thought to be mediated by neuroleptic
blockade of muscarinic receptors. Thus, patients maintained on neuroleptics may become
hyperthermic when exposed to high environmental temperature, and several deaths have been
reported. On the other hand, an early use of chlorpromazine was to facilitate the lowering of
body temperature prior to cardiac surgery because of decrease in body temperature due to
cold setting.

Endocrine systems.
Dopamine released by the hypothalamus passes through the hypothalamicoadenohypophyseal
portal system to the pituitary where it functions to inhibit the release of prolactiv. The
antidopaminergic effects of neuroleptics trhus account for the increasse in serum prolactin
that is consistently seen in patients treated with these drugs.Neurolpetic-induced
hyperprolactinemia is sometimes associated with galactorrhea, menstrual changes, and
A number of other adverse effects of antipsychotic drugs may have an endocrine component.
These include sexual dysfunction and undesired weight gain.

Peripheral antimuscarinic action is ofter associated with one or more signs of an atropin-
like syndrome. Thus, blurred vision, exacerbation of narrow angle glaucoma, dry mouth,
sinus tachycardia, constipation, urinary retention. and decreased sweating may occur.
Liver dysfunction, usually in the form of cholestatic jaundice, was associated with
chlorpromazine use. The condition is usually reversible on discontinuation of neuroleptic use.
If treatment is to continue, the agent from another chemical class should be chosen. Periodic
liver function tests are indicated in patients chronically treated with phenothiazines.

Hematological disorders
Blood dyscrasias, including agranulocytosis, leukopenia, thrombocytopenic purpura are rare.
However, because of the possibly fatal outcome of these disorders .patients and their families
should be warned to report sore throat or other signs of infection.

Dermatological effects
With long-term treatment , ususual sensitivity to the sun and discoloration of the skin may
occur. A possibly related condition is deposition of fine particulate matter in the lens and
cornea of the eye. Ocular changes have most often been associated with long term, high-dose
therapy with thioridazine. Under these circumstances, regular examinations of the eye are

It is generally assumed that some measures of tolerance develops to the sedative and
hypotensive effects of neuroleptics. Physical dependence on antipsychotic drugs is seldom
reported. However, a withdrawal syndrome including vomiting and movement disorders has
been described. For this reason, gradual reduction in dosage following long-term treatment is

A prototyp of neuroleptics is chlorpromazine. It has multiple metabolites. Its large apparent
volume of distribution (Vd = 22 L/kg) results in low plasma concentrations. When given
orally it is incompletely absorbed with a bioavailability of about 30%. T1/2 varies between 2
and 24 hours. Plasma steady state concentrations are reached in around 1 week.

Neuroleptics can be divided according to the structure:
with aliphatic side chain (group )1: chlorpromazine, levomepromazine are profoundly
sedating, moderatery antimuscarinic, with moderate extrapyramidal effect,
  piperazine side chain (group 2): fluphenazine, perphenazine, trifluoroperazine,
prochlorperazine: little sedation, little antimuscarinic action, high extrapyramidal effect
  piperidine side chain (group 3): thioridazine moderately sedation, much antimuscarinic
action, little extrapyramidal effect,
Butyrophenones:          haloperidol, droperidol are similar to group 3 phenothiazines
Diphenylbutylpiperidines : fluspirilen and pimozide are long-acting
Dihydroindolones: molidone
Thioxanthines:          chlorprothixene, flupenthixol
Oxypertine and loxapine similar to phenothiazines in toxicity
Clozapine has higher affinity for D3-D4 receptors, the risk of agranulocytosis
Sulpirid and remoxipride : little sedation and extrapyramidal effects

Pregnancy and lactation, cautions: elderly, coma due to cerebral depressants, epilepsy, hepatic
impairment (phenothiazines). Avoid in children, cardiac disturbance, hypokalemia
(fluspirilen, pimozid). Avoid in basal ganglia disease, other as with phenothiazines

        Striatum                                      ACh


                                            Substantia nigra

Fig 1: Representation of relationships between cholinergic (ACh), dopaminergic (DA) and
GABA-producing neurons in the basal ganglia.
GABA and dopaminergic neurons are regulating the stimulating action of the cholinergic
neuron on the striated muscle. Administration of a neuroleptic agent results in the inhibition
of dopaminergic receptors at the postsynaptic membrane of the cholinergic neuron. The
extrapyramidal syndrom due to desinhibition of the cholinergic neuron occurs.

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