Here is an overview of Antipsychotics,starting from basic pathophysiology of Psychosis and Schizophrenia,breifing the Neuropharmacology and lastly introduction of drugs with special reference to side effects and clincal uses.
Neuroleptic: synonym for antipsychotic drug.
Antipsychotics are the drugs currently used in the prevention
They have also been termed neuroleptics, because they
suppress motor activity and emotionality.
Psychosis (from the Greek , psyche, "mind/soul", and -osis,
"abnormal condition or derangement") refers to an abnormal
condition of the mind.
A syndrome of chronic disordered thinking and disturbed
behavior (schizophrenia, mania, depression)
The most important types of psychosis are:
• Affective disorders (e.g. depression, mania)
• Organic psychoses (mental disturbances caused by head
injury, alcoholism, or other kinds of organic disease).
• A chronic mental disorder of a
type involving a breakdown in
the relation between thought,
emotion, and behaviour, leading
to faulty perception,
inappropriate actions and
feelings, withdrawal from reality
and personal relationships into
fantasy and delusion, and a
sense of mental fragmentation.
• The disorder is characterized by
a divorcement from reality in the
mind of the person (psychosis).
• PARANOID : a person feels extremely suspicious (everyone
plotting against me), persecuted (opressed), grandiose (
great), or experiences a combination of these emotions.
• DISORGANIZED : a person is often incoherent but may not
• CATATONIC : a person is withdrawn, mute, negative and often
assumes very unusual postures ( motor symptoms).
• RESIDUAL : a person is no longer delusion or hallucinating
(psychotic), but has no motivation or interest in life. These
symptoms can be most devastating.
• UNDIFFERENTIATED : a person meet the criteria for
schizophrenia but cant be classified as a particular type.
There are four major
pathways for the
in brain :
I. The Nigro-Striatal
II. The Mesolimbic
III. The Mesocortical
Schizophrenia results from excess activity of dopamine
neurotransmission in Mesolimbic and Mesocortical Pathways
All antipsychotic drugs block dopamine receptors.
Stimulant drugs which act through dopamine can produce schizophrenic-
like behaviors (eg.amphetamines).
Levodopa, a dopamine precursor, can exacerbate schizophrenic
symptoms, or occasionally elicit them in non-schizophrenic patients.
Higher levels of dopamine receptors measured in brains of schizophrenics
Brain [DA] increases during psychotic episodes but not during remissions.
The role of dopamine in Schizophrenia is quite complex :
• Positive Symptoms are thought to be result of OVERACTIVITY
in Mesolimbic pathway ( activating D2 receptors ).
• While, negative symptoms may result from a DECREASE
ACTIVITY in Mesocortical pathway (D1 receptors).
• Nigrostriatal and Tuberoinfundibular pathways appear to be
normal in Schizophrenia.
Glutamate : excitatory Neurotransmitter
NMDA Receptors : Ionotropic Glutamate Receptors
It is observed that NMDA hypofunction on one hand
• Decrease DA in Mesocortical Pathway so Increase Negative
And on the other hand
• Increase DA in Mesolimbic Pathway , hence, Increase Positive
• Evidence : NMDA rec Antagonists (Phencyclidine,ketamine)
produce both Positive and Negative Psychotic Symptoms.
• Many effective antipsychotic drugs, in addition to blocking
dopamine receptors, also act as 5-HT-receptor antagonists.
• Many 'atypical‘ antipsychotic drugs produce fewer
extrapyramidal side effects than dopamine-selective
compounds, as they also combine with 5-HT2A-receptors.
• Whether 5-HT2A-receptor blockade accounts directly for their
antipsychotic effects, or merely reduces undesirable side
effects associated with D2-receptor antagonists, remains
• e.g. chlorpromazine,
• e.g. haloperidol,
• e.g. chlorprotixen,
Distinction between ‘typical’ and ‘atypical’ groups is not
clearly defined, but rests on:
• Incidence of extrapyramidal side-effects (less in ‘atypical’
• Efficacy in treatment-resistant group of patients
• Efficacy against negative symptoms.
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.
• Most striatal neurons have D1 responses and most accumbens
neurons have D2 responses.
MECHANISM OF ACTION
• Daily treatment with neuroleptics for several weeks produces a
reversible cessation of firing of midbrain DA neurons. These
inactivated neurons are said to be in a state of “depolarization
• The time antipsychotics take for the clinical response to be
manifested is thought to correlate with this delayed induction of
depolarization blockade of mesolimbic DA neurons.
• DA-ergic blockade in basal ganglia (nigrostristal pathway) appears to
cause the extrapyramidal symptoms, while that in tubero-
hypophyseal pathway induces endocrine disorders, and in central
trigger zone - is responsible for antiemetic action.
1.Central Nervous System :
• In a psychotic patients they reduce irrational behaviour, agitation and
aggressiveness and controls psychotic symptoms. Disturbed thought
and behaviour are gradually normalised, anxiety is relieved.
Hyperactivity, hallucinations and delusions are suppressed.
• All phenothiazines, thioxanthenes and butyrophenones have the
same antipsychotic efficacy, but potency differs .
• Chlorpromazine, triflupromazine, thioridazine have low potency,
produce more sedation and cause greater potentiation of hypnotics,
• The sedative effect is produced immediately while antipsychotic effect
takes weeks to develop. Moreover, tolerance develops to the sedative
but not to the antipsychotic effect.
• antiemetic effect : inhibit chemoreceptor trigger zone or directly
depress the medullary vomiting center.
• temperature-regulating effect : produce hypothermia
2. Autonomic Nervous System :
Neuroleptics have varying degrees of
• α--adrenergic blocking activity
• anticholinergic property of neurolrptics is weak and may be graded
• The phenothiazines have weak H1- antihistaminic and anti-5-HT
action as well.
• Chlorpromazine : potent a local anaesthetic.
• However, not used because of its irritant action.
• Produce hypotension (primarily postural) by α-adrenergic blocked.
• High doses of chlorpromazine : produce ECG changes – QT
prolongation and suppression of T wave.
• Increase prolactin : which may result in galactorrhea and
gynecomastia. They reduce gonadotropin secretion but amenorrhea
and infertility occur only occasionally.
• ACTH release in response to stress is diminish.
• Decreased release of ADH may result in an increase in urine volume.
TYPE MANIFESTATIONS MECHANISM
Dry mouth, loss of
impotence, failure to ejaculate
Parkinson’s syndrome; akathisia,
Tardive dyskinesia Dopamine receptor
Toxic confusional state Muscarinic blockade
Endocrine system Galactorrhea; amenorrhea;
secondary to dopamine
a) Parkinsonism : usually
of mild degree responds
to anticholinergic drugs or
b) Akathisia : is a subjective
sense of restlessness
usually (inability to sit)
accompanied by mild to
responds to α-adrenergic
Acute dystonia :
• Due to the blocked of DA-
• Reactions are involuntary
spasms, protruding tongue,
fixed upward gaze,
• Occur commonly in the first
few weeks, often declining
with time, and are
reversible on stopping
• Tardive dyskinesia :
• develops after months or years in
20-40% of patients treated with
typical antipsychotic drugs
• Irreversible and highly disabling.
• Involuntary and excessive oral-
facial movements but also of
trunk n limbs.
• it is associated with a gradual
increase in the number of D2
receptor in striatum (up-
regulation), which is less marked
with the atypical antipsychotic
• DA released by neurons of the tuberoinfundibular pathway acts via D2
receptors as an inhibitor of prolactin.Thus blocking D2 receptors
therefore increases the plasma prolactin concentration, resulting
breast swelling, pain and lactation, which can occur in men as well as
3. Neuroleptic malignant syndrom :
• Rare but serious complication.
• It occurs in 1% to 2% of patients and is fatal in almost 10% of those
• This is observed early in treatment and is characterized by a near
complete collapse of the autonomic nervous system, causing, for
example, fever, muscle rigidity, diaphoresis, mental confusion and
• Immediate medical intervention with bromcriptine (DA agonist) and
dantrolene is nessesary.
• Tends to decrease with continued use. Antihistaminic (H1) property of
phenothiazines contributes to their sedative and antiemetic properties.
• Blocking muscarinic receptors : produce blurring of vision and
increased intraocular pressure, dry mouth and eyes, constipation and
• Blocking α-adrenoreceptors : orthostatic hypotension.
• Weight gain is a common and troublesome side-effect, probably
related to 5-HT antagonism.
6.Idiosyncratic and hypersensitivity Reactions :
• with older phenothizines, such as chlorpromazine.
• usually mild,obstructive and reversible
• Leukopenia and agranulocytosis :
• rare, but potentially fatal, and occur in the first few weeks.
• The incidence of leukopenia (usually reversible) is higher (1-2%) with
clozapine,provided the drug is stopped at the first sign of leukopenia or
anemia, the effect is reversible.
• Olanzapine appears to be free of this disadvantage.
• Urticarial skin reactions are common but usually mild. Excessive
sensitivity to ultraviolet light may also occur.
(e.g. violent patients with a range of psychopathologies including mania,
toxic delirium, schizophrenia and others):
• classic antipsychotic drugs (e.g. chlorpromazine, haloperidol) can
rapidly control hyperactive psychotic states
• note that the intramuscular dose is lower than the oral dose of the
same drug because of presystemic metabolism.
• The major use of antipsychotic drugs
is in the treatment of schizophrenia
and other psychotic disorders .
• The traditional neuroleptics are most
effective in treating positive
symptoms of schizophrenia
(delusions, hallucination and thought
• 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.
• Nausea and Vomiting :
• The neuroleptics (most commonly prochlor-perazine), are useful in
treatment of drug induced nausea.
• Other uses :
• Neuroleptics are used in combination with narcotic analgetics for
treatment of chronic pain with severe anxiety.
• Chlorpromazine is used to treat intractable hiccups.
• Droperidol is a component of neuroleptanesthesia.
• Prometathazine is not a good antipsychotic drug, but the agent is
used in treating pruritus because of its antihistaminic properties.