ANTIPSYCHOTIC AGENTS

By Dr Mary Onyango
Indications for Antipsychotic Drugs

Schizophrenia

Schizoaffective disorders

Acute control of mania

Tourette’s syndrome

Huntington’s chorea and ballism

Intractable hiccups
 Introduction
Psychosis is a thought disorder characterized
by disturbances of reality and perception,
impaired cognitive functioning, and
inappropriate or diminished affect (mood).

Psychosis denotes many mental disorders.

Schizophrenia is a particular kind of psychosis

characterized mainly by a clear sensorium but a
marked thinking disturbance.
 Schizophrenia - symptoms
Positive Symptoms
Negative Symptoms
Hallucinations
Blunted emotions
Delusions (bizarre, persecutory)
Anhedonia
Disorganized Thought
Lack of feeling
Perception disturbances
Inappropriate emotions

FUNCTION
Mood Symptoms
Cognition Loss of motivation
New Learning Social withdrawal
Memory Insight
Demoralization
Suicide
 The Nature of Schizophrenia
• Psychotic illness characterised by hallucinations,
delusions and thought disorder (positive symptoms),
together with social withdrawal and flattening of
emotional responses (negative symptoms).
• Acute episodes (mainly positive symptoms)
frequently recur and develop into chronic
schizophrenia, with predominantly negative
symptoms.
• Positive/active symptoms include thought disturbances,
delusions, hallucinations

• Negative/passive symptoms include social withdrawal, loss of

drive, diminished affect, paucity of speech. impaired
personal hygiene
 Schizophrenia

• Pathogenesis is unknown.
• Onset of schizophrenia is in the late teens -
early ‘20s.
• Genetic predisposition -- Familial incidence.
• Multiple genes are involved.
• Afflicts 1% of the population worldwide.
• May or may not be present with anatomical
changes.
 Psychosis-Producing Drugs

1) Levodopa
2) CNS stimulants
a) Cocaine
b) Amphetamines
c) Khat, cathinone, methcathinone
3) Apomorphine
4) Phencyclidine
 Etiology of Schizophrenia

Characterized by several structural and

functional abnormalities in the brains of
schizophrenic patients:

1) Enlarge cerebral ventricles.

2) Atrophy of cortical layers.
3) Reduced volume of the basal ganglia.
The Dopamine Hypothesis
Schizophrenia results from excess activity of
dopamine neurotransmission because:

 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.
 Dopamine System
There are four major pathways for the
dopaminergic system in the brain:

I. The Nigro-Stiatal Pathway.

II. The Mesolimbic Pathway.
III. The Mesocortical Pathway.
IV. The Tuberoinfundibular Pathway.
 Schizophrenia - Dopamine Hypothesis
 Repeated administration of stimulants like amphetamines and
cocaine, which enhance central dopaminergic neurotransmission, can
cause a psychosis that resembles the positive symptoms of
schizophrenia
 Low doses of amphetamine can induce a psychotic reaction in
schizophrenics in remission
 Stress, a major predisposing factor in schizophrenia, can produce a
psychotic state in recovered amphetamine addicts.
 Carlsson and Lindqvist (1963) first proposed that drugs such as
chlorpromazine and haloperidol alleviate schizophrenic symptoms by
blocking DA receptors and thereby reduce DA function.
 The antipsychotic medications, which have been the main stay for
treatment for nearly 50 years, have in common their ability to block
dopamine D2 receptors
 Schizophrenia - Dopamine Hypothesis
 A strong correlation between the affinity of
antipsychotic drugs for DA receptors and their clinical
potency
 But no clear and consistent abnormality in DA function
has been detected in schizophrenic patients.
 Some early studies with postmortem tissue revealed
increased numbers of DA receptors (in particular D2-
like) in schizophrenic patients, but there are serious
problems with these findings. But long-term
administration of antipsychotics produces increases in
D2 receptors in animals.
 Other transmitter systems involved..

• Glutamatergic system dysfunction

• e.g. effect of phencyclidine – blocker of NMDA type of
glutamate receptors
• G-protein signaling abnormalities

• Serotoninergic system abnormalities

• most antipsychotics also affect serotonin receptors

 Dopamine and serotonin theory of

schizophrenia
 Schizophrenia - Serotonin Hypothesis
 correlation between DA affinity and antipsychotic efficacy has
become weaker as a result of recently developed atypical
antipsychotic medications that also show substantial affinity for 5HT2
receptors
 Alteration of 5-HT transmission in the brains of schizophrenics
patients have been reported in post-mortem studies and serotonin-
agonists challenge studies
 There are widespread and complex changes in the 5-HT system in
schizophrenics patients
 These changes suggest that 5-HT dysfunction is involved in the
pathophysiology of the disease
 Schizophrenia - Glutamate Hypothesis
• Preclinical as well as clinical studies provide evidence of
hypofunction of NMDA receptors as a primary, or at least, a
contributory process in the pathophysiology of schizophrenia
• Several clinical trials with agents that act at the glycine
modulatory site on the NMDA receptor have revealed consistent
reductions in negative symptoms and variable effects of cognitive
and positive symptoms
• These studies also provide evidence that suggests the effects of
clozapine on negative symptoms and cognition may be through
activation of the glycine modulatory site on the NMDA receptor.
 A HYPOTHESIS IN TRANSITION
 All antipsychotic drugs which block dopamine receptors do not reverse all
symptoms
 positives are more responsive
 negatives may even be exacerbated

 Antipsychotics blocking DA and 5-HT receptors seem better for both positive and
negative symptoms

 DA metabolites in CSF & plasma not significantly elevated in schizophrenics

 Antipsychotic drugs block DA receptors immediately but antipsychotic

benefits take several days to weeks to occur
Classification of Antipsychotic drugs
• Distinction between ‘typical’ and ‘atypical’
groups is not clearly defined, but rests on:
– Incidence of extrapyramidal side-effects (less in
‘atypical’ group)
– Efficacy in treatment-resistant group of
patients
– Efficacy against negative symptoms.
 Phenothiazines
• Chlorpromazine:
Pharmacologic effects and mechanism:
(1) CNS: a. neuroleptic effect--- D1, D5---D1-like receprtors
D2-4------D2-like receptors

Antipsychotic drugs probably owe their therapeutic effects mainly to blockade of

D2-receptors (lies in midbrain-cortex and midbrain-limbic system ).
b. antiemetic effect--- inhibit chemoreceptor trigger zone or directly depress
the medullary vomiting center.
c. temperature-regulating effect--- produce hypothermia
 Antipsychotic/Neuroleptics
1) Phenothiazines

• Aliphatic Piperidine Piperazine*

Chlorpromazine Thioridazine Fluphenazine
Trifluopromazine Piperacetazine Perphenazine
Mesoridazine

Trifluoperazine

* Most likely to cause extrapyramidal effects.

 Antipsychotic/Neuroleptics
Piperazine
Piperidine
Aliphatic
Effect

[Drug dose]
 Phenothiazines
Pharmacologic effects:
(2) autonomic nervous system: block α-adrenergic
and M-Cholinergic receptors and result in
hypotension, dry mouth, constipation and blurred
vision.
(3) Endocrine system: increase the release of
prolactin and decrease corticotropin release and
secretion of pituitary growth hormone.
 Antipsychotics/Neuroleptics
• Antipsychotics produce catalepsy (reduce motor
activity).
– BLOCKADE OF DOPAMINE RECPTORS IN BASAL GANGLIA.

• Antipsychotics reverse hyperkinetic behaviors

(increased locomotion and stereotyped behavior).
– BLOCKADE OF DOPAMINE RECPTORS IN LIMBIC AREAS.

• Antipsychotics prevent the dopamine inhibition of

prolactin release from pituitary.
– BLOCKADE OF DOPAMINE RECEPTORS IN PITUITARY.
hyperprolactinemia
Atypical Antipsychotics In Vivo Binding Affinities

Haloperidol Clozapine Risperidone Olanzapine

Quetiapine Ziprasidone
5HT2A D2 D1 Alpha 1 Musc H1 5HT1A (agonist)

Casey 1994
 Therapeutic uses
• (1) treatment of psychotic disorders:
schizophrenia, mania, paranoid states,
alcoholic hallucinosis.
• (2) treatment of nausea and vomiting of
certain causes.
• (3) anesthesia in hypothermia (used with
pethidine and promethazine).
 Adverse Effects

• Tardive dyskinesia comprises mainly

involuntary movements of face and tongue,
but also of trunk and limbs, appearing after
months or years of antipsychotic treatment.
It may be associated with proliferation of
dopamine receptors (possibly presynaptic)
in corpus striatum. Treatment is generally
unsuccessful.
 Adverse Effects

• Extrapyramidal motor disturbances: (1)

Parkinson-like symptoms; (2) akathisia; (3)
acute dystonias.
Treatment: anticholinergic
 Adverse Effects

• Pseudodepression and Schizophrenia-like

syndrome.
• Seizures.
• Cardiac toxicity and endocrine effects.
 Adverse Effects
• Other side-effects (dry mouth, constipation,
blurred vision, hypotension, etc.) are due to
block of other receptors, particularly α–
adrenoceptors and muscarinic ACh
receptors.
Contact dermatitis, blood dyscrasias,
obstructive jaundice sometimes occurs with
phenothiazines.
 Thioxanthenes
• Chlorprothixene: mild antipsychotic action,
and antianxiety and antidepressant action.
 Antipsychotic/Neuroleptics

2) Thioxanthines
Thiothixene
Chlorprothixene

Closely related to phenothiazines

 Antipsychotic/Neuroleptics

3) Butyrophenones
Haloperidol
Droperidol
 Butyrophenones
• Haloperidol: control psychomotor excitement.
• Adverse effects: severe extrapyramidal
symptoms.
 Antipsychotic/Neuroleptics
Butyrophenone
Phenothiazine
Thioxanthene
Effect

[Drug dose]
Antipsychotic/Neuroleptics
Newer Drugs

Pimozide
Molindone
Loxapine
Clozapine
Olanzapine
Qetiapine
Risperidone
Sertindole
Ziprasidone
Olindone
 Others
• Clozapine:
• (1) be effective in treating some patients
with psychosis unresponsive to standard
neuroleptic drug.
• (2) blocks D4 receptor and have low affinity
for D1 and D2 dopamine receptors.
• (3) lacks extrapyramidal side effects.
• (4) must monitor the granulocyte counts
weekly.
 Others

• Risperidone: be used first episode in and

chronic schizophrenia.
 Clinical Efficacy of Antipsychotic Drugs
• Antipsychotic drugs are effective in controlling
symptoms of acute schizophrenia, when large doses
may be needed.
• Long-term antipsychotic treatment is often effective
in preventing recurrence of schizophrenic attacks,
and is a major factor in allowing schizophrenic
patients to lead normal lives.
 Clinical Efficacy of Antipsychotic Drugs
• Depot preparations are often used for maintenance
therapy.
• Antipsychotic drugs are not generally effective in
improving negative schizophrenic symptoms.
• Approximately 40% of chronic schizophrenic patients
are poorly controlled by antipsychotic drugs;
clozapine may be effective in some of these
‘antipsychotic-resistant’ cases.
 Pharmacokinetics
Absorption and Distribution
• Most antipsychotics are readily but incompletely
absorbed.
• Significant first-pass metabolism.
• Bioavailability is 25-65%.
• Most are highly lipid soluble.
• Most are highly protein bound (92-98%).
• High volumes of distribution (>7 L/Kg).
• Slow elimination.
**Duration of action longer than expected, metabolites are present
and relapse occurs, weeks after discontinuation of drug.**
 Pharmacokinetics

Metabolism
• Most antipsychotics are almost completely
metabolized.
• Most have active metabolites, although not
important in therapeutic effect, with one
exception. The metabolite of thioridazine,
mesoridazine, is more potent than the parent
compound and accounts for most of the
therapeutic effect.
 Pharmacokinetics

Excretion
• Antipsychotics are almost completely metabolized
and thus, very little is eliminated unchanged.
• Elimination half-lives are 10-24 hrs.
 Antipsychotic/Neuroleptics
Clinical Problems with antipsychotic drugs
include:
1) Failure to control negative effect
2) Significant toxicity
a) Parkinson-like symptoms
b) TardiveDyskinesia (10-30%)
c) Autonomic effects
d) Endocrine effects
e) Cardiac effects
3) Poor Concentration
 Antipsychotic/Neuroleptics

 Some antipsychotics have effects at

muscarinicacetylcholine receptors:

• dry mouth
• blurred vision
• urinary retention
• constipation
Clozapine
Chlorpromazine
Thioridazine
 Antipsychotic/Neuroleptics
 Some antipsychotics have effects at a-
adrenergic receptors:
• orthostatic hypotension
Chlorpromazine
Thioridazine

 Some antipsychotics have effects at H1-

histaminergic receptors:
• sedation
Risperidone
Haloperidol
 Antipsychotic/Neuroleptics

 Blockade of D2 receptors in lactotrophs

in breast increase prolactin
concentration and may produce breast
engorgement and galactorrhea.
 Antipsychotic/Neuroleptics

Neuroleptic Malignant Syndrome

Is a rare but serious side effect of neuroleptic

(antipsychotic) therapy that can be lethal. It
can arise at any time in the course of
treatment and shows no predilection for age,
duration of treatment, antipsychotic
medication, or dose.
 Antipsychotic/Neuroleptics
Neuroleptic Malignant Syndrome
• Occurs in pts. hypersensitive to the Ex.Py. effects of
antipsychotics.
• Due to excessively rapid blockade of postsynaptic
dopamine receptors.
• The syndrome begins with marked muscle rigidity.
• If sweating is impaired, a fever may ensue. The
stress leukocytosis and high fever associated with
this syndrome may be mistaken for an infection.
• Autonomic instability with altered blood pressure
and heart rate is another midbrain manifestation.
• Creatinekinaseisozymes are usually elevated,
reflecting muscle damage.
 Antipsychotic/Neuroleptics

Drug Interactions
• Additive effects with sedatives.
• Additive effects with anticholinergics.
• Additive effects with antihistaminergics.
• Additive effects with -AR blocking drugs.
• Additive effects with drugs with quinidine-like
action (thioridazine).