Anti Psychotics

Neuroleptics
Major Tranquilizers

Dr . Khadija Mastoor
 Learning Objectives
• Classify Anti-Psychotics
• Describe the mechanism of action of antipsychotic
• drugs.
• Describe the pharmacological effects of
• anti-psychotics
• Enumerate the psychiatric and non psychiatric indications of Anti-
Psychotics
• Discuss the adverse effects of Anti- Psychotics
• Tabulate differences between typical and atypical agents
 Case History

• A 19-year-old male student is brought into the clinic by his mother

who has been concerned about her son’s erratic behaviour and
strange beliefs. He destroyed a TV because he felt the TV was
sending harassing messages to him. In addition, he reports hearing
voices telling him that family members are trying to poison his food.
As a result, he is not eating. After a diagnosis is made, haloperidol
is prescribed on an outpatient basis. The drug improves the
patient’s positive symptoms but he developed severe adverse
effects including akathesia
Group of drugs used to treat schizophrenia

Schizophrenia ?
 PSYCHOSIS & SCHIZOPHRENIA

PSYCHOSIS:
• A general term for a state of mind in which
thinking becomes irrational and/or disturbed.
Delusions, Hallucinations, and other severe
thought disturbances.

Schizophrenia:
• Particular kind of psychosis
• Characterized by:
• Hallucinations ---
perception in the absence of stimulus – e.g. seeing
movement in peripheral vision, hearing faint noises.
--------- auditory, visual, olfactory, tactile.

• Delusions ---
• Fixed belief that is either false, imaginary, or derived from
deception.
• Patient believe that he is under constant police surveillance

• Decline in social and occupational

functioning
 Schizophrenia:
The affected person may

• Talk to himself
• Dress in layers in any weather
• Fail to bathe and get a haircut
• Gain an odd interest in ordinary things (like religion)
• May even believe he is God
• See things
• Feel people are out to get them
• Believe in all sorts of conspiracies
Why patient’s develop
Schizophrenia?

Genetic disorder with high inheritability

 What is a cause of schizophrenia?

• Dopamine hypothesis…..
• is caused by relative excess of functional activity of
DOPAMINE in
• Mesolimbic-mesocortical pathways (mentation
&mood)
• Nigrostriatal pathways(extrapyramidal
function)
• Tuberoinfundibular pathways (control of
prolactin)
 Dopamine Hypothesis
of Schizophrenia

Mesocortical Nigrostriatal
pathway pathway
Hypoactivity (part of EP system)
Negative symptoms
Cognitive impairment

Mesolimbic
pathway
Tuberoinfundibular pathway
Hyperactivity:
(inhibits prolactin release)
Positive symptoms
Adapted from Inoue and Nakata. Jpn J Pharmacol. 2001;86:376.
Serotonin hypothesis of Schizophrenia
• Traditional antipsychotics bind D2 receptors 50
times more avidly than D1 or D3 receptors

BUT
• Several atypical antipsychotics drugs have much
less effect on D2 receptors and are effective in
schizophrenia
• especially Serotonin receptor subtypes -5HT2A and
5 HT 2C

• Protect against extrapyramidal consequences of

D2 antagonisms
Classification of Antipsychotics
 History
Reserpine & Chlorpromazine
• First drugs found to be useful to reduce
psychotic symptoms in schizophrenia.

• Chlorpromazine is a neuroleptic?
Produces catalepsy in rodents & EPS in
humans.
Clozapine (1959) …
First atypical antipsychotic . Fewer EPS
Classification of antipsychotic drugs
• Typical antipsychotics • characteristics of
or 1st generation typical drugs

• Chlorpromazine • Suppresses positive

• Haloperidol symptoms
• Fluphenazine • Acts by blocking D2
• receptors mainly
Thioridazine
• Extrapyramidal
symptoms…marked
 Atypical antipsychotics or 2nd generation
antipsychotics

• Atypical antipsychotics Characteristics of atypical

or 2nd generation antipsychotics
antipsychotics
• Suppresses negative
• Clozapine symptoms mainly
• Olanzapine • Mainly block D4 receptors
• Aripiprazol • Also block 5-HT2
• Risperidone • Have weak D2-blocking
effect
 Mechanism of Action
Dopamine receptor blockage in brain

Five pathways
• Mesolimbic-mesocortical pathway --------------------------------- behavior
• Nigrostriatal pathway ---------------------------------- voluntary movement
• Tuberoinfundibualr pathway ------------------- inhibit prolactin secretion
• Medullary-periventricular pathway ------------------------ eating behavior
• Incertohypothalamic pathway -------------------------- sexual behavior

Antipsychotics action is now thought to be

produced by their ability to block
effect of dopamine to inhibit the
activity of adenyl
cyclase in
Mesolimbic andinMesofrontal
the pathways
Serotonin receptor blockage in brain

Newer atypical agents

• Clozapine
D4 = α1 > 5 HT2 > D2 = D1

. Olanzapine

5HT2A > H1>D4>D2>α1>D1

 Pharmacological Actions
Actions of antipsychotic drugs reflect blockage at

ANTI PSYCHOTICS

X X
Dopamine Serotonin
Receptors Receptors
X X X
Cholinergic α-adrenergic H1-histamine
receptors receptors receptors
 Central nervous system actions

• In patients with schizophrenia:

Antipsychotics produce following effects;

1. Reduce agitation& aggressiveness

2. Suppress hallucinations and delusions
3. Relieve anxiety
4. Correct disturbed thought and behavior
 Anti psychotic actions
• Reduce hallucinations and agitation
• By blocking -----
Dopamine receptors or serotonin receptors

• In: Mesolimbic system of the brain

• Antipsychotic action usually takes

------------------------
Several weeks
 Extra pyramidal effects

• Parkinsonian symptoms
• Akathasia (motor restlessness)
• Tardive dyskinesia (inappropriate postures of neck, trunk and
limbs).

Cause of these symptoms

Blockage of dopamine receptors in Nigrostriatal pathways

Common with Rare with

Haloperidol --------- (very high) Risperidone -------------------- low
Fluphenazine ------ (high) Atypical agents
Thiothixene ------- (medium) Olanzapine --------------------- very low
Quetiapine --------------------- very low
Ziprasidone -------------------- very low
Aripiprazole -------------------- very low
 Anti-emetic effects

• Most of antipsychotics have anti emetic effects

• Mediated by blocking: D2 dopamine receptors

• Of the: Chemoreceptor trigger zone of medulla

Exception ------------------------- Thioridazine

 Anti muscarinic effects

• All neuroleptics cause anti cholinergic effects

Common with:

• Thioridazine
• Chlorpromazine
What are these effects?
 Psychological effects

Unpleasant subjective effects in non-psychotic individuals.

• Sleepiness
• Restlessness
• Autonomic effects

In contrast
• Psychotic individuals show :
• Improvement in their performance
 Endocrine effects

Older anti psychotics

• Amenorrhea-Galactorrhea
• False positive pregnancy tests
• Increased libido --- women
• Decreased libido & Gynecomastia ---
men

Cause of these symptoms

prolactin
Dopamine
 Cardiovascular effects
• Orthostatic hypotension
• Decreased peripheral resistance
• Decreased mean arterial pressure
• Decreased stroke volume
• Increased heart rate
Hypotension
Seen commonly with
Chlorpromazine ------------ High
Thiothixene ----------------- Medium
Clozapine ------------------- Medium
Less common with
Fluphenazine ----- very low
Ziprasidone -------- very low

Seen with use of: High dose Phenothiazines

Caused by: α receptor blockage (autonomic effect)

• ECG changes:
• Prolongation of QT interval
• Risk is more with ----- Atypical antipsychotic agents
 Clinical uses

Therapeutic Uses of anti psychotics

 Clinical uses

• Psychiatric
Indications

• Non- Psychiatric
Indications
 Psychiatric Indications
Schizophrenia
• --- primary indication

• Traditional typical agents

– most effective in treating
positive symptoms
(delusions, hallucinations and
thought disorders)
 Psychiatric Indications

• Newer agents (Atypical) –

effective in treating
 Negative symptoms
(withdrawal, blunted emotions,
reduced ability to
relate to people)
 Resistant cases
• Schizoaffective disorders
---
both
schizophrenia and affective
disorders
 Schizoaffective disorders

Psychotic aspect is treated with ---

• Anti psychotics
+
• Anti depressants
• Lithium
• Valproic acid

Manic episodes in bipolar disorder

Anti psychotic agents

Olanzapine (atypical antipsychotic)
has been approved as monotherapy
In acute phase (upto 4 weeks) of mania
Tourette’s syndrome
• a neurological disorder characterized by tics - involuntary, rapid, sudden
movements or vocalizations that occur repeatedly in the same way.

In patients with senile dementia of the Alzheimer disease

----- to control disturbed behavior

To control agitation or psychosis in depressed patients.

Along with antidepressants
 Non psychiatric Indications

• Anti emetics --
prevention of Nausea &
Vomiting
• (Most older antipsychotics with
exception of thioridazine)

• Prochlorperazine
Treatment of intractable hiccups
• Benzquinamide
Chlorpromazine

Treatment of Pruritis
Promethazine

Neuroleptanesthesia
Droperidol (butyrophenon) in combination with opioids & Fentanyl
 Neuroleptanesthesia
• State of analgesia and amnesia is produced when
fentanyl is used with droperidol and nitrous oxide

• Provides adequate analgesia and sedation during

surgery while maintaining a sufficient level of
consciousness to permit the patient to respond to
questions during the surgical procedure.

• The disadvantages of neuroleptanesthesia include chest

wall rigidity
 Drug Choice
Based mainly on differences in
Pharmacological properties
• Variable absorption after oral administration
• Readily pass in to the brain
• Large volume of distribution
• Metabolized by P-450 enzyme system
• Fluphenazine & Haloperidol: IM formulation ------ in non compliant patients

Side effects
• Haloperidol ----- severe extra pyramidal syndrome
 Superior side effects profile of newer agents and low to absent risk of tardive dyskinesia

Efficacy
 New antipsychotics in some trials is more effective than older ones for treating negative symptoms
 Superiority over Haloperidol in terms of overall response (+ve & -ve symptoms) of Clozapine,
Olanzapine, and Risperidone has been demonstrated in clinical trials
 Adverse Effects
• Occur in almost all patients
but Significant in about 80
%.
 Behavioral effects
 Neurological effects
 Autonomic effects
 Metabolic& Endocrine
effects
 Toxic or Allergic reactions
 Ocular complications
 Cardiac toxicity
 Neuroleptic Malignant
Syndrome
Behavioral effects
 Pseudo depression
 Toxic confusional state
• May be due to drug induced akinesia
• Usually responded to
• Treatment with antiparkinsonism drugs.
• Reducing the dose

Neurological effects
 Extrapyramidal reactions
• Typical Parkinsonian syndrome ---
• Treated with anti muscarinic agents or amantadine
 Tardive dyskinesia ----- motor disorder
long term treatment.due to supersensitivity of
dopamine receptors.
Involuntary movements --- lateral jaw movements, “fly catching” motions of tongue
Treated by:
May disappear with in 3 months on discontinuation of neuroleptics
May be irreversible and persist after discontinuation of therapy
• Autonomic nervous system

• Antimuscarinic adverse effects

-------------- Urinary retention, Dry mouth, Constipation,
Mydriasis --- blurred vision, Dry skin --- increased body temp,
Dry eyes.

• α - adrenergic receptor blockage effects

(common with --- chlorpromazine)
• -------------- Orthostatic hypotension, Impaired ejaculation.
 Metabolic & Endocrine effects

 Weight gain ------- Clozapine & Olanzapine

 Hyperglycemia ---
secondary to obesity & insulin resistance

 Hyperprolactinemia ----
• Amenorrhea
• Galactorrhea
• Infertility
• Impotence
 Toxic or Allergic reaction

• Agranulocytosis ------------- Clozapine

• Between 6th & 8th week of treatment

• Reversible upon discontinuance of drug
• Blood count for first 6 months of treatment and every
3 weeks thereafter.
 Ocular Complications

• Visual impairment due to Deposits in the anterior

portions of eye (cornea and lens)
-------- complication of Chlorpromazine

• Retinal deposits ---- “browning of vision”

-------- complication of Thioridazine
 Cardiac Toxicity
• T wave abnormalities
• Ventricular arrhythmias
• Conduction block

Seen with
Thioridazine ----- doses > 300 mg / day

• QT prolongation

Seen with
Ziprasidone (Atypical antipsychotic)
 Neuroleptic Malignant Syndrome
Life threatening
• Muscle rigidity
• High Fever --- impaired sweating
• Leukocytosis
• Autonomic instability
• Elevated creatine kinase enzyme

Caused by:
rapid dopamine receptor blockage
Treated by:
• Muscle relaxants --- Diazepam
• Dantrolene
• Dopamine agonist: Bromocriptine
• Cooling by physical means