Antipsychotic drugs

Phenothiazines
Aliphatic side chain:
-Chlorpromazine
-Triflupromazine

Piperidine side chain:

-Thioridazine

Piperazine side chain:

-Trifluoperazine
-Fluphenazine
Butyrophenones
-Haloperidol
-Trifluperidol
-Penfluridol

Thioxanthenes
-Flupenthixol

Other heterocyclics
-Pimozide, Loxapine
• Atypical antipsychotics
-Clozapine
-Risperidone
-Olanzapine
-Quetiapine
-Aripiprazole
-Ziprasidone
 Schizophrenia - symptoms
Positive Symptoms(↑↑DA) Negative Symptoms(↓↓NMDA)
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
• 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
 Prognosis of Schizophrenia

• 10% continuous hospitalization

• < 30% recovery = symptom-free for 5
years
• 60% continued problems in
living/episodic periods
 Etiology

• A gene encodes for neuregulin-1 has

been associated with schizophrenia.
• Hereditary Influences may account for
10% of schizophrenia cases
• Prenatal Biological Trauma 5-10% cases
of schizophrenia
• Perinatal biological trauma
 Schizophrenia Pathophysiology
Schizophrenia Pharmacologic
Pathophysiology Profile of APDs

Past Excess dopaminergic Dopamine D2-receptor

activity
Present
-Renewed interest in the
role of serotonin (5-HT)
Future
-NMDA
Imbalance in cortical
communication and
cortical-midbrain
integration, involving
multiple neurotransmitters
antagonists
Combined 5-HT2/D2
antagonists
NMDA agonists
More selective antagonists
Mixed agonist/antagonists
Neuropeptide analogs
Dopaminergic Pathways and Innervation
 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.

 Some early studies with postmortem tissue revealed increased

numbers of DA receptors (in particular D2-like) in schizophrenic
patients
Serotonin Hypothesis of Schizophrenia
• Hallucinogens such as LSD (lysergic acid
diethylamide) and mescaline are serotonin (5-HT)
agonists
• 5-HT2A-receptor blockade is a key factor in the
mechanism of action of the main class of atypical
antipsychotic drugs such as clozapine and
quetiapine.
• 5-HT2A-receptor modulate the release of dopamine
in the cortex, limbic region, and striatum.
 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.
 ANTIPSYCHOTICS
• Pre-90’s
– “Typical”, conventional, traditional neuroleptics,
major tranquilizors
– Modeled on D2 antagonism
– EPS/TD
• Post-90’s
– “Atypical”, novel, 2nd generation
– Modeled on 5-HT2/D2 antagonism
– Less EPS, prolactin effects
– Weight gain, sedation, diabetes
 Adverse Effects
• Sedation ‑ initially considerable; tolerance usually develops
after a few weeks of therapy; dysphoria
• Postural hypotension ‑ results primarily from adrenergic
blockade; tolerance can develop
• Anticholinergic effects ‑ include blurred vision, dry mouth,
constipation, urinary retention; results from muscarinic
cholinergic blockade
• Endocrine effects ‑ increased prolactin secretion can cause
galactorhea; results from antidopamine effect
• Hypersensitivity reactions ‑ jaundice, photosensitivity,
rashes, agranulocytosis can occur
• Idiosyncratic reactions ‑ malignant neuroleptic syndrome
• Weight gain
• Neurological side effects -
 Neurological Side Effects of antipsychotics
REACTION FEATURES TIME OF PROPOSED TREATMENT  
MAXIMAL RISK MECHANISM

Acute dystonia Spasm of muscles of 1 to 5 days Unknown Diphenhydramine,

tongue, face, neck, promethazine  
back; may mimic
seizures; not hysteria
Akathisia Motor restlessness; 5 to 60 days Unknown Reduce dose or
not anxiety or change drug:
"agitation" antiparkinsonian
agents,  

benzodiazepines or
propranololc may
help
Parkinsonism Bradykinesia, 5 to 30 days Antagonism Antiparkinsonian
rigidity, variable of dopamine agents helpful-
tremor, mask facies, trihexyphenidyl,  

shuffling gait procyclidine,

benztropines
a. Many drugs have been claimed to be helpful for acute dystonia. Among the most commonly employed treatments are diphenhydramine
hydrochloride, 25 or 50 mg intramuscularly, or benztropine mesylate, 1 or 2 mg intramuscularly or slowly intravenously, followed by oral
medication with the same agent for a period of days to perhaps several weeks thereafter. b. For details regarding the use of oral antiparkinsonian
agents, see the rest of slides c. Propranolol often is effective in relatively low doses (20-80 mg per day). Selective beta1-adrenergic receptor
antagonists are less effective. d. Despite the response to dantrolene, there is no evidence of an abnormality of Ca2+ transport in skeletal muscle;
with lingering neuroleptic effects, bromocriptine may be tolerated in large doses (10-40 mg per day).
 REACTION FEATURES TIME OF PROPOSED TREATMENT
MAXIMAL RISK MECHANISM  

Neuroleptic Catatonia, stupor, Weeks; can Antagonism Stop neuroleptic

malignant fever, unstable blood persist for days of dopamine immediately:
syndrome pressure, after stopping may dantrolene or
myoglobinemia; can neuroleptic contribute bromocriptine may
be fatal help:  

antiparkinsonian
agents not effective

Perioral tremor Perioral tremor (may After months or Unknown Antiparkinsonian

("rabbit" syndrome) be a late variant of years of agents often help
parkinsonism) treatment  

Tardive dyskinesia Oral-facial After months or Excess Stop neuroleptics,

dyskinesia; years of function of then Diazepam,
widespread treatment (worse dopamine Change to  
choreoathetosis or on withdrawal) hypothesized clozapine/olanzapine,
dystonia
 Adverse Effects - EPS
Details on two main extrapyramidal disturbances (EPS):
• Parkinson-like symptoms
– tremor, rigidity
– direct consequence of block of nigrostriatal DA2 R
– reversible upon cessation of antipsychotics

• Tardive dyskinesia
• involuntary movement of face and limbs
• less likely with atypical antipsychotics (AP)
• appears months or years after start of AP
• ? result of proliferation of DA R in striatum
» presynaptic?
• treatment is generally unsuccessful
Weight gain – 40% - weight gain now attributed to
ratio of binding to D2 and 5-HT2 receptors; possibly
also histamine (for newer antipsychotics anyway)
Sexual dysfunction
• result from NE and SE blockade
• erectile dysfunction in 23-54% of men
• retrograde ejaculation in
• loss of libido and anorgasmia in men and women

Seizures - <1% for generalized grand mal

Neuroleptic malignant syndrome (1-2% early in trt)
• combination of motor rigidity, hyperthermia, and
autonomic dysregulation of blood pressure and heart
rate (both go up)
• can be fatal in 5-20% of cases if untreated
• treatment – discontinue meds; give trts for fever
and cardiac problems
Sensitivity to sun
• some phenothiazines collect in skin
(chlorpromazine)
• sunlight causes pigmentation changes – grayish-
purple (look bruised)
•in eye, brown cornea, brownish cloud to vision and
possibly permanent impairment
Agranulocytosis - <1% (with clozapine)
• reduced white blood cell count
• lowered resistance to infection
• can be fatal
Jaundice – elevated bilirubin in liver - < ½%
Limitations Of Conventional Antipsychotics

Approximately one-third of patients with

schizophrenia fail to respond
Limited efficacy against
Negative symptoms
Affective symptoms
Cognitive deficits

High proportion of patients relapse

Side effects and compliance issues

Antipsychotic Drugs – New Generations “atypical”

About 40-60% do not respond to phenothiazines or

cannot handle side effects
• Questions remain about the efficacy of
phenothiazines and haloperidole for negative
symptoms
• Drugs needed that are low in extrapyramidal side
effects and at least equal in efficacy for positive
symptoms, perhaps better for negative
 Antipsychotic Drugs – New Generations
“atypical”
• clozapine
• risperidone
• olanzapine
• sertindole
• Quetiapine
• Aripiprazole
• Ziprasidone
 Clozapine (1989)
• Selectively blocks dopamine D2 receptors,
avoiding nigrostriatal pathway
• α-blockade
• Also blocks H1
• More strongly blocks 5-HT2 receptors in cortex
which then acts to modulate some dopamine
activity
• Among non-responders to first generation meds or
those who cannot tolerate side effects, about 30%
do respond to Clozapine
 Clozapine
• Extrapyramidal side effects are minimal
• May help treat tarditive dyskinesia
• S/E- orthostatic hypotension effects, sedation,
weight gain, increased heart rate
• Increased risk for seizures (2-3%)
• Agranulocytosis in 1%
• Agranulocytosis risks increase when co-
administered with carbamazepine
 Risperidone (1994)
• Fewer side effects than Clozapine
• Marketed as first line approach to treatment
• Blocks selective D2, norepinephrine, and 5-HT2
• effective for positive and negative symptoms
• Extrapyramidal side effects low (but are shown at
high doses)
• Shares sedation, weight gain, rapid heart beat,
orthostatic hypotension, and elevated prolactin
• No agranulocytosis risks
• Increased risk of stroke in elderly
• May cause anxiety/agitation (possible OCD)
 Olanzipine – 1996

• Improved negative symptom reduction

• Argued to be better than risperidone in
extrapyramidal issues
• Does not cause prolactin elevation
• reduced agranulocytosis risks
 Sertindole – 1995
• Improved negative symptom reduction
• Low risk for extrapyramidal side effects – major advantage
• No sedation and very mild prolactin elevation– major advantages
• Shares orthostatic hypotension, tachycardia, and weight gain
• Common side effects are rhinitis and reduced ejaculatory volume (not
associated with disturbed function)
• concern about sudden cardiac death or episodes due to cardiac arrhythmia led
to its voluntary removal in 1998
 Quetiapine - 1997

• No increased risks for extrapyramidal symptoms

• Shares sedation (sleepiness), orthostatic hypotension, weight gain
• Does cause anticholinergic side effects (like older and Clozapine) – dry
mouth, constipation
• Does not elevate prolactin

Ziprasidone - 2001
• Similar to advantages of others, but argued not to cause weight gain
• May induce cardiac arrhythmias
• Also has anxiolytic and antidepressant activity
 Non- psychiatric Indications
• As Antiemetics
-chlorpromazine, prochlorperazine, haloperidol

• Anaesthesia
-droperidol (with fentanyl)

• Intractable Hiccups
-chlorpromazine
-haloperidol
 MCQs
Q1. A female suffering from psychosis, taking
fluphenazine now complains of sudden onset of
high grade fever, muscle rigidity and altered
sensorium. The diagnosis is:
A. Malignant hyperthermia
B. Tardive dyskinesia
C. Akathisia
D. Neuroleptic malignant syndrome

• Ans- D - Neuroleptic malignant syndrome

Q2. Antipsychotic drug induced parkinsonism is
treated by:
A.Levodopa
B.Selegiline
C.Amantadine
D.Central anticholinergic drugs

• Ans- D (Trihexyphenidyl
Procyclidine
Biperiden )
Q3. Least extrapyramidal side effects are seen
with:
A.Clozapine
B.Haloperidol     
C.Trifluoperazine
D.Chlorpromazine

• Ans- A- Clozapine
Q4. Risperidone is associated with the risk of:
A.Cerebrovascular accidents
B.Agranulocytosis
C.Diabetes Insipidus       
D. Gout

• Ans- A - Cerebrovascular accidents

Q5. The antipsychotic drug that can also be used
as antiemetics:
A.chlorpromazine
B.Clozapine
C.Aripiprazole
D.Loxapine

• Ans- A - chlorpromazine
Q6. The antipsychotics that can also be used as
anaesthetic drug:
A.Chlorpromazine
B.Penfluridol
C.Clozapine
D.Droperidol

• Ans- D - Droperidol
Q7. The antipsychotic drug that can also be used
to treat Intractable Hiccups:
A.Clozapine
B.Chlorpromazine
C.Haloperidol
D.Ziprasidone

• Ans- B, C - Chlorpromazine, Haloperidol

Thank you
Bibliography
• Essentials of Medical Pharmacology -7th edition by KD Tripathi
• Goodman & Gilman's the Pharmacological Basis of Therapeutics  12th
edition by Laurence Brunton (Editor)
• Lippincott's Illustrated Reviews: Pharmacology  - 6th edition by Richard A.
Harvey
• Basic and Clinical pharmacology 11th edition by Bertram G Katzung
• Rang & Dale's Pharmacology -7th edition 
by Humphrey P. Rang
• Clinical Pharmacology 11th edition By Bennett and Brown, Churchill
Livingstone
• Principles of Pharmacology 2nd edition by HL Sharma and KK Sharma
• Review of Pharmacology by Gobind Sparsh