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Pharmacology of
Antipsychotic drugs
Antipsychotic drugs,
neuroleptic or antischizophrenic drugs are
used mainly to manage
psychosis (including
delusions or hallucinations
and disordered thought )
particularly in
schizophrenia and bipolar
depression
 It is a chronic disabling disorder
which affects people during late
adolescence or early adulthood
 Schizophrenia has a strong genetic
component and is probably due to
biochemical abnormality
(dysfunction of D-ergic neurons)
 There is some evidence for
involvement of 5-HT
 Patients with schizophrenia have
problems with seeing things,
hearing voices, imagining things,
having terrifying thoughts
(positive symptoms)
 Apathy , blunted emotions,
anhedonia and reduced ability to
react with people ‘social
withdrawal’
(Negative symptoms)
Schizophrenia: Symptoms
Negative Symptoms
Positive Symptoms
 Blunted emotions
• Hallucinations
 Social withdrawal
Delusions
• Thought disturbances
 Loss of motivation
impaired personal hygiene
“Dopamine hypothesis”
Schizophrenia has a strong
genetic component and
probably reflects too much
dopamine activity in the
mesolimbic system which is
the part of brain that controls
seeing, hearing, imaging etc…..
“Dopamine hypothesis” - Evidences
Drugs that increase dopamine may
produce positive psychotic
symptoms (e.g. Cocaine,
amphetamine)
All known antipsychotics drugs
capable of treating positive
psychotic symptoms block the
dopamine receptors (D2)
Antipsychotic
Drugs
Antipsychotics are broadly
divided into two groups: The typical
= 1st generation and the atypical =
2nd generation antipsychotics
Atypical drugs are preferred as a
first line treatment because they:
1- have fewer side effects
2- have additional benefits for the
“
-ve
symptoms ” of
schizophrenia
Mechanism of Action
 All antipsychotic drugs block D2
receptors in the brain & periphery
Atypical antipsychotics exert part of
their action through blocking of 5-HT2A
receptors
 Antipsychotics take days or weeks to
work, suggesting that secondary effects
(e.g. increase in number of D2-receptors
in limbic structure) may be more
important than direct effect of D2receptor block.
Many antipsychotics block
other receptors e.g.
acetylcholine (M), noradrenaline
(α ) and histamine (H1) receptors
Typical antipsychotic Drugs
1- Phenothiazine derivatives:
Chlorpromazine, promethazine,
Fluphenazine
2- Butyrophenone derivatives:
Haloperidol, droperidol
Atypical antipsychotic drugs
Risperidone , Clozapine , Olanzapine
Aripiprazole
Pharmacological Actions
1- Antipsychotic effects
 Though blocking D2 receptors in the
mesolimbic system, antipsychotic drugs
relieve hallucination, improve thoughts.
The additional blocking effects of atypical
antipsychotics on 5-HT2 receptors can
treat the negative symptoms of
schizophrenia
2- Autonomic effects:
Anticholinergic effects , dry mouth,
constipation and blurred vision
Blocking of α–adrenergic receptors
hypotension
3- Exrapyramidal effects
Blocking of D2 receptors in the
nigrostriatal pathway causes unwanted
parkinsonian-like symptoms; rigidity and
tremors. Clozapine and risperidone
exhibit a low incidence of these
symptoms ( block D4)
4- Antiemetic effect
Blocking D2 receptors both centrally in
the CTZ in the medulla and peripherally
in the stomach
5- Endocrine effects: Amenorrheagalactorrhea, false–positive pregnancy
tests in women and decreased libido and
gynecomastia in men (due to blockade
of D2 in the pituitary leading to an
increase in prolactin release)
6-Antipsychotics block H1 receptors
causing sedation and confusion
7- Antipsychotic depress the
hypothalamus affecting thermoregulation (hypothermia)
Therapeutic Uses
1- Treatment of schizophrenia
Typical antipsychotics are
most effective in treating positive
symptoms
Atypical antipsychotics with
serotonin blocking activity are
effective
in
many
patients
resistant to the traditional
agents, especially in treating
negative symptoms
2- Treatment of other psychotic
disorders e.g. mania and mood
(bipolar) disorders
3- Prevention of severe nausea
and vomiting (drug-induced
nausea)
4Droperidol
is
used
in
combination with fentanyl in
neuroleptanalgesia
5- Due to its antihistaminic effects,
promethazine is used in cases of
pruritus and as a preoperative
sedative
6- To induce hypothermia in
certain
major
operations
(Chlorpromazine)
7- Chlorpromazine is used to
treat intractable hicough ‫حازوقه‬
Adverse Effects
Extrapyramidal Symptoms (EPS)
Dopamine Vs Acetylcholine
Dopamine (inhibitory) and ACh (excitatory)
have a reciprocal relationship in the
Nigrostriatal pathway
A delicate balance allows for normal
movement
Dopamine blockade by antipsychotic drugs
results in relative increase in cholinergic
activity causing EPS
When high potency antipsychotics are
chosen, we often prescribe anticholinergic
medication like benztropine
Antipsychotics have a wide range of
side effects
1- Sedation (drowsiness) is a common side
effect of antipsychotics (?) This can be dealt
with by taking medication at night just before
going to bed
2- Movement disorders; Extrapyramidal side
effects are common with the typical
antipsychotics ; include dystonia, akathisia
parkinsonian- like syndrome Treatment:
anticholinergic drugs (benztropine)
Tardive dyskinesia
 It is the most important adverse effect of
long-treatment with typical antipsychotic
drugs and is characterized by excessive
movement of the lips, tongue and jaw, limbs
 Tardive dyskinesia may be irreversible and
is postulated to result from increased number
of dopamine receptors that are synthesized in
response to long-term dopamine receptor
blockade, which leads to neuronal
supersensitivity to dopamine
Atypical drugs have lower incidence of EPS &
tardive dyskinesia as they block 5-HT2A
receptors and have less D2 receptor
blocking effect
3-Autonomic effects:Orthostatic
hypotension !!!!, (α-adrenoceptor blockade)
and anticholinergic adverse effects (urinary
retention, constipation, ppt of glaucoma,…..)
4- Endocrine and metabolic effects:
hyperprolactinemia in the form of
galactorrhea, amenorrhea in women,
gynecomastia and changes in libido &
impotence in men
5- Allergic reactions: Agranulocytosis
(common with clozapine), cholestatic
jaundice and skin eruptions
6-Occular complications: may cause
retinal pigmentation, corneal and lens
opacities (Chlorpromazine)
7- Clozapine and chlorpromazine tend to
lower an individual’s seizure threshold
Neuroleptic Malignant Syndrome
An idiosyncratic, life-threatening
neurological disorder associated with
antipsychotic therapy
Idiosyncracy: An unusual or unexpected
sensitivity exhibited by an individual to a
particular food or drug. Idiosyncrasy is
usually determined genetically and it may be
due to a biological deficiency (e.g. an
inability to metabolize a drug).
Neuroleptic Malignant Syndrome
Clinical manifestations include:
Encephalopathy, Hyperpyrexia,
delirium
Autonomic instability (BP)
Rigidity of muscles
Elevated creatine phosphokinse (CPK)
due to increased muscular activity
and rhabdomyolysis (destruction of
muscle tissue)
Pathophysiology
The mechanism is thought to depend on
dopamine activity due to:
Dopamine receptor blockade
Genetically reduced function of
dopamine receptor
There is an increased calcium release
from the sarcoplasmic reticulum of muscle
cells which can result in rigidity and cell
breakdown
Treatment involves:
Immediate discontinuation of
antipsychotic drug
Treat hyperthermia
Hydration, maintain vital functions
Dantrolene sodium: a muscle
relaxant that acts by abolishing
excitation contraction coupling in
muscle cell
Typical antipsychotics
Chlorpromazine
Phenothiazine class
Increased prolactin
(gynaecomastia)
Hypothermia
Anticholinergic effects
Hypersensitivity reactions
Obstructive jaundice
Ocular complications
EPS
Fluphenazine
Phenothiazine class but:
does not cause jaundice
causes less hypotension
causes more EPS
Halopirodol
Butyrophenone class
As chlorpromazine but does not
cause jaundice
Fewer anticholinergic side effects
Strong EPS tendency
Atypical Drugs
Differences between typical
and atypical groups
receptor profile
Serotonin receptors (5-HT2A) are
involved
incidence of extrapyramidal side
effects (less in atypical group)
efficacy (specifically of Clozapine in
treatment of resistant group of
patients
efficacy against negative symptoms
Clozapine
 Dibenzodiazepine class
 Potent antagonist at D4-receptors
 Selectively blocks 5-HT2A receptors
 Sedation
 Extrapyramidal side effects are minimal
 Low incidence of Tardive dyskinesia
 Increased risk for seizures (2-3%)
Clozapine
 Agranulocytosis in 1% (regular granulocyte
counts weekly is required)
 Agranulocytosis risks increase when coadministered with carbamazepine
 Anticholinergic side effects
 Weigh gain
 Shows efficacy in 'treatment-resistant'
patients
 Effective against negative and positive
symptoms
Risperidone
 Largely replacing clozapine. No risk of
agranulocytosis
 Low incidence of EPS and minimal
sedation
 Weight gain
 Resperidone is approved for the
treatment of autism and bipolar
depression
Aripiprazole
 Recently approved drug
 Long acting (plasma half-life ∼3 days)
 No effect on prolactin secretion
 No weight gain
 Less incidence of dystonias and
Tardive dyskinesia
 D2 partial agonist profile may account for paucity of
side effects
Advantages & disadvantages
of Clozapine
Advantages
Disadvantages
Effective in the
Clozapine has the
treatment of
risk of inducing
negative and
agranulocytosis
positive symptoms Clozapine tends to
of schizophrenia
lower an individual
More effective than seizure threshold
classical agents for
resistant cases
Advantages
Incidence of
extrapyramidal
symptoms is lowest
Tardive dyskinesia
is extremely rare
with clozapine
Disadvantages
Atypical drugs
cause weigh gain
Atypical drugs may
exacerbate DM &
hyperlipidemia
Are more
expensive than
typical
antipsychotics