Pharmacology I, Antipsychotic (Neuroleptic) Drugs

1. Antipsychotic (Neuroleptic) Drugs
Pharmacology Team
Naim Kittana, Ansam Sawalha, Adham Abu Taha,
Suhaib Hattab, and Waleed Sweileh
An-Najah National University
Faculty of Medicine and Health Sciences
Department of Biomedical Sciences
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2. Psychosis
• Psychosis is a thought disorder characterized by disturbances of reality and
perception, impaired cognitive functioning, and inappropriate or diminished
mood.
• Psychosis denotes many mental disorders.
• Schizophrenia is a particular kind of psychosis characterized mainly by a clear
sensorium but a marked thinking disturbance.
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3. Schizophrenia
• Pathogenesis is unknown
• Onset of schizophrenia: late teens early twenties
• Genetic predisposition -- Familial incidence
• Multiple genes are involved
• Afflicts 1% of the population worldwide.
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4. Schizophrenia
A. Positive Symptoms.
• They include:
– Delusions: strange belief
– Hallucinations: auditory (hear voices
inside their heads), visual, olfactory,
– Thought disorder: disorganized thinking,
word salad, neologisms
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5. – When they talk, their voice can sound flat, like they have no emotions
Flat or blunted affect and emotion
– Poverty of speech (alogia)
– Inability to experience pleasure (anhedonia)
– Lack of motivation (avolition)
These symptoms are progressive
and non-responsive to medication.
Negative Symptoms of Schizophrenia
• They are considered to be the loss or absence of normal traits or abilities,
and include features such as:
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6. The dopamine hypothesis of schizophrenia
• Proposes that the disorder is caused by a relative excess of functional
activity of the neurotransmitter dopamine in specific neuronal tracts in
the brain.
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7. Basis of dopamine hypothesis of schizophrenia
1. Many antipsychotic drugs block brain postsynaptic dopamine receptors
(especially D2 receptors) in the mesolimbic-frontal system in the CNS.
2. Dopamine agonist drugs (e.g., amphetamine, levodopa) exacerbate
schizophrenia.
3. An increased density of dopamine receptors has been detected in certain
brain regions of untreated schizophrenics.
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8. • The dopamine hypothesis of schizophrenia is not fully satisfactory
because:
1. Antipsychotic drugs are only partly effective in most patients.
2. Many effective drugs have a much higher affinity for other receptors,
including serotonin receptors, than for D2 receptors.
3. Antagonists of the NMDA receptor such as phencyclidine, when
administered to nonpsychotic subjects, produce much more
"schizophrenia-like" symptoms than do dopamine agonists
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9. • Serotonin hypothesis as an alternative to the dopamine hypothesis of the
nature of schizophrenia.
• Most of the atypical drugs cause less extrapyramidal dysfunction than
standard drugs.
• With the exception of haloperidol, all antipsychotic drugs block H1
receptors to some degree.
The Serotonin hypothesis of schizophrenia
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10. Antipsychotics/Neuroleptics
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11. Antipsychotics/Neuroleptics
• Antipsychotics are the drugs currently used in the prevention of psychosis.
• They have also been termed neuroleptics
** These drugs are not a cure **
SCHIZOPHRENIA IS FOR LIFE
There is no remission
• Schizophrenics must be treated with medications indefinitely, in as much
as the disease in lifelong and it is preferable to prevent the psychotic
episodes than to treat them.
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12. Antipsychotics/Neuroleptics
Typical (Traditional) Atypical
- Chlorpromazine
- Fluphenazine
- Prochlorperazine
- Haloperidol
- Droperidol
- Clozapine
- Aripiprazole
- Olanzapine
- Resperidone
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More likely to produce
extrapyramidal side
effects (EPS).

13. Typical “Traditional”, “1st generation”, “conventional”
• Competitive inhibitors at a variety of receptors
• Their antipsychotic reflects competitive blocking D2 receptors
• More likely to cause Extrapyramidal Side Effects (EPS)
• EPS correlates to the affinity towards D2 receptors, e.g. Haloperidole
highly likely to cause EPS, while it is much less with Chlorpromazine
• No one drug is clinically more effective than another.
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14. Atypical “2nd generation”
• Lower incidence of EPS
• Associated with higher risk of metabolic side effects: diabetes,
hypercholesterolemia & weight gain
• Therapeutic activity is related to blockade of both serotonin and dopamine
receptors.
• First-line therapy for schizophrenia to avoid EPS
• Efficacy is comparable to that of 1st generation
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15. Refractory patients
• 10-20% of schizophrenic patients do not respond to either typical or
atypical drugs
• Clozapine can be effective for these patients, with minimal risk of EPS.
• Serious Side effects of Clozapine:
- Bone marrow suppression
- Severe agranulocytosis (must monitor white blood cell counts)
- Seizures
- Cardiovascular side effects
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16. Mechanism of action
• Dopamine antagonism:
All of the 1st and most of 2nd generation block D2 receptors in the brain
and periphery
• Serotonin receptor (5-HT2A) blocking activity:
Most of the 2nd generation exert part of their action via blocking 5-HT2A
receptors
• Many of these drugs also block cholinergic, adrenergic and histaminergic
receptors.
• It is not clear whether this contributes to the therapeutic action, but it is
clear to cause side-effects.
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17. Therapeutic uses
1. Schizophrenia
Their antipsychotic effects include:
– Decreasing the positive symptoms: symptoms of thought disorders,
paranoid features, delusions, hostility, hallucinations
– to a lesser degree decreasing the negative symptoms: Decreased
withdrawal, apathy, and blunted affect, mainly by 2nd generation like
Clozapine.
– These drugs restrain acute psychotic attacks and delay subsequent
relapses.
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18. 2. Prevention of severe nausea and vomiting:
• Conventional antipsychotic agents: they have strong antiemetic activity
due to dopamine D2-receptor blockade in the chemoreceptor trigger
zone of the medulla.
• The most commonly used:
– Prochlorperazine: marketed only as an antiemetic
– Promethazine: has no antipsychotic activity
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19. 3. Other selected therapeutic uses:
a. Agitated and disruptive behavior, secondary to other disorders
b. Intractable hiccups: mainly Chlorpromazine
c. Pruritus: mainly Promethazine
d. Motor and phonic tics of Tourette disorder: Pimozide,
Risperidone and Haloperidol
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20. Adverse effects and contraindications
• The adverse effects of antipsychotic agents are due to their antagonist
actions at receptors in:
 CNS
– Dopamine D2-receptors
– Histamine H1-receptors
– (and possibly serotonin receptors)
 Periphery
– Muscarinic cholinoceptors
– α-adrenoceptors
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21. Central nervous system adverse effects
1. Extrapyramidal syndromes
• Related to dopamine-receptor blockade in the basal ganglia (and
elsewhere in the CNS)
• Leads to an imbalance in dopamine and acetylcholine actions in the
nigrostriatal pathway.
• These effects are a major cause of noncompliance.
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22. Extrapyramidal effects
• Most likely occurs with typical drugs due to high affinity for
postjunctional dopamine D2-receptors in the basal ganglia.
• Can sometimes spontaneously remit.
• It includes:
 Acute dystonia,
 Akathisia,
 Parkinson’s like syndrome and
 Tardive dyskinesia.
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23. Extrapyramidal syndromes include the following:
1. Acute dystonia
– is a neurological movement
disorder, in which sustained
muscle contractions cause
twisting and repetitive
movements or abnormal
postures
– This condition is often elicited
during the first week of
therapy.
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24. Acute dystonia can be controlled with:
1. Centrally acting antimuscarinic drugs: e.g. benztropine
2. Antihistamine: diphenhydramine (which has central anticholinergic
activity)
3. By reducing the antipsychotic drug dose, which may lead to an increase
in psychotic symptoms.
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25. 2. Akathisia:
Irresistible compulsion to be in motion.
• This condition can develop as early as the first 2 weeks of treatment or as
late as 60 days into therapy.
• Akathisia can be controlled by drugs:
1. with antimuscarinic activity
2. β-receptor antagonist propranolol.
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26. 3. Parkinsonian-like syndrome
– Parkinsonian-like syndrome is characterized by tremors, bradykinesia,
rigidity, and other signs of parkinsonism.
– This syndrome can develop from 5 days to weeks into treatment.
– Parkinsonian-like syndrome can be controlled with:
• antimuscarinic drugs (e.g., benztropine, biperiden) or
• reducing the antipsychotic drug dose.
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27. 4. Tardive dyskinesia (10—20%)
• CNS disorder characterized by:
- Twitching of the face and tongue
- Involuntary motor movements of the trunk and limbs
• More likely with conventional antipsychotic agents than atypical agents.
• Tardive dyskinesia: occurs after months to years of drug exposure
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28. • more likely to occur in:
– the elderly or
– in institutionalized patients who receive long-term, high-dose therapy.
• The only effective treatment for tardive dyskinesia is the discontinuation
of treatment.
4. Tardive dyskinesia
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29. Neuroleptic malignant syndrome
• Due to excessively rapid blockade of postsynaptic dopamine receptors.
• This syndrome is characterized by:
– Autonomic instability with altered blood pressure and heart rate.
– Muscle rigidity
– Diaphoresis
– Profound hyperthermia
– Myoglobinemia
• This condition occurs, often explosively, in 1% of patients; it is associated
with a 20% mortality rate.
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30. Treatment of neuroleptic malignant syndrome
1. Discontinuing drug therapy
2. Initiating supportive measures, including the use of bromocriptine to
overcome the dopamine receptor blockade
3. Muscle relaxants such as dantrolene and diazepam to reduce muscle
rigidity.
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31. Sedation
• Mechanism: Due to a central histamine H1-receptor blockade.
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Confusional state with memory impairment
• This effect is likely with antipsychotic agents with pronounced antimuscarinic
activity.
Seizures
• Seizures are especially common with Chlorpromazine and Clozapine.

32. Autonomic Nervous system adverse effects
A. α-Adrenoceptor blockade: Manifests as postural hypotension
B. Atropine-like effects:
 Dry mouth
 Constipation
 Urinary retention
 Visual problems)
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33. Endocrine and metabolic disturbances
A. Hyperprolactinemia: Due to dopamine (D2)-receptor antagonist
activity in the pituitary
- In women, these disturbances include:
 Amenorrhea (absence of menstruation)
 Galactorrhea (milky nipple discharge unrelated to the
normal milk production of breast-feeding)
 Loss of libido
- In men, these disturbances include:
 Gynecomastia (swelling of the breast tissue in males)
 Infertility and erectile dysfunction
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34. Other adverse effects
A. Withdrawal-like syndrome:
• Nausea, vomiting, insomnia, and headache
• These symptoms may persist for up to 2 weeks.
The symptoms can be minimized with a tapered reduction of drug
dosage.
B. Blood dyscrasias:
– Clozapine may induce agranulocytosis in up to 3% of patients
– Therefore it is used only when other drug groups prove ineffective.
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