Transcript PHARMACOLOGY OF ANTIPSYCHOTIC DRUGS (NEUROLEPTICS)

抗精神失常药
PHARMACOLOGY OF
ANTIPSYCHOTIC DRUGS
(NEUROLEPTICS)
‫دکتر محمد بهداد‬
‫متخصص روانپزشکی‬
SOME DEFINITIONS

Neuroleptic: synonym for antipsychotic
drug; originally indicated drug
w/antipsychotic efficacy but with
neurologic (extrapyramidal motor) side
effects
 Typical neuroleptic: older agents
fitting this description
 Atypical neuroleptic: newer agents:
antipsychotic efficacy with reduced or
no neurologic side effects

NEUROLEPTICS ON THE
UUHSC DRUG LIST
TYPICAL NEUROLEPTICS:
 PHENOTHIAZINES:
 Chlorpromazine (Thorazine ® )
 Thioridazine (Mellaril ® )
 Fluphenazine (Prolixin ® )
 THIOXANTHENE
 Thiothixene (Navane® )
 OTHER
 Haloperidol (Haldol ® )
NEUROLEPTICS ON THE UUHSC DRUG
LIST (Continued)
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ATYPICAL NEUROLEPTICS:
 Risperidone (Risperdal ® ; most
frequently prescribed in U.S.)
Clozapine (Clozaril ® )
 Olanzapine (Zyprexa ® )
 Quetiapine (Seroquel ® )
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KEY CONCEPTS:
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All neuroleptics are equally effective in treating
psychoses, including schizophrenia, but differ in
their tolerability.
All neuroleptics block one or more types of
DOPAMINE receptor, but differ in their other
neurochemical effects.
All neuroleptics show a significant delay before they
become effective.
All neuroleptics produce significant adverse effects.
GENERAL CHARACTERISTICS OF TYPICAL
NEUROLEPTICS
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The older, typical neuroleptics are effective
antipsychotic agents with neurologic side
effects involving the extrapyramidal motor
system.
Typical neuroleptics block the dopamine-2
receptor.
GENERAL CHARACTERISTICS OF TYPICAL
NEUROLEPTICS
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Typical neuroleptics do not produce a
general depression of the CNS, e.g.
respiratory depression
Abuse, addiction, physical dependence
do not develop to typical neuroleptics.
GENERAL CHARACTERISTICS OF TYPICAL
NEUROLEPTICS
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Typical neuroleptics are generally more
effective against positive (active)
symptoms of schizophrenia than the
negative (passive) 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
THERAPEUTIC EFFECTS OF TYPICAL
NEUROLEPTICS
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All appear equally effective; choice usually
based on tolerability of side effects
Most common are haloperidol (Haldol ® ),
chlorpromazine (Thorazine ®) and thioridazine
(Mellaril ®)
Latency to beneficial effects; 4-6 week delay
until full response is common
70-80% of patients respond, but 30-40%
show only partial response
THERAPEUTIC EFFECTS OF TYPICAL
NEUROLEPTICS (Continued)
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Relapse, recurrence of symptoms is
common ( approx. 50% within two
years).

Noncompliance is common.
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Adverse effects are common.
ADVERSE EFFECTS OF TYPICAL
NEUROLEPTICS
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Anticholinergic (antimuscarinic) side
effects:
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Dry mouth, blurred vision, tachycardia,
constipation, urinary retention, impotence
ADVERSE EFFECTS OF TYPICAL
NEUROLEPTICS
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Antiadrenergic (Alpha-1) side effects:
 Orthostatic hypotension w/ reflex
tachycardia
 sedation
ADVERSE EFFECTS OF TYPICAL
NEUROLEPTICS
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Antihistamine effect: sedation, weight
gain
KEY CONCEPT: DOPAMINE-2
RECEPTOR BLOCKADE IN THE BASAL GANGLIA
RESULTS IN EXTRAPYRAMIDAL MOTOR SIDE
EFFECTS (EPS).
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DYSTONIA
NEUROLEPTIC MALIGNANT
SYNDROME
PARKINSONISM
TARDIVE DYSKINESIA
AKATHISIA
ADVERSE EFFECTS OF TYPICAL
NEUROLEPTICS (Continued)
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Increased prolactin secretion (common with all;
from dopamine blockade)
Weight gain (common, antihistamine effect?)
Photosensitivity (v. common w/ phenothiazines)
Lowered seizure threshold (common with all)
Leucopenia , agranulocytosis (rare; w/
phenothiazines)
Retinal pigmentopathy (rare; w/ phenothiazines)
ADVERSE EFFECTS OF TYPICAL
NEUROLEPTICS (Continued)
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Chlorpromazine and thioridazine produce
marked autonomic side effects and sedation;
EPS tend to be weak (thioridazine) or
moderate (chlorpromazine).
Haloperidol, thiothixene and fluphenazine
produce weak autonomic and sedative
effects, but EPS are marked.
MECHANISMS OF ACTION
OF TYPICAL NEUROLEPTICS
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DOPAMINE-2 receptor blockade in
meso-limbic and meso-cortical systems
for antipsychotic effect.
DOPAMINE-2 receptor blockade in basal
ganglia (nigro-striatal system) for EPS
DOPAMINE-2 receptor supersensitivity
in nigrostriatal system for tardive
dyskinesia
LONG TERM EFFECTS OF D2 RECEPTOR
BLOCKADE:
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Dopamine neurons reduce activity.
Postsynaptic D-2 receptor numbers increase
(compensatory response).
When D2 blockade is reduced, DA neurons
resume firing and stimulate increased # of
receptors >> hyper-dopamine state >>
tardive dyskinesia
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MANAGEMENT OF EPS
Dystonia and parkinsonism: anticholinergic
antiparkinson drugs
Neuroleptic malignant syndrome: muscle
relaxants, DA agonists, supportive
Akathisia: benzodiazepines, propranolol
Tardive dyskinesia: increase neuroleptic dose;
switch to clozapine
ADDITIONAL CLINICAL USES OF TYPICAL
NEUROLEPTICS
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Adjunctive in Rx of acute manic episode
Tourette’s syndrome (esp. Haldol ® )
Rx of drug-induced psychoses
Phenothiazines are effective antiemetics,
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Esp. prochlorperazine (Compazine ® )
Also, anti-migraine effect
GENERAL CHARACTERISTICS OF
ATYPICAL NEUROLEPTICS
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Effective antipsychotic agents with greatly
reduced or absent EPS, esp. reduced
Parkinsonism and tardive dyskinesia
All atypical neuroleptics block dopamine and
serotonin receptors; other neurochemical
effects differ
Are effective against positive and negative
symptoms of schizophrenia; and in patients
refractory to typical neuroleptics
PHARMACOLOGY OF
CLOZAPINE (CLOZARIL ®)
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FDA-approved for patients not responding to
other agents or with severe tardive
dyskinesia
Effective against negative symptoms
Also effective in bipolar disorder
Little or no parkinsonism, tardive dyskinesia,
PRL elevation, neuro-malignant syndrome;
some akathisia
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Blockade of alpha-1 adrenergic
receptors
Blockade of muscarinic cholinergic
receptors
Blockade of histamine-1 receptors
PHARMACOLOGY OF CLOZAPINE
(Continued )
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Other adverse effects;
 Weight gain
 Increased salivation
 Increased risk of seizures
 Risk of agranulocytosis requires
continual monitoring
PHARMACOLOGY OF OLANZAPINE
(ZYPREXA ® )
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Olanzapine is clozapine without the
agranulocytosis.
Same therapeutic effectiveness
 Same side effect profile
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PHARMACOLOGY OF QUETIAPINE
(SEROQUEL ®)
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Quetiapine is olanzapine without the
anticholinergic effects.
Same therapeutic effectiveness
 Same side effect profile
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Highly effective against positive and
negative symptoms
Adverse effects:
 EPS incidence is dose-related
 Alpha-1 receptor blockade
 Little or no anticholinergic or antihistamine
effects
 Weight gain, PRL elevation
HYPOTHESIZED MECHANISMS OF
ACTION OF ATYPICAL NEUROLEPTICS
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Combination of Dopamine-4 and
Serotonin-2 receptor blockade in cortical
and limbic areas for the “pines”
Combination of Dopamine-2 and
Serotonin-2 receptor blockade (esp.
risperidone)
General Therapeutic Principles for Use of
Neuroleptics in Schizophrenia
(NIH Consensus Statement, 1999)
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Use atypical for:
 1st acute episode w/ + or +/- symptoms
Switch to atypical if:
 Breakthrough after Rx w/ typical
Use typical (depot prep) when:
 Patient is noncompliant
General Therapeutic Principles for Use of
Neuroleptics in Schizophrenia
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If response is inadequate to:
 Typical; switch to Atypical
 Atypical; raise dose or switch to another
Atypical
 Typical and Atypical; switch to Clozaril ®
For maintenance, lifetime Rx is required.
Extrapyramidal Symptoms
Description and Management
Akathesia / Dystonia
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Akathesia
- feeling of restlessness, desire to move
legs or walk
Dystonia
-slow sustained contractions or spasms
that result in involuntary movement
Drug Induced Parkinsonism
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Muscle stiffness/ Cogwheeling
Shuffling gait
Stooped posture
Masked facies
Tremor
Management of
Akathesia/Dystonia/Drug Induced
Parkinsonism
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Akathesia
- Symptoms usually abate with reduction of dose
or discontinuation of the medication
- Addition of anxiolytic or b-blocker may be
helpful
Dystonia / Drug Induced Parkinsonism
-require immediate intervention
-administration of anticholinergic or
antiparkinson medication
-reduce dose or change medication
Tardive Dyskinesia
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Repetitive rhythmic involuntary movements
Examples
-Tongue thrusting
-Lip smacking
-Chewing movements
-Grunting/Humming
Mangement of Tardive Dyskinesia
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Prevention is the key
Screening recommended every 3 to 6
months using tools such as the
Abnormal Involuntary Movement Scale
(AIMS)
When identified, reduce or eliminate the
causative agent
Neuroleptic Malignant
Syndrome
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High Fever
Muscle Rigidity
Change in Mental Status
Autonomic Instability
Profuse Diaphoresis
Fatality rate of 10-30%
Management of Malignant
Neuroleptic Syndrome
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Hospital transfer
Withhold neuroleptic medication
Hydration to correct fluid losses and hypotension
Benzodiazepines and physical restraints as needed
Cooling with antipyretics, cooling blankets
Dopamine agonists (Bromocriptine, amatadine)
Avoid Dantrolene
Psychiatry, neurology, and renal consults as
appropriate
(Benzor 2009)
Hyperprolactinemia
Symptoms and management
Hyperprolactinemia Symptoms
Men
Women
Galactorrhea
Galactorrhea
Gynecomastia
Amenorrhea/Oligomennorrhea
Decreased libido
Acne/Hirsutism
Infertility
Infertility
Erectile Dysfunction
Dyspareunia
Osteoporosis
Osteoporosis
Hyperprolactinemia Management
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Do not check prolactin levels in asymptomatic
patients
In symptomatic patients, evaluate other
potential causes of symptoms (thyroid
disease, pregnancy, low testosterone)
Consider an MRI in patients whose history
may suggest a pituitary lesion or not well
explained by the drug in question
Consider endocrinology referral
Consider discontinuing drug in consultation
with patient and psychiatrist
(Miller 2004)
Metabolic Syndrome
Monitoring and Management
Metabolic Syndrome
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In 2004, FDA issued a black box warning on
hyperglycemia and diabetes associated with atypical
antipsychotics
The American Diabetic Association published a
consensus statement in conjuction with the American
Psychiatric Association, the American College of
Endocrinology outlining management of metabolic
sequelae of antipsychotic use
(ADA, Diabetes Care
2004)
Baseline Monitoring
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Document any Personal/Family History
of Obesity, Diabetes, Hyperlipidemia, or
Heart Disease
Weight and Height Measurements (BMI)
Waist Circumference
Fasting Plasma Glucose
Fasting Lipid Profile
Baseline Monitoring
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Initiate standard treatment for any patients
found to be hypertensive, diabetic, or with
elevated lipids
Nutritional and physical activity counseling for
patients who are overweight or obese
Patients and family should be informed of the
risks of weight gain and diabetes.
Patients and families should be advised on how
to recognize the signs and symptoms of
diabetes.
Weight measurements
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Weight should be monitored monthly
for the 1st 3 months
For patients who have gained > 5%;
consider changing agent
Rapid discontinuation of medication
should be avoided
3 Months
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Weight
Fasting plasma glucose
Lipid profile
Blood Pressure
Patients who develop worsening blood
sugar or lipids should consider
switching agents
Annual Assessments
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Family / Personal history
Weight
Blood pressure
Fasting Plasma Levels
Waist Circumference
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Lipids (may be done every 5 years)
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Monitoring Schedule
Baseline 4
8
12
Every
weeks weeks weeks 3
Months
Every
Year
Personal/ Family
history
x
Weight
x
Waist
x
Blood Pressure
x
x
x
Fasting glucose
x
x
x
Lipid Profile
x
x
Every
5
years
x
x
x
x
x
x
x
x
Epilogue
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Morrato et al examined the testing of fasting
glucose and lipids in patients receiving
atypical antipsychotic medications
Laboratory claims for 18, 876 US patients
enrolled in a commercial health plan receiving
antipsychotic medications from 2001 through
2006
Comparisons before and after the FDA letter
campaign and ADA consensus statement
Survey Question #3
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(1)
(2)
(3)
(4)
(5)
Which of the following best describes the
percentage of patients on antipsychotic
medication who had an annual fasting
glucose in study by Morrato et al ?
20%
40%
60%
80%
95%
Effect of ADA and FDA on Annual
Glucose Screening
Extrapyramidal syndromes include the following:
Acute dystonia: sustained muscle contractions cause
1.
twisting and repetitive movements or abnormal postures
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2.
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This condition is often elicited during the first
week of therapy.
Akathisia is the 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.
Parkinsonian-like syndrome
3.
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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.
Acute dystonia
b.
Tardive dyskinesia (10—20%)
CNS disorder characterized by:
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twitching of the face and tongue
involuntary motor movements of the trunk and
limbs
More likely with conventional antipsychotic agents.
Tardive dyskinesia generally occurs after months to
years of drug exposure; it may be exacerbated or
precipitated by the discontinuation of therapy.
Orofacial movements
Dystonic posture
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Tardive dyskinesia is often irreversible.
more likely to occur in the elderly or in
institutionalized patients who receive long-term, highdose therapy.
The only effective treatment for tardive dyskinesia is
the discontinuation of treatment.
Cholestatic jaundice, which is caused
c.
primarily by chlorpromazine
d.
Photosensitivity
1.
The effect is specific to chlorpromazine
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2.
it includes dermatitis (5%), rash, sunburn, and
pigmentation, and it may be irreversible.
Chlorpromazine and high-dose thioridazine also
produce retinitis pigmentosa