Download Neuroleptics (Anti-psychotic Drugs)

Neuroleptics
(Anti-psychotic Drugs)
Kaukab Azim, MBBS, PhD
Drug List
Typical Neuroleptics
(First generation anti-psychotics)
Phenothiazines
Chlorpromazine
Butyrophenones
Haloperidol
Thioridazine
Atypical Neuroleptics
(second Generation anitpsychotics
Others
Thiotixene
Clozapine
Molindone
Olanzapine
Fluphenazine
Qietiapine
Prochlorperazine*
Risperidone
Aripiprazole
* Will be covered in another lecture
Learning Outcomes
By the end of the course the students will be able to
☛ Outline the dopamine hypothesis of schizophrenia.
☛ Explain the mechanism of action of each drug in each class.
☛ Describe the antipsychotic action of neuroleptics.
☛ List the main pharmacokinetic features of neuroleptics
☛ Outline the use of depot preparations of fluphenazine and haloperidol
☛ Describe the main adverse effects of neuroleptics
☛ List the main contraindications of neuroleptics
☛ Outline the main therapeutic uses of neuroleptics.
Pharmacodynamics of Neuroleptics
Mechanism of action
☛ Neuroleptics block many different receptors.
☛ The therapeutic effects of neuroleptics are though
to result from competitive blockade of dopamine
(mainly D2) and/or serotonin (mainly 5-HT2A)
receptors.
☛ The adverse effects of neuroleptics seem to result
from the blockade of D2 receptor in the substantia
nigra as well as from blockade of a variety of
receptors both in the central and autonomic
nervous system
Pharmacodynamics of Neuroleptics
Neuroleptic can be broadly classified into the following
groups:
1. Typical agents
☛ (which can be further subdivided in low potency and
high potency agents)
☛ These drugs have high D2 antagonism and low 5-HT2A
antagonism.
2. Atypical agents
☛ These drugs have low (clozapine) or moderate D2
antagonism and high 5-HT2A antagonism.
Pharmacodynamics of Neuroleptics
Pharmacological effects
a.In normal individuals:
☛ Dysphoric effects are common (this can explain why this drugs
have negligible abuse liability)
b. In schizophrenic patients
☛ Positive schizophrenic symptoms(delusion,hallucinations &
thought disorders) usually subside in 1-4 weeks and are about
equally affected by typical and atypical agents.
☛ Negative schizophrenic symptoms(withdrawal,blunted emotions
& reduce ability to relate to people) are minimally affected by
typical neuroleptics but more so by atypical neuroleptics (the
higher blockade of 5-HT2 receptors may contribute to this effect).
Pharmacodynamics of Neuroleptics
Other effects
☛ Inhibition of nausea and vomiting (due
to blockade of D2 receptors mainly in
the CTZ, but also in the stomach
☛ Inhibition of thermo-regulation (due to
inhibition
of
the
hypothalamic
thermostat)
Pharmacokinetics of Neuroleptics
☛ Variable oral bioavailability (0.25-0.70)
☛ Large Vd.
☛ Extensive metabolism by the liver.
☛ Long half-lives (12-55 hours) for most compounds .
☛ Administered PO, IM , IV. For some compounds depot
preparations are available (i.e. fluphenazine
decanoate, haloperidol decanoate)(depot:It is a
special preparation of the medication, which is given
by injection. The medication is slowly released into
the body over a number of weeks)
Receptor Affinity of Typical and Atypical
Neuroleptics
D2
D4
5-HT2A
H1
M
Alpha1
Typical agents (first generation neuroleptics)
Chlorpromazine
+++
0
++
++
+++
+++
Thioridazine
+++
0
++
+
+++
+++
Fluphenazine
+++
0
+
0
0
+
Haloperidol
+++
0
+
0
0
+
Atypical agents (second generation neuroleptics)
Clozapine
++
++
+++
+
+++
+++
Aripiprazole
+++
0
++
+
0
++
Quitiapine
+
+
++
+
+
++
Olanzapine
++
+
+++
++
+++
++
Risperidone
+++
+
+++
+
0
+++
Relative incidence of Adverse Effects of
Neuroleptics
Extra
Pyramidal
Symptoms
Prolactin
Elevation
Sedation
Anticholinergic
Effects
Postural
Hypertension
Medium
Present
High
High
High
Thioridazine
Low
Present
High
High
High
Fluphenazine
High
Present
Low
Low
Low
Haloperidol
High
Present
Low
Low
Low
Clozapine
Very Low
None
High
High
High
Quetiapine
Very Low
None
Medium
Low
Medium
Olanzapine
Very Low
None
Medium
High
Medium
Risperidone
Medium
Present
Medium
Low
Medium
Aripiprazole
Very Low
None
Low
Low
Medium
Drug
Chlorpromazine
Extrapyramidal Adverse Effects of
Neuroleptics
Syndrome
Features
Proposed
mechanism
Treatment
Acute dystonia
Spasms of muscles of
tongue, face, and neck
Unknown
Anti-Parkinson
Drugs
Akathisia
Motor restlessness
Unknown
Anti-Parkinson
Drugs
Benzodiazepines
Propranolol
Parkinsonism
Bradykinesia, rigidity,
tremor
Dopamine
Antagonism
Anti-Parkinson
Drugs
Tardive dyskinesia
Oral-facial, dyskinesia,
choreoathetosis,
Dystonias
Up-regulation of
D2 receptors
Prevention.
Treatment is
unsatisfactory
Etiology
Tardive Dyskinesia
Long term treatment with typical neuroleptics endowed with
strong extrapyramidal effects (the risk of the syndrome is much
lower with atypical neuroleptic)
Symptoms and signs
☛ Tardive dyskinesia is characterized by:
a.
The buccal-lingual masticatory syndrome (grimacing(foul smell),
chewing, tongue protrusion, lip smacking(make a noise with the
lip), puckering(gather into a small wrinkles)
b.
Choreiform(jerky involantary movement), athetoid(Twist) or
rhythmic movements of neck and trunk (torsion and torticollis)
arms and legs (pill rolling, toe tapping and writhing(Twist)
Tardive Dyskinesia
Clinical course and prognosis
☛ Early signs of tardive dyskinesia can be reversible
☛ If the disease is not detected or allowed to persist, it
can
become
irreversible
even
with
drug
discontinuation.
Therapy
☛ Prevention is important
☛ No drug treatment is satisfactory.
☛ Switching to an atypical neuroleptic (clozapine) is the
favored first-line therapeutic strategy.
CNS
Adverse Effects of Neuroleptics
☛ Sedative effects, usually perceived unpleasant by normal individuals
(dysphoria, dizziness).
☛ Extrapyramidal effects.
☛ Seizures,(neuroleptics lower the convulsive threshold).The risk is substantial
with clozapine (2-5%).
☛ Neuroleptic malignant syndrome (catatonia(person become mute or
stuporous), stupor(a condition of near unconsciousness), fever, unstable
blood pressure, myoglobinuria). It can be fatal. Dantrolene is the drug of
choice, bromocriptine may help.
Gastrointestinal system
☛ Xerostomia, constipation.
☛ Cholestatic jaundice (mainly with chlorpromazine)
☛ Sialorrhea (with clozapine. Up to 70 %)
Adverse Effects of Neuroleptics
Genitourinary system
☛ Urinary retention, urinary incontinence.
☛ Sexual dysfunction (erectile dysfunction, ejaculatory
abnormalities).
Metabolic/Endocrine system
☛ Hyperprolactinemia (can lead to amenorrhea,
galactorrhea, anovulation in women, gynecomastia
and azoospermia in men)
☛ Weight gain (mainly with clozapine and olanzapine)
☛ Hyperglycemia, diabetes (mainly with clozapine and
olanzapine)
☛ Poikilothermia (with high doses)
Adverse Effects of Neuroleptics
Cardiovascular system
☛ Orthostatic hypotension (manly with lower potency drugs)
☛ Cardiac arrhythmias (mainly with thioridazine) [patients with long
Q-T intervals are at greater risk]
☛ Myocarditis (with clozapine. The disease can be lethal)
Other adverse effects
☛ Cornea, lens and retinal deposits (mainly with thioridazine)
☛ Blurred vision
☛ Urticaria, skin rash (phenothiazines, 1-5%).
☛ Photosensitivity (phenothiazines)
☛ Agranulocytosis (with clozapine. About 1%)
Neuroleptic Drug Interactions of
Clinical Importance
Neuroleptic
Interacting drug
Effect of the interaction
☛
All
Class 1 and class 3
anti-arrhythmics
☛ Quinolones
Life threatening arrhythmias
Low potency typical
and most atypicals
Anti-cholinergics
Increased anti-muscarinic effects
Phenothiazines
SSRIs
Inhibition of phenothiazine metabolism
Haloperidol
Azoles
Inhibition of haloperidol metabolism
Haloperidol
Lithium
Extrapyrimidal effects and/or lithium
toxicity are increased
Clozapine
Caffeine
Inhibition of clozapine metabolism
Clozapine
SSRIs
Inhibition of clozapine metabolism
Clozapine
Ritonavir
Strong inhibition of clozapine metabolism
Risperidone
SSRIs
Inhibition of risperidone metabolism
Summary of Adverse Effects of
Neuroleptics
Typical neuroleptics
☛ Low potency drugs (most phenothiazines and thioxanthenes) have
low extrapyramidal effects and high or intermediate sedative,
antimuscarinic and hypotensive effects.
☛ High
potency
drugs
(fluphenazine,
prochlorperazine,
butyrophenones) have high extrapyramidal effects and low sedative,
antimuscarinic and hypotensive effects.
☛ All drugs increase serum prolactin levels.
☛ All drugs, but thioridazine, have good antiemetic effects.
☛ All drug can cause cardiac arrhythmias, due to an increase in QT
intervals.
Summary of Adverse Effects of
Neuroleptics
Atypical neuroleptics
☛ All drugs have low or negligible extrapyramidal effects
☛ All drugs have negligible effects on serum prolactin
levels.
☛ All drugs can cause cardiac arrhythmias, due to an
increase in QT intervals
☛ Most drugs have significant sedative, antimuscarinic
and hypotensive effects.
Contraindications and Precautions of
Neuroleptics
Contraindications / Precautions
Explanations
States of CNS depression
Addictive effects
Parkinson’s disease
Blockade of D2 receptors can worsen the
disease
Seizure disorders
Neuroleptic lower the seizure threshold
Catatonia
The risk of neuroleptic malignant is
increased
Long Q-T intervals, cardiac arrhythmias
The risk of polymorphic ventricular
tachycardia is increased
Glaucoma
Several neuroleptics have pronounced antimuscarinic effects
Catatonia is a state of neurogenic motor immobility, and behavioral abnormality manifested by stupor.
Contraindications and Precautions of
Neuroleptics
Contraindications / Precautions
Explanations
Bone Marrow suppression
(clozapine)
The risk of clozapine induced agranulocytosis
is increased
Hypovolemia, hypotension
Several neuroleptics have alpha1 blocking
activity
Prostatic hypertrophy
Several neuroleptics have pronounced antimuscarinic effects
History of breast cancer
Some breast cancers are prolactin-dependent
Elderly
Sensitivity to anti-cholinergic effects is
increased.
Therapeutic Uses of Neuroleptics
Psychiatric indications
☛ Acute psychosis (manic phase of bipolar disorder, etc.)
☛ Agitation, delirium (in mentally retarded or demented patients)
☛ Irritability, in autistic children and adolescents (risperidone)
☛ Schizophrenia, schizoaffective disorders
☛ Tourette’s syndrome
☛ Huntington’s disease
☛ Alcoholic hallucinosis
Therapeutic Uses of Neuroleptics
Nonpsychiatric indications
☛ Nausea and vomiting (some phenothiazines)
☛ Neuroleptanalgesia (droperidol & fentanyl)
☛ Pruritus (promethazine)
Notes
☞ Atypical neuroleptics seem to have higher efficacy, particularly
for negative symptoms, cognition and mood. However the issue
is still controversial.
☞ Only clozapine has shown superiority over other neuroleptics in
randomized clinical trials for the management of treatment
resistant schizophrenia.