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
Others
Atypical Neuroleptics
(second Generation anitpsychotics
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.
Pathways of Dopaminergic System
Pathway
Connections
Function
From midbrain ventral tegmentum to:
☞ Amygdala
☞ Olfactory tubercle
☞ Septal nuclei
☞ Nucleus accumbens
☞ Arousal
☞ Memory
☞ Stimulus processing
☞ Motivational
behaviour
From midbrain ventral tegmentum to:
☞ Prefrontal cortex
☞ Frontal cortex
☞ Cognition
☞ Communication
☞ Social function
☞ Response to stress
☞ Movement
Nigrostriatal
From substantia nigra to:
☞ Caudate Nucleus
☞ Putamen
Tuberoinfundibular
From hypothalamic arcuate nuclei and
periventricular neurons to:
☞ Posterior pituitary
☞ Regulation of
prolactin release
Mesolimbic
Mesocortical
The Dopamine Hypothesis of Schizophrenia
• The dopamine hypothesis of schizophrenia
proposes that the illness results from an
abnormality in dopamine neurotransmission in
mesolimbic and mesocortical pathways.
• The hypothesis is supported by the following
observations:
1. Most antipsychotic drugs block D2 receptors
and there is a very good correlation between
clinical potency of these drug and their in vitro
affinity for these receptors.
2. Dopaminergic agents (cocaine, amphetamines,
levodopa, etc.) can induce a schizophrenic-like behavior
and exacerbate the symptoms of schizophrenia.
3. An increased density of dopamine receptors has been
found in caudate nucleus and a decreased density in
the prefrontal cortex of untreated schizophrenics.
4. The earliest sign of brain disturbances in schizophrenia
is a decrease in blood flow in a region of the basal
ganglia (a region very rich in dopamine receptors)
The dopamine hypothesis has been further elaborated by
Weinberger who proposed that:
1. An increase activity in the mesolimbic pathway would
account for the positive symptoms of schizophrenia.
2. A decreased activity in the mesocortical pathway
would account for the negative symptoms of
schizophrenia.
3. The activity of the mesocortical pathway normally
inhibits the mesolimbic pathway. Therefore the
primary defect in schizophrenia should be a reduction
in this activity.
The dopamine hypothesis of schizophrenia is not fully
satisfactory but provide a useful model for future research.
The Serotonin Hypothesis of Schizophrenia
• The discovery that indole hallucinogens such as
LSD (lysergic acid diethylamide) and mescaline
that are serotonin (5-HT) agonists led to the
search for endogenous hallucinogens in the
urine, blood, and brains of patients with
schizophrenia.
• This proved fruitless, but the identification of
many 5-HT-receptor subtypes led to the crucial
discovery that 5-HT-receptor stimulation was
the basis for the hallucinatory effects of these
agents.
• It has been found that 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.
• These drugs are inverse agonists of the 5-HT2A
receptor; that is, they block the constitutive activity
of these receptors. These receptors modulate the
release of dopamine in the cortex, limbic region,
and striatum.
• Stimulation of 5-HT2A receptors leads to
depolarization of some glutamate neurons, but also
postsynaptic NMDA receptors.
The Glutamate Hypothesis of Schizophrenia
• Glutamate is the major excitatory neurotransmitter in
the brain.
• Phencyclidine and ketamine are noncompetitive
inhibitors of the NMDA receptor that exacerbate both
cognitive impairment and psychosis in patients with
schizophrenia.
• This was the starting point for the hypothesis that
hypofunction of NMDA receptors, located on
GABAergic interneurons, leading to diminished
inhibitory influences on neuronal function,
contributed to schizophrenia.
• The diminished GABAergic activity can induce
disinhibition of downstream glutamatergic activity,
which can lead to hyperstimulation of cortical
neurons through non-NMDA receptors.
• Ampakines are drugs that potentiate currents
mediated by activation of AMPA-type glutamate
receptors.
• In behavioral tests, ampakines are effective in
correcting behaviors in various animal models of
schizophrenia and depression.
• They protect neurons against neurotoxic insults, in
part by mobilizing growth factors such as brainderived neurotrophic factor.
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
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 5HT2A 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 usually subside in
1-4 weeks and are about equally affected by typical
and atypical agents.
• Negative schizophrenic symptoms are minimally
affected by typical neuroleptics but more so by
atypical neuroleptics (the higher blockade of 5-HT2
receptors may contribute to this effect).
Other effects
• Inhibition of nausea and vomiting (due to blockade
of D2 receptors mainly in the CTZ
• 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)
Receptor Affinity of Typical and Atypical
Neuroleptics
D2
D4
5-HT2A
H1
Typical agents (first generation neuroleptics)
0
++
++
Chlorpromazine +++
+++
0
++
+
Thioridazine
+++
0
+
0
Fluphenazine
+++
0
+
0
Haloperidol
Atypical agents (second generation neuroleptics)
++
++
+++
+
Clozapine
+++
0
++
+
Aripiprazole
+
+
++
+
Quitiapine
++
+
+++
++
Olanzapine
+++
+
+++
+
Risperidone
M
Alpha1
+++
+++
+++
+++
0
+
0
+
+++
+++
0
++
+
++
+++
++
0
+++
Adverse Effects of Neuroleptics
CNS
• 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, stupor,
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 %)
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: the inability to maintain a constant
core temperature (with high doses)
Cardiovascular system
• Orthostatic hypotension (mainly 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%)
Relative incidence of Adverse Effects of Neuroleptics
Drug
Extra
Pyramidal
Symptoms
Prolactin
Elevation
Sedation
Anticholinergic
Effects
Postural
Hypotension
Chlorpromazine
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
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 Prevention. Treatment
of D2 receptors is unsatisfactory
Tardive Dyskinesia
Occurrence
Typical neuroleptics (with high extrapyramidal effects):
• Incidence is about 5% per year.
• Prevalence is about 20% with long term treatment.
Atypical neuroleptic:
• Incidence is about 1% per year.
Etiology
• Long term treatment with typical neuroleptics
endowed with strong extrapyramidal effects (the risk of
the syndrome is much lower with atypical neuroleptic).
Pathogenesis
• The exact cause is unknown. Proposed mechanisms are:
A. Up-regulation of D2 receptors in caudate-putamen.
B. Disturbed balance between dopaminergic and
cholinergic system
C. Dysfunction of GABAergic and noradrenergic system
D. Neurotoxicity (via free radicals).
Symptoms and signs
• Tardive dyskinesia is characterized by:
A. The buccal-lingual masticatory syndrome
(grimacing, chewing, tongue protrusion, lip
smacking, puckering)
B. Choreiform, athetoid or rhythmic movements
of neck and trunk (torsion and torticollis) arms
and legs (pill rolling, toe tapping and writhing)
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.
Neuroleptic Drug Interactions of
Clinical Importance
Neuroleptic
All
Low potency
typical and most
atypicals
Interacting drug
Effect of the interaction
-Class 1 and class 3
anti-arrhythmics
-Quinolones
Life threatening
arrhythmias
Anti-cholinergics
Increased anti-muscarinic
effects
Phenothiazines
SSRIs
Haloperidol
Azoles
Inhibition of phenothiazine
metabolism
Inhibition of haloperidol
metabolism
Neuroleptic
Interacting
drug
Haloperidol Lithium
Clozapine
Clozapine
Caffeine
SSRIs
Clozapine
Ritonavir
Risperidone SSRIs
Effect of the interaction
Extrapyramidal effects and/or
lithium toxicity are increased
Inhibition of clozapine metabolism
Inhibition of clozapine metabolism
Strong inhibition of clozapine
metabolism
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.
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
Blockade of D2 receptors can worsen the
disease
Neuroleptic lower the seizure threshold
The risk of neuroleptic malignant is
increased
Parkinson’s disease
Seizure disorders
Catatonia
Long Q-T intervals,
cardiac arrhythmias
Glaucoma
The risk of polymorphic ventricular
tachycardia is increased
Several neuroleptics have pronounced
anti-muscarinic effects
Catatonia is a state of neurogenic motor immobility, and behavioral abnormality
manifested by stupor.
Contraindications and Precautions of
Neuroleptics
Contraindications / Precautions
Bone Marrow suppression
(clozapine)
Explanations
The risk of clozapine induced
agranulocytosis is increased
Several neuroleptics have alpha1
Hypovolemia, hypotension
blocking activity
Prostatic hypertrophy
Several neuroleptics have pronounced
anti-muscarinic effects
History of breast cancer
Some breast cancers are prolactindependent
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.
GOOD LUCK