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Chapter 29:
Antipsychotic Agents &
Lithium
1
Introduction
• The term psychosis refers to a variety of mental
disorders characterized by one or more of the
following symptoms:
1) Diminished and distorted capacity to process
information and draw logical conclusions
2) Hallucinations, usually auditory or visual, but
sometimes tactile or olfactory
3) Delusions (false believes)
4) Incoherence or marked loosening of
associations
5) Catatonic or disorganized behavior
6) Aggression or violence
2
Introduction
• The psychotic disorders include schizophrenia,
the manic phase of bipolar (manic-depressive)
illness, acute idiopathic psychotic illnesses, and
other conditions marked by severe agitation
3
Nature of Psychosis & Schizophrenia
• Schizophrenia is a particular type of psychosis
characterized mainly by a clear sensorium but
a marked thinking disturbance
• Because it affects young people, is often
chronic and is usually highly disabling
• There is a strong hereditary factor in its
aetiology, and evidence suggestive of a
fundamental
biological
disorder
(neurodevelopmental disorder)
4
Nature of Psychosis & Schizophrenia
• The main clinical features of the disease are:
• Positive symptoms:
– Delusions (often paranoid in nature)
– Hallucinations, usually in the form of voices which are often
exhortatory in their message
– Thought disorder, comprising wild trains of thought, garbled
sentences and irrational conclusions, sometimes associated
with the feeling that thoughts are inserted or withdrawn by
an outside agency
– Abnormal behaviours, such as stereotyped movements and
occasionally aggressive behaviours
• Negative symptoms:
– Withdrawal from social contacts
– Flattening of emotional responses
– Lack of motivation
5
Nature of Psychosis & Schizophrenia
• The clinical phenotype varies greatly,
particularly with respect to the balance
between negative and positive symptoms
• The pathogenesis
unknown
of
schizophrenia
is
• Pharmacological evidence is consistent with
DA hyperactivity hypothesis. There is also
evidence of glutamate & 5-HT involvement
• Schizophrenia has familial incidence
6
Neurochemical theories
• Came mainly from analyzing the effects of
antipsychotic and propsychotic drugs-from
pharmacology rather than from neurochemistry
• The main neurochemical theories centre on
dopamine and glutamate, although other
mediators, particularly 5-HT, are also receiving
attention
7
Neurochemical theories
I.
The Dopamine theory of schizophrenia
•
It is based on multiple lines of evidence
suggesting that excessive dopaminergic activity
underlies schizophrenia
•
It is still highly relevant to understanding the
major dimensions of schizophrenia, such as
positive and negative symptoms, cognitive
impairment, and possibly depression
8
Neurochemical theories
I.
The Dopamine theory of schizophrenia
•
It is also essential to understanding the MOA of
most and probably all antipsychotic drugs
•
However, the dopamine hypothesis is far from a
complete explanation of all aspects of
schizophrenia,
especially
the
cognitive
impairment
9
The Serotonin Hypothesis of Schizophrenia
II. The Serotonin theory of schizophrenia
• 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
•
5-HT2A-receptors modulate the release of
dopamine, norepinephrine, glutamate, GABA
and acetylcholine in the cortex, limbic region,
and striatum
10
Neurochemical theories
III. The Glutamate theory of schizophrenia
•
Glutamate
is
the
major
neurotransmitter in the brain
•
Phencyclidine and ketamine are noncompetitive
inhibitors of the N-methyl-D-aspartate (NMDA)
receptor can exacerbate both cognitive
impairment and psychosis in patients with
schizophrenia
•
Hypofunction of NMDA receptors, located on
GABAergic
interneurons
contributed
to
schizophrenia
excitatory
11
Antipsychotic Agents
• Are able to reduce psychotic symptoms in a wide
variety of conditions, including schizophrenia,
bipolar disorder, psychotic depression, senile
psychoses, various organic psychoses, and druginduced psychoses
• They are also able to improve mood and reduce
anxiety and sleep disturbances, but they are not
the treatment of choice when these symptoms are
the primary disturbance in nonpsychotic patients
12
Antipsychotic Agents
• Their antipsychotic actions appear to reflect a
blockade at dopamine and/or serotonin
receptors
• Many of these agents also block cholinergic,
adrenergic, and histaminergic receptors. The
undesirable side effects of these agents are
often a result of actions at these other
receptors
13
Antipsychotic Agents
Typical antipsychotic
Drugs
a) Low Potency
Chlorpromazine
Thioridazine
Thiothixene
Prochlorperazine
b) High potency
Haloperidol
Pimozide
Molindone
Fluphenazine
Atypical antipsychotic
drugs
Loxapine
Clozapine*
Asenapine
Olanzapine
Quetiapine
Paliperidone
Risperidone
Sertindole
Ziprasidone Zotepine
Aripiprazole
14
Dopaminergic Systems
• Five dopaminergic systems or pathways are
important for understanding schizophrenia and
the mechanism of action of antipsychotic drugs:
1) Mesolimbic-mesocortical pathway: the one
most closely related to behavior and psychosis
2) Nigrostriatal pathway: it is involved in the
coordination of voluntary movement. Blockade of
the D2 receptors in the nigrostriatal pathway is
responsible for EPS
15
Dopaminergic Systems
3) Tuberoinfundibular
system:
it
releases
dopamine into the pituitary portal circulation.
Dopamine
released
by
these
neurons
physiologically inhibits prolactin secretion from
the anterior pituitary
4) Medullary-periventricular pathway: it may be
involved in eating behavior
5) Incertohypothalamic pathway: It appears to
regulate the anticipatory motivational phase of
copulatory behavior in rats
16
Mechanism of action
1) Typical antipsychotic agents
• The clinical efficacy of the typical neuroleptic
drugs correlates closely with their relative ability
to block D2 receptors in the mesolimbic system
of the brain
•
The binding affinity of the typical is very strongly
correlated with clinical antipsychotic and
extrapyramidal potency: the typical antipsychotic
drugs must be given in sufficient doses to
achieve 60% occupancy of striatal D2 receptors
18
Mechanism of action
1) Typical antipsychotic agents
• These drugs vary in potency: chlorpromazine is a
low-potency drug, and fluphenazine is a highpotency agent
•
No one drug is clinically more effective than
another
19
Mechanism of action
1) Typical antipsychotic agents
• Antagonism of the of dopamine in the
nigrostriatal system is the major factor in the
extrapyramidal side effects (EPS) seen with
these agents
•
EPS are produced when the occupancy of striatal
D2 receptors reaches 80% or higher
•
Antagonism of dopamine’s neurohormonal action
in the anterior pituitary accounts for the
hyperprolactinemia associated with antipsychotic
administration
20
Mechanism of action
2) Atypical antipsychotic drugs
• These drugs have complex pharmacology but
they share a greater ability to alter 5-HT2Areceptor activity than to interfere with D2-receptor
action
•
They do not have very high affinity for the D2
receptor: effective at lower occupancy levels of
the dopamine receptors (30–50%)
•
The posses high occupancy of 5-HT2A receptors
•
As a result, they have fewer extrapyramidal
adverse effects than the older, traditional agents
21
Mechanism of action
2) Atypical antipsychotic drugs
• Atypical antipsychotic drugs are inverse agonists
of the 5-HT2A receptor; that is, they block the
constitutive activity of these receptors
•
In most cases, they act as partial agonists at the
5-HT1A receptor, which produces synegistic
effects with 5-HT2A receptor antagonism
22
Differences among Antipsychotic Drugs
• All effective antipsychotic drugs block D2
receptors, the degree of this blockade in relation
to other actions on receptors varies considerably
among drugs
• Most of the newer atypical agents appear to exert
part of their unique action through inhibition of
serotonin receptors (5-HT), particularly 5-HT2A
receptors
• The antipsychotics also have variable antagonist
actions at muscarinic, α-adrenergic, and
histaminergic receptors in brain and peripheral
tissue
23
α1
D2
H1
M
5H2A EPS
Chlorpromazine +++ +++
++
++
++
Thioridazine
++
+++
+
++
++
Haloperidol
+++
++
-
±
+
Flupenthixol
+++
++
++
-
+++
D2
α1
H1
M
5H2A EPS
Adverse effects
First generation
++ Increased prolactin (gynaecomastia)
Hypothermia Anticholinergic effects
Hypersensitivity reactions
Obstructive jaundice
+ As chlorpromazine but does not cause
jaundice
+++ As chlorpromazine but does not cause
jaundice
Fewer anticholinergic side effects
++ Increased prolactin (gynaecomastia)
Restlessness
Adverse effects
Second generation
Sulpiride
+++ -
-
-
-
Clozapine
++
++
++
+++ -
++
+
Increased prolactin (gynaecomastia)
Risk of agranulocytosis (∼1%): regular
blood counts required
Seizures
Sedation
Salivation
Anticholinergic side effects
Weight gain
α1
D2
H1
M
5H2A
EPS
Adverse effects
Second generation
Risperidone ++
++
++
++
+++
+
Sertindole
++
-
-
+++
+
Quetiapine +
+++
-
+
+
+
Aripiprazole +++
(PA*)
+
+
-
++
-
Zotepine
+
+
+
+
-
++
++
Weight gain
EPS at high doses
Hypotension
Ventricular arrhythmias (ECG
checks advisable)
Weight gain
Nasal congestion
Tachycardia
Agitation
Dry mouth
Weight gain
Weight gain
Hypotension
Cardiac dysrhythmias
Clinical Uses
A. Psychiatric Indications (schizophrenia)
• The principal goals for the management of a
chronic schizophrenic disorder are the minimizing
of symptoms and the prevention of exacerbations
• All of the antipsychotic drugs can reduce the
hallucinations and delusions (positive symptoms)
associated with by blocking dopamine receptors
in the mesolimbic system of the brain
• No one drug or combination of drugs selectively
affects a particular symptom complex
26
Clinical Uses
A. Psychiatric Indications (schizophrenia)
•
For approximately 70% of patients with
schizophrenia typical and atypical antipsychotic
drugs are of equal efficacy for treating positive
symptoms
•
Atypical drugs ameliorate the negative
symptoms and cognition, diminished risk of
tardive dyskinesia and other forms of EPS, and
are favored for lesser increases in prolactin
levels
27
Clinical Uses
A. Psychiatric Indications (schizophrenia)
•
Drug choice is determined mainly by the
patient’s past responses and the drug’s potential
for producing adverse effects
•
The clinical trend is to prescribe the higherpotency atypical agents
28
Clinical Uses
A. Psychiatric Indications (schizophrenia)
•
Other indications for the use of antipsychotics
include:
a) Tourette's syndrome
b) Disturbed
behavior
Alzheimer's disease
in
patients
with
c) Psychotic depression (with antidepressants)
29
Clinical uses
B. Nonpsychiatric Indications
1. Antiemetics
•
Prochlorperazine & benzquinamide are useful in
the treatment of drug-induced nausea
•
This action is due to DA receptor blockade, both
centrally (in chemoreceptor trigger zone of the
medulla) & peripherally (on receptors in the
stomach)
•
The atypical antipsychotic drugs are not used as
antiemetics
30
Clinical uses
B. Nonpsychiatric Indications
1. Antipruritic:
some
phenothiazines
with
considerable H1 receptor-blocking action e.g
prochlorperazine
2. Preoperative sedation (promethazine)
3. Neuroleptanesthesia (droperidol)
31
Adverse reactions
• Antipsychotic drugs are characterized by high
therapeutic indices with respect to mortality, but
side effects occur routinely at therapeutic doses,
mostly as extensions of pharmacological actions
• The characteristic neurological symptoms caused
by these agents are particularly troublesome,
often limit the tolerated dose, and may interfere
with the desired benefits and patient compliance
32
Adverse Reactions
A. Behavioral Effects
• The older typical antipsychotic drugs are unpleasant to
take
• Many patients may experience "pseudodepression"
due to drug-induced akinesia usually responds to
treatment with antiparkinsonism drugs
• Pseudodepressions may be due to higher doses than
needed in a partially remitted patient, in which case
decreasing the dose may relieve the symptoms
• Toxic-confusional states with very high doses of drugs
that have prominent antimuscarinic actions
33
Adverse Reactions
B. Extrapyramidal side effects (EPS)
•
The inhibitory effects of dopaminergic neurons are
normally balanced by the excitatory actions of
cholinergic neurons in the striatum
•
Blocking dopamine receptors alters this balance,
causing a relative excess of cholinergic influence,
which results in extrapyramidal motor effect
•
Two extrapyramidal conditions, acute dystonic
reactions (spastic retrocollis or torticollis) and
akathisia (uncontrollable restlessness), occur early
during treatment, while parkinsonism tends to evolve
gradually over days to weeks
34
Adverse Reactions
B. Extrapyramidal side effects (EPS)
•
Occur most commonly with the high-potency
typical antipsychotics (e.g. haloperidol and
fluphenazine)
•
Drugs that exhibit strong anticholinergic activity,
such as thioridazine (low-potency typical), show
fewer EPS, because the cholinergic activity is
strongly dampened
36
Adverse Reactions
B. Extrapyramidal side effects (EPS)
• Atypical antipsychotics (clozapine and
risperidone) exhibit a lower potential for
causing extrapyramidal symptoms, which
has been attributed to their blockade of 5HT2A receptors
37
Adverse Reactions
B. Extrapyramidal side effects (EPS)
• Parkinsonism can be treated with antimuscarinic
drugs (e.g. benzotropine), or amantadine.
(Levodopa should never be used in these
patients)
• Akathisia and dystonic reactions preferably
treated with a sedative antihistamine with
anticholinergic properties, eg, diphenhydramine,
which can be given either parenterally or orally
38
Adverse Reactions
C. Tardive dyskinesia
•
The most important
antipsychotic drugs
•
Develops after months or years in 20-40% of
patients
treated
with
first-generation
antipsychotic drugs
•
Patients
display
involuntary
movements,
including lateral jaw movements and “flycatching” motions of the tongue
unwanted
effect
of
40
Adverse Reactions
C. Tardive dyskinesia
•
Its seriousness lies in the fact that it is a
disabling and often irreversible condition
•
It is caused by relative cholinergic deficiency
secondary to supersensitivity of DA receptors in
the
caudate-putamen
(D2-receptor
upregulation?)
•
Appropriately managed by reducing the dose or
to switch to one of the newer atypical agents
(quetiapine or clozapine, the atypical agents with
the least likelihood of causing tardive dyskinesia)
42
Adverse Reactions
D. Neurologic Effects
•
Neuroleptic malignant syndrome is a rare
medical emergency occurs in patients who are
extremely sensitive to the EPS of antipsychotic
agents
•
It occurs in about 1% of patients receiving
antipsychotic and about 10% of these cases are
fatal
•
It is characterized by muscle rigidity, fever as a
result of sweating impairment, altered mental
status and stupor, unstable blood pressure, and
myoglobinemia
43
Adverse Reactions
D. Neurologic Effects
•
Muscle-type creatine kinase levels are usually
elevated, reflecting muscle damage
•
This syndrome is believed to result from an
excessively rapid blockade of postsynaptic
dopamine receptors
•
Treatment necessitates discontinuation of the
antipsychoyic drug and supportive therapy
44
Adverse Reactions
C. Autonomic Nervous System Effects
• Antipsychotics
have
variable
antagonistic
interactions at peripheral adrenergic, cholinergic,
and histsmine receptors; thus, the drugs’ effects
on the ANS are complex and unpredictable
1) α-adrenergic-blocking actions (chlorpromazine,
mesoridazine):
orthostatic
hypotension
or
impaired ejaculation
45
Adverse Reactions
C. Autonomic Nervous System Effects
2) Antimuscarinic
effects
(thioridazine,
chlorpromazine, clozapine, and olanzapine):
blurred vision, dry mouth (exception: clozapine
increase salivation), confusion, constipation, and
urinary retention
46
Adverse Reactions
E. Toxic or Allergic Reactions:
1) Agranulocytosis: clozapine in ~1-2%.
•
Because of the risk, weekly blood counts are
mandatory for patients receiving clozapine for
the first 6 months of treatment and every 3
weeks thereafter
2) Cholestatic jaundice
3) Urticarial skin reactions (common but
usually mild)
47
Adverse Reactions
F. Metabolic & Endocrine Effects
1) Weight gain, especially with clozapine and
olanzapine, and requires monitoring of food
intake, especially carbohydrates
2) Hyperglycemia secondary to weight gainassociated insulin resistance
3) Hyperlipidemia
48
Adverse Reactions
F. Metabolic & Endocrine Effects
• Endocrine changes occur because of effects
of antipsychotic drugs on the hypothalamus
or pituitary, including their antidopaminergic
actions
•
In the pituitary, older typical antipsychotic
drugs, as well as risperidone and
paliperidone, block D2 receptors, leading to
an increase in prolactin release
49
Adverse Reactions
F. Metabolic & Endocrine Effects
• Atypical neuroleptics are less likely to
produce prolactin elevations because their
diminished D2 antagonism
•
Amenorrhea and increased libido have been
reported in women, whereas decreased libido
and gynecomastia have been observed in
men
50
Adverse Reactions
G. Ocular Complications:
1) Opacities of the cornea and lens: due to
deposition the anterior portions of the eye
are
a
common
complication
of
chlorpromazine therapy
2) Pigmentary retinopathy associated with
"browning" of vision: high doses of
thioridazine
51
Adverse Reactions
H. Cardiac Toxicity
• Thioridazine & mesoridazine: overdose
associated
with
major
ventricular
arrhythmias, cardiac conduction block, and
sudden death
•
Patients should be given the usual "ABCD"
treatment for poisonings
52
Adverse Reactions
H. Cardiac Toxicity
• Ziprasidone carries the greatest risk of QT
prolongation and therefore should not be
combined with other drugs that prolong the
QT interval, including thioridazine, pimozide,
and group 1A or 3 antiarrhythmic drugs
53
Drug Interactions
1) Pharmacodynamic interactions:
• Additive/ potentiation effects with:
a. Sedatives and analgesics, alcohol, & OTC
sedatives and hypnotics, antihistamines, and
cold remedies
b. α-adrenoceptor-blockers
c. Anticholinergics
d. Drugs with quinidine-like action (thioridazine)
55
Drug Interactions
1) Pharmacodynamic interactions:
• Antipsychotic drugs inhibit the actions of
dopaminergic agonists and levodopa and worsen
the neurological symptoms of Parkinson’s disease
• The hypotensive effects of an antipsychotic may
be increased by diuretics, captopril, and other
antihypertensive medications
56
Drug Interactions
2) Pharmacokinetic interactions:
• Sedatives
or
anticonvulsants
(e.g.,
carbamazepine, oxcarbazepine, phenobarbital,
and phenytoin) that induce CYPs can enhance
the metabolism of antipsychotic
•
SSRIs (e.g. fluvoxamine, fluoxetine) compete for
CYP450 enzymes and can elevate circulating
levels of antipsychotic drugs
57