Download Antipsychotic/Neuroleptic Agents and Lithium

Antipsychotic/Neuroleptic Agents and Lithium
Schizophrenia
Definition
1. It is a mental disorder characterized by
a. disintegration of thought processes
b. disintegration of emotional responsiveness.
2. It most commonly manifests itself as
a. Auditory hallucinations
b. Paranoid
c. Bizarre delusions
d. Disorganized speech and thinking
e. Accompanied by significant social or occupational dysfunction
Types of Schizophrenia
1. Positive Symptoms/Florid Schizophrenia
a. It is manifested as having one of the following abnormal
behaviours which is absent in a normal human being
i. Delusion
ii. Hallucination
iii. Disorganized behaviour
2. Negative Symptoms/Deficit Schizophrenia
a. It is manifested as NOT having one of the normal behaviours
which is present in a normal human being
i. Social withdrawal
ii. Mood disturbance (Anhedomia)
iii. Reduced motivation
Types of Antipsychotic Drugs
1. Typical Antipsychotics – use in the Tx of Florid Schizophrenia
a. High potency
i. Haloperidol
b. Low potency
i. Chlorpromazine
2. Atypical Antipsychotics p – use in the Tx of Deficit Schizophrenia
a. Clozapine
Hypothesis of Schizophrenia’s Pathogenesis
1. Dopamine hypothesis
a. Overactivity of Dopamine in the Mesolimbic pathway of the
brain
i. Mesolimbic pathway is important in the integration of
human’s behaviour
ii. All humans have irrational thought, but it doesn’t take
into serious matter as it is easily swept away
iii. But in the increase in the activity of the Mesolimbic
pathway, the irrational is somehow taken seriously and
lead to delutions
b. After administering a Dopamine enhancing drug, subject
appeared to develop Psychosis
c. By administering the Antipsychotic drug to subject, the potency
of the drug is directly propotional to the binding of Dopamine
receptors, specifically the D2 receptors
2. Serotonin Hypothesis
a. 5-HT2A receptors are receptors that modulate the release of
Dopamine from
i. Cortex
ii. Limbic region
iii. Striatum
b. Stimulation of these receptors also can cause the depolarization
of Glutamate neurons, by which may modulate behaviour of a
human being
Typical Antipsychotic
Drugs
Haloperidol
Pharmacokinetic
Absorption

Readily absorp orally

Udergoes extensive 1st pass
metabolism, **lower
compared to that of
Chlorpromazine
Distribution

Is it highly lipophilic drug;
therefore it can easily
distributed to all
compartments of the body,
particularly and importantly
the BBB

Highly protein bound
Metabolism

Undergoes hepatic
metabolism
Excretion

Excreted via urine
Mechanism of Action

Competitively inhibits the D2 receptors at
o Mesolimbic area
(desirable
effect)

Inhibition of this area will reduce the
activity of the Dopamine in the
integration of behaviour

Hence, lead to the reduce in
hyperactivity of the Mesolimbic
pathway (antipsychosis effect)
o Nigrostriatal Tract
(undesirable
effect)

This area involve in the extrapyramidal
motor tract, controlling the involuntary
movement of the body

Inhibition of this will lead to
Extrapyramidal Symptoms (EPS) which
include

Dystonia

Parkinsonism

Akathasia

Tardive dyskinesia
o Tuberinfundibular area
(undesirable effect)

This area regulate the release of
Prolactin through inhibitory pathway of
Dopamine

Inhibition of this pathway will lead to
uncontrol release of Prolactin presented
with Galactorrhea
Adverse Effects
Extrapyramidal Symptoms
o Acute dystonia (characteristic side effect of Haloperidol)

Sustained muscular contraction of

Neck

Eyes

Throat

Occurs immediately after treatment
o Akathasia

Continuous restless movement

Occurs within the 1st week of treatment
o Parkinsonism

Neurological syndrome characterized by

Tremor

Hypokinesia,

Rigidity

Postural instability

Occurs after one week of treatment
o Tardive dyskinesia

Spastic facial distortion with tongue movement

Occurs after 6 months of treatment

Orthostatic hypotension

Dry mouth

Histaminic side effects
o Sedation
o Due to inhibition of central H1 receptors
SERIOUS SIDE EFFECT

Narcoleptic Malignant Syndrome
o Life threatening neurological disorder, manifested with

Muscle rigidity

High grade fever

Cognitive changes (Detorium)

Increased level of Creatine Kinase indicating
muscle damage
o Treated with

Dantrolene – muscle relaxant

Bromocriptine – Dopamine receptor agonist

Comparison
Haloperidol
High Extrapyramidal symptoms
High potency
Less Histaminic side effects
Chlorpromazine
Less Extrapyramidal symptoms
Low potency
More Histaminic side effects
Atypical Antipsychotic
Drugs
Clozapine
Pharmacokinetic
Absorption
 Complete absorption after oral
admin
 Nevertheless, bioavailibility is 65% due
to 1st pass metabolism
Distribution
 Readily distributed across body
compartments
Metabolism
 Extensively metabolized by CYP450
into few active metabolites
o Norclozapine
 This enzyme can be either
o Inhibited by
 Theophylline
 Ciprofloxacin
 Fluvosamine
o Induced by
 Cigarette smoke
Excretion
 Excreted via urine and bile



Mechanism of Action
Preferentially inhibit D4 receptors
compared to that of Typical
Antipsychotic
o Collectively, it has more activity
towards D4 receptors of the
Mesolimbic system compared to
other part of the brain
 This explains why Clozapine
has less Extrapyramidal
Symptoms
Clozapine is also a partial agonist at the
5-HT1A and 5-HT2A receptors, putatively
improving
o Depression
o Anxiety
o Negative cognitive symptoms
It is also a strong antagonist of
o Adrenergic receptors
o Histaminic receptors
o Cholinergic receptors
Adverse Effects
Common








Extreme
constipation
Night-time drooling
Muscle stiffness
Sedation
Tremors
Orthostasis
Hyperglycemia
Weight gain
Severe Side Effects
Agranulocytosis
o Due to unstable
intermediary
metabolite that
produces
oxidative stress in
white cells and
leads to cell
death
 Cardiac toxicity
 Diabetic
Ketoacidosis

Mania
Definition
 The presence of which is a criterion for certain psychiatric diagnoses, is a state of abnormally elevated or irritable
o Mood
o Euphoria
o Racing thought
o Talkativeness
o Arousal, and/ or
o Energy levels
 It is the opposite of depression
Mood Stabilizer
Drugs
Lithium
Pharmacokinetic
Absorption
 Readily absorp orally
Distribution
 Has a very narrow therapeutic index;
requires close monitoring of plasma
level
Excretion
 Excreted via urine
Mechanism of Action
 Attenuate the signalling via Phosphotidyl
Biphosphate (PIP2) 2nd messenger
coupled receptors
o It inhibits the resynthesis of of PIP2
Nevertheless, the MOA is still remain
uncertain





Adverse Effects
Tremor
Ataxia
Confusion
Diabetes insipidus
o Though inhibition
of Adenylyl
Cyclase in the
Principal cells at
the Collecting
Duct
Thyroid dysfunction
o Litium reduces the
production of
Thyroxine (T4)
o It also reduced
de-iodination of
T4 to T3