Pharmacology of Drugs for Psychotic Disorders

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• What are Psychotic Disorders?

• Psychotic disorders are a group of serious illnesses that affect

the mind

• They make it hard for someone to think clearly, make good

judgments, respond emotionally, communicate effectively,
understand reality, and behave appropriately

• When symptoms are severe, people with psychotic disorders

have trouble staying in touch with reality and often are unable
to handle daily life

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• What is Schizophrenia?

• Schizophrenia is a severe mental disorder in which a patient

experiences a set of visual and/or auditory hallucinations,
accompanied by a number of antisocial behavior patterns

• The anti social patterns include

 poor grooming, involuntary movements, incomprehensible

speech patterns, and incapacity to understand speech

• In some cases, schizophrenia may result in a state in which a

patient loses all connection to the outside world and remains
in a fetal position for long periods of time

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Categories of Signs and symptoms of Schizophrenia
Negative symptoms
 are fundamental to schizophrenia due to their predominance
in the prodromal (a mild change in personality and function)
phase and their tendency to be fairly stable over the course of
the disorder
 They comprise many dimensions such as affect (flattening),
volition (apathy), speech (poverty), pleasure (anhedonia), and
social life (withdrawal)

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Positive symptoms

• are self-affection symptoms which include: hallucinations,

delusions(false belief), and severe thought disorganization

• They usually associated with higher dopamine D2 receptor

activity and

• can be treated with both first generation and second

generation anti psychotics

Cognitive symptoms

• Lack of memory and deficiency of attention are the core

element of cognitive symptoms

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 Clinical picture
 Socially disorganized behaviors

 occasionally aggressive and violent aimlessly.

 Talking irrelevantly

 Suspiciousness

 Thoughts of being harmed or controlled by some external

agencies.

 Laughing, smiling or crying without any obvious reason.

 Talking to self or imaginary figures

 Remaining quit and withdrawn, neglecting personal care and

disturbed sleep
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• Neurotransmitter changes
 Dopamine theory : Amphetamine and Cocaine causes
increased dopamine that leads to psychotic symptoms;
excess dopamine is the cause of schizophrenia.
 Serotonin theory : LSD (lysergic acid diethylamide ) is a
nonselective 5-HT agonists and causes psychotic
symptoms; excess serotonin is the cause of Schizophrenia.
 Glutamate theory: Phencyclidine is NMDA-antagonist
and cause psychotic symptoms; low level of glutamate is the
cause of schizophrenia.

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 Dopamine - functions

• Motor control - nigrostriatal system

 Deficiency results in rigidity, tremor and difficulty initiating

movement

• Behavioral effects - mesolimbic system

 Over activity leads to abnormal behavior

• Endocrine control - tubero-infundibular system

 Dopamine and dopamine agonists suppress prolactin release

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 Schizophrenia - Dopamine hypothesis

• Amphetamine can produce a syndrome similar to the ‘positive’

features of schizophrenia

• Levodopa may aggravate the condition

• Apomorphine and bromocriptine (D2 agonists) produce

behavioral abnormalities in animals

• D2 receptor antagonists are effective in controlling the positive

features of the disorder

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 Anti-psychotic Drugs

• Antipsychotic drugs also known as

 Major tranquilizers because they tranquilize and sedate

mitigate or eliminate the symptoms of psychotic disorders but

they do not cure them

 Initially called neuroleptics because they were found to cause

neurolepsy, which is an extreme slowness or absence of

movement

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 Classification of antipsychotic drugs

1. Typical Antipsychotics b. Butyrophenone derivatives

a. Phenothiazine derivatives • Haloperidol
• Aliphatic derivatives c. Thioxanthine derivatives
– Chlorpromazine. • Thioridazine
• Piperidine derivatives. 2. Atypical Anti-psychotics
– Thioridazine. • Olanzapine
• Piperazine derivatives • Clozapine
– Fluphenazine. • Risperidone
• Loxapine

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 Chlorpromazine
Chlorpromazine was first used to treat schizophrenia in 1954
Original created as an antihistamine anti-allergic.
Heralded the modern era of antipsychotic therapy
Later research shed light on the pharmacological mechanism
of chlorpromazine and served as a basis for the development of
many other anti-psychotic drugs such as haloperidol and
olanzapine

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 M.O.A:-
• Cause blockade of postsynaptic dopaminergic (D2)
receptors and to a smaller extent 5 – HT receptors.

• They also block muscarinic receptors

• Modify the function of the mesolimbic system and

reduce the incoming sensory stimuli by acting on the
brainstem reticular formation

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 Pharmacological actions
CNS

• Antipsychotic action;

• CPZ by blocking D2 receptors and possible alpha 1 , 5 HT2

& H1 in the limbic system improves greatly the behavior,
calm the hyperactive patients, improves thought and
relieves hallucinations in the schizophrenic patients.

• Decrease of spontaneous motor activity.

• Central skeletal muscle relaxations.

• Normalization of sleep disorders

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• Decrease of seizure threshold

– Should not be used in an epileptic untreated patients or those

undergo withdrawal from CNS depressants.

– Depression of basal ganglia and relieve of tremors of

Parkinsonism but high doses can precipitate Parkinsonism (by
blocking D2 receptors).

• Hypothermia,

– Inhibition of heat regulating centre and

– Inhibition Vasomotor centre lead to vasodilatation of

coetaneous blood vessels and increased heat loss.

– Heat production also is decreased by inhibiting shivering

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• Increase of prolactin production by blocking D2 receptors in
pituitary and hypothalamus.

• Decrease of growth hormone, ACTH & Gonadotropin hormones.

• Increased appetite and weight gain (stimulate feeding center).

• Inhibition of vasomotor reflexes.

• Antiemetic action by blocking Dopaminergic receptors in CTZ.

On autonomic system

• Strong alpha blocking activity

• Anti-adrenergic activity by blocking of uptake of catecholamine

into nerve ending.

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• Weak anti-muscarinic activity

• Strong anti-serotonin action

• Weak anti-histaminic action

On peripheral nerves

• Membrane stabilizing effect ( local anesthetic effect )

On kidney

• Weak anti-diuretic action

– Increasing of A D H release or

– A direct action on the renal tubules.

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On CVS

• Depressant (Quinidine - like) action on the heart.

• Vasodilatation and hypotension through alpha blocking activity,

anti-adrenergic action, inhibition of vasomotor centre and cardiac

depressant action.

• CPZ should not be given IV due to a sudden fall in blood pressure

• Tachycardia
– reflex to hypotension and due to its anti-cholinergic effect

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 Therapeutic use
• To control Psychosis

• Anxiety is relived

• Hallucinations and delusion are suppressed

• Disturbed thought and behavior are gradually normalized

• Antiemetic action : Depressed CTZ in medulla oblongata

Side effects
CNS

– Drowsiness, lethargy, confusion,  appetite

Due to alpha blocking effect: Faintness , palpitation , postural

hypotension, inhibition of ejaculation
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 Due to anti cholinergic effect

– Nasal stuffiness , dry mouth, blurred vision, retention of urine,

constipation.

• Due to D2 blocking effect on corpus striatum.

– Parkinsonism

– Acute muscular dystonia

Other side effect

• Hypothermia, Jaundice, galactorrhea, amenorrhea,

gynaecomastia, infertility, opacities in the cornea and lens, and
hypersensitivity reactions.

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• Parkinsonian symptoms remit if the drug is withdrawn and

may be suppressed by the administration of antimuscarinic

drugs

• However they may unmask or worsen tardive dyskinesia.

• drug withdrawal at the earliest signs of tardive dyskinesia

may halt its full development.

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 Drug interactions
• They enhance the effects of sedatives, hypnotics, anesthetics, and
analgesics

• They interfere with the antihypertensive effect of guanethidine by

blocking its uptake into nerve ending.

• They augment the effect of antiarrhythmic drugs.

• They block the action of dopaminergic agonists e.g. levodopa

used in parkinsonison and the condition may be aggravated.

• They induce the hepatic microsomal enzymes and decrease the

effect of other drugs.

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• Chlorpromazine hydrochloride tablet 75-300 mg/day P.o. in
divided does or 25 – 50 mg IM

• The patient should be confined to bed for 30 minutes following

IM injection in order to avoid postural hypotension

• Thioridazine >> CPZ, but less in producing extrapyrimidal side

effect and sedation

• Butyrophenones
• Are more potent than CPZ and used for severe forms of psychosis

• More Extra pyramidal side effect

 Haloperidol 1 – 15 mg/d P.o

 Fluphenazine 12.5–00 mg Im every 3–4 wk

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 Comparisons Between the Two Classes of Drugs

• Phenothiazines
• Butyrophenones
• Low potency
– High potency
• Are sedative
– Non-sedative
• Block D2 receptors
– Block D2 receptors
• metabolism and removal is
– Metabolism and removal
complex and among the
is quicker
slowest of any group of
– Cause extra pyramidal
drugs
symptoms (EPS)
• cause EPS

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 Atypical Anti-psychotics
• They were developed in an attempt to minimize the side effects of
typical anti-psychotics

• fewer extra pyramidal symptoms because they are more selective.

They also regulate both positive and negative symptoms

• Mode of Action
• Antagonize Dopamine on D2 receptors but appear to be more
selective in targeting the intended pathway to a larger degree
than typical antipsychotics.

• They also interact with other neurotransmission systems,

particularly with the serotonergic and noradrenergic pathways

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 Side Effects
• Glucose Metabolism Disorders such as hyperglycemia, and
worsening of pre-existing diabetes ( This was particularly seen
with patients treated with olanzapine and clozapine)

• Weight Gain has been seen with patients taking Olanzapine;

• QTc prolongation which occurs when there is an abnormally long

delay between the electrical excitation and relaxation of the
ventricles of the heart which can cause death

• Choice of Antipsychotics
• Selection is influenced by the degree of sedation required and the
patient's susceptibility to extrapyramidal side-effects
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• Atypical antipsychotics may be appropriate if extrapyramidal
side-effects are a particular concern

• Clozapine is used for schizophrenia when other antipsychotics

are ineffective or not tolerated.

• Prescribing of more than one antipsychotic at the same time is

not recommended

• Chlorpromazine has a marked sedating effect and is useful for

treating violent patients without causing stupor.

• Agitated states in the elderly can be controlled without

confusion, a dose of 10 to 25 mg once or twice daily usually
being adequate.

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• Fluphenazine, haloperidol, and trifluoperazine are also of

value but their use is limited by the high incidence of

extrapyramidal symptoms.

• Haloperidol may be preferred for the rapid control of

hyperactive psychotic states

• it causes less hypotension than CPZ and is therefore also

popular for agitation and restlessness in the elderly

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