Antipsychotics

Antipsychotics

Presenter: MBI MBI

Designation: MBBS IV

Rotation: Psychiatry

Facilitator: Dr. Ayugi

Objectives

• Understand the role of Dopamine in

CNS.

• Outline and categories common

antipsychotic.

• Describe the mechanism of action of

antipsychotics and their adverse effects.

Dopamine

• Dopamine is a catecholamine

neurotransmitter present in CNS.

• Its synthesized from the conversion of

tyrosine to dopa (the rate-limiting step),

followed by decarboxylation to form

dopamine.

• Its largely recaptured following its

release from nerve terminals, by a

specific dopamine transporter.

• It is metabolized by monoamine oxidase

(MOA) and catechol-O-methyl

transferase (COMT), the main products

being dihydroxyphenylacetic acid

(DOPAC) and homovanillic acid (HVA,

the methoxy derivative of DOPAC).

• DOPAC and HVA, and their sulfate

conjugates, are then excreted in the

urine.

Dopamine ReceptorsType Subgrou

p

Mechanism

D1 • D1

• D5

G protein coupled receptor.

Increase intracellular levels of cAMP

by activating adenylate cyclase.

Ultimate effect can be excitation

(via opening of sodium channels) or

inhibition (via opening of potassium

channels)

D2 • D2

• D3

• D4

G protein coupled receptor.

Decrease intracellular levels of

cAMP by inhibiting adenylate

cyclase. Ultimate effect usually

inhibition of the target neuron.

Distribution Functional

Role

D1 D2

D1 D5 D2 D3 D4

Cortex Arousal, mood +++ - ++ - +

Limbic

System

Emotion,

stereotypic

behaviour

+++ + ++ + +

Striatum Motor control +++ + ++ + +

Ventral Prolactin

secretion

- - ++ + -

Dopaminergic Pathways in the Brain

1. Nigrostriatal pathway.

2. Mesolimbic/mesocortical pathways.

3. Tuberohypophyseal system.

Key

Ac; nucleus accumbens

Str; Corpus striatum

Am; Amagdala

Hip; Hippocampus

SN; Substantia nigra

Nigrostriatal pathway

• Accounts for about 75% of the

dopamine in the brain, consists of cell

bodies in the substantia nigra whose

axons terminate in the corpus striatum.

• Substantia nigra dopamine system is

essential for motor control.

• First, dopamine sets the effort threshold

for initiating behaviors. As a

consequence, high levels of dopamine

lead to high levels of motor activity and

"impulsive" behaviour.

• The second important effect is as a

learning response. When a motor

response is followed by an increase in

dopamine activity, the basal ganglia

circuit is altered in a way that makes the

same response easier to evoke when

similar situations arise in the future.

Mesolimbic/mesocortical pathways

• Its cell bodies occur in groups in the

midbrain and fibers project, also via the

medial forebrain bundle, to parts of the

limbic system, especially the nucleus

accumbens and the amygdaloid nucleus

and to the frontal cortex.

• The ventral tegmental area (VTA) is the

origin of the dopaminergic cell bodies of

the mesocorticolimbic dopamine system

is strongly associated with the reward

system of the brain.

• Dopamine is released in areas such as

the nucleus accumbens and prefrontal

cortex as a result of rewarding

experiences such as food, sex and

neutral stimuli that become associated

with them.

Tuberohypophyseal system

• Is a group of short neurons running from

the ventral hypothalamus to the median

eminence and pituitary gland, the

secretions of which they regulate.

• Dopamine is the primary

neuroendocrine inhibitor of the secretion

of prolactin from the anterior pituitary

gland

Antipsychotics• Antipsychotics (also known as neuroleptics or

major tranquilizers) are a class of psychiatric

medication primarily used to manage psychosis.

• They bind to these receptors to varying degrees

(D1 to D5 subtypes). However, the clinical efficacy

of the drugs correlates closely with their relative

ability to block D2 receptors in the mesolimbic

system of the brain.

• Most also block other monoamine receptors,

especially 5-HT2.

1st Generation Antipsychotics (Typical)

I. Butyrophenones

• Butyrophenones are a class of

pharmaceutical drugs derived from

butyrophenone.

• Examples include Haloperidol.

II. Phenothiazines

• is an organic compound that occurs in

various antipsychotic and antihistaminic

drugs (promethazine).

• Chlorpromazine is such a drug First

synthesized on December 11, 1950,

chlorpromazine was the first drug

developed with specific antipsychotic

action.

1st Generation Antipsychotic Adverse Effects

• Akathisia (60%); restlessness that manifests itself

with an inability to sit still or remain motionless.

• Anticholinergic side effects.

• Sedation.

• Orthostatic hypotension.

• Weight gain.

• Amenorrhea, Oligomenorrhea , Galactorhoea.

• Gynaecomastia, erectile dysfunction and priapism.

• Cholestatic jaundice.

• Extrapyramidal symptoms (EPS) Dystonia and

Tardive dyskinesia.

• Neuroleptic Malignant Syndrome (NMS).

Extrapyramidal Tract

Extrapyramidal system is part of the motor

system that causes involuntary reflexes and

movement, and modulation of movement (i.e.

coordination).

Extrapyramidal Motor dysfunction

Acute dystonias are involuntary

movements (restlessness, muscle

spasms, protruding tongue, fixed upward

gaze, torticollis, i.e. involuntary spasm of

neck muscles resulting in turning of the

head, etc). They occur commonly in the

first few weeks, often declining with time,

and are reversible on stopping drug

treatment.

Tardive Dyskinesia • Develops after months or years in 20-40% of patients treated

with first-generation antipsychotic drugs.

• it is a disabling and often irreversible condition, which often

gets worse when antipsychotic therapy is stopped and is

resistant to treatment.

• The syndrome consists of involuntary movements, often of

the face and tongue, but also of the trunk and limbs, which

can be severely disabling.

• Its theorized that there is an associated with a gradual

increase in the number of D2-receptors in the striatum, which

is less marked during treatment with the atypical than with

the first generation of antipsychotic drugs.

• Another possibility is that chronic block of inhibitory dopamine

receptors enhances catecholamine and/or glutamate release

in the striatum, leading to excitotoxic neurodegeneration.

Neuroleptic Malignant Syndrome

Life-threatening neurological disorder

manifesting with;

• Fever >38°C.

• Confused or altered consciousness.

• Diaphoresis.

• Rigid muscles.

• Autonomic imbalance i.e. hypertensive

urgency.

2nd Generation Antipsychotic (Atypical)

• Group of antipsychotic drugs used the

treatment for;

• Schizophrenia.

• Bipolar disorder.

• Autism.

• And as an adjunct in major depressive

disorder.

Clozapine

• Clozapine is the first of the atypical

antipsychotics to be developed.

• It was first introduced in Europe in 1971,

but was voluntarily withdrawn by the

manufacturer in 1975 after it was shown

to cause Agranulocytosis.

• Clozapine has shown high affinity for

D4-receptors subtype.

Clozapine Side Effects

• Hypotension, tachycardia.

• Wieght gain.

• Sialorrhea.

• Dyspepsia, nausea and vomiting.

• Anemia, agranulocytosis, thrombocytopenia.

• Enuresis, impotence, change in libido,

dysmeorrhea.

• NMS.

• Fatigue, weakness, seizure, slurred speech

• Myocarditis.

Olanzapine

• Olanzapine is structurally similar to

clozapine. Used in the treatment of

• Schizophrenia.

• Bipolar disorder.

Olanzapine Side Effects• Weight gain.

• Hypertriglyceridemia,

Hypercholesterolemia.

• NMS.

• Somnolence.

• EPS.

• Hyperprolactinemia.

• VTE.

• Hyperglycemia, DKA, Diabetic coma.

• Seizures.

Risperidone

• Risperidone antipsychotic drug which is

mainly used to treat;

• Schizophrenia (including adolescent

schizophrenia)

• Schizoaffective disorder.

• Bipolar disorder.

• Autism.

Side Effects of Risperidone• Somnolence.

• Insomnia.

• Agitation and anxiety.

• Rhinitis.

• Headache, tachycardia, orthostatic

hypotension, NMS.

• Hyperprolactinemia and gynaecomastia

(children).

• Dyspepsia, nausea and vomiting.

• Seizures.

• DM type 2.

• TTP and agranulocytosis.

Recap

Distinction between typical and atypical

groups is not clearly defined but rests on:

• receptor profile.

• incidence of extrapyramidal side

effects (less in atypical group).

• efficacy (specifically of clozapine) in

'treatment-resistant' group of patients

efficacy against negative symptoms.

References

• Rang & Dale’s Pharmacology 6th edition

pg. 545-548.

• A Textbook of Neuroanatomy pg. 45-52,

191-212.

• Lippincott's Illustrated Reviews:

Pharmacology, 4th Edition pg. 152-158.

• Richard S. Snell 2010. Clinical

Neuroanatomy 7th edition

• Medscape drug app.