5. Anti-psychotics

Question 1

Other names for antipsychotics?

Answer 1

– Neuroleptics
– Antischizophrenic Drugs
– Major Tranquillisers

Question 2

Common property of antipsycotics?

Answer 2

Antagonising the actions of dopamine in the brain.

Question 3

Schizophrenia

Answer 3

Affects ~1% of the population
– Can occur from an early age
– Can be chronic and highly disabling
– Strongly hereditary

Clinical features:
– Positive Symptoms: Delusions, hallucinations, thought disorders
– Negative Symptoms: Withdrawal from social contact and flattening of emotional responses

Question 4

What is the dopamine theory of schizophrenia?

Answer 4

– Amphetamine produces symptoms almost indistinguishable from schizophrenia
– D2-receptor agonists produce similar symptoms in animals and exacerbate symptoms in humans
– Strong correlation between clinical potency of antipsychotics and D2 blocking action
– ↑ dopamine content in restricted area of the temporal lobe of schizophrenics (amygdala)
– ↑ dopamine synthesis and release in the striatum of schizophrenics

Question 5

What are the 4 dopamine pathways?

Answer 5

Nigrostriatal
Mesocortical
Mesolimbic
Tuberohypophyseal

Question 6

What is the glutamate theory for schizophrenia?

Answer 6

– NMDA receptor antagonists (e.g. phencyclidine and ketamine) produce psychotic symptoms
– ↓ glutamate and receptor density reported in post- mortem schizophrenic brains
– Transgenic mice with ↓ NMDA receptor expression show stereotypic schizophrenic behaviours and ↓ social interactions
• respond to antipsychotics
– Glutamate and dopamine exert excitatory and inhibitory effects respectively on GABAergic striatal neurones which project to the thalamus and constitute a sensory ‘gate’
– Too little glutamate or too much dopamine disables the ‘gate’ allowing uninhibited sensory input to reach the cortex
– Excess dopamine could be responsible for the positive symptoms and reduced glutamate for the negative symptoms

Question 7

What are the 3 classes for first generations or classical antipsychotics?

Answer 7

• Phenothiazines
– chlorpromazine, fluphenazine, pipotiazine

• Butyrophenones
– haloperidol

• Thioxanthines
– flupentixol, zuclopenthixol

Question 8

What the 3 groups of second generation or “atypical” antipsychotics?

Answer 8

• Benzamides
– Amisulpride (selective D2 and D3 receptor antagonists)

• Dibenzodiazepines
– clozapine and olanzapine (very unselective receptor blocking profile)

• Others
– Risperidone, paliperidone (mixture of receptor types blocked)
– Quetiapine (α adrenoceptor blocker)
– Aripiprazole (Dopamine and 5-HT antagonist)

Question 9

Purpose of ‘Atypical’ or Second Generation neuroleptics?

Answer 9

Overcome some of the problems of the classical
neuroleptics
Show efficacy in treatment-resistant patients
Improve the negative as well as positive symptoms

Question 10

Distinction between typical and atypical groups is not clearly defined, but rests on:

Answer 10

– receptor profile
– incidence of extrapyramidal side-effects
– efficacy in treatment-resistant group of patients
– efficacy against negative symptoms

Question 11

Receptors that have an affinity for anti-psycotics?

Answer 11

D1 and D2
Alpha-1
H-1
mACh
5-HT2

Hence anti-psychotics antagonise the receptors

Question 12

Pharmacological Effects of Antipsychotics

Behavioural Effects

Answer 12

– Apathy and reduced initiative
– Display few emotions, drowsy (Can be easily stirred from this)
– Aggressive tendencies inhibited
– Effects are distinct from those produced by hypnotics and anxiolytics

Question 13

What are two main negative effects of anti-psycotics?

Answer 13

1. Tardive Dyskinesia
   - Slower progression
   • slowly developing tardive dyskinesia
   – one of the most serious problems with antipsychotics
2. Extrapyramidal Motor Disturbances:
   • acute, reversible Parkinson-like symptoms
   – due to block of nigro-striatal dopamine receptors

Question 14

Features of tarditive dyskinesia in anti-psycotics?

Answer 14

– Involuntary movements of face and limbs
– Appears after months/years of treatment
– Associated with proliferation of dopamine
receptors in the corpus striatum
– Treatment is generally unsuccessful
– Less common with newer antipsychotics

Question 15

Endocrine effects of anti-psycotics?

Answer 15

↑ prolac n secre on by blocking D2 receptors in the pituitary

Question 16

Unwanted effects of anti-psycotics:

Anti-muscarinic action?

Answer 16

– Blurring of vision, dry mouth & eyes, constipation – Can help attenuate extrapyramidal actions

Question 17

Unwanted effects of anti-psycotics:

α-adrenoreceptor blocking actions

Answer 17

– Orthostatic hypotension

Main use for stopping drugs

Question 18

Unwanted effects of anti-psycotics

H1-receptor blocking actions

Answer 18

– Sedative and anti-emetic actions

Question 19

Unwanted side effects of antipsychotics?

Answer 19

Postural hypotension Sedation
Weight gain 
Endocrine actions Diabetes
Autonomic actions (atropine-like) 
Extrapyramidal actions
Jaundice
Leucopoenia and agranulocytosis Skin reactions (itchy rash) Neuroleptic malignant syndrome

Question 20

Individual variation to chloropromazine?

Answer 20

Different patients experience different effects at the same dose.

i.e. clinical effect is patient dependent

Question 21

Pharmacological response to first episode schizophrenia?

Answer 21

Choice of antipsychotic should consider side-effect profile Titrate to minimum effective dose
Adjust dose according to response and tolerability within BNF limits Evaluate over 6-8 weeks
–> EFFECTIVE
Continue at established dose
–> NOT EFFECTIVE
Change drug and follow above advice. If not effective give Clozapine
–> NOT TOLERATED OR POOR COMPLIANCE
Depot or compliance aid given

Question 22

Which antipsychotics are given for:

Schizophrenia

Answer 22

– both classical and atypical depending on side effects

Question 23

Which antipsychotics are given for:

acute behavioural emergencies and mania?

Answer 23

– chlorpromazine, haloperidol

Question 24

Which antipsychotics are given for:

Treatment of emesis?

Answer 24

– Prochlorperazine

Question 25

Which antipsychotics are given for:

Huntingdon’s disease?

Answer 25

– e.g. olanzapine, risperidone and quetiapine

Question 26

Which antipsychotics are given for:

Depression?

Answer 26

– flupentixol

Rarely

Question 27

Correlation between potency and affinity for D2 receptors

Answer 27

As dose/potency increases so does the affinity for the IC receptors

Question 28

Side effects of anti-psychotics on receptors due to affinity:
D1/D2

Answer 28

Dysphoria and depression
Extrapyramidal symptoms, including:
Akathisia
Parkinsonism due to effects on the nigrostriatal pathway
Tardive dyskinesia (long-term use)

Drugs are mainly ANTAGONISTS of the receptor

Question 29

Side effects of anti-psychotics on receptors due to affinity:
Alpha-1

Answer 29

Alpha-1 blockers (also called alpha-adrenergic blocking agents) constitute a variety of drugs that block alpha-1-adrenergic receptors in arteries, smooth muscles, and central nervous system tissues. By blocking alpha-1 receptors it causes the smooth muscles and arteries to dilate.

Question 30

Side effects of anti-psychotics on receptors due to affinity:
H1

Answer 30

Antagonising effect leads to drowsiness

Question 31

Side effects of anti-psychotics on receptors due to affinity:
mACh

Answer 31

“SLUDGE”

Salivation: stimulation of the salivary glands

Lacrimation: stimulation of the lacrimal glands (tearing)

Urination: relaxation of the internal sphincter muscle of urethra, and contraction of the detrusor muscles

Diarrhea

Gastrointestinal distress: Smooth muscle tone changes causing gastrointestinal problems, including cramping

Emesis: Vomiting[2]

Question 32

Side effects of anti-psychotics on receptors due to affinity:
5-HT2

Answer 32

A second generation of antipsychotics, commonly referred to as the atypical antipsychotics, block D2 receptors as well as a specific subtype of serotonin receptor, the 5HT2A receptor. It is believed that this combined action at D2 and 5HT2A receptors treats both the positive and the negative symptoms.