Antipsychotics

Question 1

Identify other names for Antipsychotics.

Answer 1

AKA
– Neuroleptics
– Antischizophrenic Drugs
– Major Tranquillisers

Question 2

What is the common property of antipsychotics ?

Answer 2

Common property of antagonising the actions of dopamine in the brain (effectiveness of this class of drugs correlates well with affinity for D2 receptors i.e. ability to inhibit D2 receptors)

Question 3

Identify the main clinical uses of antipsychotics.

Answer 3

Mainly used in the treatment of schizophrenia and other psychotic illnesses. Some used clinically for other conditions:

– Emesis
– Huntingdon’s disease
– Depression

Question 4

Identify the main theories of Schizophrenia.

Answer 4

Dopamine Theory

Glutamate Theory

Question 5

Describe the Dopamine theory.

Answer 5

– Amphetamine produces symptoms almost indistinguishable from schizophrenia (by increasing catecholamine release including dopamine, but also NA)
– D2-receptor agonists produce similar symptoms in animals and exacerbate symptoms in humans (served to show that dopamine specifically served a role)
– Strong correlation between clinical potency of antipsychotics and D2 blocking action (suggests correlation between dopamine levels and schizophrenia)
– ↑ dopamine content in restricted area of the temporal lobe of schizophrenics (amygdala)
– ↑ dopamine synthesis and release in the striatum of schizophrenics

Question 6

Identify the main nervous pathways whose disregulation will result in mood and behavior changes.

Answer 6

Mesocortical and mesolimbic (both dopamine pathways)

Question 7

Describe the Glutamate theory of Schizophrenia.

Answer 7

– 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
• 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 8

Identify the main classes of antipyschotic drugs.

Answer 8

FIRST GENERATION (FGAs) AKA CLASSICAL

SECOND GENERATION (SGAs) AKA ATYPICAL

Question 9

Identify the main FGAs.

Answer 9

• Phenothiazines
– chlorpromazine, fluphenazine

• Butyrophenones
– haloperidol

• Thioxanthines
– flupentixol

Question 10

Identify the main SGAs, and state the receptor each one works on.

Answer 10

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

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

• Others
– Risperidone, paliperidone (mixture of receptor types blocked)

Question 11

What are the main differences of SGAs cf FGAs ?

Answer 11

Distinction between typical and atypical groups is not clearly defined, but rests on:
– receptor profile (mainly other than dopamine)
– incidence of extrapyramidal side-effects
• (less in atypical group)
– efficacy in treatment-resistant group of patients (atypical more efficacious e.g. Clozapine)
– efficacy against negative symptoms (aypical more efficacious, but also improve positive symptoms)

Question 12

State the clinical uses of Clozapine.

Answer 12

If patient doesn’t respond to first or second generation drugs, and adequate compliance (AKA treatment resistant), use Clozapine

Question 13

What drugs should you use if there is only positive symptoms ? both negative and positive ?

Answer 13

Both: Second gen (improve negative as well as positive)

Positive: either first or second gen

Question 14

Which of FGAs or SGAs is more effective at controlling symptoms of schizophrenia ?

Answer 14

No real evidence that SGAs are more effective than the first generation classical neuroleptics in controlling symptoms

Question 15

Identify all the receptors that antipsychotics may have affinities to. State the function of each of these.

Answer 15

• Cholinergic (muscarinic) receptor (PSNS receptor on target tissue, also found in CNS)
• Alpha-adrinergic receptor (SNS, especially in vasculature)
• Dopamine receptor
• Serotonin receptor
• H1 Histamine receptor (involved in anaphylaxis, triple response)

Question 16

Describe general trends in relative receptor affinity (including all receptors) of antipsychotic drugs.

Answer 16

• Common ground: dopamine antagonism
• FGAs have greater affinity for D1 receptor than SGAs antipsychotics
• Range of different affinities to D2
• Slightly more affinity to alpha 1 receptor in SGAs

Question 17

Identify the main pharmacological effects of antipyschotics.

Answer 17

1) Behavioral effects
– 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 (can rouse this apathetic state, whereas in anxiolytic/hypnotic use cannot)

Question 18

Identify the common side effects of antipsychotics.

Answer 18

Two main types of motor disturbances:
• acute, reversible Parkinson-like symptoms
– due to block of nigro-striatal dopamine receptors
• slowly developing, irreversible, tardive dyskinesia
– one of the most serious problems with antipsychotics

The following vary by drug, depending on receptor profile:
• Endocrine actions (generally due to dopamine receptor antagonists in tuberhypophyseal pathway)
– ↑ prolactin secretion by blocking D2 receptors in the pituitary, weight gain
• Anti-muscarinic actions
– Blurring of vision, dry mouth and eyes, constipation, urinary retention
– Can help attenuate extrapyramidal actions
• α-adrenoreceptor blocking actions
– Orthostatic hypotension
• H1-receptor blocking actions
– Sedative and anti-emetic actions

Also:
• Sexual dysfunction
• Arrhythmias 
• Neuroleptic malignant syndrome
• Jaundice
• Leukopenia and agranulocytosis
• Diabetes 
• Skin reactions (itchy rash)

Question 19

How may you cease the acute, reversible Parkinson-like symptoms associated with antipsychotics ?
How many you cease tardive dyskinesia associated with antipsychotics ?

Answer 19

Ceasing or changing treatment

Treatment generally unsuccessful

Question 20

Which of the two classes of antipsychotics is more associated with motor disturbances (i.e. Parkinson-like symptoms and tardive dyskinesia) ?

Answer 20

Reduced risk of these two with SGAs

Question 21

What are the main clinical features of tardive dyskinesia ? How long after treatment does this appear ? What is the pathophysiology behind it ?

Answer 21

Involuntary movements of face and limbs

Appears after months/years of treatment

Associated with proliferation of dopamine
receptors in the corpus striatum

Question 22

How common is neuroleptic malignant syndrome as a result of antipsychotic use ? What are its main features ? When does it usually arise ?

Answer 22

Neuroleptic malignant syndrome
– Rare, but life threatening
– Fever, muscle rigidity, altered mental status,
autonomic dysfunction
– Often occurs upon initiation or change of dose

Question 23

Which antipsychotic is especially associated with jaundice as a side effect ?

Answer 23

Chlorpromazine (but better regulation of doses now, so does not require much monitoring)

Question 24

Which antipsychotic is especially associated with leukopenia and agranulocytosis as a side effect ? How common is it ?

Answer 24

Clozapine

Rare, can be fatal

Question 25

Why might diabtes arise as a side effect of antipsychotic treatment ?

Answer 25

Due to interference with tuberohypophyseal pathway and change in endocrine regulation

Question 26

Identify general trends in SE frequency in FGAs vs SGAs.

Answer 26

FGA: more strong associated with prolactin elevation
SGA: diabetes and weight gain more common

Question 27

Given the number of available antipsychotics available, how must you decide which one to prescribe ?

Answer 27

1)
- Choice of antipsychotic should consider side-effect profile (different patients will tolerate different SEs, and different antipsychotics have different SE profiles)
- Titrate to minimum effective dose (start low and build up to dose where control of symptoms)
- Adjust dose according to response and tolerability within BNF limits
- Evaluate over 6-8 weeks

2)
IF (1) or (4) effective, continue at established dose

3)
IF (1) not tolerated or poor compliance (e.g. due to lack of insight), use depot (oily injection into muscle, with slow release of antipsychotic over course of few weeks) or compliance aid (then evaluate again after few weeks)

4)
IF (1) ineffective (and good adherence), change drug and follow initial advice.

5) If (4) ineffective, Clozapine

Usually start with FGA or SGA, then if not effective then try drug from other class.
If tried two and compliance and tolerance normal, but ineffectiveness, then prescribe Clozepine (treatment for treatment resistant patients), but monitor carefully (due to SEs).

Do NOT substitute from one brand to generic substitution because this can change PK profile, and therefore alter patient’s response to drug.

Question 28

Identify different factors which must be monitored during treatment with antipsychotics, and explain why these must be monitored.

Answer 28

Antipsychotics associated with numerous SEs.

Must monitor:

• BP
• Prolactin
• ECG
• HbA1C/random glucose/fasting glucose
• BMI/weight

Question 29

Why may an antipsychotic drug be ineffective ?

Answer 29

Individual variations exist in effectiveness of drug (e.g. may not be a correlation between dose taken and peak plasma concentration i.e. ineffective i.e. must change drug)