HUF 2-69 Schizophrenia and neuroleptic drugs Flashcards
Symptoms of schizophrenia
Positive Symptoms:
- Delusion (paranoid)
- Hallucination
- Thought disorder (outside agency)
- Abnormal movements (aggressive behaviour)
Negative Symptoms:
- Social withdrawal
- Flattening of emotions
Cognitive Symptoms:
- Unable to make sense of everyday world
- Unable to link thoughts with outside events
- Cannot understand other people’s normal behaviour
Dopamine pathways related to schizophrenia
- Mesocortical pathway dysfunction
=> Negative and cognitive symptoms - Mesolimbic pathway overactivity
=> Positive symptoms
Neuroleptic drugs or antipsychotics
- Block mesolimbic DA transmission (+ve. symptoms)
- For:
Schizophrenia
Manic phase of bipolar disorders
Acute idiopathic psychotic disorders
Severe agitation / aggressive behaviours
Typical (1st gen.): bind tightly to D2 receptors
e.g. Chloropromazine, Thiothixene, Haloperidol
Atypical (2nd gen.): bind loosely to D2 receptors but also 5HT-2A
Clinical evidence related to therapeutic actions of antipsychotics
- Affinity towards D2R => clinical efficacy of anti-psychotic effects
(↑ D2 affinity => ↓ dose needed) - ↑ DA receptor density and [DA] in corpus striatum in brains of schizophrenic patients (postmortem examinations)
Typical antipsychotics can antagonise multiple receptors with diff. potencies
Preferentially bind to D2, D4 than 5-HT2A
Can also bind to muscarinic, α and H1
- Antagonism to D2R => Treat positive symptoms
- Effective among 70% of patients
- Sedative (CNS depressing)
Basic research evidence related to therapeuric actions of antipsychotics
- Drugs that ↑ central dopaminergic activity => +ve. symptoms
- Normal people with repeated amphetamine intake
=> Psychosis
∵ Amphetamine ↑ release of DA from neurons - D2R Antagonists and drugs that block neuronal DA storage => Control +ve. symptoms
- Prevent amphetamine induced psychotic symptoms
- e.g. Reserpine: ↓ DA at presynaptic side
Major mechanism of antipsychotics actions
Mesolimbic D2R antagonism
- DA theory of schizophrenia: hyperactivity of central DA => psychosis
- +ve. symptoms of schizophrenia related to hyperactivity of mesolimbic DA system
High potency typical antipsychotics tend to cause more serious adverse effects
- Exaggeration of -ve. symptoms
- Blockade of nigrostriatal pathway
=> Extrapyramidal symptoms (EPS) - Blockade of tuberoinfundibular pathway in hypothalamus
=> dysregulate PRL secretion
Extrapyramidal symptoms (EPS)
Originated in brainstem; modulated by nigrostriatal pathway
Reversible (Benzatropine: anticholinergic drugs):
- Acute dystonia (days): muscle spasm affecting tongue, face, neck, back
- Akathisia (days to weeks): motor restlessness, continual pacing
- (Pseudo-)Parkinsonism (a few weeks): difficulty in initiating movement
Irreversible:
- Tardive dyskinesia (years): abnormal movements of facial ms, trunk, limbs (upreg. of D2R)
Major undesirable endocrine effects of typical antipsychotics
- PRL release from pituitary gland under control of central DA transmission
- D2R blockade of tuberoinfundibular pathway
=> ↓ DA suppression of PRL release
=> Men: gynaecomastia
Women: galactorrhea
Unpredictable life-threatening neurological disorder
Neuroleptic malignant syndrome
- ↑ body temp. > 38°, sweating
- Confused or altered consciousness (agitation , delirium, coma)
- Rigid muscles, muscle cramps, tremors
- Autonomic imbalance e.g. unstable BP
- Typical antipsychotics (haloperidol, chlorpromazine): greatest risk of neuroleptic malignant syndrome
Antagonism of other receptors => Undesirable effects of antipsychotics
Block α => postural hypotension
Block H1 => Sedation / Drowsiness
Block M => dry mouth, urinary retention
- Potency of receptor blockade
- High potency drugs tend to have fewer sedative effects and less postural hypotension
∵ less dosage needed
Atypical (2nd. gen) antipsychotics
- Lower risk of EPS
- Relative lower affinity for D2R (transient D2R occupancy; rapid dissociation from D2R)
- High affinity towards 5-HT2A R
- Better improvement in -ve. symptoms
“Atypicality” of atypical antipsychotics
- 5-HT2A antagonism: high preference toantagonize 5-HT2AR than to D2R (high 5-HT2A/D2 blocking ratio)
- increase DA transmission in nigrostriatal pathway
=> ↓ risks of EPS - Rapid dissociation from D2R (transient binding)
=> ↓ risks of EPS (nigrostriatal pathway)
Commonly used atypical antipsychotics
Clozapine
Olanzapine
Risperidone
Clozapine
- Weak D2R antagonist; greater antagonist activity at D1, D4 and 5-HT2AR
- Risk of agranulocytosis (fatal in long run)
∴ Blood monitoring needed - Not recommended for 1st-line treatment
- Reserved for patients who DO NOT respond to conventional antipsychotic therapy or who have tardive dyskinesia
- Metabolic changes (glucose metabolism) ; weight gain
Olanzapine
Olanzapine
- Receptor binding profile similar to clozapine
- Higher affinity for 5-HT2AR than D2R
- Less likely yo produce serious undesirable effects e.g. agranulocytosis
Risperidone
- Higher affinity for 5-HT2AR than D2R
- Higher daily dose => higher EPS risk
Weight gain due to atypical antipsychotics
- Olanzapine, Clozapine
Possible mechanisms:
- Antagonise H1R => Excessive eating, food craving
- Antagonise M => ↓ pancreatic insulin release (hyperglycemia)
- Affect adrenergic system => Hyperglycemia, ↓ lipolysis
Other common undesirable side effects of atypical antipsychotics
- Type I hypersensitivity (allergic rxn)
- QT-interval prolongation: block cardiac K+ channels (inward rectifiers) e.g. Clozapine, Risperidone
Block α => postural hypotension
Block H1 => Sedation / Drowsiness
Block M => dry mouth, urinary retention
PK profile of antipsychotics
- Highly lipophilic; metabolised in liver
- High binding to plasma proteins
- High first-pass metabolism via oral routes
- Elimination: multiphasic pattern; not strictly first order
∴ t1/2 hard to be predicted (8-40 hrs) - Patients respond differently to individual antipsychotics
=> Be careful when switching between antipsychotics
Potential DDI of antipsychotics
- Interact with Parkinson treatment drugs
- ↑ synaptic [DA] e.g. Levodopa
- Direct stimulation of DAR (DA agonist) - Potentiate sedative effects of other CNS depressants
e. g. hypnotics/anxiolytics, 1st gen antihistamines
Typical and atypical antipsychotics are equally effective towards +ve. symptoms
- Choice of antipsychotics depends on:
Tolerance to EPS risk
Effectiveness of managing -ve. symptoms
Cost
Notes:
1. Use anticholinergic drugs to block motor side effects of antipsychotics (e.g. benzatropine)
2. Several weeks to see clinical effects of antipsychotics (time lag); undesirable effects, weight gain
∴ Patient education => patient is following treatment regimen
