Antipsychotics Flashcards
What are the mechanisms of antipsychotics?
Mesolimbic Tract – blockade of dopamine receptors here likely is the common MOA
* Overactivity in this region is responsible for positive symptoms of schizophrenia
Mesocortical (MC) Tract – blockade causes negative symptoms
* Responsible for higher order thinking and executive functions
Nigrostriatal (NS) Tract – blockade causes Extrapyramidal SEs (EPSE)
* Modulates body movement
Tuberoinfundibular Tract – blockade leads to hyperprolactinemia
What are the typical antipsychotics?
Chlorpromazine, Haloperidol
What are the differences between chlorpromazine and haloperidol?
Both have a1 blockade, resulting in postural hypotension, dizziness
Haloperidol doesn’t have H1 receptor activity unlike chlorpromazine - won’t have the sedation, weight gain
Haloperidol also doesn’t have M1 receptor activity unlike chlorpromazine - won’t have dry mouth, constipation, blur vision
What do typical antipsychotics do?
Control positive symptoms
What are the atypical antipsychotics?
Amisulpride, Clozapine, Olanzapine, Risperidone
What do the atypical antipsychotics do?
Control positive symptoms of schizophrenia, but produce less extrapyramidal side effects
What are the dopamine blockade points of Clozapine?
- Potent 5-HT2A receptor antagonism vs weak D2 antagonism → lower EPS and higher efficacy against negative symptoms
- High D4:D2 antagonism → favours action in prefrontal cortex over striatum
What are the dopamine blockade points of olanzapine?
Potent 5-HT2A receptor antagonism vs weak D2 antagonism → lower EPS and higher efficacy against negative symptoms
What are the dopamine blockade points of amisulpride?
Few side effects due to selectivity for D2/D3 receptors
High D2:D1 reduces impact of antagonism in striatum
High D3:D2 antagonism favours action on nucleus accumbens over striatum
What are the dopamine blockade points of risperidone?
High D2:D1 reduces impact of antagonism in striatum
What is the side effect profile of amisulpride?
Absence of α1-adrenoreceptor block, antihistaminergic and anticholinergic side effects
Has adverse effects on mammary glands & tissues – D2/D3 in tuberoinfundibular pathway
* Increased prolactin secretion due to dopamine receptor block in anterior pituitary gland
* Breast swelling, pain, lactation; Presents as gynecomastia in males
What are the precautions for using antipsychotics?
CVD – see doctor if you experience any unexplained chest pain
→ QTc prolongation – contraindicated
→ ECG required esp if physical exam identifies CV risk factors, or if there is personal Hx of CVD, or if patient is being admitted and naïve to antipsychotics
Parkinson’s disease – antipsychotics may worsen EPSE
Epilepsy and conditions predisposing to seizures
Depression
Myasthenia gravis
Prostatic hypertrophy
Angle-closure glaucoma
Severe respiratory disease
Hx of jaundice
Blood dyscrasias (esp clozapine)
Elderly w dementia – inc mortality and stroke risks
What are the steps in the schizophrenia treatment algorithm?
- Use a single 1st or 2nd generation antipsychotic (except clozapine)
- Try a 2nd one if inadequate or no response
- Try clozapine if inadequate or no response (routine blood tests for agranulocytosis required)
- Add/Replace w antipsychotics or ECT if still inadequate or no response
What are the criteria for being considered a non-responder to an antipsychotic agent?
- Compliance to an adequate trial of at least 2-6 weeks
- Must be at optimal therapeutic dose
- Clozapine: up to 3 months, addition of augmenting agent 8-10 weeks
What are the antipsychotic options for non-compliant patients?
Long-acting injectables eg IM risperidone microspheres, IM aripiprazole LAI, IM haloperidol decanoate
What are the options to treat acute agitation for cooperative patients?
PO lorazepam 1-2mg OR
PO antipsychotic options
→ Haloperidol (tab/solution) 2-5mg with pre-treatment ECG
→ Risperidone (tab/orodispersible/solution) 1-2mg
→ Quetiapine (immediate release tab) 50-100mg
→ Olanzapine (orodispersible tab) 5-10mg
What are the options to treat acute agitation for uncooperative patients?
IM lorazepam 1-2mg
IM olanzapine 5-10mg – must not be given within 1h of lorazepam
→ 2nd dose ≥2h after 1st dose, 3rd dose ≥4h after 2nd dose
IM aripiprazole (immediate release) 9.75mg (less hypotensive than IM olanzapine)
IM haloperidol 2.5-10mg w pre-treatment ECG
IM promethazine 25-50mg
Haloperidol and Promethazine can be given in combination
What are the options to treat catatonia?
PO/IM lorazepam
What are the treatment options for depressive Sx or negative Sx of chronic schizophrenia?
use antidepressants - eg SSRI, SNRI, mirtazapine
What are the general monitoring requirements for antipsychotics?
Weight gain - monitor BMI Q1/52 for 1st 6 weeks, or every visit (at least Q1/12 for 3/12 for SGA)
Q3/12 when dose stabilized
DM - monitor FBG or HbA1c:
Low risk: annual
High risk: 4/12 after initiating new AP (3/12 if SGA) then annually
Hyperlipidemia - monitor lipid panel
Low risk: every 2-5 years
High risk: Q6/12 (SGA: 1st check at 3/12)
Hyperprolactinemia - monitor plasma prolactin at baseline
BP - monitor 3/12, after initiating SGA then annually
EPSE - do EPSE exam weekly for 1st 2/52 after initiation of new AP or until dose stabilized
1st gen AP: Q6/12 for low risk, Q3/12 for high risk
2nd gen AP: Q12/12 for all risk levels
What are the drug specific monitoring requirements?
Clozapine (leukopenia/agranulocytosis) - monitor WBC and ANC weekly for 1st 18/52, then monthly
Ziprasidone (QTc prolongation) - Repeat ECG if risks/symptoms of QTc prolongation
How does acute dystonia present?
→ Occur within 1st few weeks of treatment, but is reversible
→ Parkinsonism-like syndrome eg cogwheel rigidity and tremor at rest
What is the cause of acute dystonia in schizophrenia treatment?
D2 antagonism in nigrostriatal pathway (connection of substantia nigra to striatum)
What is tardive dyskinesia?
→ Tardive – develop slowly (eg months-years of treatment)
→ Dyskinesia – repetitive and stereotyped involuntary movements of face, tongue, limbs
What is akathisia?
- involuntary movements & compulsion to act, assoc w restlessness, anxiety, agitation
- correlated directly during medication duration
Why can antipsychotics cause tardive dyskinesia and akathisia?
Likely due to upregulation or supersensitivity of dopamine receptors in nigrostriatal system
What are the considerations for treating pregnant women with schizophrenia?
Watch for gestational diabetes if taking olanzapine, clozapine
What are the considerations in treating breastfeeding women with schizophrenia?
Olanzapine, quetiapine suitable
Clozapine: patients should continue drug if already started, don’t breastfeed
What are the considerations in treating schizophrenic patients with renal impairment?
PO aripiprazole preferred, avoid sulpride and amisulpride
What are the considerations in treating schizophrenic patients with hepatic impairment?
sulpride, amisulpride preferred
What are the considerations in treating elderly with schizophrenia
- Avoid drugs with high propensity for α1-adrenergic blockade (orthostatic hypotension) or anticholinergic side effects (constipation, urinary retention, delirium)
- Start low go slow, simplify regimen when possible
- Avoid adverse interactions, long T1/2 drugs
- FGAs and SGAs reported to inc mortality and stroke in dementia patients
How should therapeutic outcomes of schizophrenia be monitored?
Effectiveness – Mental State Exam, Psychiatric Rating Scales
Adverse Effect – metabolic parameters (fasting plasma glucose, lipids, BW, BP etc), EPSE
Patient’s self-assessment
Time course of treatment response:
Early improvement
→ 1st week: dec agitation, aggression, hostility
→ 2-4 weeks: dec paranoia, hallucinations, bizarre behaviours; improved organisation in thinking
Late improvement
→ 6-12 weeks: dec delusions, negative Sx
→ 3-6 months: cognitive Sx may improve w SGAs
