Antipsychotics Flashcards
Atypical (Second-generation) Antipsychotics drug list
Aripiprazole Brexpiprazole Cariprazine Iloperidone Lurasidone Quetiapine Risperidone Ziprasidone
Special Use Atypical Antipsychotics
drug list
Clozapine
Olanzapine
Typical (First-generation) Low-Potency Agents drug list
Chlorpromazine
Typical (First-generation) High-Potency Agents drug list
Haloperidol
Things that fall under psychosis
Positive symptoms:
hallucinations
delusions
disorganized thinking or speech
Negative symptoms:
declining self care
flattened affect
anhedonia
Biological basis of schizophrenia
glutamate, serotonin, dopamine
Major Dopamine Pathways
Mesolimbic-mesocortical pathways
- Behavior and cognitive function
- Excess mesolimbic DA likely causes positive symptoms
- DA loss likely mediates negative symptoms
- DA blockade mediates antipsychotic action
Nigrostriatal pathway
- Coordination of voluntary movement
- Dopamine imbalance leads to EPS
Tuberoinfundibular system
- Dopamine inhibits prolactin secretion
Therapeutic Potency of Typical Antipsychotics
What you need to know:
Efficacy Correlates with D2, but not D1 (top), receptor binding affinity
Measured by displacing selective antagonists
D2 affinity also correlates with extrapyramidal toxicity
Dopaminergic Sites of Antipsychotic Action
on preynaptic membrane– shuts off release
on post-synaptic membrane
Regulation of receptor expression as an adaptive response
Summary: Mechanism of Action- typical drugs
Block dopamine receptors
- Especially D2
- Clinical efficacy correlates with this action
Messy pharmacology; side effects result from action at muscarinic, histamine, and adrenergic receptors
Summary: Mechanism of Action- atypical drugs
Exhibit higher affinity for 5-HT2A receptors than D2 receptors
Also block DA receptors, including D2
- Clinical efficacy is not necessarily correlated with D2 blockade
Newer agents are partial agonists at 5-HT1A and D2 receptors and antagonists at 5-HT2A receptors
Drug Choice: Compare and Contrast
Typical (1st Gen):
Relatively high risk of EPS and tardive dyskinesia
Highly effective against positive symptoms
Overall efficacy may be equivalent
Intermediate risk of weight gain
Lower cost
Atypical (2nd Gen)
Less prone to cause EPS and tardive dyskinesia
Efficacious for positive and negative symptoms
Overall efficacy may be equivalent
Variable risk of weight gain
Higher cost
General Adverse Effects
More Common: Extrapyramidal Symptoms (EPS) - Akathisia - Parkinsonism - Dystonias Tardive dyskinesia Metabolic dysfunction Prolactin elevation Anticholinergic effects Sedation
Rare: Seizures Orthostatic hypotension Neuroleptic malignant syndrome QT prolongation Sudden death
Adverse effects - manifestations and mechanisms- Autonomic nervous system
Loss of accommodation, dry mouth, difficulty urinating, constipation– Muscarinic cholinoceptor blockade
Orthostatic hypotension, dizziness, sedation, failure to ejaculate, impotence–α-Adrenoceptor blockade
Adverse effects - manifestations and mechanisms- Central nervous system
EPS: Parkinson’s syndrome, akathisia, dystonias- Dopamine-receptor blockade
Tardive dyskinesia- Supersensitivity of dopamine receptors
Adverse effects - manifestations and mechanisms- Endocrine system
Amenorrhea-galactorrhea, infertility, impotence
– DA-receptor blockade; hyperprolactinemia
Adverse effects - manifestations and mechanisms- other
Weight gain - Possibly combined H1 and 5-HT2 blockade
Adverse Motor System Effects- acute onset
Extrapyramidal symptoms
Usually occurs within days of treatment initiation
Direct result of D2 blockade in basal ganglia
Treatable
Adverse Motor System -
Late-Onset
Effects
Tardive dyskinesia
Occurs after years of antipsychotic use
Imbalance of cholinergic (relative deficiency) and dopaminergic (relative supersensitivity) activity
May be irreversible
Extrapyramidal Symptoms (EPS)
More commonly associated with haloperidol, fluphenazine, thiothixene, and trifluoperazine
Uncommon with most of the atypical agents
Akathisia: inability to sit still, restlessness
- Consider dose reduction, if feasible
- Lorazepam, propranolol, or benztropine
Parkinsonian syndrome: resting tremor, difficulty initiating movement
- Benztropine
- Amantadine
Dystonia: involuntary muscle contractions, abnormal postures
- Switch to a different antipsychotic
- Benztropine or diphenhydramine (prophylactic with IM haloperidol)
Tardive Dyskinesia
Motor dysfunction - stereotypical, repetitive, involuntary movements
- Lateral jaw movements, lip smacking or sucking, twisting and protrusion of the tongue, purposeless movements of the extremities
Causes
- Imbalance of neurotransmitters in the basal ganglia: ACh deficiency and supersensitivity of DA receptors
Treatment
- Decrease the dose of the antipsychotic
- – Initially the dyskinesia will get worse
- – Over the next several weeks it may improve
- Consider switching to quetiapine or clozapine
Receptor Occupancy and Clinical Response
D2 receptor occupancy > 60% provides antipsychotic effects
D2 receptor occupancy > 80% causes EPS
Atypical agents combine weak D2 antagonism with 5-HT2A antagonism/inverse agonism, permitting therapeutic efficacy at doses below the D2 receptor occupancy threshold for EPS
Metabolic Effects: Weight Gain
Very common
Requires monitoring food intake, BMI, and fasting blood sugar and lipids
Hyperglycemia may develop, can be serious, and complicates pre-existing diabetes
Hyperlipidemia and hypertension
Possibly associated with combined H1 and 5-HT2 blockade
Relative Risk:
Highest risk: Clozapine, Olanzapine
Intermediate risk: Iloperidone, Paliperidone, Quetiapine, Risperidone (and most typical agents)
Low risk: Asenapine
Lowest risk: Aripiprazole, Lurasidone, Ziprasidone
Endocrine Effects: Hyperprolactinemia
Increased secretion of prolactin caused by block of dopamine receptors in the pituitary
Most pronounced with older typical antipsychotics as well as risperidone and paliperidone
Galactorrhea, amenorrhea, and infertility in females
Gynecomastia, infertility, loss of libido, and impotence in males
Atypical antipsychotics with reduced D2 antagonism, such as aripiprazole, clozapine, iloperidone, olanzapine, and quetiapine cause no or minimal increases in prolactin