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
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
Rare (0.5-1.0%) but life-threatening (10-20% mortality)
Tetrad of clinical features:
- Fever
- Muscle rigidity
- Mental status changes
- Autonomic instability
Treatment
- Cardiovascular support
- Stop antipsychotics and anticholinergics
- Antipyretics for symptoms
- Dopamine agonist (e.g., bromocriptine) can be used, evidence for efficacy is limited
- Muscle relaxants (e.g., diazepam or dantrolene)
Pharmacological Promiscuity of Antipsychotics
Neuroleptic drugs-
antagonists at : cholinergic, alpha adrenergic, dopamine, serotonin, H1 histamine receptor
Haloperidol
High affinity D2 antagonist with relatively lower affinity for other receptors:
D2 > D4 > α1 > 5-HT2A > D1 > H1
Highly effective against positive symptoms; some effect on negative symptoms
Greater potential for extrapyramidal side effects than some typical (and all atypical) antipsychotics
Chlorpromazine
Relatively promiscuous with high affinity for several receptors:
α1 > H1 ≈ D2 = 5-HT2A > D4 > D1
Low potency as an antipsychotic; useful for other indications (e.g., antiemetic)
Greater potential for antimuscarinic and anti-alpha-adrenergic side effects
Atypical Antipsychotics
Called “atypical” because they dissociate clinical efficacy and EPS
Now considered first-line treatment (except clozapine and olanzapine) for schizophrenia and other psychotic disorders
Clozapine (Clozaril)
Original atypical antipsychotic (discovered 1959, FDA approval 1989)
Antagonist at 5-HT2A, M1, α1, and H1 receptors with high affinity, modest affinity for D2 receptors
More efficacious than other antipsychotics, but most dangerous (life-threatening agranulocytosis)
Can also cause myocarditis and de novo seizures
Causes severe weight gain and hyperglycemia
Significant sedation, orthostatic hypotension, and antimuscarinic side effects
Essentially devoid of extrapyramidal motor side-effects
Most useful for treatment-resistant schizophrenia or suicidal ideation
Olanzapine (Zyprexa)
Antagonist at 5-HT2A, 5-HT2C, D1-4, α1, and H1 receptors with high affinity, modest affinity for M1-5 receptors
Weight gain is severe and profound
Eli Lilly has paid over $1bn in settlements to people who claimed they developed Type II diabetes
Also illegally marketed for off-label use in Alzheimer patients (caused increased risk of death)
Recently subject to Risk Evaluation and Mitigation Strategy restrictions due to two unexplained deaths in June 2013
Not recommended for patients with diabetes
Combination with SSRI fluoxetine makes it especially useful in bipolar depression
Risperidone (Risperdal)
Antagonist with high affinity for 5-HT2A, D2, and a1 receptors, little affinity for muscarinic receptors
Highest potential for EPS and hyperprolactinemia relative to other atypical agents (dose-dependent)
Sedation and weight gain also common
Risk for intraoperative floppy iris syndrome should be considered before cataract surgery
Approved for use in children
Available as oral, long-acting microspheres, and intramuscular formulations
Paliperidone is the major active metabolite of risperidone
Aripiprazole
is a partial agonist
Partial D2 agonist that can achieve only 75% functional blockade; also partial agonist at 5-HT1A
Antagonist at 5-HT2A receptors
Relatively lower affinity for other receptors
Often used in bipolar depression
Efficacious against positive and negative symptoms of schizophrenia as well as depression
Very low incidence of more common side-effects, including less weight gain and hyperglycemia
Minimal hyperprolactinemia and sedation
Minimal EPS, except akathisia
Approved for use in children
Notable side effects: dizziness, hypotension, nausea, vomiting
Quetiapine
Antagonist with relatively low affinity for both D2 and 5-HT2A receptors, yet has antipsychotic activity
Higher affinity for H1 and α1 receptors leads to sedation and orthostatic hypotension
Weight gain and hyperglycemia/hyperlipidemia are also common
Minimal EPS and no prolactin elevation
Somnolence is significant and has lead to inappropriate, wide-spread, off-label use as a sleep aid
QT interval prolongation potential makes it a poor choice for those with cardiac conditions or family history of sudden cardiac death
Ziprasidone
Antagonist at D2, 5-HT2A, and 5-HT1D receptors
Agonist at 5-HT1A receptors
Also moderately blocks 5-HT and NE reuptake transporters
Has antipsychotic activity against positive and negative symptoms
Minimal EPS and prolactin elevation
Minimal weight gain and hyperglycemia (advantage)
Minimal risk of sedation and antimuscarinic effects
QT interval prolongation; contraindicated in patients with recent MI, arrhythmia, uncompensated HF, or in the presence of other drugs that prolong the QT interval
Lurasidone
Newer agent approved for treatment of schizophrenia and bipolar depression (recent marketing)
Antagonist at D2 and 5-HT2A receptors with high affinity
Partial agonist at 5-HT1A receptors
No significant affinity for muscarinic M1 and histamine H1 receptors
Similar side effect profile to ziprasidone, except more sedation and no QT prolongation
New 2nd Generation Antipsychotics
Brexpiprazole (Rixulti) and cariprazine (Vraylar)
FDA approval July and September 2015, respectively
Brexpiprazole approved for SZ and as adjunctive therapy for major depressive disorder
Cariprazine approved for SZ and bipolar disorder
Partial agonist activity for 5-HT1A and D2 receptors and antagonist activity for 5-HT2A receptors
Psychiatric Indications for 2nd generation antipsychotics
Primarily used acute control and maintenance of schizophrenia
Also useful in management of:
Acute mania
Bipolar disorder, schizoaffective disorders
Behavioral disturbances in dementias
Behavioral disturbances in children and adolescents
Disorders associated with problems of impulse control
Psychotic depression, treatment-resistant depression
Tourette’s syndrome
Drug-induced psychoses
Non-Psychiatric Indications
Antiemesis
- Due to dopamine receptor blockade in the medulla and stomach
- Prochlorperazine (Compazine), Promethazine (Phenergan)
- Metoclopramide (Reglan), Ondansetron (Zofran)
Neuroleptanesthesia (analgesia & amnesia)
- Droperidol (a butyrophenone D2 blocker) + fentanyl + nitrous oxide
A 42-year-old woman develops akathisias, parkinsonian-like dyskinesias, galactorrhea, and amenorrhea as a consequence of psychotropic drug therapy. What drug-receptor-based mechanism, occurring in the central nervous system, most likely caused these responses?
Blockade of dopamine receptors Blockade of muscarinic receptors Blockade of serotonin receptors Stimulation of glutamate receptors Stimulation of nicotinic receptors
Blockade of dopamine receptors
A 33-year-old female patient who has been treated with haloperidol presents at the ED. Her husband reports that she has complained of rapidly worsening fever and muscle stiffness, and she has “the shakes” (tremor). Her level of consciousness is diminishing. Her temperature is 104ºF, and her blood creatine kinase level is elevated. What is the most likely explanation for these findings?
Allergic response to her medication Neuroleptic malignant syndrome Overdose Parkinsonism Tardive dyskinesia
Neuroleptic malignant syndrome
Chlorpromazine and haloperidol can be considered prototypes of two relatively old but still-used antipsychotic drug classes: the phenothiazines and the butyrophenones, respectively. While many of the actions and side effects of these drugs are qualitatively similar, they are different quantitatively: that is, in terms of incidence and severity. Which effect or side effect typically occurs more frequently, is usually more severe, and has a relatively rapid onset, with haloperidol?
Extrapyramidal symptoms Intense atropine-like side effects Lethal blood dyscrasias Orthostatic hypotension Urinary retention
Extrapyramidal symptoms
haloperidol much more potent at those D2 receptors
We perform a meta-analysis on the ability of various antipsychotic drugs to cause constipation, urinary retention, blurred vision, and dry mouth—all of which reflect significant blockade of muscarinic receptors in the peripheral nervous system. Which of the following drugs most likely caused these unwanted effects?
Chlorpromazine Fluphenazine Haloperidol Olanzapine Sertraline
Chlorpromazine
it is more potent at muscarinic and other receptor subtypes than at D2
Clozapine, as an example of the “atypical” antipsychotics, seldom is used as first-line therapy of schizophrenia. Compared with the older antipsychotics, it is associated with a much higher risk of a serious adverse response. What is that greater risk?
Agranulocytosis Extrapyramidal side effects Hypoglycemia Hypotension, severe Ventilatory depression or arrest
agranulocytosis
Chlorpromazine has been prescribed for a patient with SZ, and the patient has been taking the drug, at usually effective doses, for about 6 months. Today he comes to the hospital with other medical conditions that require surgery and the administration of other drugs, and we decide it is unwise to stop the chlorpromazine and risk psychotic behavior while we perform other interventions. What other signs/symptoms that the patient may also have or acquire as a result of surgery and drug therapy are most likely to be affected beneficially by the continued use of chlorpromazine?
Epilepsy and the risk of seizures Hypotension Nausea and vomiting Urinary retention caused by abdominal surgery Dry mouth caused by antimuscarinics
Nausea and vomiting
