Pharmacology Flashcards
A 55-year-old man is brought to the emergency room because of fever and increasing confusion for the past 2 days. He has paranoid schizophrenia treated with chlorpromazine. He appears diaphoretic. His temperature is 40°C (104°F), pulse is 115/min, respirations are 31/min, and blood pressure is 158/105 mm Hg. Neurologic examination shows psychomotor agitation and incoherent speech. There is generalized muscle rigidity. His deep tendon reflexes are decreased bilaterally. Serum laboratory analysis shows a leukocyte count of 11,300/mm3 and serum creatine kinase concentration of 945 U/L. The most appropriate drug for this patient acts by inhibiting which of the following?
This schizophrenic patient’s presentation of fever, altered mental status, muscle rigidity, decreased DTRs, autonomic instability (hypertension, tachycardia, diaphoresis), and elevated serum creatine kinase is indicative of neuroleptic malignant syndrome (NMS). Initial treatment of NMS should target the patient’s rigidity and hyperthermia to prevent progression into rhabdomyolysis.
Cholinesterase
6%
Physostigmine is a cholinesterase inhibitor that decreases the total breakdown of acetylcholine, thereby increasing parasympathetic activity. It can be used to treat anticholinergic toxicity, which can also cause fever, confusion, and agitation in affected patients. However, anticholinergic toxicity causes dry skin, not diaphoresis, and would not lead to muscle rigidity.
Postsynaptic dopamine D2 receptors and serotonin 2A receptors
20%
Clozapine is an atypical antipsychotic used primarily for treatment-refractory schizophrenia that acts by postsynaptic blockade of dopamine D2 receptors and also inhibition of serotonin 2, α-adrenergic, and histamine H1 receptors. There is no evidence that this patient’s schizophrenia is poorly controlled. Furthermore, this patient has NMS, which requires immediate treatment. The addition of another antipsychotic may worsen this patient’s NMS given its antidopaminergic properties.
Ryanodine receptor on the sarcoplasmic reticulum
65%
Dantrolene is a muscle relaxant that prevents the release of calcium into the myocyte cytoplasm by inhibiting the ryanodine receptor on the sarcoplasmic reticulum. After discontinuation of the offending drug (i.e., chlorpromazine), dantrolene is indicated in the treatment of NMS because it decreases muscle rigidity and thereby body temperature and the risk of rhabdomyolysis. Although dantrolene is most commonly given, alternative pharmacotherapy includes bromocriptine, amantadine, and possibly apomorphine. Benzodiazepines are also usually given to patients with NMS associated with psychomotor agitation, as seen here.
Histamine H1 receptor and serotonin 2 receptors
4%
Cyproheptadine is a first-generation H1 antihistamine that is indicated in the treatment of serotonin syndrome because of its nonselective antiserotonergic activity. This condition has a similar presentation to NMS; but serotonin syndrome also tends to cause hyperreflexia, myoclonus, nausea, vomiting, and diarrhea. In addition, serotonin syndrome generally occurs in the context of polypharmacy with drugs that increase serotonin levels (e.g., SSRI, MAOI, SNRI), none of which are taken by this patient.
Beta adrenergic receptors
3%
Propranolol is a nonselective beta blocker that decreases sympathetic activation. It can be used for symptom reduction caused by increased adrenergic tone in patients with thyroid storm, which shares some clinical features with NMS (fever, hypertension, tachycardia, and altered mental status). However, thyroid storm usually causes hyperreflexia and occurs in patients with hyperthyroidism. It would not explain this patient’s muscle rigidity or hyporeflexia.
Bacterial cell wall synthesis
2%
Inhibition of bacterial cell wall synthesis by forming a complex with murein is the mechanism of vancomycin, a broad-spectrum antibiotic that may be indicated if gram-positive sepsis is suspected. Although sepsis can also cause altered mental status, tachycardia, tachypnea, and fever, it would not typically cause hypertension, hyporeflexia, or hypertonia.
A 42-year-old woman comes to the physician for evaluation of a 6-month history of irregular menstrual periods. Her last period was 3 months ago. Previously, her periods occurred at regular 28-day intervals and lasted 4–5 days with moderate flow. She has also noticed breast tenderness and scant nipple discharge. She has type 2 diabetes mellitus and refractory bipolar I disorder. Current medications include metformin, glipizide, lithium, and risperidone. Physical examination shows no abnormalities. A urine pregnancy test is negative. Which of the following is the most likely cause of the changes in her menstrual cycle?
his patient’s history of menstrual irregularities and nipple discharge are suggestive of hyperprolactinemia.
Dysregulation of theca and granulosa cell steroidogenesis
3%
Dysregulation of theca and granulosa cell steroidogenesis is seen in polycystic ovarian syndrome, which can cause menstrual cycle irregularities, as seen in this patient. PCOS should also be considered in patients with diabetes mellitus, such as this woman, as insulin resistance plays a key role in the pathophysiology of both PCOS and diabetes mellitus. However, this woman lacks other typical clinical features of PCOS, including signs of hyperandrogenism and virilization (e.g., hirsutism and acne vulgaris). Finally, PCOS would not explain this patient’s nipple discharge.
Reduced renal elimination of prolactin
8%
Reduced renal elimination of prolactin can cause hyperprolactinemia in patients with chronic renal failure due to reduced renal elimination of prolactin. However, this patient has no evidence of renal failure (e.g., hypertension, edema, features of uremia).
Impaired production and release of thyroxine
4%
Impaired production and release of thyroxine are seen in hypothyroidism. An increase in TRH stimulates prolactin secretion causing hyperprolactinemia and its associated symptoms, such as oligomenorrhea and nipple discharge. Hypothyroidism is also a side effect of lithium, which this patient takes. However, this woman lacks other signs and symptoms of hypothyroidism (e.g., fatigue, cold intolerance, weight gain, constipation), making another cause more likely.
Failure of ovaries to respond to gonadotropins
3%
Failure of the ovaries to respond to gonadotropins occurs in ovarian failure, which may present with menopause. Although this patient has amenorrhea, she lacks other characteristic features of menopause, such as sweating, hot flashes, and mood swings. Furthermore, ovarian failure would not explain her nipple discharge.
Blockade of pituitary dopamine receptors
83%
Blockade of pituitary dopamine receptors is likely to have caused this patient’s hyperprolactinemia. Dopamine secreted by the hypothalamus normally inhibits the secretion of prolactin from the anterior pituitary. Although typical antipsychotics are most commonly associated with this side effect, atypical antipsychotics, especially risperidone, can also cause hyperprolactinemia. Risperidone antagonizes D2 dopaminergic receptors, decreasing dopamine’s tonic inhibition of prolactin secretion and resulting in hyperprolactinemia. Prolactin acts directly on breast epithelial cells to stimulate milk production (hence this patient’s galactorrhea). Because prolactin inhibits GnRH secretion, hyperprolactinemia can also result in hypogonadotropic hypogonadism (hence this patient’s amenorrhea).
A 47-year-old woman comes to the physician because of repetitive tongue twisting and abnormal movements of the hands and legs that started several days ago. She has a 2-year history of schizophrenia that has been controlled with fluphenazine. Two weeks ago, she was switched to risperidone. Examination shows protrusion of the tongue and smacking of the lips. She makes twisting movements of the arms and frequently taps her right foot. Which of the following is the most likely diagnosis?
It is common for this condition to first appear after initiating treatment with an anticholinergic drug, reduction in antipsychotic medication dose, or, as in this case, changing to a less potent antipsychotic medication due to an unmasking effect.
Tourette syndrome
1%
Tourette syndrome is a tic disorder characterized by rapid, involuntary motor and vocal tics that occur several times daily on most days. It is not associated with antipsychotic drug treatment, but with attention deficit hyperactivity disorder and obsessive-compulsive disorder. Onset is typically before the age of 18.
Neuroleptic malignant syndrome
1%
Neuroleptic malignant syndrome (NMS) is a life-threatening condition that usually appears within the first 2 weeks of treatment with antipsychotic medications (most often typical antipsychotics). Repetitive involuntary movements would not be seen in NMS. Instead, NMS is characterized by hyperthermia, muscular rigidity, autonomic instability, and mental status change.
Akathisia
10%
Akathisia is the most common form of neuroleptic-induced extrapyramidal symptoms, usually manifesting within a few weeks of treatment and manifesting with restlessness and a compelling urge to move. While constant movements, as seen in this patient, may occur, they are not entirely involuntary, repetitive, or purposeless and are more a result of an inability to sit still.
Acute dystonia
7%
Acute dystonia typically presents within hours to days after the intake of antipsychotics and manifests with painful and lasting muscle spasms that predominantly affect the head, neck (torticollis), and tongue. Unlike in this patient, movements are nonrepetitive and affect a single muscle group.
Tardive dyskinesia
79%
Tardive dyskinesia (TD) is a neuroleptic-induced extrapyramidal symptom (EPS) that usually manifests months to years after the initiation of maintenance antipsychotic therapy with purposeless, repetitive, involuntary orofacial and extremity movements often with a choreiform and/or athetotic characteristic (e.g., lip smacking, twisting movements of the arms). As with other forms of EPS, TD generally occurs more frequently in conjunction with typical antipsychotics (e.g., fluphenazine), which this patient has received for 2 years, and to a lesser extent with atypical antipsychotics (e.g., risperidone). Cross-tapering to clozapine or quetiapine, which have a very low risk of EPS, should be considered for patients with TD but TD can be irreversible and persist even after discontinuation of the offending drug. Vesicular monoamine transporter-2 inhibitors (e.g., valbenazine, deutetrabenazine) can be used to treat moderate to severe TD.
See “Overview of extrapyramidal symptoms” table.
Pseudoparkinsonism
2%
Pseudoparkinsonism usually develops days to weeks after initiating therapy with an antipsychotic drug and manifests with the classic symptoms of parkinsonism (e.g., cogwheel rigidity, stiff gait, tremor). Repetitive choreiform or athetotic movements as seen in this patient would not be present.
A 29-year-old man comes to the physician for worsening restlessness over the past several days. Three weeks ago, he was started on trifluoperazine for the treatment of schizophrenia. He reports that, since then, he has often felt compelled to pace around his house and is unable to sit or stand still. He is switched to an alternative antipsychotic medication. Four weeks later, the patient reports improvement of his symptoms but says that he has developed increased drowsiness, blurred vision, and dry mouth. The patient was most likely switched to which of the following drugs?
Anterior capsular cataracts and pigmented corneal deposits are other possible adverse effects of this particular medication.
Metoclopramide
6%
Chlorpromazine
63%
The patient developed akathisia (restlessness), a common extrapyramidal symptom that typically occurs 1–8 weeks after the initiation of antipsychotic therapy. The initial management of akathisia consists of switching to an antipsychotic drug with a lower risk of extrapyramidal symptoms (as was done for this patient) or lowering the dose of the prescribed antipsychotic. When compared to high-potency typical antipsychotics (e.g., haloperidol, fluphenazine, trifluoperazine), low-potency typical antipsychotics (e.g., chlorpromazine, thioridazine) have a lower risk of extrapyramidal symptoms. However, low-potency typical antipsychotics are associated with a higher risk of anticholinergic effects (e.g., blurred vision, dry mouth) and antihistaminergic effects (e.g., drowsiness), as observed in this patient. Additional α-1 receptor blockade effects may cause orthostatic hypotension.
See “Overview of adverse effects of antipsychotics” table.
Trimipramine
12%
Fluphenazine
9%
Fluphenazine is a high-potency typical antipsychotic drug. Unlike the drug given to this patient, fluphenazine has low anticholinergic and antihistaminergic activity and carries a higher risk of extrapyramidal symptoms (e.g., akathisia); it would not be prescribed to a patient who developed akathisia from trifluoperazine therapy.
Haloperidol
10%
Haloperidol is a high-potency typical antipsychotic drug. Unlike the drug given to this patient, haloperidol has low anticholinergic and antihistaminergic activity and carries a higher risk of extrapyramidal symptoms (e.g., akathisia); it would not be prescribed for maintenance therapy to a patient who developed akathisia from trifluoperazine therapy
Two weeks after hospitalization for acute psychosis, a 27-year-old woman with a history of paranoid schizophrenia comes to the physician because of difficulty walking and shaking movements of her hands. Current medications include fluphenazine, which was started during her recent hospitalization. Examination shows a shuffling gait, rigidity in the upper extremities, and a low-amplitude tremor of her hands that improves with activity. Mental status examination shows no abnormalities. Treatment with a drug with which of the following mechanisms of action is most likely to provide relief for this patient’s current symptoms?
This patient presents with symptoms of Parkinson disease (bradykinesia, muscle rigidity, resting tremor) after several weeks of treatment with high-potency typical antipsychotics. This suggests drug-induced pseudoparkinsonism.
β-adrenergic antagonist
8%
β-adrenergic antagonists such as propranolol are the preferred treatment for essential tremor. Unlike this patient’s tremor, essential tremor typically manifests as a bilateral tremor of the hands that worsens with voluntary movements but resolves at rest. Moreover, essential tremors are sporadic or hereditary in nature and are not associated with consumption of antipsychotic drugs.
GABA agonist
14%
GABA agonists, such as benzodiazepines, are not indicated for drug-induced pseudoparkinsonism but are used as a second-line treatment for drug-induced acute dystonia (second-line due to its anticholinergic properties). This extrapyramidal symptom (EPS) manifests within hours to days of antipsychotic treatment with painful and lasting muscle spasms of the eye, tongue, neck (torticollis), and back muscles. After acute treatment of the dystonia, the offending antipsychotic drug should be replaced with an antipsychotic that has a lower risk for EPS.
Dopamine antagonist
21%
Immediate discontinuation of the offending antipsychotic drug and replacement with the weak dopamine antagonist clozapine is recommended in patients who develop signs of tardive dyskinesia. This extrapyramidal symptom (EPS) involves involuntary choreoathetoid movements of the mouth (repetitive chewing and lip-smacking), face, and extremities, which develop after months to years of treatment. Although switching to an atypical antipsychotic drug generally reduces the risk of EPS progression, another drug is more likely to provide immediate relief for this patient’s pseudoparkinsonism.
Histamine antagonist
8%
The histamine antagonist diphenhydramine is not indicated for drug-induced pseudoparkinsonism but is used as a second-line treatment for drug-induced acute dystonia (second-line due to its anticholinergic properties). Acute dystonia manifests within hours to days of antipsychotic treatment with painful and lasting spasms of the eye, tongue, neck (torticollis), and back muscles. After acute treatment of the dystonia, the offending antipsychotic drug should be replaced with an antipsychotic with a lower risk of extrapyramidal symptoms.
Muscarinic antagonist
49%
Antipsychotic-induced pseudoparkinsonism is generally treated with dose reduction or discontinuation of the offending drug. However, if this does not suffice or is not feasible due to active psychotic illness, pharmaceutical treatment should be initiated to provide symptomatic relief. Centrally-acting muscarinic antagonists, e.g., benztropine and trihexyphenidyl, are the preferred treatment for pseudoparkinsonism associated with antipsychotic drugs in most patients. Elderly patients, however, should be treated with amantadine to avoid the potential anticholinergic side effects of muscarinic antagonists (e.g., dry mouth, constipation, urinary retention, cognitive impairments, delirium)
A 36-year-old woman with schizophrenia comes to the office for a follow-up appointment. She has been hospitalized 4 times in the past year, and she has failed to respond to multiple trials of antipsychotic medications. Six weeks ago, she was brought to the emergency department by her husband because of a bizarre behavior, paranoid delusions, and hearing voices that others did not hear. She was started on a new medication, and her symptoms have improved. Laboratory studies show:
Hemoglobin 13.8 g/dL
Leukocyte count 1,200/mm3
Segmented neutrophils 6%
Eosinophils 0%
Lymphocytes 92%
Monocytes 2%
Platelet count 245,000/mm3
This patient was most likely started on which of the following medications?
This patient has treatment-resistant schizophrenia (failure to respond to multiple trials of antipsychotic medications). She was most likely started on the gold standard antipsychotic for treatment-resistant schizophrenia. However, she now has agranulocytosis, which is a known side effect of this medication.
Fluphenazine
2%
Fluphenazine is a high-potency antipsychotic that can cause extrapyramidal and anticholinergic adverse effects, neither of which are seen in this patient. This patient’s agranulocytosis is not an expected adverse effect.
Risperidone
6%
Risperidone is an atypical antipsychotic that can cause hyperprolactinemia, which may lead to gynecomastia. This patient’s agranulocytosis is not a typical adverse effect.
Olanzapine
2%
Olanzapine is an atypical antipsychotic that is commonly used as first-line treatment for schizophrenia. Adverse effects include weight gain, hyperglycemia, and orthostatic hypotension, but it does not typically cause agranulocytosis. Furthermore, it is rarely used for refractory schizophrenia, making it an unlikely cause of this patient’s symptoms.
Quetiapine
3%
Quetiapine is an atypical antipsychotic that can cause sedation, metabolic syndrome, hyperglycemia, and weight gain. This patient’s agranulocytosis is not a typical adverse effect.
Promethazine
1%
Promethazine is a low-potency antipsychotic that can cause extrapyramidal and anticholinergic adverse effects, neither of which are seen in this patient. This patient’s agranulocytosis is not an expected adverse effect.
Chlorpromazine
5%
Chlorpromazine is a medium-potency antipsychotic used for schizophrenia in addition to bipolar disorder, attention deficit hyperactivity disorder, and nausea. It can cause extrapyramidal and anticholinergic symptoms, but this patient’s agranulocytosis is not a typical adverse effect.
Lithium
5%
Lithium is used in the treatment of bipolar disorder and can cause hypothyroidism, nephrogenic diabetes insipidus, and fine tremors, none of which are seen in this patient. Furthermore, lithium is not used in the management of treatment-resistant schizophrenia and would not explain this patient’s agranulocytosis.
Clozapine
76%
Clozapine is used primarily for schizophrenia resistant to first-line pharmacological therapy. While it is highly effective in the treatment of schizophrenia, it has serious adverse effects, which can include the life-threatening agranulocytosis seen in this patient. About 1–2% of all patients who begin taking clozapine eventually develop agranulocytosis (usually in the first months of treatment), though this risk falls substantially after the first year. The most common symptoms of agranulocytosis are oral ulcerations, fever, malaise, and increased susceptibility to infections such as pneumonia.
A 25-year-old woman is brought to the physician by her husband because she has appeared increasingly agitated over the last week. She feels restless, has not been able to sleep well, and has been pacing around her house continuously in an attempt to relieve her symptoms. Two weeks ago, she was diagnosed with schizophrenia and treatment with fluphenazine was initiated. Today, physical examination is interrupted multiple times because she is unable to sit or stand still for more than a couple minutes. Which of the following is the most likely diagnosis?
his patient has escalating agitation, restlessness, poor sleep, continuous pacing, and the inability to remain still for more than a few minutes. She likely has the most common subtype of extrapyramidal symptoms (EPS).
Restless legs syndrome
7%
In restless legs syndrome (RLS), patients experience disturbed sleep caused by an urge to move, similar to this patient. However, in RLS, movement typically relieves the urge to move, whereas this patient does not find relief. This patient also has symptoms during the day as well as at night, whereas the symptoms of RLS have a circadian rhythm. Restless legs syndrome is not associated with antipsychotic medications.
Pseudoparkinsonism
1%
Pseudoparkinsonism, a subtype of EPS, can be induced by antipsychotic drugs and it appears within days to weeks of treatment initiation. However, pseudoparkinsonism is characterized by tremors, cogwheel rigidity, and a shuffling gait.
Athetosis
2%
Athetosis may occur as a feature of tardive dyskinesia, which can occur as an EPS following months to years of exposure to antipsychotic drugs. However, this patient has only been taking fluphenazine for 2 weeks. Furthermore, athetosis is characterized by slow, continuous, involuntary writhing movements, which are not present here.
Akathisia
80%
Akathisia describes the symptoms of motor restlessness seen here. It is an extrapyramidal side effect of antipsychotic medications, especially high-potency typical antipsychotics (e.g., fluphenazine). The onset of akathisia is typically within 1–8 weeks of treatment initiation, as seen here. If feasible, this patient should have her fluphenazine dosage reduced or she should be switched to an antipsychotic drug with a lower risk of EPS. For persistent akathisia, the first-line pharmacotherapy is a beta blocker (e.g., propranolol). Benzodiazepine or benztropine therapy can be considered for akathisia refractory to beta blocker therapy.
Other important forms of EPS are pseudoparkinsonism, acute dystonic reactions, and tardive dyskinesia. Pseudoparkinsonism occurs within the same timeframe as akathisia but is characterized by tremors, cogwheel rigidity, and a shuffling gait. Acute dystonic reactions occur more immediately (within hours to days), and tardive dyskinesia occurs later (months to years).
See “Overview of extrapyramidal symptoms” table.
Inadequately treated schizophrenia
2%
Schizophrenia can cause agitation due to distressing delusions or hallucinations. This patient does not report changes in her thoughts or perceptions but instead seems agitated by her own restlessness and inability to remain still.
Tardive dyskinesia
3%
Tardive dyskinesia is a potentially irreversible and disabling side effect of prolonged exposure (months to years) to dopamine receptor antagonists such as antipsychotics and certain antiemetics. It is a subtype of EPS and involves motor symptoms. However, this patient has only been taking fluphenazine for 2 weeks. Furthermore, the most common manifestations of tardive dyskinesia are purposeless, repetitive, involuntary orofacial and extremity movements often with a choreiform and/or athetotic characteristic.
Drug-induced mania
4%
Drug-induced mania can be caused by medications such as stimulants and corticosteroids, and antidepressant medications can induce hypomania or mania in patients with bipolar disorder. This patient’s restlessness, poor sleep, and anxiety would fit with the diagnosis of drug-induced mania, but she is not taking antidepressants, corticosteroids, or stimulants. Mania is not a typical side effect of antipsychotics and is not a subtype of EPS
