Free USMLE Step 1 Sample Questions
The following two USMLE Step 1 sample questions from TrueLearn’s SmartBank test some of the high-yield material you’re sure to see on exam day. Each question is followed by an authoritative answer explanation, complete with rich visuals, a focused Bottom Line statement, and supporting references (including page numbers from First Aid for the USMLE Step 1). Finally, each question also includes a unique TrueLearn Insight.
TrueLearn Insights are where our expert author team provides Step-wise strategies and tables to help you master the exam. Inspired by our authors’ own experience studying and tutoring for Step 1, they address common student struggles through detailed insider advice. As a supplement to our thorough answer explanations, TrueLearn Insights provide added value not available from any other USMLE question bank.
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First Step 1 Sample Question: Pharmacology
A 22-year-old man comes to the emergency department with shortness of breath and cough. His symptoms began yesterday after a hike with his girlfriend but have severely worsened. He has no other medical problems and does not use tobacco. His temperature is 37.1°C (98.8°F), pulse is 95/min, respirations are 24/min, and blood pressure is 110/80 mm Hg. The patient is in mild distress. End expiratory wheezes are heard bilaterally. The most appropriate next step in treatment is a medication that has which of the following mechanisms of action?
- A. Binds equally to both β1 and β2 receptors
- B. Competitively blocks leukotriene receptors
- C. Increases the level of cAMP in smooth muscle cells
- D. Inhibits adenylyl cyclase
- E. Inhibits phosphodiesterase
- F. Nonselective agonist at muscarinic receptors
The Answer and Explanation
Did you get it right? The correct answer is: C
This patient presents with an acute asthma exacerbation and should be managed with a β2 agonist such as albuterol. Asthma is characterized by hyperresponsive bronchi, and many asthma exacerbations occur as a result of allergen-induced bronchoconstriction. Albuterol is a short-acting β2 agonist that causes bronchodilation and is used frequently in the treatment of acute asthma exacerbations. It preferentially binds to β2 receptors > β1 receptors and causes bronchodilation. Albuterol and other β2 agonists bind to β2 receptors, resulting in activation of adenylyl cyclase.
Activation of adenylyl cyclase converts ATP into cAMP and increased levels of cAMP stimulate protein kinase A, resulting in smooth muscle relaxation. In the lungs, this results in bronchodilation. Long-acting β2 agonists, such as salmeterol and formoterol, have a similar mechanism of action but are used as daily prophylaxis in patients with moderate or severe asthma.
Illustration © TrueLearn, LLC
Incorrect Answer Explanations
Answer A: Albuterol is a β2 agonist and binds at β2 receptors > β1 receptors. It does have some β1 agonist activity, and this explains why many patients experience tachycardia in response to treatment with albuterol.
Answer B: Montelukast and zafirlukast block leukotriene receptors and are often used in the treatment of aspirin-induced asthma and exercise-induced asthma. By blocking leukotriene receptors, these drugs help decrease both inflammation and bronchial hyperreactivity. As such, they are used as prophylactic medications and would have no role in the treatment of an asthma exacerbation as was seen in this patient.
Answer D: As mentioned above, albuterol binds to β2 receptors and activates adenylyl cyclase. This results in an increase in cAMP and smooth muscle relaxation (bronchodilation). By contrast, a drug that causes inhibition of adenylyl cyclase would decrease levels of cAMP and, thus, would cause bronchoconstriction.
Answer E: Theophylline is an alternative bronchodilator that acts via blockade of phosphodiesterases. A downstream effect of theophylline is elevation of intracellular cAMP, and this medication does play a role in bronchodilation much like that of ß2 agonists. However, unlike albuterol, theophylline is not routinely used in the treatment of acute asthma exacerbation. Instead, it can be used for maintenance therapy in patients with severe asthma.
Answer F: A nonselective agonist at muscarinic receptors would cause bronchoconstriction and would worsen this patient’s symptoms. Stimulation of M1 and M3 muscarinic receptors activates phospholipase C that, in turn, causes an increase in levels of IP3, leading to smooth muscle contraction. Methacholine is a nonselective muscarinic receptor agonist that is used to help diagnose asthma since it will cause bronchoconstriction in patients with bronchial hyperreactivity. By contrast, muscarinic antagonists such as tiotropium and ipratropium are often used in the treatment of asthma; however, these drugs would not be used before albuterol in a patient with an acute asthma exacerbation.
Bottom Line
Short-acting beta-2 agonists, such as albuterol, are used as first-line pharmacotherapy for patients with acute asthma exacerbations. By binding to beta-2 receptors, albuterol activates adenylyl cyclase and causes an increase in cAMP that, in turn, causes smooth muscle relaxation and bronchodilation.
TrueLearn Insight
Asthma medications are heavily tested on the USMLE Step 1. Make sure that you are comfortable with the mechanism of action for these drugs.
| Pharmacotherapy for Asthma | ||
| Drug | Mechanism of Action | Clinical Use |
| Albuterol | Stimulates β2 receptors → ↑ cAMP → smooth muscle relaxation (bronchodilation)Short acting | Asthma exacerbationsRescue inhaler for mild symptoms |
| Salmeterol | Stimulates β2 receptors → ↑ cAMP → smooth muscle relaxation (bronchodilation)Long acting | Prophylaxis for patients with moderate to severe asthma |
| Inhaled corticosteroids(fluticasone) | Inhibit NF-κβ → ↓ TNF-α and ↓ inflammatory agents | First-line pharmacotherapy for patients with chronic asthma |
| Montelukast | Block leukotriene receptors → ↓ inflammation and bronchial hyperreactivity | Prophylaxis; especially in patients with aspirin-induced asthma or exercise-induced asthma |
| Zileuton | Inhibits 5-lipoxygenase pathway → blocks conversion of arachidonic acid to leukotrienes | Prophylaxis; especially in patients with aspirin-induced asthma or exercise-induced asthma |
| Omalizumab | Binds to unbound serum IgE → blocks IgE binding to FcεR1 | Used in patients with allergic asthma that is resistant to treatment with inhaled steroids and long-acting β2 agonists |
| Theophylline | Inhibits phosphodiesterase → ↓ cAMP hydrolysis → ↑ cAMP → smooth muscle relaxation (bronchodilation) | Used in patients with severe, chronic asthma |
| Cromolyn | Prevents mast cell degranulation | Can prevent acute asthma symptomsRarely used clinically |
For more information, see:
Acute Exacerbations of Asthma in Adults: Home and Office Management: UpToDate
Beta Agonists in Asthma: Acute Administration and Prophylactic Use: UpToDate
First Aid for the USMLE Step 1 2019: 238, 672.
First Aid for the USMLE Step 1 2020: 674, 687.
First Aid for the USMLE Step 1 2021: 698, 712.
First Aid for the USMLE Step 1 2022: 712.
First Aid for the USMLE Step 1 2023: 695, 708.
First Aid for the USMLE Step 1 2024: 693, 706
First Aid for the USMLE Step 1 2025: 693, 704.
Second Sample Question: Hydrochlorothiazide Mechanism Of Action
A 20-day-old girl is brought to the emergency department for vomiting and decreased oral intake. She has only had 2 wet diapers over the last 24 hours. She was born at 39 weeks of gestation via home delivery; she has not received recommended newborn screening but is up to date on all recommended vaccines. She is exclusively breastfed. Physical examination shows scleral icterus and bilateral cataracts. There is palpable hepatomegaly. Laboratory studies show a normocytic anemia, elevated liver enzymes, and hypoglycemia. The ammonia level is normal. Newborn screening is pending. Which of the following enzymes is most likely deficient in this patient?
- A. Aldolase B
- B. Fructokinase
- C. Galactokinase
- D. Galactose-1-phosphate uridyltransferase
- E. Glucose-6-phosphatase
The Answer and Explanation
Did you get it right? The correct answer is: D
| Disorders of Galactose Metabolism | ||
| Disorder | Affected Enzyme | Clinical Features |
| Galactokinase Deficiency | Galactokinase | Infantile cataracts → no social smile; failure to track objects |
| Classic Galactosemia | Galactose-1-phosphate uridyltransferase | CataractsFailure to thriveJaundiceHepatomegalyVomitingRenal dysfunctionMetabolic acidosisHemolytic anemia↑ risk of Escherichia coli sepsis |
This patient’s symptoms and laboratory findings are consistent with classic galactosemia. Classic galactosemia is caused by an autosomal recessive defect that results in an absence of galactose-1-phosphate uridyltransferase (GALT). GALT is involved in the metabolism of galactose and serves to catalyze the conversion of galactose-1-phosphate to glucose-1-phosphate; as a result, patients with GALT deficiency accumulate excess levels of galactose-1-phosphate.
Galactose-1-phosphate is toxic and causes liver dysfunction (eg, hepatomegaly, hypoglycemia) and renal dysfunction in patients with classic galactosemia. Patients typically present as newborns and additional clinical features can include infantile cataracts, failure to thrive, vomiting, and hemolytic anemia. Patients are also at risk of sepsis secondary to E coli.
Restricting lactose intake (via cessation of breastfeeding) and initiation of soy milk–based formula can improve both hepatic and renal function. It may also cause regression of the cataracts.
Illustration of galactose metabolism. Galactose-1-P is the deficient enzyme in classic galactosemia. Illustration © TrueLearn, LLC
Incorrect Answer Explanations
Answer A: Hereditary fructose intolerance is caused by an autosomal recessive deficiency of aldolase B. Symptoms of hereditary fructose intolerance include jaundice, cirrhosis, vomiting, and hypoglycemia. Patients are typically older given that symptoms manifest in response to fruit, juice, or honey. This patient is exclusively breastfed, so it is unlikely that her symptoms would be caused by a deficiency in aldolase B. In addition, cataracts, renal dysfunction, and hemolytic anemia are not features of hereditary fructose intolerance.
| Disorders of Fructose Metabolism | ||
| Disorder | Affected Enzyme | Clinical Features |
| Essential Fructosuria | Fructokinase | Benign condition; patients are asymptomatic Fructose in the blood and urine |
| Hereditary Fructose Intolerance | Aldolase B | Symptoms begin following consumption of fruit, juice, or honey Jaundice Cirrhosis Vomiting Hypoglycemia Urine dipstick will be negative |
Answer B: Essential fructosuria is caused by an autosomal recessive defect in fructokinase. This is a benign condition and patients are typically asymptomatic. Diagnosis is made via the presence of fructose in the blood and urine.
Answer C: Galactokinase deficiency is less severe than classic galactosemia and does not result in liver dysfunction, renal dysfunction, and anemia. Infantile cataracts are the main feature of galactokinase deficiency, and examination often reveals an absent social smile or an inability to track objects.
Answer E: Von Gierke disease (type I glycogen storage disease) is caused by a deficiency in glucose-6-phosphatase. Patients typically present as infants with severe fasting hypoglycemia, hepatomegaly, and increased serum levels of triglycerides, lactate, and uric acid. Cataracts, jaundice, and anemia are not features of Von Gierke disease.
Bottom Line
Classic galactosemia is caused by a deficiency in galactose-1-phosphate uridyltransferase. Patients typically present as newborns with a combination of vomiting, jaundice, hepatomegaly, infantile cataracts, failure to thrive, hypoglycemia, hemolytic anemia, and renal dysfunction. There is also an increased risk of sepsis secondary to Escherichia coli.
TrueLearn Insight
| Inborn Errors of Metabolism | ||||
| Disorder | Deficient Enzyme | Inheritance | Manifestations | USMLE High-Yield Association |
| Classic Galactosemia (Galactosemia Type I) | Galactose-1-phosphate uridyltransferase | Autosomal recessive | Accumulation of galactitol → cataractsJaundiceIntellectual disabilityFailure to thrive | Symptoms begin after introduction of milk (contains lactose/galactose) |
| Essential Fructosuria | Fructokinase | Autosomal recessive | No clinical signs Fructose in urine | Often found incidentally with a positive urine test for reducing sugars (differential is glucosuria in diabetes mellitus) |
| Galactokinase Deficiency (Galactosemia Type II) | Galactokinase | Autosomal recessive | Accumulation of galactitol → cataractsTypically no other manifestations | Symptoms begin after introduction of milk (contains lactose/galactose)NOT associated with other findings of galactosemia (jaundice, etc) |
| Hereditary Fructose Intolerance | Aldolase B | Autosomal recessive | Accumulation of fructose-1-phosphate → hepatic cell failureJaundiceVomiting → poor feeding → hypoglycemiaHyperuricemia → renal failure | Symptoms begin after introduction of formula, fruits, or vegetables (contain fructose) |
| Phenylketonuria Type I | Phenylalanine hydroxylase | Autosomal recessive | MicrocephalyIntellectual disabilityBehavior problemsSeizures Musty odor of sweat or urineHypopigmentation of hair or skin | Typically discovered on newborn screening |
| Phenylketonuria Type II | Tetrahydrobiopterin | Autosomal recessive | Lack of cofactor needed for phenylalanine hydroxylase | Prolactin level is high (because tetrahydrobiopterin is necessary to synthesize dopamine; low levels of dopamine lead to high levels of prolactin) |
For more information, see:
Galactosemia: Clinical Features and Diagnosis on UpToDate
First Aid for the USMLE Step 1 2019: 80.
First Aid for the USMLE Step 1 2020: 80.
First Aid for the USMLE Step 1 2021: 80.
First Aid for the USMLE Step 1 2022: 78, 72, 554.
First Aid for the USMLE Step 1 2023: 78, 72.
First Aid for the USMLE Step 1 2024: 78, 72First Aid for the USMLE Step 1 2025: 78, 72
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