Let’s examine a clinical scenario involving a 73-year-old man who experiences hypotension during surgery following bowel perforation repair. Can you identify the potential mechanisms leading to his decreased response to repeated doses of epinephrine despite minimal intraoperative blood loss? Reflect on the pharmacological principles at play, including receptor desensitization and tissue responsiveness. Enhance your understanding of this important pharmacological concept and its implications in managing intraoperative hypotension.
A 73-year-old man with no significant past medical history develops a bowel perforation and subsequently undergoes surgical repair. He develops significant hypotension while under general anesthesia. Intraoperative blood loss is minimal. A large dose of epinephrine is administered, which temporarily raises the patient’s blood pressure. Several subsequent doses of epinephrine are administered, causing a much weaker response. Which of the following mechanisms is likely contributing to the decreased effects of this medication?
A. Increased activity of intracellular arrestin proteins
B. Increased number of extracellular receptors
C. Increased production of secondary messenger molecules
D. Decreased breakdown of the medication
E. Decreased sequestration of extracellular receptors
Scroll down for the correct answer!
The correct answer to today’s USMLE® Step 1 Question is…
A. Increased activity of intracellular arrestin proteins
Before we get to the Main Explanation, let’s look at the incorrect answer explanations. Skip to the bottom if you want to see the correct answer right away!
Incorrect Answer Explanations
B. Increased number of extracellular receptors
Incorrect: If more extracellular receptors were available, there would be more binding to the agonist (medication), making it more likely to maintain or increase a cellular response (i.e., drug effect).
C. Increased production of secondary messenger molecules
Incorrect: Since medications/drugs work by binding to a cellular receptor and causing effects via secondary messengers, an increase in secondary messengers is more likely to maintain or increase a cellular response (i.e. drug effect).
D. Decreased breakdown of the medication
Incorrect: Since more medication would be available, this is unlikely to lead to decreased effect.
E. Decreased sequestration of extracellular receptors
Incorrect: Decreased sequestration of receptors to bind the medication would result in more receptors available for drug binding and thus more intracellular changes (i.e., effect) from the medication.
Main Explanation
Desensitization and tolerance are important concepts in pharmacodynamics and refer to a decreased effect of a drug (e.g., alcohol, heroin) or medication over time following subsequent doses. Over time, as an agonist binds to its cellular receptor, it may lose its ability to produce a robust response within cells via secondary messengers. Desensitization (also called tachyphylaxis) generally occurs rapidly and can occur after the first dose of a medication. On the other hand, tolerance occurs always after repeated doses and may take weeks or months. In this patient, he is likely experiencing desensitization (tachyphylaxis) to epinephrine, so repeated doses exert a weaker effect than the original dose.
Desensitization and tolerance can occur via many mechanisms, with several of the most common mechanisms outlined below:
- Downregulation of receptor expression. For example, chronic opioid use results in downregulating the number of receptors available to bind the opioid or may increase the degradation or sequestration of receptors. This results in stronger doses of opioids needed to produce the same effect.
- Uncoupling of receptors to secondary messengers. This is often mediated by proteins called arrestins, which bind to G-protein-coupled receptors to prevent interaction with secondary messengers. They can also tag these receptors for endocytosis. This is common in desensitization (tachyphylaxis).
- Exhaustion of intracellular intermediary molecules. This can occur with drugs such as amphetamines, which eventually lead to the depletion of secondary messengers within cells.
- Increased breakdown of agonists. For example, this can occur with chronic alcohol use, as “tolerance” increases with repeated chronic use due to more rapid degradation of ethanol.
- Physiologic adaptation in the body. For example, this can occur with thiazide diuretics due to increased activity of the renin-angiotensin-aldosterone system.
Major Takeaway
Desensitization (tachyphylaxis) and tolerance can occur via several cellular mechanisms, and both lead to a decreased effect of an agonist (drug or medication) over time. Desensitization generally occurs after a few doses (can occur after the first dose), whereas tolerance takes weeks to months.
References
- Katzung & Trevor’s Pharmacology Examination and Board Review, 12th Edition. McGraw-Hill Education/Medical (2018)
- Rang and Dale’s Pharmacology. Elsevier (2019)
- Drug Hypersensitivity and Desensitizations: Mechanisms and New Approaches. International Journal of Molecular Sciences (2017).
- GPCR desensitization: Acute and prolonged phases. Cellular Signaling (2018)

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