A 31-year-old man comes to the office due to persistent nasal congestion and rhinorrhea. The patient has a history of allergic rhinitis and recently moved across the country to start a new job. His nasal symptoms worsened after the move, and he started using an over-the-counter intranasal decongestant spray that initially provided prompt relief. However, after a few days, he had to increase the frequency and number of sprays per nostril needed for adequate symptom control. On examination, the nasal turbinates are swollen and pale with a clear nasal discharge. Which of the following mechanisms is most likely responsible for this patient's increased medication use?

Question

A 31-year-old man comes to the office due to persistent nasal congestion and rhinorrhea.  The patient has a history of allergic rhinitis and recently moved across the country to start a new job.  His nasal symptoms worsened after the move, and he started using an over-the-counter intranasal decongestant spray that initially provided prompt relief.  However, after a few days, he had to increase the frequency and number of sprays per nostril needed for adequate symptom control.  On examination, the nasal turbinates are swollen and pale with a clear nasal discharge.  Which of the following mechanisms is most likely responsible for this patient's increased medication use?

Quizplus · Accepted Answer

11ec160b_3c35_9b29_9249_bd475886ce07_MD0001_00 This patient has rhinitis medicamentosa due to the use of a nasal decongestant spray containing an alpha-adrenergic agonist (eg, oxymetazoline). Intranasal application of alpha agonists induces vasoconstriction of superficial blood vessels in the nasal mucosa, reducing rhinorrhea and congestion. Although these agents are highly effective for symptom control, use for more than a few days is associated with rebound rhinitis and dosage escalation due to tachyphylaxis. Tolerance to alpha-adrenergic decongestants develops quickly due to receptor internalization. Both alpha- and beta-adrenergic receptors undergo a conformational change on ligand binding, allowing them to activate heterotrimeric G proteins involved in signal transduction. However, the change in conformation also results in the binding of arrestin, a protein that prevents further G protein activation and links the receptor complex to clathrin, facilitating receptor endocytosis and depletion from the cell surface. As alpha-adrenergic receptors become increasingly scarce along the blood vessels of the nasal mucosa, the release of endogenous catecholamines is no longer sufficient to provide adequate vasoconstrictive stimulation. The resulting congestion/rhinorrhea can be relieved only with increasing doses of exogenous alpha agonists. Treatment involves cessation of the culprit decongestant, sometimes with use of intranasal corticosteroids to relieve severe symptoms. (Choice A) Accelerated drug metabolism can lead to tolerance when a substance induces the enzymes responsible for its degradation (ie, cytochromes P450). This mechanism is responsible for the tolerance seen with ethanol and barbiturates. (Choice B) Decreased receptor affinity due to intracellular domain modification (eg, phosphorylation) can play a role in receptor desensitization. However, desensitization of adrenergic receptors is better explained by the decoupling of G proteins (which are blocked by arrestins) and subsequent receptor internalization. (Choice C) Tolerance to adrenergic agonists develops due to the binding of arrestins to stimulated adrenergic receptors, preventing G proteins from interacting with the receptor. G proteins themselves do not become depleted during this process. (Choice E) Parasympathetic stimulation of the nasal mucosa causes vasodilation, increases plasma extravasation, and stimulates glandular mucous secretion. Patients with rhinitis medicamentosa have increased parasympathetic tone (physiologic antagonism) that contributes to the congestion/rhinorrhea. Educational objective: Activation of adrenergic receptors results in arrestin binding and receptor internalization. This effect is responsible for the tolerance effect seen with alpha-adrenergic (eg, decongestants, vasopressors) and beta-adrenergic (eg, bronchodilators) agonists.

A 31-Year-Old Man Comes to the Office Due to Persistent