A 50-year-old man is brought to the ER with severe dizziness and confusion. He states that he had an episode of chest pain and took several tablets of nitroglycerin. His current medications include a daily aspirin for heart attack prevention, an occasional acetaminophen for headaches and occasionally tadalafil for erectile dysfunction. His blood pressure is 50/20 mmHg and his heart rate is 120 beats/min. Which of the following cellular changes is most likely responsible for this patient's symptoms?

Question

A 50-year-old man is brought to the ER with severe dizziness and confusion.  He states that he had an episode of chest pain and took several tablets of nitroglycerin.  His current medications include a daily aspirin for heart attack prevention, an occasional acetaminophen for headaches and occasionally tadalafil for erectile dysfunction.  His blood pressure is 50/20 mmHg and his heart rate is 120 beats/min.  Which of the following cellular changes is most likely responsible for this patient's symptoms?

Quizplus · Accepted Answer

The interaction between nitrates and phosphodiesterase inhibitors used in erectile dysfunction (tadalafil, sildenafil, vardenafil) is well known and very important to understand. Nitrates are converted to nitric oxide by vascular smooth muscle cells, and nitric oxide causes increased intracellular cGMP as a second-messenger. Increased cGMP concentration leads to vascular smooth muscle relaxation. Additionally, cGMP is metabolized within the cells by phosphodiesterase, and phosphodiesterase inhibitors will lead to increased intracellular cGMP. cGMP accumulation in vascular smooth muscle cells due to both enhanced synthesis (nitrates) and inhibited degradation (PDE inhibitors) is responsible for profound hypotension due to extreme vasodilatation when these drugs are used together. (Choice A) Receptor downregulation or tachyphylaxis occurs with many drug classes including topical glucocorticoids, opiates, L-dopa and more. It is one mechanism by which the body develops tolerance to drugs on a cellular level, but it is not the cause of hypotension in this patient who took nitrates together with a PDE inhibitor. (Choice B) G_s protein phosphorylation leads to activation of the G_s protein, a stimulatory protein which acts as a part of the adenylate cyclase second messenger system. It has no role in cGMP pathways that are affected by nitrates and PDE inhibitors. (Choice D) Tyrosine kinase overactivity would lead to an exaggeration of the effects of insulin or insulin-like growth factor. Tyrosine kinase has no role in the effect of nitrates or PDE inhibitors on vascular smooth muscle. (Choice E) Enhanced phospholipid metabolism would lead to an increase in the production of prostaglandins (via diacylglycerol) and inositol triphosphate (leading to calcium release from the endoplasmic reticulum). This is the inositol triphosphate second-messenger system, and it mediates the effects of alpha-1 adrenergic receptors, angiotensin II receptors, oxytocin receptors and vascular vasopressin receptors. It is not involved in the action of nitrates or PDE inhibitors. (Choice F) Tolerance refers to the need for a larger dose of drug to achieve the same clinical effect achieved previously with a smaller dose of drug. Development of tolerance can occur by multiple mechanisms such as a change in cellular response to drug (decreased receptors, decreased response to receptor stimulation), as well as increased rate of drug elimination by the body. Tolerance is not the reason for this patient to experience hypotension with this drug combination. Educational Objective: Using nitrates together with phosphodiesterase (PDE) inhibitors used for erectile dysfunction and pulmonary hypertension causes a profound systemic hypotension because they both increase intracellular cGMP which causes vascular smooth muscle relaxation. Their use together is absolutely contraindicated.

A 50-Year-Old Man Is Brought to the ER with Severe