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{{WBRQuestion
{{WBRQuestion
|QuestionAuthor={{YD}} (Reviewed by {{YD}})
|QuestionAuthor= {{YD}} (Reviewed by {{YD}})
|ExamType=USMLE Step 1
|ExamType=USMLE Step 1
|MainCategory=Pharmacology, Physiology
|MainCategory=Pharmacology, Physiology
Line 23: Line 23:
|Prompt=A 52-year-old man presents to the physician's office complaining of headache and blurry vision. His past medical history is only significant for dyslipidemia. He states that he often uses an electronic sphygmomanometer while resting at home. His blood pressure was elevated on several previous occasions in the past, but he has not been receiving any anti-hypertensive medication. In the clinic, the patient's blood pressure is 158/92 mmHg, heart rate is 72/min, and temperature is 36.8 °C (98.24 °F). The physician decides to start the patient on a medication that also inhibits the breakdown of bradykinin. Based on the diagram below, at which level of the renin-angiotensin pathway does the prescribed medication act?
|Prompt=A 52-year-old man presents to the physician's office complaining of headache and blurry vision. His past medical history is only significant for dyslipidemia. He states that he often uses an electronic sphygmomanometer while resting at home. His blood pressure was elevated on several previous occasions in the past, but he has not been receiving any anti-hypertensive medication. In the clinic, the patient's blood pressure is 158/92 mmHg, heart rate is 72/min, and temperature is 36.8 °C (98.24 °F). The physician decides to start the patient on a medication that also inhibits the breakdown of bradykinin. Based on the diagram below, at which level of the renin-angiotensin pathway does the prescribed medication act?


[[Image:WBR RAAS pathway.png|500px]]
[[Image:WBR RAAS pathway.png|700px]]
|Explanation=The renin-angiotensin aldosterone system (RAAS) is a major hormonal cascade that plays a significant role in the homeostatic control of arterial blood pressure, tissue perfusion, and extracellular volume. The RAAS pathway begins by the secretion of renin, the rate-limiting processing enzyme, mainly from the juxtraglomerular (JG) apparatus, composed of JG cells and macula densa, that mainly line the afferent arteriole of the renal glomerulus. Renin is synthesized as a preprohormone.
|Explanation=The [[renin-angiotensin aldosterone system]] ([[RAAS]]) is a major hormonal pathway that plays a significant role in the control of arterial blood pressure, tissue perfusion, and extracellular volume. The RAAS pathway begins by the expression and secretion of [[renin]], the rate-limiting processing enzyme that is synthesized as a [[preprohormone]]. Renin is mainly synthesized and stored in the juxtraglomerular (JG) apparatus, composed of JG cells and [[macula densa]]. The JG apparatus lines the afferent arteriole of the renal [[glomerulus]].  


Four factors interplay to regulate the secretion of renin:<br>
Four important factors interplay to regulate the secretion of renin:<br>
1- Renal baroreceptor in the afferent arteriole to sense alterations in renal perfusion pressures<br>
1- Renal [[baroreceptor]] in the afferent arteriole that senses alterations in renal perfusion pressures<br>
2- NaCl delivery based on chloride concentrations at the level of the macula densa cells in the distal tubules. As NaCl falls, renin secretion increases<br>
2- NaCl delivery, based on chloride concentrations, at the level of the macula densa cells in the [[distal tubules]]. As NaCl falls, renin secretion increases<br>
3- Sympathetic nerve stimulation by beta-1 adrenergic receptors. Renin secretion and sympathetic nerve stimulation ''act in concert'' <br>
3- Sympathetic nerve stimulation by beta-1 adrenergic receptors. Renin secretion and sympathetic nerve stimulation ''act in concert'' <br>
4- Negative feedback by direct inhibition
4- Negative feedback by direct inhibition


Renin cleaves the N-terminal portion of angiotensinogen, a compound that is mainly expressed by the liver at a stable rate. Angiotensinogen cleavage reults in the formation of angiotensin I, a biologically inert decapeptide. Angiotensin I is hydrolyzed by ACE (kininase II), an enzyme on plasma membranes of endothelial cells, neuroepithelial cells, and renal proximal tubule cells. ACE acts by removing the C-terminal dipeptide to form angiotensin II, an octapeptide. Also, ACE has a role in metabolizing bradykinin and kallidin, which are important vasodilator peptides. Unlike angiotensin I, angiotensin II is an active potent vasoconstrictor. Angiotensin II is the primary effector of numerous actions.
Renin cleaves the N-terminal portion of [[angiotensinogen]], a compound that is mainly expressed by the liver at a stable rate. Angiotensinogen cleavage results in the formation of [[angiotensin I]], a biologically inert decapeptide. Angiotensin I is hydrolyzed by angiotensin-converting enzyme ([[ACE]]) or kininase II, an enzyme on plasma membranes of endothelial cells, neuroepithelial cells, and renal proximal tubule cells. ACE acts by removing the C-terminal dipeptide to form angiotensin II, an octapeptide. Also, ACE has a role in metabolizing [[bradykinin]] and [[kallidin]], which are important vasodilator peptides. Unlike angiotensin I, angiotensin II is an active potent vasoconstrictor. Angiotensin II is the primary effector of numerous actions.


The prescribed medication to treat the patient's hypertension is most likely an angiotensin-converting enzyme (ACE) inhibitor. It is indicated as first line agent for the management of hypertension, and has compelling indications in specific cases such as diabetic nephropathy and left ventricular hypertrophy. Classical adverse effects of ACE-I are angioedema, cough, and hyperkalemia. Cough is caused by the action of ACE-I that inhibits the physiological breakdown of bradykinin induced by ACE, resulting in the accumulation of bradykinin with activation of inflammatory peptides and release of histamine.
The prescribed medication to treat the patient's hypertension is most likely an ACE-inhibitor. It is indicated as first line agent for the management of hypertension, and has compelling indications in specific cases such as diabetic nephropathy and left ventricular hypertrophy. Classical adverse effects of ACE-I are [[angioedema]], [[cough]], and [[hyperkalemia]]. Cough is caused by the action of ACE-I that inhibits the physiological breakdown of bradykinin induced by ACE, resulting in the accumulation of bradykinin with activation of inflammatory peptides and release of histamine.
|AnswerA=A
|AnswerA=A
|AnswerAExp=Renin is the enzyme that converts angiotensinogen to angiotensin I. Renin inhibitors act at this level.
|AnswerAExp=Renin is the enzyme that converts angiotensinogen to angiotensin I. Renin inhibitors act at this level.
Line 50: Line 50:
First Aid 2014 page 530
First Aid 2014 page 530
|RightAnswer=B
|RightAnswer=B
|WBRKeyword=Angiotensin, Angiotensinogen, RAAS, Pathway, Receptor, Blocker, Converting, Adverse effect, Adverse, Enzyme, ACE, Inhibitor, ACE inhibitor, Cough, Bradykinin, Side, effect
|WBRKeyword=Angiotensin, Angiotensin I, Angiotensin II, Angiotensin 1, Angiotensin 2, AldosteroneAngiotensinogen, RAAS, Pathway, Receptor, Blocker, Converting, Adverse effect, Adverse, Enzyme, ACE, Inhibitor, ACE inhibitor, Cough, Bradykinin, Side, effect
|Approved=Yes
|Approved=Yes
}}
}}

Latest revision as of 01:31, 28 October 2020
Author [[PageAuthor::Yazan Daaboul, M.D. (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type ExamType::USMLE Step 1
Main Category MainCategory::Pharmacology, MainCategory::Physiology
Sub Category SubCategory::Vascular
Prompt [[Prompt::A 52-year-old man presents to the physician's office complaining of headache and blurry vision. His past medical history is only significant for dyslipidemia. He states that he often uses an electronic sphygmomanometer while resting at home. His blood pressure was elevated on several previous occasions in the past, but he has not been receiving any anti-hypertensive medication. In the clinic, the patient's blood pressure is 158/92 mmHg, heart rate is 72/min, and temperature is 36.8 °C (98.24 °F). The physician decides to start the patient on a medication that also inhibits the breakdown of bradykinin. Based on the diagram below, at which level of the renin-angiotensin pathway does the prescribed medication act?

]]

Answer A AnswerA::A
Answer A Explanation AnswerAExp::Renin is the enzyme that converts angiotensinogen to angiotensin I. Renin inhibitors act at this level.
Answer B AnswerB::B
Answer B Explanation AnswerBExp::ACE is the enzyme that converts angiotensin I to angiotensin II. ACE-inhibitors act at this level.
Answer C AnswerC::C
Answer C Explanation AnswerCExp::ACE-I does not act at the level of the AT-I receptor.
Answer D AnswerD::D
Answer D Explanation AnswerDExp::Angiotensin II receptor blockers (ARB) act at this level of the pathway.
Answer E AnswerE::E
Answer E Explanation AnswerEExp::ACE-I does not act at this level of the pathway.
Right Answer RightAnswer::B
Explanation [[Explanation::The renin-angiotensin aldosterone system (RAAS) is a major hormonal pathway that plays a significant role in the control of arterial blood pressure, tissue perfusion, and extracellular volume. The RAAS pathway begins by the expression and secretion of renin, the rate-limiting processing enzyme that is synthesized as a preprohormone. Renin is mainly synthesized and stored in the juxtraglomerular (JG) apparatus, composed of JG cells and macula densa. The JG apparatus lines the afferent arteriole of the renal glomerulus.

Four important factors interplay to regulate the secretion of renin:
1- Renal baroreceptor in the afferent arteriole that senses alterations in renal perfusion pressures
2- NaCl delivery, based on chloride concentrations, at the level of the macula densa cells in the distal tubules. As NaCl falls, renin secretion increases
3- Sympathetic nerve stimulation by beta-1 adrenergic receptors. Renin secretion and sympathetic nerve stimulation act in concert
4- Negative feedback by direct inhibition

Renin cleaves the N-terminal portion of angiotensinogen, a compound that is mainly expressed by the liver at a stable rate. Angiotensinogen cleavage results in the formation of angiotensin I, a biologically inert decapeptide. Angiotensin I is hydrolyzed by angiotensin-converting enzyme (ACE) or kininase II, an enzyme on plasma membranes of endothelial cells, neuroepithelial cells, and renal proximal tubule cells. ACE acts by removing the C-terminal dipeptide to form angiotensin II, an octapeptide. Also, ACE has a role in metabolizing bradykinin and kallidin, which are important vasodilator peptides. Unlike angiotensin I, angiotensin II is an active potent vasoconstrictor. Angiotensin II is the primary effector of numerous actions.

The prescribed medication to treat the patient's hypertension is most likely an ACE-inhibitor. It is indicated as first line agent for the management of hypertension, and has compelling indications in specific cases such as diabetic nephropathy and left ventricular hypertrophy. Classical adverse effects of ACE-I are angioedema, cough, and hyperkalemia. Cough is caused by the action of ACE-I that inhibits the physiological breakdown of bradykinin induced by ACE, resulting in the accumulation of bradykinin with activation of inflammatory peptides and release of histamine.
Educational Objective: A classical adverse effect of ACE-I is dry cough. ACE-inhibitors act by inhibiting the breakdown of bradykinin, resulting in the accumulation of bradykinin with activation of inflammatory peptides and release of histamine.
References: Atlas SA, The renin-angiotensin aldosterone system: pathophysiological role and pharmacologic inhibition. J Manag Care Pharm. 2007;13(8):S9-20.
Karlberg BE. Cough and inhibition of the renin-angiotensin system. J Hypertens Suppl. 1993;11(3):S49-S52.
First Aid 2014 page 530]]

Approved Approved::Yes
Keyword WBRKeyword::Angiotensin, WBRKeyword::Angiotensin I, WBRKeyword::Angiotensin II, WBRKeyword::Angiotensin 1, WBRKeyword::Angiotensin 2, WBRKeyword::AldosteroneAngiotensinogen, WBRKeyword::RAAS, WBRKeyword::Pathway, WBRKeyword::Receptor, WBRKeyword::Blocker, WBRKeyword::Converting, WBRKeyword::Adverse effect, WBRKeyword::Adverse, WBRKeyword::Enzyme, WBRKeyword::ACE, WBRKeyword::Inhibitor, WBRKeyword::ACE inhibitor, WBRKeyword::Cough, WBRKeyword::Bradykinin, WBRKeyword::Side, WBRKeyword::effect
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