RAS Inhibitors

Question 1

Describe the short term and long term effects of Neurohormonal activation in heart failure?

Answer 1

Short term - compensatory response to CO decrease

Long term - maladaptive vasoconstriction, Na/water retention, LV remodeling (hypertrophy, apoptosis, fibrosis)

Question 2

What are the counter-regulatory vasodilators that oppose the long term maladaptive effects of neurohormonal activation?

Answer 2

Natriuretic peptides

Prostaglandins

Question 3

What factors will increase renin release?

Answer 3

Drop in blood pressure
Decreased NaCl sensed at macula densa
Increased sympathetic stimulation (NE at beta 1)

Question 4

What is ACE2?

Answer 4

Different form of converting enzyme that forms the peptide Angiotensin 1-7

Question 5

What is the function of Angiotensin 1-7?

Answer 5

Vasodilator, antiproliferative peptide

Counters the adverse cardiac and atherogenic effects of excess angiotensin II

Question 6

What drugs are ACE inhibitors?

Answer 6

Captopril
Enalapril
Lisinopril
Fosinopril

Question 7

What drugs are Angiotensin Receptor Blockers (ARB)?

Answer 7

Losartan

Valsartan

Question 8

What drugs are renin inhibitors?

Answer 8

Aliskiren

Question 9

What are the major effects of Angiotensin II?

Answer 9

Vasoconstriction (increased TPR, increased BP)

Increased aldosterone, increased Na reabsorption (slow BP increase)

Altered cardiovascular structure - hypertrophy (protooncogenes, growth factors, ECM proteins)

Question 10

What effect will ACE inhibitors have on bradykinin?

Answer 10

ACE breaks down bradykinin

ACE inhibitors = increased levels of bradykinin = increased prostaglandin levels = inflammatory vasodilator response = lowered BP, cough, angioedema

Question 11

What are some adverse effects of captopril?

Answer 11

Sulfhydryl drug side effects

Dysgeusia
Skin rashes
Nephropathy
Neutropenia

Question 12

Which ACE inhibitor is excreted partly in the bile and therefore less influenced by renal function?

Answer 12

Fosinopril

Question 13

Why does plasma renin increase when ACE inhibitors are used?

Answer 13

Normally Angiotensin II feedback inhibits renin release, but ACE inhibitors are blocking formation of AII

Question 14

What occurs to aldosterone levels with long term ACE inhibitor therapy?

Answer 14

“ACE escape”

Aldosterone levels rise due to alternative pathways that stimulate release

Question 15

What are some of the pathophysiologic effects of aldosterone?

Answer 15

Na reabsorption/K secretion, volume overload - hypertension, edema

Increased collagen synthesis, fibrosis, hypertrophy - LV remodeling

Increased platelet activation, inflammation, endothelial dysfunction - Ischemic events

Question 16

What drugs can be used to prevent the pathophysiologic effects of aldosterone that can occur with prolonged used of ACE inhibitors?

Answer 16

Mineralocorticoid receptor antagonists
Spironolactone
Eplerenone

Question 17

What must be monitored when a patient is on ACE inhibitor, Beta blocker, and mineralocorticoid receptor?

Answer 17

Serum K+

All of these drugs increase serum K+ so need to monitor for hyperkalemia

Question 18

How do AT1 receptors differ from AT2 receptors?

Answer 18

AT1 - vasconstriction, aldosterone release, adrenergic potentiation (the normal things we associate with angiotensin II release)

AT2 - vasodilation, antiproliferation, differentiation, expressed during development and in failing heart

Question 19

Which angiotensin receptors do ARBs act on?

Answer 19

AT1

Question 20

Why are ARBs not as good at reducing infarction rates in coronary artery disease as ACEIs?

Answer 20

ARBs only block AT1 response, leading to potentiation of AT2 response

AT2 response has some detrimental effects like increased plaque rupture

Question 21

What are shared beneficial effects of ACEIs, ARBs, and renin inhibitors?

Answer 21

Antihypertensive

Regression of LVH

Inhibition of vascular hyperplasia

Renal function preserved in diabetes

Question 22

What are shared adverse effects of ACEIs, ARBs, and renin inhibitors?

Answer 22

Dizziness, hypotension (espec. if dehydrated)

Hyperkalemia

Risk of renal failure in renal artery stenosis

Teratogenic (risk of fetal malformation)

Question 23

Why do RAS inhibitors increase the risk of renal failure in renal artery stenosis?

Answer 23

Renal artery is already constricted, efferent arteriole stays constricted to maintain GFR

If use RAS inhibitor, will dilate the efferent arteriole, decreasing the GFR and renal perfusion

Question 24

What stimulates release of natriuretic peptides and what do they cause?

Answer 24

Release stimulated by atrial or ventricular distention

Cause decreased sodium reabsorption and increased excretion

Question 25

What does the term compensated heart failure refer to?

Answer 25

Activation of RAS causing sodium reabsorption is balanced by the activation of ANP/BNP causing sodium excretion

Question 26

What does the term decompensated heart failure refer to?

Answer 26

RAS overwhelms ANP/BNP, causing increased rebasorption of sodium and volume overload

Question 27

What is the best biomarker for severity of heart failure?

Answer 27

BNP (specifically NT-proBNP)

Question 28

How is ANP/BNP broken down?

Answer 28

Neutral endopeptidase called neprilysin

Question 29

What is LCZ696?

Answer 29

A neprilysin inhibitor