RAS Inhibitors Flashcards
Describe the short term and long term effects of Neurohormonal activation in heart failure?
Short term - compensatory response to CO decrease
Long term - maladaptive vasoconstriction, Na/water retention, LV remodeling (hypertrophy, apoptosis, fibrosis)
What are the counter-regulatory vasodilators that oppose the long term maladaptive effects of neurohormonal activation?
Natriuretic peptides
Prostaglandins
What factors will increase renin release?
Drop in blood pressure
Decreased NaCl sensed at macula densa
Increased sympathetic stimulation (NE at beta 1)
What is ACE2?
Different form of converting enzyme that forms the peptide Angiotensin 1-7
What is the function of Angiotensin 1-7?
Vasodilator, antiproliferative peptide
Counters the adverse cardiac and atherogenic effects of excess angiotensin II
What drugs are ACE inhibitors?
Captopril
Enalapril
Lisinopril
Fosinopril
What drugs are Angiotensin Receptor Blockers (ARB)?
Losartan
Valsartan
What drugs are renin inhibitors?
Aliskiren
What are the major effects of Angiotensin II?
Vasoconstriction (increased TPR, increased BP)
Increased aldosterone, increased Na reabsorption (slow BP increase)
Altered cardiovascular structure - hypertrophy (protooncogenes, growth factors, ECM proteins)
What effect will ACE inhibitors have on bradykinin?
ACE breaks down bradykinin
ACE inhibitors = increased levels of bradykinin = increased prostaglandin levels = inflammatory vasodilator response = lowered BP, cough, angioedema
What are some adverse effects of captopril?
Sulfhydryl drug side effects
Dysgeusia
Skin rashes
Nephropathy
Neutropenia
Which ACE inhibitor is excreted partly in the bile and therefore less influenced by renal function?
Fosinopril
Why does plasma renin increase when ACE inhibitors are used?
Normally Angiotensin II feedback inhibits renin release, but ACE inhibitors are blocking formation of AII
What occurs to aldosterone levels with long term ACE inhibitor therapy?
“ACE escape”
Aldosterone levels rise due to alternative pathways that stimulate release
What are some of the pathophysiologic effects of aldosterone?
Na reabsorption/K secretion, volume overload - hypertension, edema
Increased collagen synthesis, fibrosis, hypertrophy - LV remodeling
Increased platelet activation, inflammation, endothelial dysfunction - Ischemic events
What drugs can be used to prevent the pathophysiologic effects of aldosterone that can occur with prolonged used of ACE inhibitors?
Mineralocorticoid receptor antagonists
Spironolactone
Eplerenone
What must be monitored when a patient is on ACE inhibitor, Beta blocker, and mineralocorticoid receptor?
Serum K+
All of these drugs increase serum K+ so need to monitor for hyperkalemia
How do AT1 receptors differ from AT2 receptors?
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
Which angiotensin receptors do ARBs act on?
AT1
Why are ARBs not as good at reducing infarction rates in coronary artery disease as ACEIs?
ARBs only block AT1 response, leading to potentiation of AT2 response
AT2 response has some detrimental effects like increased plaque rupture
What are shared beneficial effects of ACEIs, ARBs, and renin inhibitors?
Antihypertensive
Regression of LVH
Inhibition of vascular hyperplasia
Renal function preserved in diabetes
What are shared adverse effects of ACEIs, ARBs, and renin inhibitors?
Dizziness, hypotension (espec. if dehydrated)
Hyperkalemia
Risk of renal failure in renal artery stenosis
Teratogenic (risk of fetal malformation)
Why do RAS inhibitors increase the risk of renal failure in renal artery stenosis?
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
What stimulates release of natriuretic peptides and what do they cause?
Release stimulated by atrial or ventricular distention
Cause decreased sodium reabsorption and increased excretion
What does the term compensated heart failure refer to?
Activation of RAS causing sodium reabsorption is balanced by the activation of ANP/BNP causing sodium excretion
What does the term decompensated heart failure refer to?
RAS overwhelms ANP/BNP, causing increased rebasorption of sodium and volume overload
What is the best biomarker for severity of heart failure?
BNP (specifically NT-proBNP)
How is ANP/BNP broken down?
Neutral endopeptidase called neprilysin
What is LCZ696?
A neprilysin inhibitor
