L15- RAS inhibitors Flashcards
Discuss the pathway of heart failure and neurohormonal activation
Poor ventricular function or Myocardial damage leads to insufficient SV, CO and tissue perfusion
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-> Neurohormonal Activation:
1) Increased sympathetic
2) Vasoactive peptides like RAS, Vasopressin, Endothelin, Natriuretic
3) Inflamm mediators like PGs and cytokines
–> Vasoconstriction, Salt and water retention, hypertrophy/remodeling
**–> Further ventricular dysfunction and heart failure **
Why are NSAIDs avoided in heart failure?
renal function depends on prostaglandin synthesis
What triggers Renin release?
Decreased CO, volume, vascular resistance, BP leads to
decreased glomerular BP, decrease NaCl sensed at macular Densa and increased NE release
All act to increase Renin
What is ACE and how does it work/what does it do?
What about ACE2?
ACE = cleaves AG1 to AG2 in the lungs
ACE2 = makes AG1-7 from excess AG2 and AG1-7 is a counter-regulatory peptide that acts as a dilator and reduces atherogenic effects
What are the 3 different forms/classes of RAS inhibitors and some drugs within each category?
ACE-Inhibitors = Captopril, Enalapril, Lisinopril -“Prils”
Angiotensin Receptor Blockers (ARBs) = Losartan and Valsartan
**Renin Inhibitors **= anti-HTN not used in HR = Akiskiren
What are all the effects of Ag2?
1) Rapid Presser Response - vasoconstriction and enhanced sympathoadrenal activity
2) Slow Presser response - increase Aldosterone to increase Na reabsorption
3) Alter CV structure by increasing TGF-Beta nd increasing Fibrosis
4) Hemodynamic alteration of CV structure - vascular and cardial hypertrophy and remodeling
What is the relation of RAS to bradykining and Prostaglandins?
ACE converts AG1 to AG2
**ACE also inactivates Bradykinin **
BRadykinin is a Potent endothelium dependent vasodilator that acts on the B2 receptor to release NO
What are the adverse effects of ACE inhibitors?
Chronic Cough
Angioedema
What are the ACE-Inhibitors and the differences between them?
First Generation - Sulfhydryl
Captopril - Sulfhydryl group, renal excretion (can lead to kidny dysfunction!), Short halflife
_Second Generations: no sulfhydril _
Enalapril - no sulfhydryl (carboxyl instead), pro-drug convered and longer hlaf life, renal excretion (Can lead to kidney dysfunction!)
Fosinopril - Prodrug with Bile exretion so less effects on kidney
What are the common adverse effects of Sulfhydryl drugs?
Dysguesia, skin rash, nephropathy, neutropenia
What are the Mineralcorticoid receptor antagonists? Side effects?
Sprinolactone and eplerenone
USed when increased Aldosterone which can cause volume overload, fibrosis, hypertrophy etc
Eplenerone - no side effects
Spironolactone - Gynecomastia and irregular menstrual periods
What anti-HTN drugs raise serum K+? significance?
ACE inhibitors, Beta blockers, and MRA
Careful for hyerkalemia leading to increased malaise, palpitations, weaness that can lead to sudden death!
What are the signaling pathways, tissue responses, expression and blockers for angiotensin receptor subtype AT1?
AT1 signal with increased phospholipase and tyrosine kinase, decreased Adenylyl cyclase;
AT1 cause vasoconstriction, aldosterone, Adrenergic potentiation, myocyte hypertrophy, vascular hypertrophy, and hyperplasia
See down-regulation in CHF
_Blocked by ARBs -AT-1 selective!!!!! _
What are the signaling pathways, tissue responses, expression and blockers for angiotensin receptor subtype AT2?
AT2 signal through Tyrosine phosphatase
**AT2 cause vasodilation, antiproliferation and differentiation **
**AT2 bad effects cause Plaque rupture and adverse vascular remodeling **
AT2 expressed only during development and increased in CHF
Differences between ACE-Inhib and ARBs?
ACE reduces AG2 and responses to BOTH AT1 and AT2
ARB are antiogensin receptor blockers blocking AT1 response and so potentiation of AT2 response which could be bad in CAD bc could see plaque rupture
