Discuss the pathway of heart failure and neurohormonal activation
Poor ventricular function or Myocardial damage leads to insufficient SV, CO and tissue perfusion
--> 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?
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
Benefits of using ACE, ARB or Renin inhibitor?
Fall in BP that can be potentiated in combination with Diuretic
regression of LVH and icnreased survival in CHF
Inhibition of vascular hyperplasia
Renal Function preserved in Diabetes!!!
Adverse effects in using ACE, ARB, Renin inhib?
Dizziness and hypotension - potentiated with dehydration
Renal failure if Renal Artery Stenosis!!!
Explain compensated vs decompensated heart failure?
Compensated = adequate Na excretion from kidneys (ANP can balance RAS)
Decompensated = RAS wining over ANP
What are the A, B, and C types of Natriuretic peptides? Released from where to act on where and do what?
A-type released from stretch in Atria
B-type released from Ventricular stretch
C-type released from vascular endothelium - ONLY acts Locally
Supress RAS, Vasodilate to lower TPR, Incrase natriuresis and lose Na
What is used as a biomarker for dysfunction in CHF?
Pro-BNP used to measure release of ANP and is cleavage product from propeptide to make Pro-BNP and BNP
How do the natriuretic peptides work? what stops them?
activate guanylyl clcase A to convert GTP to cGMP and cause increased NA excretion, vasodilation, lusitropy etc
Neprylisin is the endopeptidase that breaks them down