L15 Flashcards
What is the role of neurohormones in response to heart failure short term?
Adaptive responses to ↓CO Take the stress off the heart How: - Vasoconstriction - Na & H2O retention
What is the role of neurohormones in response to heart failure long term?
The short term response has been dragged out - were beneficial but now MALADAPTIVE
What type of HF should you sue RAS inhibitors and BB for?
HF with reduced EF
Why does HF result in ↑renin?
↓CO --> ↓circulating blood volume & ↓BP 3 mechanisms to ↑renin: 1. ↓Pre-glomerular BP 2. ↓NaCl at macula densa 3. ↑NE due to HR sympathetic activation
What is ACE2? Fxn?
Enzyme (not ACE)
Counter adverse effects of excess AGT2
- Vasodilation
- Anti-proliferative
What is the normal fxn of ACE?
AGT1 –> AGT2
What are the 3 ACE inhibitors you need to know?
Captopril
Enalapril
Lisinopril
What are the 2 receptors AGT2 can bind?
AT1 & AT2
3 ways to pharm block the RAAS system
- ACE inhibitors
- Angiotensin receptor blockers
- Renin inhibitors
What are 2 angiotensin receptor blockers you need to know?
Losartan
Valsartan
What is the renin inhibitor you need to know?
Aliskiren
What is normal AGT2 fxn to create a rapid ↑BP?
Change TPR:
- Vasoconstrict
- ↑Sympathetics
What is normal AGT2 fxn to create slow ↑BP?
Change renal fxn
- ↑NA reabsorption
- ↑Aldosterone = acts directly on ENAC
What is normal AGT2 fxn leading to vascular and cardiac hypertrophy?
↑Proto-oncogenes
↑GF
↑Extracellular matrix proteins (collagen)
+ Hemodynamics like ↑afterload and ↑wall tension
How is the RAAS system connected to bradykinin and prostaglandins?
ACE enzyme
- AGT1 –> AGT2
- Inactivates bradykinin
What is the fxn of bradykinin and PGs? What are their adverse effects?
↓BP Opposes the action of RAAS Adverse - Cough - Angioedema
How do ACE inhibitors change bradykinin levels?
No bradykinin inactivation
Captopril
- Fxn
- Excretion
- Dosing
- SEs
ACE inhibitor
Renal excretion - impt for HF
Low dose to avoid SE of higher doses:
- Change in taste, rashes, nephropathy, neutropenia
Enalapril
- Fxn
- Excretion
ACE inhibitor w/ longer t1/2 than capto
Renal excretion - watch HF pts
Fosinopril
- Fxn
- Excretion
ACE inhibitor w/ longer t1/2 than capto
Renal/bile excretion
- Less sensitive to renal fxn = good for cardiac pts
What are the plasma values for AGT2, aldosterone and renin for pts on ACE inhibitors
↓AGT2 & aldosterone
↑renin - lose neg FB
Doesn’t matter b/c the downstream effects of renin are blocked by these meds
What is the mechanism of aldosterone?
↑Na retention via ENAC
K wasting
What are some of the pathophysologic effects of aldosterone?
Volume overload w/ ion imbalance
LVH b/c more collagen synthesis –> remodeling
Endothelial dysfxn -> ischemic vessels
How can you block the effects of aldosterone?
Mineralcorticoid receptor antagonists
- Spironolactone
- Eplerenone
What happens to AT1 receptors during CHF? Why?
Partial ↓ regulated B/c heart is trying to compensate for damage These receptors aren't heart friendly: - Vasoconstrict - ↑aldosterone release - ↑sympa - Hypertrophy
Why are angiotensin receptor blockers used for HF?
B/c selectively block AT1 receptors Allow all AGT2 produced to work at AT2 receptors: - Vasodilation - Anti-proliferative - Differentiation Can reverse some of the damage done
Why does it make sense that renin and ACE inhibitors block action at both AT1 and AT2 receptors?
B/c stop AGT2 production - can’t work at either
Renin inhibitors causes plasma levels of: Renin AGT1 AGT2 Aldosterone Bradykinin & PGs
↓of all!!!
Stops at the renin - so everything downstream must also go down!
No change to bradykinin/PGs
Angiotensin receptor blockers cause plasma levels: Renin AGT1 AGT2 Aldosterone Bradykinin & PGs
↓Aldosterone
But lose feedback onto renin:
↑renin - ↑AGT1 - ↑AGT2
ACE inhibitors cause plasma levels: Renin AGT1 AGT2 Aldosterone Bradykinin & PGs
↓AGT2
↓Aldosterone
- ↑Bradykinin & PGs
↑Renin - ↑AGT1 due to loss of neg FB
What are 4 shared benefits of ACE, renin inhibitors, and ARBs
- Anti-HTN
- Reverse LVH (huge!!!!)
- ↓vascular hyperplasia
- Renal fxn unaffected in diabetics
What are the shared adverse effects of ACE, renin inhibitors, and ARBs?
Hyperkalemia
↑risk kidney failure if you have renal artery stenosis
- YOU KNOW THIS
Teratogenic
What is the normal fxn of atrial and brain natriuretic peptides - ANP & BNP?
Balances RAAS: ↓Na reabsorption Vasodilation ↓Sympa ↓Renin
What is compensated HF?
ANP balances RAAS to maintain BV
How is ANP measured?
Short t1/2 so can’t measure directly
Measure cleavage product = NT-proBNP
IMPT b/c used as myocardial injury
- ↑ed levels w/ worse HF
