ACE Inhibitors and Angiotensin Receptor Blockers

mechanism for why ACE inhib/ARBs help w HF (<40% EF)?

HF = dec SV and CO causes increase in sympathetics (B blocker helps so that B1 isnt stimulated) and RAAS (ACE or ARB helps) without meds, sympathetics and RAAS cause vasoconstriction (Increased afterload) and volume overload (increased preload, also from ADH) = dilated, nonfunctional L ventrical = further heart failure *reduce progression and mortality from HF* with ACE/ARB --> vasodilation of arterioles (decreased afterload), vasodilation of venules (decreased preload), decreased N

What drug has been approved for treatment of hereditary angioedema? How does it work? are most pts w angioedema treated with this?

Icatibant injection - bradykinin B2 receptor antagonist - for more severe cases no, corticosteroids and antihistamines are usually enough

What is the short negative feedback loop for Renin?

Increases in renin secretion increase the formation of Ang II Ang II stimulates AT1 receptors on the JGA to stop renin release

How does Sacubitril work?

Inhibits Neprilysin. Neprilysin degrades BNP (potent vasodilator). Sacubitril inhibits Neprilysin, therefore increasing BNP and dec vasoconstriction, sodium retention, and dec maladaptive remodeling of the heart

Which ACE Inhibitor has the longest half life and can be given once per day?

Lisinopril

What is angioedema? Why are ACE inhibitors thought to cause it?

Rapid swelling of the nose, throat, mouth, lips and tongue. - can occur after short therapy or years of therapy --> thought to be caused by accumulation of bradykinin, causing induction of auto-antibodies. tx w discontinuing ACEI, protecting airway, treating w epi, steroids, antihistamines SWITCH TO ARB AND DO NOT TRY ACEI AGAIN

How are almost all ACE inhibitors eliminated?

Renal

What is the rate limiting step in the formation of Ang II?

Renin converting Angiotensinogen -> Ang I.

What drug is Entresto?

Sacubitril (neprolysin inhibitor) + Valsartan (ARB)

ACE inhibitors end with? What is the one ACE inhibitor that doesn't?

"pril" (Captopril, Enalapril, Fosinopril, Lisinopril, Quinapril, Ramipril, etc..) - Enalaprilat is a prodrug that is given IV

Which pt's are most likely to develop renal insufficiency while on an ACE inhibitor or ARB?

- Older pt's - dry pt's (on diuretics) - pt's with bilateral or unilateral renal artery stenosis - pt's using chronic NSAIDs (these cause vasoconstriction of AA).

How are ACE inhib and ARBs beneficial to normotensive pt's with T1 or T2DM?

- They dec the permeability of the filtering membrane, so it is not damaged by proteins

How can an ACE inhibitor or ARB cause renal insufficiency?

- When renal perfusion is low, Ang II acts to constrict the efferent arteriole to inc/maintain GFR. - thus an ACE inhibititor or ARB can cause acute renal failure in pt's who are in a stay of low renal perfusion (unilateral or bilateral renal artery stenosis, high dose diuretics, heart failure)

How can you monitor whether an ACE Inhib or ARB is causing renal insufficiency/acute renal failure in your pt?

- may cause inc in serum creatinine or inc in BUN.

What are the ethnic differences in response to ACE Inhibitors and ARBs?

1. AA's responded better to diuretics and calcium channel blockers 2. Whites responded better to ACE inhibitors and beta blockers

Why are ACE Inhibitors and ARBs given after an MI?

An MI triggers many chemical remodelers, including Ang II, which induce hypertrophy -> block this with ACE or ARB

What allergic reaction can occur with ACE inhibitors but not with ARBs?

Angioedema

What is the long negative feedback loop for Renin?

Angiotensin II stimulates AT1 receptors to inc BP, which in turn inhibits renin release. -due to increase in BP (baroreceptors)

How does Aliskerin work?

Binds to renin and inhibits the conversion of angiotensinogen to Ang I thus decreasing the production of Ang I, Ang II, and Aldosterone.

What effect does Ang II have on cardiovascular structure?

Causes hypertrophy and remodeling of the myocardium. especially post MI

How do you dose an ACE inhibitor for a person with CHF or post-MI?

Start low and titrate up until you are at the highest dose where the pt is still hemodynamically stable (BP not too low, aren't getting dizzy).

What would you start a diabetic patient on if they had hypertension? why?

an ACE inhibitor or ARB - because likely they are going to develop proteinuria so start them on an anti-HTN that can slow this likely future problem

you can give _____ acutely if someone has very low BP

angiotensin II

What is another important substrate of ACE?

bradykinin - a potent vasodilator and promoter of inflammation - ACE cleaves this into inactive fragments - with an ACE inhibitor, bradykinin is allowed to circulate and be active and causes persistent dry cough.

antacids will _______ of captopril and probenecid will _____ of captopril.

decrease absorption decrease clearance

What kind of cough does an ACE Inhibitor cause? When does it occur? What do we think causes it?

dry, bothersome cough - occurs 1-6 weeks into therapy - caused by accumulation of bradykinin or substance P (both normally broken down by ACE)

What are the adverse effects of Aliskiren?

generally well tolerated but, angioedema, GI upset, hyperkalemia, can kill your baby if you take it while pregnant

What is the most common adverse effect of an ACE inhibitor?

hypotension

How does Ang II affect GFR in patients with renal artery stenosis, or those with CHF?

in these patients, the kidney senses hypotension. So Ang II constricts the efferent arteriole to inc GFR.

How does Ang II affect peripheral resistance? (3 ways)

increases peripheral resistance 1. direct vasoconstriction by binding to AT1 receptors of vascular smooth muscle. 2. inc outflow of NE, dec reuptake of NE 3. Release of catecholamines from the adrenal medulla = overall = increases TPR, therefore inc BP.

ARBS are used for all the same things as ACEIs but are not _______. Renal protective effects are still ____.

interchangeable under study used for HTN, CHF, as a substitute when coughing occurs in ACE

If your pt develops a cough while on an ACE inhibitor, what should you rule out?

rule out heart failure (although normally this would be a wet cough from pulmonary edema)

What is Aliskiren used for?

treatment of HTN as monotherapy or in combo with other anti-HTN.

Describe the RAAS (many steps)

1. Dec perfusion to the kidney is detected via the JGA 2. JGA releases Renin 3. Renin converts Angiotensinogen (from the liver) into Ang I 4. Ang I is converted to Angiotensin II via ACE in the lungs. 5. Angiotensin II causes many effects: a. inc in sympathetic activity (inc NE release, dec NE reuptake) b. inc in Na+ reabsorption in the proximal tubule, with K+ excretion and H2O retention c. Inc aldosterone secretion from the adrenal cortex which adds to the effects of (b) d. Acts on AT1 receptors to cause vasoconstriction e. stimulates pit gland to release ADH, which inc H2O reabsoprtion in collecting duct = Overall -> water and salt retention, inc circulating volume. Increased perfusion to the JGA.

What are the 4 indications for an ACE inhibitor?

1. HTN 2. Left ventricular systolic HF (HFrEF) 3. MI 4. Renal protection (reduce proteinuria) in diabetic or non-dM nephropathy

What are the 7 adverse effects of ACE inhibitors?

1. Hypotension 2. Dry Cough 3. Hyperkalemia 4. Renal effects (acute renal failure/insufficiency) 5. Fetopathic 6. skin rash (maculopapular rash) 7. Angioedema 8. dysgeusia (alteration or loss of taste) 9. netiropenia (usually in hypertensive pts)

How does Ang II affect renal function?

1. Inc Na+ reabsorption in the proximal tubule; with K+ excretion and H2O retention 2. stimulates adernal cortex to release Aldosterone, which furthers the effects of #1 3. Typically causes a net dec in GFR by constriction the afferent arteriole, but in the case of renal artery hypotension, it can constrict the efferent arteriole and inc GFR.

Why do we give ACE inhib or ARBs to patients with proteinuria or renal impairment?

1. These slow the progression of renal disease by decreasing BP 2. Decrease the damage Ang II has been shown to cause to the glomerulus, which can inc proteinuria

What are the 5 adverse effects of ARBs?

1. angioedema (still occurs but at lesser rate than ACEI's) 2. Hypotension 3. Hyperkalemia 4. Renal effects (same as ACEIs) 5. Fetopathic exception from ACEIs - no bradykinin increase :)

What are the 4 main side effects of Entresto (Sacubitril/Valsartan)?

1. hypotension 2. hyperkalemia 3. renal effects 4. Fetopathic!!!!!!!!! pretty much same as ARBS

What are the 3 major drug interactions for ACE inhibitors?

1. hypotensive agents and diuretics - additive effects can inc the likelihood of renal insufficiency 2. drugs that inc serum potassium (K+ sparing diuretics or K+ supplements) 3. NSAIDS (these block the vasodilation of the AA, and ACE inhibitor block constriction of EA -> can worsen renal insufficiency).

How do ACE Inhib and ARBs reduce proteinuria? (4)

1. reduce glomerular HTN 2. reduce the glomerular hyperpermeability by reducing Ang II 3. Anti-inflammatory effects 4. anti-platelet effects

What is the block box warning for Aliskiren?

Fetopathic - should be discontinued as soon as pregnancy detected

How do you dose an ACE inhibitor for a person with proteinuria?

Dose based on pt's BP, Monitor proteinuria and inc until there is no more protein

Which ACE Inhibitor is a prodrug?

Enalaprilat --> converted to Enalapril

What is the only approved use of Entresto (Sacubitril/Valsartan)?

Only approved for HFrEF pt's who are already on ACEI/ARB and beta blocker