Pharmacology of Angiotensin Converting Enzyme (ACE) Inhibitors Flashcards
Describe the important components of Renin-Angiotensin- Aldosterone System (RAAS)
RAAS maintains normal BP homeostasis
1. angiotensinogen (pro-hormone) is cleaved via enzyme renin to Angiotensin I
2. Angiotensin I is cleaved via ACE to Angiotensin II
3. Angiotensin II can be converted to Aldosterone, but primarily it activates AT1 and AT2 receptors
What is the effect of AT1 receptor activation by Angiotensin II on intravascular volume?
increased intravascular volume
-increases Na+ reabsorption
-increases H2O retention
-increases vasoconstriction
-increased BP
What is the effect of AT1 receptor activation by Angiotensin II on vascular and cardiac cells?
mediates hypertrophy (increase in size) and remodeling
-in the vasculature (blood vessels) migration, proliferation, and hypertrophy are stimulated in smooth muscle cells
-in the cardiac (heart) hypertrophy of cardiac myocytes and increased extracellular matrix protein production by fibroblasts leads to myocardial stiffness
What is the goal when targeting AT1 and AT2 receptors?
maximize AT2 effects while minimizing AT1 effects
What are the effects of AT2 receptor activation?
-vasodilation
-antifibrotic
-anti-inflammatory
-decreased oxidative stress
-antiproliferation
What are substrates of angiotensin converting enzyme (ACE)?
angiotensin I and bradykinin
What is the MOA of ACE inhibitors?
- competitive inhibitor of ACE to inhibit synthesis of Ang II from Ang I
- inhibit bradykinin inactivation (increased bradykinin)= lowers BP and cardiovascular protective
What are the antihypertensive effects of ACE Inhibitors?
-decreased peripheral vascular resistance
-decrease aldosterone secretion
-inhibit breakdown of vasodilatory bradykinins
-enhance vasodilatory prostaglandin synthesis
What are the heart related effects of ACE Inhibitors?
-reduce cardiac myocyte hypertrophy
-can slow and reverse cardiac remodeling
-inhibit collagen deposition in target organs (heart and kidney)
What are the renal effects of ACE Inhibitors?
-decrease aldosterone production
-normalize Na+ excretion and reabsorption
-decrease arterial pressure= dilate arterioles in kidney
-decrease proteinuria
-reduce kidney scarring and fibrosis
What is the role of ACE Inhibitors in diabetes mellitus patients?
may delay diabetic nephropathy due to its renal protective effects
What is the role of ACE Inhibitors in HFrEF patients?
symptom improvement due to heart protective effects
Describe the chemistry of Captopril
sulfhydryl group (only one like it), synthetic analogue of dipeptide, competitive inhibitor of ACE, active as administered
What are the approved indications of Captopril?
-HTN (pt with normal renal function)
-left ventricular dysfunction (EF <40%) after MI
-diabetic nephropathy
Describe the chemistry of Enalapril
synthetic analogue of a tripeptide, prodrug= enalaprilat is active metabolite
What are the indications of Enalapril?
-HF
-HTN
-asymptomatic left ventricular dysfunction
NOT approved for pt with DM
Describe the chemistry of Lisinopril
lysine analog of enalaprilat, active as administered, longer t1/2 than captopril and enalapril
What are the indications of Lisinopril?
-HTN
-HF
-acute MI= improve survival post MI
Describe the chemistry of Ramipril
prodrug= ramiprilat is active metabolite, 50x more potent than captopril
What are the indications of Ramipril?
-HTN
-HF post MI
-reduction in the risk of MI, stroke, and death from cardiovascular disease
Describe the chemistry of Moexipril hydrochloride
prodrug= moexiprilat is active metabolite (1000x more active than parent)
What are the indications of Moexipril hydrochloride?
HTN
Describe the chemistry of Fosinopril
phosphinic acid that binds to Zn2+ (only one like it), prodrug = fosinoprilat is active metabolite
What are the indication of Fosinopril?
effectiveness is unaffected by race, sex, or weight
-HTN
-HF
What is the Black Box Warning of ACE Inhibitors?
fetotoxic in pregnancy due to risk of hypotension and renal failure resulting in injury or death
What are the adverse effects of ACE Inhibitors?
-dry cough (due to bradykinin accumulation)= decrease dose or switch to ARB
-angioedema (due to increased bradykinin)= do not use in patient with history of angioedema
-hypotension= monitor
-HYPERkalemia= caution in patients with renal insufficiency or taking K+ supplements
