Pharmacology of Angiotensin Converting Enzyme (ACE) Inhibitors

Question 1

Describe the important components of Renin-Angiotensin- Aldosterone System (RAAS)

Answer 1

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

Question 2

What is the effect of AT1 receptor activation by Angiotensin II on intravascular volume?

Answer 2

increased intravascular volume
-increases Na+ reabsorption
-increases H2O retention
-increases vasoconstriction
-increased BP

Question 3

What is the effect of AT1 receptor activation by Angiotensin II on vascular and cardiac cells?

Answer 3

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

Question 4

What is the goal when targeting AT1 and AT2 receptors?

Answer 4

maximize AT2 effects while minimizing AT1 effects

Question 5

What are the effects of AT2 receptor activation?

Answer 5

-vasodilation
-antifibrotic
-anti-inflammatory
-decreased oxidative stress
-antiproliferation

Question 6

What are substrates of angiotensin converting enzyme (ACE)?

Answer 6

angiotensin I and bradykinin

Question 7

What is the MOA of ACE inhibitors?

Answer 7

1. competitive inhibitor of ACE to inhibit synthesis of Ang II from Ang I
2. inhibit bradykinin inactivation (increased bradykinin)= lowers BP and cardiovascular protective

Question 8

What are the antihypertensive effects of ACE Inhibitors?

Answer 8

-decreased peripheral vascular resistance
-decrease aldosterone secretion
-inhibit breakdown of vasodilatory bradykinins
-enhance vasodilatory prostaglandin synthesis

Question 9

What are the heart related effects of ACE Inhibitors?

Answer 9

-reduce cardiac myocyte hypertrophy
-can slow and reverse cardiac remodeling
-inhibit collagen deposition in target organs (heart and kidney)

Question 10

What are the renal effects of ACE Inhibitors?

Answer 10

-decrease aldosterone production
-normalize Na+ excretion and reabsorption
-decrease arterial pressure= dilate arterioles in kidney
-decrease proteinuria
-reduce kidney scarring and fibrosis

Question 11

What is the role of ACE Inhibitors in diabetes mellitus patients?

Answer 11

may delay diabetic nephropathy due to its renal protective effects

Question 12

What is the role of ACE Inhibitors in HFrEF patients?

Answer 12

symptom improvement due to heart protective effects

Question 12

Describe the chemistry of Captopril

Answer 12

sulfhydryl group (only one like it), synthetic analogue of dipeptide, competitive inhibitor of ACE, active as administered

Question 13

What are the approved indications of Captopril?

Answer 13

-HTN (pt with normal renal function)
-left ventricular dysfunction (EF <40%) after MI
-diabetic nephropathy

Question 14

Describe the chemistry of Enalapril

Answer 14

synthetic analogue of a tripeptide, prodrug= enalaprilat is active metabolite

Question 15

What are the indications of Enalapril?

Answer 15

-HF
-HTN
-asymptomatic left ventricular dysfunction
NOT approved for pt with DM

Question 16

Describe the chemistry of Lisinopril

Answer 16

lysine analog of enalaprilat, active as administered, longer t1/2 than captopril and enalapril

Question 17

What are the indications of Lisinopril?

Answer 17

-HTN
-HF
-acute MI= improve survival post MI

Question 18

Describe the chemistry of Ramipril

Answer 18

prodrug= ramiprilat is active metabolite, 50x more potent than captopril

Question 19

What are the indications of Ramipril?

Answer 19

-HTN
-HF post MI
-reduction in the risk of MI, stroke, and death from cardiovascular disease

Question 20

Describe the chemistry of Moexipril hydrochloride

Answer 20

prodrug= moexiprilat is active metabolite (1000x more active than parent)

Question 21

What are the indications of Moexipril hydrochloride?

Answer 21

HTN

Question 22

Describe the chemistry of Fosinopril

Answer 22

phosphinic acid that binds to Zn2+ (only one like it), prodrug = fosinoprilat is active metabolite

Question 23

What are the indication of Fosinopril?

Answer 23

effectiveness is unaffected by race, sex, or weight
-HTN
-HF

Question 24

What is the Black Box Warning of ACE Inhibitors?

Answer 24

fetotoxic in pregnancy due to risk of hypotension and renal failure resulting in injury or death

Question 25

What are the adverse effects of ACE Inhibitors?

Answer 25

-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