ACE Inhibitors and ARBs

Question 1

Where is angiotensinogen synthesized and what increases its production?

Answer 1

Synthesized in liver

Production increased by corticosteroids, estrogens, thyroid hormones and angiotensin II

Question 2

What is angiotensin I?

Answer 2

Substrate for ACE that has minimal biologic activity

Question 3

Where does angiotensin II exert its effects?

Answer 3

Vascular smooth muscle (contraction)
Adrenal cortex (stimulate aldosterone synthesis)
Kidney (inhibits renin secretion)
Heart (cardiac hypertrophy)
Brain (resets baroreceptor reflex of HR to higher pressure)
Regulates fluid/electrolyte balance and arterial BP

Question 4

How does AT II compare to epinephrine in terms of vasoconstriction?

Answer 4

It is 40x more potent

Question 5

What determines the rate of synthesis of AT II and what removes it from circulation?

Answer 5

Secretion of renin from kidneys

Angiotensinase removes it rapidly

Question 6

What 2 substrates does ACE act on and where is it found in the body?

Answer 6

AT I (cleaves carboxy-terminal two AA) + bradykinin (vasodilator)
Found in luminal surface of vascular endothelial cells in most tissues

Question 7

What are the 2 receptors for AT II and what are the effects?

Answer 7

AT1 (more common) = Gq that results in smooth muscle contraction
AT2 = bradykinin/NO production that results in vasodilation

Question 8

What does aldosterone act on and what are its end effects?

Answer 8

Increases activity of ENaC and basolateral Na/K ATPase in DCT and cortical collecting renal tubules
Results in increase in Na reabsorption and K secretion –> retention of water, increase in blood V, increase in BP and hypokalemia

Question 9

What is the MOA of ACEi?

Answer 9

Inhibit ACE and prevent inactivation of bradykinin

Question 10

How to ACEi lower BP?

Answer 10

Decrease peripheral vascular resistance with minimal effects on CO (makes it good drug for athletes)

Question 11

What are ACEi used for?

Answer 11

HTN, nephropathy (+/- diabetes), heart failure, left ventricular dysfunction (after MI), AMI and prophylaxis of cardiovascular events

Question 12

Adverse effects of ACEi

Answer 12

Hypotension, acute renal failure (esp in pts with renal A stenosis), hyperkalemia (more likely in renal insufficiency/diabetes), dry cough, angioedema

Question 13

How does ACEi cause acute renal failure?

Answer 13

Both afferent and efferent arterioles are dilated and GFR is not maintained in hypoperfused states

Question 14

What is the most common side effect of ACEi?

Answer 14

Dry cough since it interferes with breakdown of bradykinin

Question 15

What can ACEi cause if given during pregnancy?

Answer 15

Teratogenicity in 1st trimester

Fetal hypotension, anuria, renal failure, fetal malformations and even death in 2nd/3rd trimesters

Question 16

What other drugs can interact with ACEi and what results?

Answer 16

K+ supplements/K+ sparing diuretics –> hyperkalemia

NSAIDs –> may block bradykinin-mediated vasodilation

Question 17

What 2 ACEi do not have an active metabolite?

Answer 17

Captopril (half life 2 hours)

Lisinopril (half life 12 hours)

Question 18

Which ACEi is used for hypertensive emergencies?

Answer 18

Enalaprilat (active metabolite of Enalapril)

Question 19

MOA of angiotensin receptor blockers (ARBs)?

Answer 19

Selective blockage of AT1 receptors with no effect on bradykinin metabolism

Question 20

What are the effects of ARBs?

Answer 20

Relaxation of vascular smooth M, pressor responses, blockage of aldosterone secretion, changes in renal function, cellular hypertrophy and hyperplasia

Question 21

Differences between ARBs and ACEi?

Answer 21

ARBs block AT1 more effectively and promote AT2 activity

ACEi increase levels of bradykinin

Question 22

Adverse effects/contraindications of ARBs?

Answer 22

Similar to ACEi with lower rates of cough and angioedema
Do not use with K supplements or K sparing diuretics
Do not give during pregnancy or in patients with nondiabetic renal disease

Question 23

Which ARB is metabolized to more potent metabolite?

Answer 23

Losartan - shortest half life of 2 hours and peak plasma levels after 1 hr

Question 24

If I want to block the secretion of renin, what drugs would I want?

Answer 24

Clonidine and propranolol

Question 25

MOA of clonidine?

Answer 25

a2-agonist at brainstem

Inhibit sympathetic vasomotor centers resulting in reduction in sympathetic activity by decreasing renin secretion

Question 26

MOA of propranolol?

Answer 26

B1-antagonist at juxtaglomerular cells
Decreases renin release –> decreases BP
Decreases CO which also contributes to BP decrease

Question 27

What’s the name of an oral renin inhibitor and how is different from ACEi, ARBs and diuretics?

Answer 27

Aliskiren
Produces dose-dependent REDUCTION in plasma activity (whereas other drugs increase plasma renin activity)
See antihypertensive effects within 2 weeks
Do not use in pregnancy or patients with kidney insufficiency

Question 28

Why use polytherapy in HTN?

Answer 28

Monotherapy may not be effective - want to add on another drug with different MOA/pattern of toxicity

Question 29

Where is renin synthesized, what stimulates its release and what does it do?

Answer 29

Synthesized/stored in juxtaglomerular apparatus in nephron
Activation of B1- adrenergic receptors stimulates release
Cleaves decapeptide angiotensin I from angiotensinogen