RAAS/HTN Pharmacology

Question 1

Describe RAAS activation in setting of decreased BP

Answer 1

Renin converts angiotensinogen to angiotensin I

Angiotensin I converted to angiotensin II by angiotensin converting enzyme (ACE)

Angiotensin II is a potent vasoconstrictor that acts to increase TPR as well as increase ECF volume by stimulating thirst, aldosterone secretion [retains sodium], and ADH secretion [retains water]

End result is increased BP

Question 2

RAAS inhibition effects on the kidney

Answer 2

Angiotensin II tone (overall increased TPR) helps maintain resistance in efferent arterioles

GFR falls due to ACE inhibition, meaning serum creatinine increases in all patients — this preserves kidney function in hyperfiltering diabetics (note that <30% increase is okay as long as there is not hyperkalemia)

Question 3

ACE inhibitors used in HTN

Answer 3

Captopril

Enalapril (enalaprilat) — prodrug available IV

Benazapril

Lisinopril

[note benazepril and lisinopril are now widely used d/t longer half life permitting 1x/day dosing]

Question 4

MOA of captopril

Answer 4

Competitive inhibitor of angiotensin converting enzyme (ACE inhibitor)

Prevents conversion of angiotensin I to angiotensin II, thus preventing vasoconstriction and CV remodeling

Also leads to increased plasma renin activity and decreased aldosterone secretion

Overall lowers BP

Question 5

Clinical applications for captopril and other ACE inhibitors

Answer 5

HTN (can add thiazide or loop diuretic as needed)

Acute HTN emergency

Heart failure with reduced EF

LV dysfunction following MI

Diabetic nephropathy

Off-label: aldosteronism, delay the progression of nephropathy, reduce risks of cardiovascular events in DM

Question 6

Potential toxicities of captopril and other ACE inhibitors

Answer 6

Cough
Angioedema (anaphylaxis)

Hypotension, HA, drowsiness, dizziness, loss of/altered taste, myalgia, weakness, polyuria, renal failure, renal insufficiency

Rarely cholestatic jaundice, agranulocytosis, neutropenia, anemia, pancytopenia, or thrombocytopenia

Question 7

Angiotensin receptor antagonists

Answer 7

Losartan

Valsartan — noteworthy: not a prodrug requiring activation

Candesartan — noteworthy: irreversible binding

Question 8

MOA of losartan

Answer 8

Competitive nonpeptide angiotensin II receptor antagonist with 1000x greater selectivity for AT1 than AT2 receptor

Blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II

Induces a more complete inhibition of the RAAS system than ACE inhibitors

Does not affect response to bradykinin

Question 9

Clinical applications of losartan and other angiotensin receptor antagonists

Answer 9

Tx of diabetic nephropathy with increased SCr and proteinuria in type 2 diabetes and HTN

HTN (alone or with other anti-HTN drugs)

HTN with LV hypertrophy to reduce risk of stroke

CKD and HTN regardless of race or diabetes status, to improve kidney outcomes

Heart failure (if intolerant of ACE inhibitors)

Off-label: marfan syndrome

Question 10

Toxicities associated with losartan

Answer 10

Hypotension
Fatigue
Dizziness
Fever
Hypoglycemia
Hyperkalemia
Diarrhea
Gastritis
Nausea
Weight gain
Anemia
Weakness
Back/knee pain
Cough (

Question 11

MOA of aliskiren

Answer 11

Direct renin inhibitor, resulting in blockade of conversion of angiotensinogen to angiotensin I

Results in decreased formation of angiotensin II, aldosterone release, and sodium retention

Note that ACE inhibitor and ARB therapy can potentially be offset by increases in plasma renin activity, which is blocked by direct renin inhibitors

Question 12

Clinical applications of aliskiren

Answer 12

Tx of HTN, alone or in combo with other antihypertensive drugs

This drug is new, expensive, and has no obvious benefits over other drug classes — but there is evidence of increased risk of adverse events

Question 13

Toxicities associated with aliskiren

Answer 13

Skin rash

Diarrhea

> 300% increase in creatine phosphokinase

Increased BUN and serum Cr

Hyperkalemia, especially if combined or predisposing factors such as renal dysfunction or diabetes mellitus

Cough

Question 14

ACE inhibitors and ARBs work well when added to what other drug class?

Answer 14

Diuretics

Question 15

Which of the antihypertensive drug classes acting on the RAAS system is contraindicated in pregnancy?

Answer 15

ACE inhibitors

[cause malformations during 1st trimester so must be discontinued ASAP if pregnancy occurs]

Question 16

Drugs interfering with angiotensin II can lead to increased efferent tone — what does this mean for their use in clinical practice?

Answer 16

Can precipitate renal failure in pts with bilateral renal stenosis

Can help preserve renal function in diabetic pts

Question 17

Are the following clinical features more likely in essential (primary) HTN, or renovascular HTN?

Duration <1 year
Age at onset > 50
Grade 3 or 4 fundi
Abdominal bruit
BUN >20
K < 3.4
Urinary casts
Proteinuria

Answer 17

Renovascular HTN

Question 18

Effects of blockade of RAAS in pts with renovascular HTN d/t unilateral renal artery stenosis [elevated plasma renin]

Answer 18

Reduced arterial pressure

Enhanced lateralization of diagnostic tests

GFR in stenotic kidney may fall

Question 19

Should renal revascularization surgery be performed in pts with renovascular HTN?

Answer 19

Probably not, surgery fails to materially recover kidney function or add clinical benefit beyond that with current drug therapy

Recommendation is to tx with drugs that block RAAS as well as statin therapy

Question 20

A definite contraindication for the use of ACE inhibitors and ARBs

Answer 20

Bilateral renal stenosis