Drugs that impact AngII

Question 1

MOA of Captopril?

Answer 1

• Competitive inhibitor of ACE

Question 2

Effx of captopril?

Answer 2

• Prevents AngI –> AngII (potent vasoconstrictor and mitogen for CV remodeling)
• ↓ levels of AngII –> ↑ plasma renin activity and ↓ aldosterone secretion
• Lowers BP

Question 3

Clinical Application of captopril?

Answer 3

• HTN, add thiazide or loop diuretic if additional ↓ needed
• Acute HTN (urgency or emergency)
• HF w/ ↓ EF (HFrEF)(ACCF/AHA)
• LV dysfunxn following MI
• Diabetic nephropathy
• Off-label: aldosteronism dx, delat the progression of nephropathy and ↓ risks of CV events HT + DM

Question 4

PKs of captopril?

Answer 4

• Rapidly absorbed, ~60% bio-avail
• Substrate of CYP2D6
• Excreted in urine, 40-50% unchanged
• half life ~1.7 hrs, ↑ w/ renal impairment

Question 5

Toxicities of captopril?

Answer 5

• Cough, hypotension, HA, drowsiness, dizziness, orthostatic dizziness
• Angioedema, anaphyllactoid rxns
• Loss of or altered taste
• Rare cholestatic jaundice, agranulocytosis, neutropenia, anemia, pancytopenia, thrombocytopenia
• myalgia, weakness, polyuria, RF, renal insuff.

Question 6

Enalapril (enalaprilit), benazepril, & Lisinopril

Answer 6

• Enalapril: another early ACEI, prodrug w/ IV active form (enalaprilate)
• Benazepril: widely used ACEI, longer half-life permitting 1x/day dosing
• Lisinopril: widely used ACEI, longer half-life permitting 1x/day dosing

Question 7

Main reasons ACEI are stopped?

Answer 7

• Cough
• Angioedema

Question 8

MOA of losartan?

Answer 8

• Competitive nonpeptide angII-R antagonist w/ 100x greater selectivity for ATI R than AT2

Question 9

Effects of Losartan?

Answer 9

• Blocks the vasoconstrictor and aldosteron-secreting effects of AngII
• Induces more complete inhibition of RAS tahn ACEI
• Does not effect response to bradykinin –> no cough

Question 10

Clinical application of losartan?

Answer 10

• Diabetic nephropathy w/ ↑ S Cr and proteinuria in T2DM and HTN
• HTN, alone or combo
• HTN w/ LVH to ↓ stroke risk
• CKD & HTN to improve kidney outcomes
• HF if intolerant of ACEI
• Off-label: Marfan syndrome

Question 11

PKs of Losartan?

Answer 11

• Extensive 1st pass metab via CYP2C9 and 3A4 to active metabolite, E-3174
• Half life: losartant = 2 hrs; E-3174 = 6-9 hrs

Question 12

Toxicities of losartan?

Answer 12

• Common in diabetic nephropathy pts
• Hypotenstion, first-dose hypotension, orthostat hypotension
• Fever, fatigue, dizziness
• Hypoglycemia, hyperkalemia
• Diarrhea, gastritis, wt gain
• anemia
• weakness, back/knee pain
• cough (< ACEI), bronchitis, nasal congestion

Question 13

Valsartan & Candesartan

Answer 13

• Valsartan: half life 6-10 hrs; not a prodrug; excreted in feces unchanged
• Candesartan: half life 5-9 hrs; relatively irreversible binding to receptor

Question 14

MOA of aliskiren?

Answer 14

• Direct renin inhibitor, resulting in blockade of conversion of angiotensinogen –> angiotensin I

Question 15

Effx of aliskiren?

Answer 15

• ↓ formation of Ang II
• ACEI and ARB therapy can potentially be offset by ↑ in plasma renin activity, which is blocked by direct renin inhibitors

Question 16

Clinical applications of aliskiren?

Answer 16

• HTN, alone or in combo

Question 17

PKs of aliskiren?

Answer 17

• Oral, poor absorption
• Max effx seen in 2 weeks
• half life = ~24 hrs
• Excreted unchanges in urine and feces

Question 18

Toxicities of aliskiren?

Answer 18

• Very rare
• Skin rash (1%), rare HS rxns
• diarrhea (2%)
• >300% ↑ in creatinine phosphokinase (1%)
• ↑ BUN and serum creatinine
• Hyperkalemia, esp w/ predisposing factors (DM, RF, etc.)
• Cough (1%)

Question 19

How do drugs that interfere with Ang II affect the kidneys?

Answer 19

↓ Ang II –> efferent tone

• can precipitate RF in pts with bilateral renal stenoisis
• can hlep preserve renal function in DM pts

Question 20

Which drugs are contraindicated in pregancy?

Answer 20

• ACEI
• Initially thought to only cause fetal harm in 2nd and 3rd trimesters, but now known to cause malformations in 1st