E2: RAAS

Question 1

Aliskiren
Class
MOA
Kinetics
Use
ADR
DI

Answer 1

Direct Renin Inhibitor
MOA: Directly inhibits renin, prevents Ang I & Ang II formation

Pharmacokinetics
Poor absorption
High fat meals ↓ absorption; elimination via hepatobiliary tract
Metabolism: 90% excreted unchanged in the feces; CYP3A4 (10% metabolized)

Therapeutic applications
Hypertension: monotherapy; combined with hydrochlorothiazide, amlodipine or valsartan

ADR
Similar to ACEi/ARBs: Avoid in pregnancy & hyperkalemia
GI: diarrhea, pain, dyspepsia, gastroesophageal reflux
Headache, nasopharyngitis, dizziness; fatigue; upper RTI; back pain & rash
No effect on bradykinin & PGs – no dry cough or angioedema

DI
hyperkalemia w/K+ salts & K-sparing diuretics
Irbesartan- ↓ Aliskiren plasma levels & efficacy
P-glycoprotein inhibitors: ↑ Aliskiren plasma level (ex: atorvastatin & ketoconazole)
Aliskiren reduce furosemide conc. by 50%

Question 2

Angiotensin-converting enzymes inhibitors suffix

Answer 2

-pril

Question 3

Angiotensin II receptors blockers (AT1 blockers) suffix

Answer 3

-artan

Question 4

Captopril Classification

Answer 4

sulfhydryl containing inhibitor

Question 5

Fosinopril Monopril) classification

Answer 5

Phosphate-containing inhibitor

Question 6

Most common classification of ACE inhibitors

Answer 6

Dicarboxylate containing inhibitor

Question 7

ADR of ACEi due to inhibition of bradykinin metabolism

Answer 7

cough

Question 8

SAR of ACEi

Answer 8

N-ring must contain carboxylic acid for binding to the cationic site in ACE (large heterocyclic rings in N-ring portion ↑ potency)
-Zinc binding group: sulfhydryl (best), carboxylate, phosphinate
-carboxylate or phosphinate binding of Zn mimics transition state

Question 9

Nomenclature of ACEi
-pril =
-prilat =

Answer 9

-pril = ester prodrug (except Captopril and Lisinopril)
-prilate = active drug

Question 10

Metabolism of ACEIs

Answer 10

Bio-activation
Dimerization
Glucuronidation
Intramolecular cyclization into diketopiperazines
** most undergo metabolism except Lisinopril and enalaprilat **

Question 11

ACEIs Indications

Answer 11

Hypertension: ↓ Systemic vascular resistance & BP in various hypertensive states
Heart failure & MI
Acute myocardial infarction
DM & CKD: Prevent/delay progression of renal disease –> renoprotection
ACEIs may ↓ nephropathy progression in DM by:
↓ glomerular capillary pressure by dilating renal efferent arterioles ↓ glomerular injury
↓ exposure of the mesangium to patient growth factor à ↓ mesangial cell proliferation & matrix production
↓ Ang (1-7) metabolism –> ↑ levels of Ang (1-7) binding to Mas receptors –> protective & antifibrotic effects
↓ proteinuria

Question 12

ADR of ACEIs

Answer 12

Dry cough
angioedema
hyperkalemia
fetopathic potential
hypotension
acute renal failure

Question 13

ACEIs DI

Answer 13

↑ plasma levels of digoxin & lithium
↑ risk of allopurinol hypersensitivity
NSAIDs/aspirin may ↓ antihypertensive response of ACEI
Antacids may ↓ bioavailability of ACEI (especially captopril and fosinopril)
Diuretics
potential excessive ↓ BP
Loop diuretics: ↓ effects
K+ sparing diuretics/K+ preps - ↑ serum K+ levels

Question 14

Captopril
excreted ____ in urine
Indication
ADR
DI

Answer 14

unchanged or changed
HF & HTN
Rash, taste disturbances
Iron salts (↓ levels) Probenecid (↑levels)

Question 15

Losartan
conversion to metabolite
Competitive antagonist of TXA2 receptor –>

Answer 15

Converted to EXP3174 (more potent metabolite) by CYP2C9 and CYP3A4

Decreased platelet aggregation

Question 16

Sacubitril/Valsartan class

Answer 16

AT1 receptor antagonist w/neprilysin inhibitor

Question 17

MOA of ARBs

Answer 17

AT1 effects: vasoconstriction, aldosterone & vasopressin secretion, Na+ reabsorption, catechol release, & left ventricular remodeling

AT2 effects: cardioprotective (vasodilation, release of NO, regression of hypertrophy & apoptosis)

Current ARBs are 10,000x more selective for AT1 subtype than AT2 & are competitive antagonists

Selective AT1 blocker is desired since blocking AT2 would reduce or eliminate cardioprotective effects

Question 18

ARBs require dosing adjustments with: renal and/or hepatic impairment?

Answer 18

only hepatic

Question 19

ACEIs require reduced dosage in: renal and/or hepatic impairment?

Answer 19

only renal

Question 20

Losartan is metabolized by CYP2C9 and 3A4 to EXP3174, is it a prodrug

Answer 20

NO, Losartan and EXP3174 have anti-htn effects

Question 21

Most ARBs are eliminated unchanged except: (3)
Why

Answer 21

Candesartan Cilextil, Olmesartan Medoxomil, Azilsartan Medoxomil because they are prodrugs

Question 22

Uses of ARBs

Answer 22

hypertension: alone or in combination with diuretics, β blockers, & CCBS

Heart failure: ARBs- reserved for intolerance/inadequate response to ACEIs (1st line agents)

Renoprotection in DM (ARBs) are drugs of choice

Question 23

ADR of ARBS

Answer 23

Teratogenic potential
angioedema (Rare) –> tounge, swelling – visit ER
Headache, dizziness, fatigue
hypotension
hyperkalemia (inhibit aldosterone release)
Other: dyspepsia, diarrhea, abdominal pain, myalgia, back pain

Question 24

DI of ARBs in general

Answer 24

Hyperkalemia when co-administered w/K+ salts, K-sparing diuretics

NSAIDs alter effect by inhibiting vasodilatory PGs

Question 25

Specific DI of Telmisartan and Losartan

Answer 25

Telmisartan - ↑ digoxin levels

Rifampin- ↓Losartan & its active metabolite levels

Question 26

Losartan is a competitive antagonist of TXA2 which ↓ ______ ________

Answer 26

↓ platelet aggregation

Question 27

Valsartan (Diovan) absorption (is or is not) affected by food

Answer 27

Food markedly decrease absorption

Question 28

MOA of Sacubitril portion of Entresto

Answer 28

Neprilysin inhibitor so it breaks down natriuretic peptide

Question 29

Active metabolite of Sacubitril

Answer 29

Esterases metabolize it to LBQ657

Question 30

Entresto Pharm effects and DI

Answer 30

Sacubitril/Valsartan
↓vascular resistance ↑blood flow
In HF, reduced ejection fraction
DI: avoid admin w/ARB, ACEi, or aliskiren