E2: RAAS Flashcards
Aliskiren
Class
MOA
Kinetics
Use
ADR
DI
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%
Angiotensin-converting enzymes inhibitors suffix
-pril
Angiotensin II receptors blockers (AT1 blockers) suffix
-artan
Captopril Classification
sulfhydryl containing inhibitor
Fosinopril Monopril) classification
Phosphate-containing inhibitor
Most common classification of ACE inhibitors
Dicarboxylate containing inhibitor
ADR of ACEi due to inhibition of bradykinin metabolism
cough
SAR of ACEi
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
Nomenclature of ACEi
-pril =
-prilat =
-pril = ester prodrug (except Captopril and Lisinopril)
-prilate = active drug
Metabolism of ACEIs
Bio-activation
Dimerization
Glucuronidation
Intramolecular cyclization into diketopiperazines
** most undergo metabolism except Lisinopril and enalaprilat **
ACEIs Indications
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
ADR of ACEIs
Dry cough
angioedema
hyperkalemia
fetopathic potential
hypotension
acute renal failure
ACEIs DI
↑ 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
Captopril
excreted ____ in urine
Indication
ADR
DI
unchanged or changed
HF & HTN
Rash, taste disturbances
Iron salts (↓ levels) Probenecid (↑levels)
Losartan
conversion to metabolite
Competitive antagonist of TXA2 receptor –>
Converted to EXP3174 (more potent metabolite) by CYP2C9 and CYP3A4
Decreased platelet aggregation
Sacubitril/Valsartan class
AT1 receptor antagonist w/neprilysin inhibitor
MOA of ARBs
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
ARBs require dosing adjustments with: renal and/or hepatic impairment?
only hepatic
ACEIs require reduced dosage in: renal and/or hepatic impairment?
only renal
Losartan is metabolized by CYP2C9 and 3A4 to EXP3174, is it a prodrug
NO, Losartan and EXP3174 have anti-htn effects
Most ARBs are eliminated unchanged except: (3)
Why
Candesartan Cilextil, Olmesartan Medoxomil, Azilsartan Medoxomil because they are prodrugs
Uses of ARBs
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
ADR of ARBS
Teratogenic potential
angioedema (Rare) –> tounge, swelling – visit ER
Headache, dizziness, fatigue
hypotension
hyperkalemia (inhibit aldosterone release)
Other: dyspepsia, diarrhea, abdominal pain, myalgia, back pain
DI of ARBs in general
Hyperkalemia when co-administered w/K+ salts, K-sparing diuretics
NSAIDs alter effect by inhibiting vasodilatory PGs
Specific DI of Telmisartan and Losartan
Telmisartan - ↑ digoxin levels
Rifampin- ↓Losartan & its active metabolite levels
Losartan is a competitive antagonist of TXA2 which ↓ ______ ________
↓ platelet aggregation
Valsartan (Diovan) absorption (is or is not) affected by food
Food markedly decrease absorption
MOA of Sacubitril portion of Entresto
Neprilysin inhibitor so it breaks down natriuretic peptide
Active metabolite of Sacubitril
Esterases metabolize it to LBQ657
Entresto Pharm effects and DI
Sacubitril/Valsartan
↓vascular resistance ↑blood flow
In HF, reduced ejection fraction
DI: avoid admin w/ARB, ACEi, or aliskiren
