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
