1) ACE cleaves the His-Leu off Ang I to create Ang II. ACEi prevent this cleavage.
2) Prevent the degradation of Bradykinin
*discovered via SA pit viper. 1st drug=Captopril
Adverse effects of ACEi
1. dry cough
2. hyperkalemia (due to blocking of RAAS)
a. k supp
b. cv conditions
c. renal insufficiency
d. other RAAS blocking drugs!
3. angioedema***must switch to CCB
4. ARF (extra caution with NSAIDS)
CI with ACEi
1. renal artery stenosis
3. black box- pregnancy ***blocking AT1 & AT2(cell growth and development)
PK of ACEi
**all cleared by kidney EXCEPT fosinopril (urinary and biliary route)
Only ACEi with a sulfhydryl group
Only ACEi that is crushable
Only ACEi that is cleared both by urine and biliary routes
ARB vs. ACEi
ARB binds to AT1 receptor with high affinity/selectivity vs. AT2. This is important because ACE is not the only enzyme that can convert Ang I to Ang II. Binding AT1 ensures selective inhibition of Ang II, meaning ARBs do not affectbradykinin.
by binding competitively to AT1, this forces Ang II to bind to AT2 receptors, which contributes to vasodilation.
Diabetic Neph- Irbesartan & Losartan
Stroke prophylaxis- Losartan
Heart Failure- Valsartan
*no dry cough
hyperkalemia (k supp, cv pts, renal insuff)
ARF (NSAID caution!)
**low risk angioedema, but put on CCB if prob
renal artery stenosis
angioedema (place on CCB)
black box- pregnancy cat d
all eliminated by LIVER and KIDNEY
Renin Inhibitors: what's so great about it?
The ONLY FDA approved direct renin inhibitor= Aliskiren (Tekturna).
Monotherapy or combo with diuretics and ARBs for Tx of HT.
Renin inhibitor: MOA
inhibits renin upstream of RAAS. **potential benefit and favorable AE profile.
Inhibiting renin prevents cleavage of Angiotensinogen to Ang I, reducing both Ang I and Ang II levels.
Renin Inhibitors: AE
*dose related GI
*Low incidence cough and angioedema
Renin Inhibitors: CI
black box- preg D
angioedema (low risk, but there)
Renin Inhibitors: PK
poor oral absorption
METABOLIZED by 3A4!!!!! (Drug-Drug: macrolides, a/depressants, a/fungal)
Aldosterone Antags (K sparing): MOA
ENaC on apical membrane of CD is affected by two ways. End result is inhibition of Na reabs and K excretion.
2 ways ENaC is inhibited by Aldosterone antagonists
1. ENaC inhibitors (direct): TRIAM/AMILORIDE
directly block reabsorption of NA on the apical side in the CD, which inactivates Na/K ATPase on basolateral side, so there is no K to be excreted on apical side
2. Aldosterone antagonists (indirect): SPIRONOLACTONE/EPLERENONE prevents aldosterone from binding to eh mineralocorticoid receptor in the nucleus, which decreases expression of ENaC and Na/K ATPase
Advantage of Eplerenone vs. Spironolactone
Newer, more selective, less adverse effects
**both of these drugs might cause Metabolic Acidosis (by blocking secretion of H along with K)
What drugs to do we know that can decrease Oxygen demand?
1. Beta Blockers
2. CCB's (esp. verapamil and diltiazem)
3. NITRATES= dec. VENOUS RETURN!
What reasons force coronary arteries to become unable to supply adequate blood flow to heart?
1. atherosclerosis (tx: Statins)
2. vasospasm (tx: Nitrates)
3. microthrombotic events (tx: a/coag,a/plate)
3 classifications of angina
1. Stable Angina (classical,typical,angina on exertion)
2. Variant Angina (Prinzmetal's)
3. Unstable Angina (UA, "angina at rest")
"angina on exertion"
typically present at 70-75% blockage
caused by unpredictable, exercise independent vasospasms.
Organic nitrates: MOA 1
1. sheer stress causes eNOS to convert arginine to NO. NO activates guanylyl cyclase, which converts GTP to cGMP. cGMP dephosphorylates MLC-P to MLC, causing relaxation.
Organic Nitrates: MOA 2
NO diffuses freely across VSM membrane and binds to heme moiety on an enzyme called soluble guanylyl cyclase (sGC) and activates it. sGC converts GTP to cGMP, causing dephos of MLC-P to MLC, causing relaxation.
Low dose vs. High dose Nitrates
Low dose: primarily venous fx (opposite CCB!) & decrease O2 demand*increase venous capacitance*decrease venous return*little change in arterial BPHigh dose: also affects arteries (inc. O2 supply)*increased coronary artery blood flow
Drug tolerance to nitrates
denitrated to NO by mitochondrial aldehyde dehydrogenase (mtALDH). prolonged exposure to nitrates leads to damage of mtALDH. this decreases bioactivation of drug and necessitates a "nitrate-free" period **usually occurs w/in 48-72 hours
"nitrate-free" period and therapy
*non-symmetrical dosing intervals (7,noon,5/ 8,2)
*long acting QD in am, remove at night
*do not use with PDEi=DECREASE BP!
3 preparations of nitrates
1. Nitroglycerin- SL, spray (bypass 1st pass); TD ointment (6-8 hrs then wipe off); TD patch (24hr, remove HS); ER cap; IV
2. ISDN- oral & chew tabs; longer acting than nitroglycerin