RAAS System Flashcards
the RAAS system is a physiologic regulator of 2 things
total peripheral resistance and blood volume
renin cleaves ____ to ____
angiotensinogen to ang I, if no renin then Angiotensinogen will be degraded
How many AA does ang 1 and ang 2 have
Ang 1 has 10 and Ang 2 has 8
Angiotensin 2 affects what 4 things after binding to the AT1 receptor
- adrenal (medullary thick ascending lib of henle, collecting duct) - increases NaCl absorption
- renal proximal tubule (increased NaCl absorption)
- Renal Efferent arterioles (vasoconstriction maintains GFR)
- Hypothalamus (thirst, increased ADH secretion)
what stimulates RAAS
decreased blood volume, Na+ depletion, increased sympathetic outflow, leads to the release of renin (rate limiting step) to start the RAAS cascade
Role of ACE
expressed in the lung. inactivates bradykinin (vasodilator), converts Ang 1 to Ang 2
what releases renin
JG cells
what 3 things regulate renin release
- intra macula densa pathway (NaCl concentration low inc renin release)
- intrarenal baroreceptor pathway ( high pressure dec renin release and visa versa)
- beta adrenergic pathway (SNA system- B1 receptor, NE release)
short loop negative feedback
releases renin - inc ang 2 - goes to AT1 transporter, once body sees response it inhibits renin release
long loop negative feedback (2)
- increased BP- increased pressure at preglomerular vessels - dec renin
- increased BP- activation of baroreflex sytem decreased sympathetic tone - decreased NE release - decreased renin release (inc parasympathetic)
diuretics and vasodilators affect on renin
decrease blood volume and decrease arterial pressure - this increases renin release
loop diuretics affect on renin
decrease NaCl reabsorption - increases renin release
NSAIDS affect on renin release
decrease PG synthesis (more pressure) - decrease renin release (PG usually blocks reabsorption of Na+)
Beta Blockers affect on renin release
decrease activation of beta 1 receptors on JG cells- decreases the renin release
ang II effect on the kidney
intrarenal blood-pressure constriction (increases GFR, GFR plateaus then decreases ) renal tubules (increases Na+ and H2O reabsorption) - this increases Na+ and H2O retention
ang II effect on the adrenal gland
cortex - increases aldosterone (Na+ reabsorption)
ang II effect on the vascular smooth muscle
vasoconstriction, increase TPR, increase arteriolar resistance, increase cardiac output
ang II effect on the CNS
increase ADH (inc H2O reabsorption), increase thirst (inc H2O ingestion)
ang II effect on the myocardium
increase contractility, hypertrophy, collagenase, increase wall thickness, remodeling of the heart can block blood flow out of the ventricle
what 3 things do drugs targeting the RAAS cascade do
- decrease vascular constriction
- decrease aldosterone secretion
- decrease ADH release
Bradykinin
vasodilator and is inhibited by ACE, causes a dry cough, activates nitric oxide, increased with an ace inhibitor
aldosterone effects
AT1 activates, Na+ and H2O retention and Mg+ and K+ loss
what 3 drugs effect the RAAS cascade
- ACE inhibitors
- AT1 blockers
- Renin inhibitors
- Aldosterone receptor antagonists
where is the ACE site of cleavage on the
Phe - His
what was the first ACE
venom of the south american pit viper - drop in bp - lead to development of catopril
enalapril
ACE inhibitor, prodrug, enalaprilat is the active form of enalapril to be used IV - because it is a prodrug it has to be metabolized in the stomach
lisinopril
ACE inhibitor, not a prodrug
ACE inhibitors are used to treat
hypertension, including those with DM, CHF, MI, CKD, left ventricular dysfunction, high coronary artery disease
adverse effects of ACEIs
dry cough, hyperkalemia (K+ sparing diuretics should not be given), angioedema (allergic reaction and swelling under the skin, can be life threatening, stop therapy to admin epi), acute renal failure
why can acute renal failure occur in patients taking ACEIs
can occur in patients with decreased renal perfusion bc ang II mediated constriction of the efferent arteriole is inhibited and decrease GFR
what drugs should ACEIs not be given with
NSAIDs - inhibits PG - NSAIDs cause vasoconstriction and PG causes vasodilation - take tylenol instead, anything that would change Ang II need to take caution
ACEI contraindications
renal artery stenosis (blockage = decrease flow), angioedema, “black box warning” pregnancy (category D) benefit may outweigh the effect
fosinopril
ACEI, not cleared by the kidney but through urinary and biliary routes,
pharmacokinetics of ACEIs
all agents are cleared via the kidneys, dose adjustments should be made in individuals with renal impairments
ACEI drug names
all end in pril
catopril
ACEI - good choice for kids because it is easily crushable
ARBs MOA
Angiotensin receptor blockers bind to the AT1 receptor with high affinity/selectivity for AT1 versus AT2, inhibit Ang 2, differs from ACEI bc ACE is not the only enzyme that can convert Ang I to Ang II, ARBs do not affect bradykinin levels (no cough)
how does ACEI and ARB affect negative feedback
disrupts the negative feedback on renin - increases renin, with ARBs
ARBS effect on the receptors
AT1 receptors occupied, AT2 receptors cause vasodilation with the high Ang II levels
losartan
ARB, diabetic nephropathy, stroke prophylaxis
irbesartan
ARB, diabetic nephropathy
valsartan
heart failure
pharmacokinetics of ARBS
liver/renal excretion
CYP metabolism
contraindications of ARBS
renal artery stenosis (blockage = decrease flow), angioedema, “black box warning” pregnancy (category D) benefit may outweigh the effect
Aliskiren
renin inhibitor - monotherapy, used in combination with diuretics and ARBS for hypertension
Aliskiren MOA
inhibits renin, works upstream RAAS (ARBs and ACEI work downstream), reduces the cleavage of angiotensinogen to ANG I. reducing both Ang I and Ang II
renin inhibitors adverse effects
dose related GI, dizziness, fatigue, cough, angioedema, headache, hyperkalemia, hypotension
renin inhibitors contraindications
black box warning, angioedema, hyperkalemia
pharmacokinetics renin inhibitors
poor absorption (oral), metabolized by CYP 3A4, t 1/2 hangs around for a long time and antihypertensive effect lasts throughout the day, anti-infective and antidepressant
aldosterone antagonist
potassium sparing diuretics, inhibit the Na+ in the CD and K+ excretion is reduced. on the apical membrane in the collecting duct, the epithelial sodium channels allows for Na+ reabsorption, driven by the activity of Na+/K+ ATPase on the basolateral membrane of the cells. Na+ reabsorption is balanced by K+ excretion and H+ secretion
two subclasses of aldosterone antagonists
- ENAC channel inhibitors
2. aldosterone antagonists
amiloride
Enac channel inhibitor
triametrene
enac channel inhibitor
eplerenone
aldosterone antagonist, metabolized by 3A4
spirnolactone
aldosterone antagonist, may cause significant GI effects, including bleeding, contraindicated in patients with peptic ulcer disease (risk of exacerbating those GI effects, use eplerenone instead!)
aldosterone antagonist
inhibits the aldosterone receptor but indirectly inhibits the activity of ENaC
advantage of eplerenone vs spironolactone
eplerenone is more selective and just works better
spironolactone- has some adverse effects
what drugs may contribute to potassium sparing drugs contraindicated for hyperkalemia
non-selective b-blockers (cause uptake of K+, inc K+ level) + aldosterone antagonist would not be good
both eplerenone and spirnolactone cause what adverse effect
metabolic acidosis
