Lecture 10: ACEIs + ARBs Flashcards
What are 4 renin secretion regulators?
Sympathetic division
Renal baroreceptors
Macula densa
Hormones
(AngII, ANP = dec. secretion)
Differentiate between AT1 and AT2 receptors
AT1 =
Widespread
Mediate: pressor effects, deleterious changes in CV morphology
AT2 =
More prominent in fetus; higher expression in patients with CV disease
Mediate: vasodilation, protective CV effects
Describe the rapid pressor and slow pressor effects of AngII
Rapid pressor =
Vasoconstriction
Slow pressor =
Salt/water retention
Plasma/volume expansion
What are two enzymes that can convert AngI to AngII?
ACE
Chymase (CHYM)
Describe the direct mechanisms for AngII mediated salt/water retention
AngII @AT1 =
Inc. Na reabsorption in PT by stimulation of NHE
Inc. Na reabsorption in DCT and CNT/CD via stimulation of NCC and ENaC, respectively
Describe indirect mechanisms for AngII mediated salt/water retention
AngII @AT1 =
Inc. Aldosterone secretion = inc. Na reabsorption in CNT/CD via ENaC
Constriction of AA and EA (EA > AA) = changes in Starling forces in PTCs = inc. sodium/water reabsorption in PT
CNS effects
Describe CNS effects at higher levels of AngII
Inc. ADH secretion = more water reabsorbed in CNT/CD
Inc. thirst = more water ingested
Does AngII decrease RPF?
Yes
AngII = inc. resistance of EA > AA = inc. RVR = dec. RBF = dec. RPF
Does AngII decrease GFR?
Hard to predict b/c of flow-dependence of GFR
AngII = dec. RPF = dec. Kf = dec. GFR
Or
AngII = Inc. resistance of EA > AA = inc. in hydraulic pressure of glomerular capillaries = Inc. GFR
Describe the renovascular effects (indirect mechanism for salt/water reabsorption in PT) of AngII
AngII increases resistance in afferent and efferent (more so!!) arterioles, resulting in increase in renal vascular resistance (RVR) = dec. in RPF
Filtration fraction always increases (indirect relationship with RPF) and leads to increase in oncotic pressure inside peritubular capillaries b/c of proteins staying behind = inc. reabsorption of sodium/water in PT
Inc. in resistance of EA = inc. RVR = dec. hydraulic pressure of PTC = inc. reabsorption of Na/H2O in PT
GFR can:
+ inc. from inc. hydraulic pressure in GC
+ dec. from dec. RPF (flow dependence)
+ not change (from balancing forces)
Define equation for filtration fraction (FF)
FF = GFR / RPF
In the Starling equation, what do the hydraulic pressure and oncotic pressure differences represent?
hydraulic pressure =
Pushing out fluid
oncotic =
Pulling in fluid
What changes in Starling forces in the PTCs occur that lead to indirect mechanism of inc. reabsorption of sodium and water in PT in presence of AngII?
Hydraulic pressure drops = difference in P decrease = pushing out fluid is low
Oncotic pressure increases with proteins that stayed behind = difference in Pi increases = pulling fluid IN is high
Describe differences in hydraulic and oncotic pressure along
AA
GC
EA
PTC
AA =
Hydraulic > Oncotic (difference = NFP)
GC =
Hydraulic > oncotic until eventually fluid filters out, oncotic inc. and filtration equilibrium achieved
EA =
Oncotic > Hydraulic
(No loss of fluid in EA so Pi stays the same, but P dec. from resistance)
PTC =
Oncotic > hydraulic
Means that fluid is being pulled into PTC (normal reabsorption in PT)
How does presence of AngII affect reabsorption in PT?
In glomerular capillaries =
+ Inc. hydraulic pressure = higher plateau
+ more rapid inc. in oncotic pressure due to dec. RPF
In PTC =
Higher oncotic pressure and lower hydraulic pressure = more driving force for reabsorption/pulling fluid in
How does RAAS respond in a volume-depleted patient?
(1) sympathetic division
Volume depletion = dec. stretch of arterial baroRs = inc. symp tone to kidneys via stimulation of beta1 on granular cells = inc. renin secretion
(2) renal baroreceptors
Volume depletion = dec. stretch = inc. renin secretion
(3) macula densa
Volume depletion = dec. NaCl delivery to macula densa = inc. renin secretion
(TGF will be on guard and the dec. in Adenosine/inc. PGE2 will counteract AngII mediated AA resistance inc.
What are drug classes that antagonize the RAAS?
Inhibitors of renin secretion = beta antagonists = propranolol, metoprolol
Renin inhibitors = aliskiren
Aldosterone antagonists = K+ sparing diuretics
ACEIs = “prils”
ARBs = “sartans”
What are indications for ACEIs and ARBs?
HTN
(Particularly pt’s with additional CVD or CKD w/ proteinuria)
MI and post-MI
HF
CKD
(Diabetic or non-diabetic)
What are AEs associated with ACEIs and ARBs?
Cough + angioedema
(ACEI)
Hypotension
(common in pt’s with inc. renin)
Hyperkalemia
Describe the mechanism for hyperkalemia side effect of ARBs and ACEIs
AngII stimulates inc. aldosterone, which can:
Directly: inc. K secretion in CNT/CD via ROMK, Na-K ATPase in principal cells
Indirectly: inc. Na reabsorption in CNT/CD via ENaC, Na-K ATPase in principal cells = lumen negative transepithelial potential (TEP) in CNT/CD = inc. K secretion
What are contraindications for ACEIs and ARBs?
Pregnancy
For which patients should ACEIs and ARBs be used with caution?
Poor renal perfusion
Renal a. Stenosis
Severe dehydration
Dec. renal perfusion = inc. renin secretion = inc. AngII, which could potentially inc. GFR….. but ACEI/ARB to these patients would decrease GFR by blocking
How can increases in serum creatinine be explained while using ACEI?
Volume depletion from diuretic = dec. GC hydraulic pressure
Atherosclerotic lesions in renal a. = dec. renal perfusion pressure
Blocking RAAS is important for maintaining GC hydraulic pressure = dec. P(GC) = dec. GFR = inc. plasma creatinine
What medication combinations should be avoided for patients with poor renal perfusion, etc?
Diuretic + ACEI or ARB
Diuretic + ACEI or ARB + NSAID
Each has own mechanism for decreasing GFR
Briefly compare ACEI and ARBs
ACEIs = block BK metabolism
ARBs block AT1 but not AT2
And since no negative feedback, increased renin = inc. AngII to stimulate AT2 receptors
What are kinin AEs and potential benefits?
AE = cough, angioedema
Potential benefits =
Vasodilation
CV protective effects
