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RAAS pharma
UVa med pharmacology block 3
| Question | Answer |
|---|---|
| Captopril | ACE inhibitor - tx HTN, HF, post-MI, nephrophathy (in IDDM)- inhibs ACE & kininase 2->reduced conc of Ang2, incr bradykinin - short acting t1/2~2hrs 2-3x/day |
| Lisinopril/analapril/fosinopril | ACE inhibitor - tx HTN, HF, post-MI, nephrophathy (in IDDM)- inhibs ACE & kininase 2->reduced conc of Ang2, incr bradykinin - long acting t1/2 = 12hrs 1x/day |
| Ramipril | ACE inhibitor - tx HTN, HF, post-MI, nephrophathy (in IDDM)- inhibs ACE & kininase 2->reduced conc of Ang2, incr bradykinin - multiple preps t1/2 ~ 4, 18, >50hrs 1x/day |
| What are the combination therapies for ACE inhibitors? | + diuretic (thiazide)-> stops RAAS activation during volume depletion + beta blocker -> blunts hyperreninemia induced by ACEI + Ca Channel blocker-> appreciable response + ARB-> blunt axns of Ang2 gen'd by non-ACE pways from elevated Ang1 induced by AC |
| What are the advantages to ACE inhibitors? | -not CI'd in px's w/bronchial asthma or CHF -do not cause nutrient loss or retention like diuretics -oppose 2ndary hyperaldosteronism caused by diuretics, decrease hypokalemia -reduce urinary protein excretion -improve ventricular hypertrophy in CHF |
| What are the toxicites of ACE inhibitors? | -severe hypotension - idiopathic or in diuretic users -renal insufficency - in px's w/low RBF, dehydratio, HF or renal dx -hyperkalemia - in px's w/reduced GFR, K sparing diuretics, or low renin -Angioedema -Birth defects -Nonproductive cough |
| Losartan | ARB - tx HTN, HF, nephropathy - competitively bind AT1 - surmountable inhibition - block vasoconstrictor & growth axns of AngII, increase circulating levels of AngII stims AT2 receptors which mediates vasodil/growth inhib - less efficacy in black px's |
| Candesartan/Irbesartan | ARB - tx HTN, HF, nephropathy - competitively bind AT1 - insurmountable inhibition - block vasoconstrictor & growth axns of AngII, increase circulating levels of AngII stims AT2 receptors which mediates vasodil/growth inhib - less efficacy in black px's |
| What are the beneficial effects of ARBs compared to ACE inhibitors? What are CI's? | Benefits: No bradykinin mediated cough or angioedema, unopposed stim of AT2R mediates vasodilation & growth inhibition CI'd in pregnancy |
| Nesiritide | synthetic BNP - tx acute cardiac failure - antagonize axns of RAAS - activates ANP-A receptor @ adrenal gland, JG cells, vasculature, post pituitary, kidney - short T1/2~3 mins, given as constant IV infusion - increases Na excretion improves hemodynamics |
| What are the functions of ANP/BNP mediated ANP-A receptor activation at different tissues? | Adrenal - inhibs aldosterone secretion JG cell - inhibs renin secretion Vasculature - vasodilator, incre permeability to plasma proteins Post Pit - inhib ADH secretion Kidney - incr GFR (relax aff>>>eff), decr Na reabsorption, red H2O transport in CCD |
| Where is Renin synthesized? | Juxtoglomerular cells in kidney |
| What is Renin's substrate? Where is this substrate made? What is the end product of this reaction? | - Substrate is angiotensinogen which is made in the liver - Renin turns angiotensinogen in angiotensin I |
| What is the rate-limiting step for angiotensin II production? | Renin secretion |
| What enzyme converts angiotensin I into angiotensin II? Where is it found? | - Angiontensin Converting Enzyme (ACE) - found on the luminal side of most vessels, with greatest concentration in the pulmonary bed |
| T or F: Glomerular hydrostatic pressure increases and glomerular oncotic pressure decreases along the length of the glomerulus | FALSE Hydrostatic pressure is unchanged and oncotic pressure increases **EXPLANATION: proteins are not typically filtered at glomerulus but fluid is, thus, oncotic pressure increases |
| What are the effects on Glomerular hydrostatic pressure if you constrict the AFFERENT arteriole? EFFERENT arteriole? | AFFERENT --> decreased EFFERENT --> increased |
| How do perfusion pressure, NaCl delivery to macula densa, and sympathetic flow affect renin secretion (the rate-limiting step)? | Perfussion pressure: HIGH pressure decreases (and vice-versa) NaCl delivery: HIGH delivery decreases (and vice-versa) Sympathetic tone: activation increases release (and vice-versa) |
| What are the names of the two angiotensin II receptors and what does each control? | AT1: most physiological function of Ang. II, both hemodynamic and growth promoting AT2: Mediates apoptosis, and tissue remodeling/healing |
| What does blockage of AT1 do to levels of Renin, Ang. I, and Ang. II? | - Blockage of AT1 leads to lack of negative feedback on JG cells, so INCREASE in Renin, Ang. I, and Ang. II levels |
| What are the therapeutic uses of Angiotensin Receptor Blockers? What is their efficacy compared to ACE inhibitors? | - hypertension, heart failure, diabetic nephropathy - about as efficacious as ACE I's **like ACE I's, less effective on black patients |
| What is the therapeutic use of ANP/BNP? How is BNP used as a prognostic marker? | - IV administration during acute cardiac failure - BNP levels closely correlate with New York Heart Association functional classification of symptomatic heart failure |
| How does Angiotensin II increase vascular resistance? | - Direct vasoconstrictor - Stimulates peripheral sympathetic system **increases NE levels - Stimulates central sympathetic output **attenuates baroreceptor-mediated reductions in sympathetic low |
| What is special about Ramipril? | Very lipophilic thus superior ACE inhibition |
| What are the four therapeutic uses of ACE inhibitors? | - Hypertension - Heart Failure - Post MI - Nephropathy |
| What subgroups have the greatest and lowest response to ACE inhibitors? How do you abolish racial differences? (don't say civil rights movement) | GREATEST -- individuals with high plasma renin LOWEST -- individuals with low plasma renin, salt-sensitive hypertensives, diabetics, blacks ***racial differences abolished by use of Thiazide diuretics |
| What does insurmountable inhibition of AT1 mean? Which Angiotensin Receptor Blockers are surmountable and which are insurmountable? | Insurmountable means that normal Ang. II effects can never be restored - Losartan is surmountable - Candesartan and Ibesartan are insurmountable |
| Where is Atrial Natriuretic Peptide (ANP) produced and in response to what? What about BNP? | - ANP made in the atria in response to stretch/volume expansion - BNP is made in atria and may be co-released with ANP (mimcs ANP's actions) |
| What are three organs that a complete RAA system has been found? What are the effects of Ang. II on these? | - Heart: ventricular hypertrophy, cardiac fibrosis, congestive heart failure - Vasculature: reduced compliance, ischemia, artherosclerosis - Kidney: increase golmerular filtration pressure, sclerosis, renal failure |
| What is the OVERALL effect of Angiontensin II? Name the systems that it affects and how it achieves this goal? | - enhace Na+ and water retention - Kidney --> increases Na and water reabsoprtion - Adrenal --> catalyzes aldosterone production - Pituitary --> promotes ADH secretion - Hypothalamus --> promotes thirst |
| How does Angiotensin II increase Na reabsorption at the PT, TAL, CCT? | PT - direct effect on Na/H exchanger - decreased hydrostatic pressure of the peritubular capillaries creates driving force TAL: Na/K/2Cl co-transporter via ALDOSTERONE CCT: Na/K exchanger via ALDOSTERONE |
| Compare the half life of Captopril and Lisinopril? How are these two drugs special? | Captopril is short acting, Lisinopril is long acting They don't circulate as prodrugs |
| What is the therapeutic mechanism of ACE inihibitor on hypertension? | - Reduce afterload (decr PVR, reduce Na & water resorption) - Reduce preload (incr venous capacitance & decr CO) - Blunts effects of catecholamines - Decr chronotropic sympathetic reflex - Inhibit remodeling/growth effects of HTN on vasculature and he |
| What is the goal in heart failure therapy? What is the therapeutic mechanism of ACE inhibitors in heart failure? Why is O2 consumtion not increased in this situation? | - GOAL: improve CO (SV * HR) - Decreased afterload increases SV and EF - Decreased preload reduces ventricular filling bringing fibers to optimal length - NO increase in O2 use b/c incr efficiency of fiber length and decr symp tone |
| How are ACE inhibitors useful post-MI and for nephropathy? | post-MI --> beneficial hemodynamics with no increase in HR (due to anti-sympathetic) and optimal fiber length (no increase in O2 consumption) nephropathy --> decreases glomerular hydrostatic pressure *since Ang II constricts EFFERENT arteriole>>AFF |
| What is the net effect of Angiotensin Receptor Blockers? | Block AT1, increase in AT2 activity due to increased Ang. II levels (AT2 is not blocked) - block vasoconstrictor effects of AT1 and increase vasodialation and growth inhibition of AT2 |
| What is the overall effect of ANP/BNP? How? | - Antagonizes the actions of the Renin-Angiotensin-Aldosterone-System - inhibits aldosterone secretion - inhibits renin secretion - vasodialator - inhibits ADH secretion - Reduces Na+ and H2O reabsorption |
| How do humoral agents affect Renin secretion? | INCREASED by: Norpei, Epi, PGI2, PGE2 DECREASED by: Ang. II (neg feedback), ANP, ADH |
Created by:
sam.mrosenfeld
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