Pharm: Raas

Front 1

Renin is synthesized as what? From where? What about the liver?

Back 1

Prorenin. From JG apparatus mostly, but also brain, adrenals, and vascular smooth muscle. Rapid inactivation by the liver.

Front 2

Secretion of renin is increased by what (4)?

Back 2

1) dec Na load at macula densa. 2) dec volume at intrarenal stretch receptors. Renal stenosis dec perfusion -> HTN. 3) dec volume at CNS or cardio-pulmonary receptors -> mediated by CNS adrenergic outflow by beta1 receptors on JG cells. 4) prostacyclin - PGI2

Front 3

Secretion of renin is decreased by (4)?

Back 3

1) "short-loop" negative feed by back AT2. 2) ANF -> causes large naturesis and loss of K. 3)Reversal of stimulatory factors like inc Na. 4) Vasopressin

Front 4

Drugs that decrease renin secretion (2)?

Back 4

1) Beta-blockers. 2) CNS adrenolytics like clonidine, methyldopa. These antagonize extrarenal stretch receptor that normally stimulates JG beta1 receptors. Act against sympathetic tone. Most effective if tubular Na is normal and plasma renin activity is elevated -> relatively ineffective if plasma renin activity is low.

Front 5

Drugs that increase renin secretion (3)?

Back 5

1) arteriole vasodilators dec BP and inc renin. 2) PDP inhibitors inhibit short-loop feedback by inhibiting formation of AT2 and by dec BP. 3) diuretics

Front 6

What does angiotensinogen form and what is the limiting factor?

Back 6

Angiotensin 1 via renin action whose concentration is the limiting factor. Although with high renin angiotensinogen can be limiting (normal blood angiotensinogen is below the Km for renin).

Front 7

Angiotensinogen is synthesized where and increased by what?

Back 7

Synthesized in liver (although local production of renin does occur - think brain and myocardium). Increased by estrogens (so pregnancy and contraceptives!), glucocorticoids, thyroid hormones, and AT2

Front 8

How is RAS activity determined? Where is this located? Try to know pathways…

Back 8

ACE/ACE2 ratio. ACE is located in endothelial cells everywhere, not just in the lungs.

Front 9

What are the effects of Na restricted and replete diets on AT2

Back 9

With restricted diets, ~30% of AT2 is from non-ACE pathways. Replete diets is ~60--70%. In tissues like myocardium, this can be as high as 80%

Front 10

What are cathepsins? Tonin? Chymases?

Back 10

1) family of endopeptidases found in PMN and RBC membranes that convert AT1 -> AT2. Some can convert Angiotensinogen -> AT2. 2) Tonin is an endopeptidase found in a variety of cells that converts angotensinogen -> AT2. 3) Chymases have serine protease activity. They are primarily expressed in Mast cells (but are expressed in heart, kidney, and vascular smooth mm), do AT1 -> AT2.

Front 11

AT-1 receptors?

Back 11

Bind AT2 and 3, coupled to many effector pathways involving G-proteins and tyrosine kinases. What they do -> Pro-proliferative, pro-hypertrophic, inc vascular smooth muscle cell (VSMC) migration, inc matrix deposition.

Front 12

AT-2 receptors?

Back 12

Involves protein phosphatases, phospholipase A2, and NO formation… Anti-proliferative, reduces remodeling and hypertrophy, reduces VSMC migration, so in general antagonizes AT-1

Front 13

AT-4 receptors?

Back 13

identical to insulin-regulated aminopeptidase -> important in memory, learning, natriuresis, and vasodilation

Front 14

3 global effects of AT2?

Back 14

1) Rapid pressor response -> direct activity on vascular smooth muscle. 2) Slow pressor response -> inc sympathetic outflow and production of aldosterone. 3) Vascular, cardiac, and renal remodeling

Front 15

Biochemical mechanism of AT? Ca regulation? Halflife?

Back 15

Stimulate PPI-PDE, inc IP3 -> inc intracellular Ca and DAG (and DAG -> PKC). 2) Ca regulation through calmodulin and others. 3) 30-60 seconds

Front 16

Actions of AT on 1) Adrenal cortex. 2) Adrenal medulla and peripheral nerve endings. 3) Arteriolar smooth muscle (includes renal arteries).

Back 16

1) inc aldosterone -> Na retention. 2) inc catecholamine release to stimulus. Enhancement of catecholamine stimulation on CV. 3) potent constriction (moreso than EPI) -> inc BP. Constriction of renal arteries causes dec GFR and inc FF -> less Na delivered to nephron = greater %Na reabsorbed

Front 17

Actions of AT on CNS (4 locations)

Back 17

1) targets area postrema -> inc sympathetic outflow to heart, blood vessels, and JG cells. 2) SFO/OVLT: inc thirst and is OUTSIDE BBB! 3) Medullary centers: affects vascular and vagal tone on heart to inc BP. 4) Pituitary: AT is excluded by BBB but centrally applied will increase ADH

Front 18

Non-hemodynamic effects of AT?

Back 18

1) inc growth factors. 2) inc matrix proteins. 3) inc transcription factors

Front 19

Actions of AT on heart?

Back 19

BAD. Prolongs inward Ca current at cardiac AP plateau, inc CO. Via AT-1 -> induces cardiac hypertrophy and deposition of matrix proteins -> stiffening

Front 20

What's the order of the DR curves for aldosterone secretion, arteriolar contraction, and EPI secretion as a function of increasing [AT2]

Back 20

Order of DR curves (think potency): aldosterone secretion, EPI secretion, arteriolar contraction

Front 21

Captopril therapeutic indications (5):

Back 21

1) CHF -> arteriolar vasodilation and no reflex tachycardia. 2) Tx HTN. 3) Dec anginal pain and reduce ischemic events. 4) Tx diabetic neuropathy: interferes with AT2 effects in kidney. 5) Post-MI w/ Beta-blocker

Front 22

Captopril bioavailability? Actions? MOA?

Back 22

1) 30% protein bound and food reduces bioavailability by 25%. 2) Reduces BP and aldosterone secretion -> risk of hyperkalemia. 3) MOA: blocks conversion of AT1 -> AT2. INC bradykinin! Blocks 100% of tissue ACE production for 24 hours. DEC both AT1/AT2 activity.

Front 23

Captopril side effects with 1) Potassium. 2) taste. 3) kinin. 4) urine

Back 23

1) hyperkalemia. 2) hypogustia (reversible). 3) Inc kinin -> nonproductive cough. 4) proteinuria.

Front 24

Captopril side effects with 5) Neutrophils. 6) skin. 7) blood sugar. 8) tramterene or amiloride

Back 24

5) neutropenia. 6) rash from hypersensitivity. 7) hypoglycemia drug interaction -> combo insulin. 8) DO NOT USE -> hyperkalemia

Front 25

Captopril: 1) unique to have what group? 2) transglomerular pressure? 3) what kind of renal activty?

Back 25

1) only one in class to have sulfhyldryl group. 2) does NOT increase by inducing vasoconstriction in efferent arterioles. 3) renal-sparing activity.

Front 26

Enalapril is useful because (2)? Active metabolite?

Back 26

1) longer halflife and bioavailablity that is not affected by food allows once-day-dosing! 2) fewer side effects b/c no sulfhydryl group (if pt. has hypersensitivity) -> carboxyl group. Used as prodrug, active metabolite is ENALAPRILAT

Front 27

Lisinopril is useful b/c?

Back 27

Once-day-dosing and not affected by food. No plasma binding either…

Front 28

Benazepril is unique b/c?

Back 28

Most potent of class.

Front 29

Losartan MOA? How is it excreted? Angioedema?

Back 29

Only blocks AT2 binding to AT-1 (noncompetitive). Should be more efficacious in reducing action of AT2. Excreted in bile. Not associated with angioedema since it doesn't alter bradykinin production.

Front 30

Losartan actions (7)?

Back 30

1) inhibit contraction of vascular smooth muscle. 2) DEC catecholamine release. 3) DEC aldosteone. 4) DEC. thirst. 5) DEC ADH. 6) DEC AT2 mediated changes in renal fxn. 7) DEC cellular hypertrophy and hyperplasia

Front 31

Losartan side effects (3)

Back 31

1) Dizziness. 2) hyperkalemia. 3) NO COUGH

Front 32

Hyzaar?

Back 32

Losartan combo with hychlorothiazide

Front 33

Valsartan interaction with food? What is diovan?

Back 33

Food decreases absorption. Diovan = valsartan + hydrocholorothiazide

Front 34

What is aliskirin? Side effect?

Back 34

Blocks renin, so no buildup of AT1, and DEC BP. Diarrhea.

Front 35

Advantage of ACE inhibitors vs. diuretics (4)?

Back 35

1) no K loss. 2) no inc in plasma urate. 3) no inc in plasma glucose. 4) no inc I nplasma lipids

Front 36

Advantage of ACE inhibitors vs. beta-blockers (3)

Back 36

1) no impaired CV reflexes -> reduced postural HTN. 2) is not contraindicated in diabetes or asthma. 3) no decrease in male libido

Front 37

Advantage of ACE inhibitors vs. ARBs (5)

Back 37

1) ARBs more effectively block AT-1 receptors. 2) ARBs indirectly activate AT2 receptors. 3) ACE can increase other forms of AT(1-7). 4) ACE inc bradykinis and other substrates. 5) ARB have not been found to be superior to ACE in risk or long-term survival

Front 38

What kind of corticoid is aldosterone? Where is it made? Where are the receptors?

Back 38

mineralcorticoid, zona glomerulosa of adrenal cortex, steroidal mech -> synthesis of RNA….

Front 39

Actions of aldosterone (2)? Effect on Na reabsorption? Effect on cardiac and vascular system?

Back 39

1) inc synthesis of Na/K ATPase and mitochondrial production of ATP and Na channel. 2) 98% -> 100%. 3) cardiac and vascular remodeling including vascular fibrosis and myocardial damage

Front 40

3 effects on aldosterone secretion? What establishes feedback?

Back 40

low Na, K, AT2. 2) K establishes feedback

Front 41

Lack of ACTH?

Back 41

leads to some atrophy of zona glomerulosa and total atrophy of rest of cortex

Front 42

fludrocortisone is what? therapeurtic indication? 2) What does it bind to?

Back 42

aldosterone agonist. replacement in adrenal insufficiency (in combo w/ glucocorticoid). 2) Binds to both mineralcorticoid and glucocorticoid receptors.

Front 43

Deoxycorticosterone acetate (DOCA) is what for what?

Back 43

aldosterone agonist for replacement in adrenal insufficiency (in combo w/ glucocorticoid)

Front 44

Spironolactone is what? Binds to what? RALES study?

Back 44

Aldosterone antagonist. Binds to mineralocorticoid, androgen, and progestin receptors. RALES found reduction in CV deaths w/ CHF

Front 45

Eplerenone is what for what? What does it bind?

Back 45

Aldosterone antagonist. Binds more specifically to mineralcorticoid receptors.

Front 46

Triamterene or Amiloride are what, act how?

Back 46

Physiological antagonists at site 4 by plugging up Na channel (K sparing diuretics)