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Chapter 20 Pharmacology
Learning Objectives
1.
2.
What are the two broad classes of pharmacologic agents used for volume control?
 Modulators of neurohormonal regulators (e.g. ACE inhibitors [-pril])
 Diuretics
What makes up the low pressure volume sensing system?
Neurons lining the atria and pulmonary vasculature respond to wall stress
In decreased wall stress, they signal the medulla, then hypothalamus, and posterior pituitary
releases ADH
 In conditions of increased stress, atrial cells secrete natriuretic peptide
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3.
What makes up the high pressure volume sensor system?
 Baroreceptors in the aortic arch, carotid sinus, and juxtaglomerular apparatus modulate ADH
 Sympathetic input to juxtaglomerular apparatus => renin secretion
4.
What are the four main systems that regulate blood volume?
[Continued in #6-10]
Renin-angiotensin aldosterone system (RAAS)
ADH
Renal sympathetic nerves
Natriuretic peptides
i. cause salt excretion in cases of Volume Overload, the others systems activate
during volume depletion
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5. Angiotensin II binds AT1R as part of the RAAS in four tissues. What are they? What are the
results?
 Adrenal Cortex
i. Releases aldosterone, which increases NaCl absorption in the kidney
 Renal Proximal Tube
i. Increases NaCl absorption
 Renal Efferent Arterioles
i. Vasoconstriction => filtration rate (GFR) increase
 Hypothalamus
i. Thirst, increased ADH
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7.
Name the four natriuretic peptides and where they are released:
ANP – atria
BNP – ventricles
CNP – vascular endothelial cells
UGN (uroguanylin) – enterocytes responding to GI salt
Which of the three natriuretic peptide receptors is thought to act as a decoy/buffer? Tell me
about the other receptors too
 NPR-C may act as a deCoy
 NPR-A and NPR-B are both transmembrane proteins with guanylyl cyclase domains, which
causes vasorelaxation
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8.
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9.
ANP and BNP bind to both NPR-A and NPR-C
How do natriuretics promote increased glomerular filtration rate (GFR)?
They cause constriction of efferent arteriole and dilation of afferent arteriole
What changes does the binding of ADH/vasopressin exert?
 ADH promotes water resorption from the collecting duct by translocating aquaporin 2 to the
apical cell membrane
10. Trace the flow of filtrate from the glomerulus to the ureter:
 Proximal convoluted tubule (PCT) => Thin descending limb (TDL) => Ascending thin limb (ATL)
=> Medullary thick ascending limb (MTAL) => Cortical thick ascending limb (CTAL) => Distal
convoluted tubule (DCT) => Cortical collecting duct (CCD) => Outer medullary collecting duct
(OMCD) => Inner medullary collecting duct (IMCD)
11. What’s the difference between the descending and ascending thin limbs of the Loop of Henle?
 The thin descending limb is more water permeable than the ascending limb
12. What do intercalated cells of the CDs contribute?
 They contribute to systemic acid-base balance via H+-ATPase
13. Describe the Underfill and Overflow theories of Na+ retention in Cirrhosis:
 Underfill: ascites formation decreases blood volume, which activates baroreceptors
i. Increase Na+ retention, similar to HF
 Overflow: the “hepato-renal reflex” causes Na+ increase and then ascites
14. What causes nephrotic syndrome? What amount of proteinuria equals nephrotic syndrome
[test Q]
 Glomerular dysfunction (caused by diabetes, lupus, amyloidosis, MCD, MG, FSG)
 3.5 g/day
15. What is the fundamental cause of Na+ retention in Heart Failure? What blood regulation system
is erroneously activated? Which drugs should be administered to treat the edema of heart
failure? Which shouldn’t be?
 Low flow => Perceived volume depletion by high-pressure volume receptors in the carotid
sinuses
 The kidney therefore activates the RAAS
 You can use any drug in this chapter,except aliskiren, conivaptan, tolvaptan, mannitol,
amiloride, or triamterene
[anything that’s part of RAAS + mannitol]
16. What is the renin inhibitor? When contraindicated (4)?
 Aliskiren
 angiodema, pregnancy, cyclosporine therapy, hyperkalemia
17. What are the two effects of ACE inhibitors? Provide some drug names in this class:
 Prevent the conversion of angiotensin I to angiotensin II (by ACE)
i. Less aldosterone secretion, less vasoconstriction
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Prevent the inactivation of bradykinin (by Kininase II)
i. More smooth muscle relaxation
Captopril is administered in an active form and is further metabolized
Enalapril & Ramipril must be metabolized in the plasma
Lisinopril is not altered
18. What are the major adverse effects of ACE inhibitors (1 common and 4 serious)?
 Cough
 angiodema, first-dose hypotension, acute renal failure, and hyperkalemia
i. do not give during pregnancy
19. What are the AT1 receptor antagnoists? What are the advantages of using AT1R antagonists
over ACE inhibitors (2)?
 -sartan drugs such as losartan & valsartan
 inhibit the renin-angiotensin pathway more fully
 avoid the side effects of cough and angiodema since they do not affect bradykinin
20. When is the BNP used? Why is it better than dobutamine? What is the big side effect (besides
the ubiquitous hypotension of this chapter)?
 nesiritide treats heart failure by decreasing pulmonary hydrostatic P, improving stroke
volume, and decreasing vascular resistance
 may be associated with a lower risk of arrhythmias
 renal dysfunction may still occur
21. What class of drug should you give for SIADH? Disadvantages of conivaptan?
 In cases of water retention, give vasopressin (ADH) receptor antagonists such as
demeclocycline, conivaptan, and tolvaptan
i. Also good for ADPKD
 Conivaptan must be administered IV, plus some undesired V1 receptor antagonist acitivity
22. What is the function of carbonic anhydrase IV (CAIV) and carbonic anhydrase II (CAII)? What
drugs inhibits?
 CAIV converts luminal HCO3- to CO2 and OH-, which converts to H2O, both diffuse into cell
 CAII converts intracellular CO2 and H2O (from first conversion) to H2CO3 (carbonic acid)
 Acetazolamide inhibits them both
23. But why does Acetazolamide cause salt excretion? Any side effects?
 The bicarbonate that Carbonic Anhydrases normally produce is used to cotransport Na+ into
the blood
 Beware metabolic acidosis, also diarrhea and weight loss are common
24. Why does the efficacy of acetazolamide decrease in time? What random disorders is it useful
for?
 The kidney compensates by upregulating sodium bicarbonate reabsoprtion
 Glaucoma, mountain sickness, gout
25. What is the osmotic diuretic? Primary use? Serious side effect?
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Mannitol
Intracranial edema, often after trauma or hemorrhage
Beware thrombophlebitis
26. Where do different drugs work in the nephron?
 Carbonic anhydrase inhibitors: PCT
 Loop diuretics: thick ascending limb (cortical & medullary)
 Thiazide diuretics: DCT
 Potassium sparing diuretics: CDs (Cortical, outer medullary, & inner medullary)
i. Also known as Collecting Duct diuretics
[Children Like To Poop]
27. How does the body save energy as it transports magnesium, sodium, and calcium from the
lumen? What drug class abolishes this measure? Signs?
 NKCC2 in TAL cells creates a lumen-positive electrical potential
 Note that this can be abolished by prolonged use of loop diuretics
i. Hypomagnesemia, hypocalcemia & hypokalemia => volume contraction alkalosis
28. What transporter do loop diuretics inactivate?
 NKCC2
[2 Cs overlapping make a lOOp]
29. What are some examples of loop diuretics? Other side effect?—what should not be coadministered? [Test Q] Which one should patients receive if they have a sulfa allergy?
 Furosemide, bumetanide, torsemide, ethacrynic acid
[Furry torso and bum, Ethyl’s crying]
 Ototoxicity – do not administer along with aminoglycosides
 Ethacrynic acid is not a sulfonamide derivative, hence the funny acid name
30. Which class of drugs inactivates NCC of the DCT?
 Thiazides
31. How come thiazides have such a modest effect? But what are their added benefits (2)? Name a
long acting thiazide:
 They act in the DCT, and most sodium reabsorption has already occurred by then
 However they also promote Ca++ uptake (preventing nephrolithiasis)
 Can also treat nephrogenic diabetes insipidus
 Chlorthalidone has longer action than hydrochlorothiazide
32. Dangers of thiazide drugs (~3)?
 Co-administration with QT interval prolonging drugs can cause torsades de pointes
 Stevens-Johnson, toxic epidermal necrolysis, photosensitivity
33. Expression of ENaC in the principal cells of the CDs is naturally modulated by which hormone?
What drugs inhibit that hormone? What drugs inhibit ENaC?
 Aldosterone increases the sodium resorption of ENaC
 Spironalactone and eplerenone prevent the action of aldosterone
 Amiloride and triamterene directly inhibit ENaC
 These are all known as collecting duct (potassium sparing) diuretics
34. What is a neat application of amiloride and triamterene?
 Liddle’s syndrome: familial hypertension disorder, autosomal dominant
35. What is an unexpected side effect of collecting duct diuretics? What do spironolactone and
eplerenone often cause?
 Hyperkalemic metabolic acidosis
i. Inhibition of Na+ uptake 1) reduces the transepithelial potential, and so
decreases the driving force for potassium secretion; (2) slows H+ secretion
 Gynemcomastia, dyspepsia, impotence, abnormal menstruation---thanks to antagonism of
the androgen receptor
36. Which of these drugs retards progression of cardiac contractile dysfunction and remodeling in
heart failure or MI? [test Q]
 ACE inhibitors