Diuretics

Question 1

Diuretic

Answer 1

Increases urine volume

Question 2

Natruietic

Answer 2

increases sodium excretion

Question 3

Aquaretic

Answer 3

increases solute-free water excretion

Question 4

What is absorbed in proximal tubule?

Answer 4

85% NaBicarb, 40% NaCl, 66% filtered NA and 60% of water, most glucose and amino acids. K 65% via paracellular pathway.
water absorbed passively to maintain constant osmolarity

Question 5

Late proximal tube

Answer 5

Most bicarb removed, leaving primarily NaCl
Na/H exhcnage continues, H no longer titrated by bicarb, urine pH falls
Activates poorly understood Cl/base exchanger, so NaCl is reabsorbed
high water perm –> osmolality and Na concentrations remain constant
Organic acid secretory mechanisms in middle third: diuretics delivered to luminal side of tubule for activity, uric acid, antibiotics, NSAIDs from blood to luminal fluid
Organic base secretory mech: creatinine, procainimide

Question 6

Drugs acting on proximal

Answer 6

Adenosite receptors: increase Na reabsorption
Adenosine A1 recptor antagonists: potent vasomotor effects on renal vasculature; blunt proximal tubule and colelcting duct NaCl reabsorption; do no affect potassium reabsorption
Caffeine: weak adenosine receptor blocker–mild diuretic
Rolofylline: investigational–failed to meet efficacy standards in HF trial

Question 7

Loop of Henle

Answer 7

Thin descending loop: no salt reabsorption, water reabsroption generated by hypertonicity of medullary interstitium
Thin ascending: water impermeable, salt reabsorbed
Thick ascending: water impermeable, salt reabsorption–“diluting segment”

Question 8

Diluting Segment

Answer 8

Thick ascending loop
25% of filtered Na reabsorbed via Na/K/2Cl cotransporter
Na/K ATPase increases intracellular K. K back diffuses into lumen, creating positive charge, thus allowing Mg and Ca to be reabsorbed via paracellular pathway
Loop diuretics cause urinary loss of Ca, Mg, Na, K

Question 9

Distal Convoulted Tubule

Answer 9

Imperm to water
10% of NaCl reabsorption via Na and Cl cotransport–blocked by thiazide diuretics
K not affected, so Ca and Mg not driven out of lume
Ca actively reabsorbed via an apical Ca channel and basolateral Na/Ca exchanger; regularted by parathyroid hormone
2-5% Na reabsorption
Na entry > K exit into cell, leaves negative charge in lumen– Cl back to blood and K out of cell. If more Na presented here, more K secretion and if bicarb presented (less easily reabsorbed than Cl, so increase of neg charge) then more K loss

Question 10

Mineralocorticoid effect

Answer 10

Distal convulated tubule

Reabsorption of Na and secretion of K in prinicpal cells by increase activity of apical channels and Na/K ATPase

Question 11

Collecting Tubule

Answer 11

ADH–argenine vasopressin (AVP) regulated free water reabsorption by increasing/inserting preformed free water channels (aquaporins). Allows them to lose just free water.

Also, increased urea transporter leads to increased medullary osmolarity.

Question 12

Renal autacoids

Answer 12

Adenosine
Prostaglandins
Peptides

Question 13

Prostaglandins

Answer 13

Role of 5PG synthesized and with receptors in kidney poorly understood
PGE regulates salt reabsorption and affects certain diuretics
PGE2 reduces Na reabsorption in TAL of Henle’s loop and ADH-mediated water transport in collecting tubule

Question 14

Natriuretic peptides

Answer 14

ANP, BNP (heart), CNP (CNS), urodilatin (kidney)
Nesiritide (BNP) used for heart failure
Vascular and sodium transport effects
Urodilatin–made in distal tubule; blunts sodium reabsorption; vascular effects–decrease afferent tone and increase efferent tone —–> Increase GFR

Question 15

Carbonic anhydrase inhibitors

Answer 15

Work at proximal tubule. Inhibit formation of H and bicarb from H20 and CO2 via inhibition of carbonic anhydrase
Acetazolamide (Diamox)
Dichlorphenamide (Daranide)
Methazolamide (Neptazane)
Dorzolamide (Trusopt) Ophthalmic
Brinzolamide (Azopt) Ophthalmic

Question 16

Carbonic anhydrase inhibitors effects renally

Answer 16

Increases excretion of Na, bicarb, K
Reabsorption of water is decreased
Urinary volume increased (you can’t reabsorb water b/c the sodium and bicarb are sitting in tubule)
Urine becomes alkaline (b/c you aren’t absorbing bicarb)Acetazolamide results in up to 85% inhibition of Na bicarb reabsorption. Results in: HYPERCHLOREMIC METABOLIC ACIDOSIS (instead of absorbing bicarb you are absorbing chlorine)?
Diuretic efficacy rapidly decreases over several days–becomes acidotics, less bicarb available in filtrate

Question 17

Carbonic anhydrase inhibitors Ocular effects

Answer 17

Ciliary body secretes bicarb from blood into aqueous humor
reduce formation of aqueous humor, thereby lowering IO pressure
In normal and glaucomatous eyes
Independent of diuretic effect and persists in presence of metabolic acidosis

Question 18

Carbonic anhydrase inhibitors anticonvulsant effects

Answer 18

Transports HCO3 from blood ----> CSF (opposite from kidney)
Uncertain MOA (change in pH, decreased CSF production in choroid plexus)

Question 19

Carbonic anhydrase inhibitors PK

Answer 19

well absorbed from GIT
distribution wide; erythrocyes and renal cortex
Elimination–Renal; dorzolamide, brinzolamide accumate in RBC, excreted in kidney. Methazolamide metab in liver, 20-30% excreted in kidney, rest unknown

Question 20

Carbonic anhydrase inhibitors USE

Answer 20

Glaucoma–open-angle
Edema–for CHF, but rare now
Metabolic alkalosis
Acute high altitude sickness–can reducse CSF formation and decrease pH of CST which increases ventilation; usually start with acetazolamide 24 hrs before ascent

Question 21

Carbonic Anhydrase inhibitors ADEs

Answer 21

Renal and metabolic: hypokalemia, hypercholremic metabolic acidosis, hyperglycemia and glucosuria, crystaluria
Nervous system (high dose): drowsiness, malaise, h/a, depression, nevousness, paresthesias
Hypersensitivity–they are sulfonamide derivatives, rarely sulfa allergies; cholestatic jaundice, fever, rash, derm, urticaria
Hematologic: anema, leukopenia, thrombocytopenia
Increased ammonia in hepatic encephalopathy. Nh4 —> NH3 in lumen (urine)

Question 22

Loop diuretics agents

Answer 22

Furosemide (Lasix)
Bumetanide (Bumex)
Torsemide (Demadex)
Ethacrynic Acid (Edecrin)

Question 23

Loop diuretics MOA

Answer 23

inhibit NaCl reabsorption in the thick ascending lum of loop of henle–inhibit Na/K/2Cl transport system
Most efficacious diuretics–large NaCl absoprtiive capacity of loop and no limit d/t acidosis
Increase renal prostaglandin synthesis via Cox2 leads to increase renal blood flow and inhibits Na reabsorption in the loop
Effects on blood flow thru vascular beds–relieve pulm congestion prior to diuretic effect, even in anephric pts.

Question 24

Loop diuretics that is NOT a sulfa derivative

Answer 24

Ethacrynic Acid

Question 25

Loop diuretic uses

Answer 25

Edema d/t CHF, acute pulm edema, nephrotic syndrome, cirrhosis.
HF–used for control of fluid overload, not shown to reduce mortality; used for sx
HTN: in pts with reduced renal function where thiazide may not be effective
Acute renal failure–to control volume and enhance K excretion
Hypercalcemia–severe cases. Must give with saline to avoid dehydration or could make it worse
Hyperkalemia–mild
Anion o/d: Br, Fl, I

Question 26

Loop diuretic ADE

Answer 26

Fluid, electrolyte, CV renal: fluid depletion, orthostatic HoTN, decrease GFR. Hypokalemic metabolic alkalosis (losing a lot of potassium and gaiting sodium), MG loss (CHECK CMP!!), Ca loss, increased UA levels (gout)
Otic effects–tinnitus, hearing loss
GI
hyperglycemia, glycouria
Hypersensitivity–sulfa
Nervous, dizzy, h/a
Hematologic: anemia, leukopenia, thrombocytopenia