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Pharmacotherapy 2/3 > Diuretics > Flashcards

Diuretics Flashcards

1
Q

What is the glomerular filtration rate?

A

amount of plasma (in ml/min) that is filtered by the kidneys normally 125 ml/min or 180L/day

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2
Q

How much filtered plasma is eliminated as urine?

A

1-2 mil/min or 1.5 - 2.0 L/day

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3
Q

What happens in the glomerulus?

A

H2O and solutes are freely filtered

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4
Q

What happens at the proximal convoluted tubule?

A

Majority of electrolytes get reabsorbed: 60-65% Na+ Cl H2O HCO3- glucose

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5
Q

What happens in the descending limb of Henle?

A

Only H2O is reabsorbed

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6
Q

What happens in the ascending limb of Henle?

A

Reabsorb: 20-25% Na+ K+ Cl- Mg2+ Ca2+

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7
Q

What happens in the distal convoluted tube?

A

Reabsorb: 4-8% Na+ K+ Cl-

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8
Q

What happens in the cortical collecting duct?

A

Secrete K+ and H+ Reabsorb Na+ (2-5%) and Cl-

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9
Q

What happens in the medullary collecting duct?

A

only reabsorb H2O (depending on whether or not ADH is present - antidiuretic hormone)

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10
Q

How much sodium is excreted in the urine?

A

1-2% of Na+ that initially is filtered

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11
Q

What are the types of transport mechanisms across renal epithelial cell membranes?

A

Passive transport: 1. convective solute flow (solvent drag). solutes are being dragged along in the direction of water 2. simple diffusion 3. channel-mediated diffusion 4. carrier-mediated (facilitated) diffusion (uniport) Active Transport: 5. ATP-mediated transport (opposite direction of concentration gradient) 6. symport (co-transport) - same direction 7. antiport (countertransport) - opposite direction

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12
Q

What are the modes of transport in the proximal tubule?

A

On interstitium/blood side: ATP- mediated transport: Na+ out of tubule, K+ into cell (60-65% Na is reabsorbed here) highly water permeable (water gets reabsorbed from the lumen into the cell) 100% of filtered glucose and amino acids reabsorbed here glucose via the SGL2 (sodium-glucose transporter-2) site of action for carbonic anhydrase (CA) inhibitors

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13
Q

What do carbonic anhydrase inhibitors do?

A

In the proximal convoluted tubule, Block carbonic anhydrase (CA) in the tubule lumen, which inhibits the Na+/H+ exchange (on the lumen side) and Na+ reabsorption

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14
Q

What are the carbonic anhydrase inhibitors?

A

Acetazolamide PO (diamox) Dorzolamide (Trusopt 2% soln) brinzolamide (Azopt 1% susp) Clinical uses: reduce aqueous humor production in glaucoma decrease CSF (cerebral spinal fluid) formation & pH –> increased ventilation and improvement in symptoms of acute mountain sickness SEs/precautions: don’t use in patients with sulfonamide allergy can cause metabolic acidosis hypokalemia kidney stones parethesias worsening of hepatic encephalopathy

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15
Q

What is the basic transport in the thick ascending limb of Henle?

A

Na+, K+, 2Cl- move from lumen to cell via symporter Na+ moves from cell to interstitium/blood and K+ moves from interstitium/blood to inside of cell via primary active transport. Mg2+ and Ca2+ move from urine to interstitial/blood via paracellular pathway reabsorb 20-25% of filtered Na impermeable to water plays an important role in the hypertonic medullary interstitium –> the concentration of urine by collecting duct (countercurrent multiplier)

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16
Q

How do loop diuretics work?

A
  • actively secreted by organic acid transporters in proximal tubular cells - exert effect on lumen (urine) side
  • Inhibit the Na/K/2Cl symporter in the ALH (ascending limb of henle), so incrase Na+, Cl-, K+, Mg2+, Ca2+ excretion in the urine
  • block kidney’s ability to concentrate the urine during hydropenia and dilute the urine during water diuresis
  • can’t make interstitium as salty when ascending limb of henle is blocked, so you can’t concentrate the urine as much - you are going to have MORE urine.
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17
Q

What is important about the thick ascending loop of henle?

A

it is important for creating concentrated urine.

you get rid of more free water with a loop diuretic than you do with other diuretics by blocking NaCl reabsorption at the ALH, you are increasing free water excretion in the medullary collecting duct

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18
Q

What are the loop diuretics and their pharmacokinetics?

A

Furosemide (Lasix)

Bumetanide (Bumex)

Torsemide (Demedex)

  • Furosemide: sulfonamide, ~50% bioavailability, 1.5-2 hr 1/2 life, >80% renal elimination
  • Bumetanide: sulfonamide, ~ 80-100% bioavailability, ~1 hr half life, 62% renal & 38% liver elimination
  • Torsemide: sulfonylurea, ~80-100% bioavailability, ~3.5 hr half life, 20% renal & 80% liver elimination
  • all are highly protein bound (>90%), so alterations in protein binding can affect the delivery of diuretics to the kidney: someone with low blood protein could impair ability to get to site of action
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19
Q

What are the main clinical uses for loop diuretics and adverse effects?

A
  • Clinical uses:
    • management of edema & edematous conditions (e.g. heart failure)
    • ascities - in combination with spironolactone
    • HTN in patients with chronic kidney disease
    • acute hypercalcemia (blocks section of tubule that absorbs excess calcium, helps excrete more calcium)
  • Adverse effects: hypokalmeia, hypomagnesemia, hyponatremia (low sodium), hypotension, dehydration (lower ECFV [extracellular fluid volume]), metabolic alkalosis. Other: ototoxicity, hyperuricemia, hyppocalcemia
20
Q

what is the basic transport in the distal convoluted tubule?

A
  • reabsorbs 4-8% of filtered Na
  • relatively impermeable to water
  • site of action for thiazide diuretics
21
Q

What are the thiazide diuretics?

A
  • Chlorothiazide (Diuril) (only one that is IV)
  • Hydrochlorothiazide (Hydrodiuril)
  • Chlorthalidone (Hygroton)
  • Indapamide (lozol)
  • Metolazone (Zaroxylyn)
  • actively secreted into the urine by the organic acid transporters in the proximal tubular cells - exert effect on lumen side (like loop diuretics)
  • inhibits the Na/Cl symporter, so increases Na+, Cl-, K+ and Mg2+ excretion in the urine
  • blocks the kidney’s ability to dilute the urine during water diuresis
  • volume of urine that you produce with thiazide diuretics is smaller than with loop diuretics
22
Q

What are the pharmacokinetics of thiazide diuretics?

A
  • Chlorothiazide
    • bioavailability 30-50%
    • 1/2 life 1.5 hrs
    • renal elimination
    • relative potency 0.1
  • Hydrochlorothiazide
    • bioavailability 70%
    • 1/2 life 12 hrs
    • renal elimination
    • relative potency 1
  • chlorthalidone
    • bioavailability 65%
    • 1/2 life 40-60 hrs
    • 65% renal, 10% bile, 25% unknown elimination
    • relative potency 1
  • indapamide
    • bioavailability 93%
    • 1/2 life 5-26 hrs
    • liver elimination
    • relative potency 20
  • metolazone
    • bioavailability 40-65%
    • 1/2 life 8-14 hrs
    • 80% renal, 10% bile, 10% liver elimination
    • relative potency 10
  • all are sulfonamides
  • all are highly protein bound (>90%)
23
Q

What are the clinical uses and adverse effects of thiazide diuretics?

A

Clinical uses:

  • HTN
  • Management of mild edema or in combination with a loop diuretic for moderate to severe edema
  • other: nephrolithiasis, nephrogenic diabetes insipidus

decreased efficacy at a GFR < 30 ml/min

Adverse effects:

  • hypokalemia, hypomagnesemia, hyponatremia (more than loop diuretics), hypochloremia, hypotension, dehydration (decreased ECFV), metabolic alkalosis
  • Other: hyperuricemia, hyperglycemia, increased cholesterol
24
Q

What is the basic transport in the collecting system?

A
  • only 2-5% of Na reabsorption
  • most important site for K+ secretion
  • site of action for K+ sparing diuretics
25
Q

What are the potassium-sparing diuretics?

A
  • actively secreted into the urine by organic BASE transporters in the proximal tubular cells - exert effect on lumen side
  • amiloride and triamterene work by inhibiting Na influx through ion channels in the luminal membrane of the collecting tubules

ENaC = epithelial Na Channel

26
Q

What are the pharmacokinetics of potassium-sparing diuretics?

A

Amiloride (dyrenium)

  • 30-90% bioavailability
  • 6-9 hr half life
  • 50% renal, 40-50% bile elimination
  • relative potency 1

Triamterene (midamor)

  • 30-70% bioavailability
  • 4 hr half life
  • 80% liver elimination- active metabolite is excreted renally
  • relative potency 0.1

neither are sulfonamides

27
Q

What are the clinical uses and adverse effects of potassium-sparing diuretics?

A

Clinical uses:

  • HTN (in combination with a thiazide to minimize K+ loss)

Adverse effects:

  • Hyperkalemia
  • amiloride (better tolerated) - n/v/d, headache
  • triamterene - hyperglycemia, photosensitization, interstitial nephritis, nephrolithiasis
  • other - metabolic acidosis, hyperuricemia
28
Q

How does a mineralocorticoid receptor (aldosterone) antagonist work?

A
  • competitively inhibits the binding of aldosterone to the mineralocorticoid receptors preventing the transcription and translation of aldosterone-induced proteins
  • ONLY diuretic that works on the blood side
29
Q

What are the aldosterone antagonists & their pharmacokinetics?

A

Spironolactone (Aldactone)

  • 70% bioavailability
  • 1.6 hr half life (half life of active metabolite - 15 hours)
  • 50% renal 40% feces elimination

Epleronone (Inspra)

  • 70% bioavailability
  • 5 hr half life
  • extensive liver elimination
30
Q

What are the clinical uses and adverse effects of aldosterone antagonists?

A

Clinical uses:

  • HTN (in combination with other agents for resistant hypertension)
  • alone for mild ascites or in combination with furosemide for moderate to severe ascites
  • heart failure

Adverse effects:

  • Hyperkalemia, hyperchloremic metabolic acidosis
  • Other - gynecomastia, impotence
31
Q

What is the basic transport in the collecting system?

A
  • final urine concentration is determined
  • ADH regulates the insertion of preformed water channels (aquaporin-2 = AQP2) into apical lumen - creates a door for water to get out
  • no ADH present = impermeable to water –> dilute urine
    • ADH present = increased water permeability –> concentrated urine
  • movement of water out of the tubule is driven by the hypertonic medullary interstitium
32
Q

What are the diuretic sites of action?

A

Proximal Convoluted tubule

  • carbonic anhydrase inhibitor: Acetazolamide
  • inhibits reabsorption of HCO3-
  • weak diuretic properties

Ascending Loop of Henle

  • Loop diuretics: bumetanide, furosemide, torsemide, ethacrynic acid
  • inhibit Na+/K+/2Cl- cotransport, resulting in retention of Na+, Cl- and water in the tubule
  • most efficacious diuretics

distal convoluted tubule

  • Thiazides
  • inhibit reabsorption of Na+ and Cl-, resulting in retention of water in the tubule
  • most commonly used diuretics

collecting tubule and duct

  • aldosterone antagonists: spironolactone,
  • Potassium-sparing diuretics: amiloride, triamterene
  • inhibit aldosterone-mediated reabsorption of Na+ and secretion of K+
  • amiloride & triamterene block Na+ channels
  • can prevent loss of K+ that occurs with thiazide or loop diuretics
33
Q

Proximal Convoluted tubule:

functions, primary transporter, diuretic

A

Functions: reabsorption of 60-65% of filtered Na+/K+/Ca2+, Mg2+, 85% of NaHCO3 and almost 100% glucose/amino acids

primary transporter: Na+/H+ (NHE3), carbonic anhydrase, Na/glucose cotransporter 2 (SGLT2)

Diuretic: carbonic anhydrase inhibitors

34
Q

Proximal Tubule

functions, primary transporter, diuretic

A

Functions: secretion of most diuretics

Primary transporter: acid and base transporter

diuretic: none

35
Q

Thin descending limb of henle

functions, primary transporter, diuretic

A

Functions: passive reabsorption of water

Primary transporter: aquaporins

Diuretic: none

36
Q

thick ascending limb of henle

functions, primary transporter, diuretic

A

Functions: active reabsorption of 25% of filtered Na+/K+/Cl-, secondary reabsorption of Ca2+ and Mg2+, impermeable to water

primary transporter: Na/K/2Cl co-transporter or symporter (NKCC2)

diuretic: loop diuretics

37
Q

distal convoluted tubule

functions, primary transporter, diuretic

A

Functions: active reabsorption of 4-8% of filtered Na+ and Cl-, Ca2+ reabsorption under PTH control

Primary Transporter: Na/Cl co-transporter or symporter (NCC)

diuretics: thiazides

38
Q

cortical collecting tubule

functions, primary transporter, diuretic

A

functions: Na+ reabsorption (2-5%) coupled to K+ and H+ secretion

primary transporter: Na channels (ENaC), K channels, aquaporins

diuretics: K+ sparing diuretics, mineralcorticoid receptor

39
Q

medullary collecting duct

functions, primary transporter, diuretic

A

functions: water reabsorption under the control of antidiuretic hormone (ADH)

primary transporter: aquaporins

diuretic: vasopressin antagonists

40
Q

What are clinical uses of diuretics?

A
  • hypertension
  • edema/edematous conditions (e.g. heart failiure, CKD, nephrotic syndrome)
  • ascites due to liver cirrhosis
  • other conditions (e.g. hypercalemia)
41
Q

What is edema?

A

clinically detectable increase in interstitial volume due to cardiac, renal or vascular disease states that reduce blood flow to kidney

edema formation occurs when there is a

  • decrease in effective arterial blood volume –> hypoperfusion of kidneys –> stimulation of renal Na+ and H2O retention (causes kidney to sense drop in circulation, makes kidney release aldosterone to make you hold onto sodium to hold onto water)
  • altered capillary hemodynamics
42
Q

What are the types of edema?

A

Peripheral edema

  • gravity dependent sites
  • evaluated as 1+ to 4+ pitting (4+ is the most severe)
  • typically 10% or 10 lb. weight gain before clinically evident

anasarca (severe): total body edema

pulmonary edema (severe): only form of edema that is dangerous/life-threatening

43
Q

What are the principles of edema management?

A
  • treat underlying cause
  • dietary sodium restriction (1-2 g/day)
  • loop diuretic: drug of choice, effective at ClCr < 30 ml/min (moderate-severe CKD) - allows most volume of urine to be excreted
  • thiazide diuretics: mild edema or adjunctive therapy. Not effective alone at ClCr < 30 ml/min
44
Q

How is peripheral edema managed?

A
  • usually outpatient
  • optimize therapies for underlying disease state
  • institute dietary sodium restriction
  • check for hidden sources of sodium
  • check for medications which can cause edema (NSAIDs, dihydropyridine calcium channel blockers, thiazolidinediones (TZDs), estrogens
  • implement non-pharm measure (raising legs)
  • start with low dose oral loop (e.g. furosemide 20-40 mg orally once daily to twice daily - may need higher starting dose if HF, nephrotic syndrome, or CKD)
  • goal: slowly reduce edema
  • titrate dose & interval based on response
  • if patient does not respond as expected, check compliance & look for mechanisms of resistance & treat accordingly
45
Q

How is acute severe edema managed?

A
  • usually managed in the hospital
  • optimize therapies for underlying disease state
  • check for hidden sources of sodium
  • check for medications which can cause edema
  • if patient is already on diuretic therapy: assess adherence with medication & sodium restriction
  • use IV bolus dosing initially
  • dose of loop diuretic will depend on previous dosing history & underlying disease state
  • double the initial dose until adequate response (1 ml/kg/hr urine output - depending on kidney function)
  • once you find the most effective dose (or maximal dose is reached), give it as often as needed (typically bid to tid)
  • if loop alone is inadequate, use combo of loop + thiazide (or K+ sparing diuretic if normal renal function or low K+). If loop is IV, administer oral thiazide 0.5 to 1 hr before loop
  • once adequate diuresis has occurred & patient is stable, switch from IV to equivalent oral regimen.
46
Q

How is ascites managed?

A
  • spironolactone diuretic of choice due to hyperaldosteronism
    • use alone only if mild ascites
    • dosing = 50-100 mg once daily with food (starting), up to 400 mg po daily (max dose)
    • titrate dose no faster than every 3-5 days
  • if moderate to severe ascites or patient has peripheral edema, use combination therapy with a loop diuretic
    • ideal ratio: 100 mg/day po spironolactone to 40 mg/day po furosemide
  • usual starting dose of oral furosemide is 40 mg dailiy. Maximal oral effective dose = 80 mg
  • can administer loop diuretic more often to improve response
  • goal fluid loss (ascites w/out edema = 500 ml/day (0.5 kg/day)
  • goal fluid loss (ascites w/edema) = 1000 ml/day (1.0 kg/day)
47
Q

How is efficacy and safety of diuretics monitored?

A
  • daily weight
  • inputs (oral and IV) & outputs (urine)
  • electrolytes (K+, Na+, Cl-, CO2, Mg2+
  • vital signs (blood pressure, HR)
  • kidney function (BUN Scr)

Pharmacotherapy 2/3 (7 decks)

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