Diuretics Flashcards
What is the glomerular filtration rate?
amount of plasma (in ml/min) that is filtered by the kidneys normally 125 ml/min or 180L/day
How much filtered plasma is eliminated as urine?
1-2 mil/min or 1.5 - 2.0 L/day
What happens in the glomerulus?
H2O and solutes are freely filtered
What happens at the proximal convoluted tubule?
Majority of electrolytes get reabsorbed: 60-65% Na+ Cl H2O HCO3- glucose
What happens in the descending limb of Henle?
Only H2O is reabsorbed
What happens in the ascending limb of Henle?
Reabsorb: 20-25% Na+ K+ Cl- Mg2+ Ca2+
What happens in the distal convoluted tube?
Reabsorb: 4-8% Na+ K+ Cl-
What happens in the cortical collecting duct?
Secrete K+ and H+ Reabsorb Na+ (2-5%) and Cl-
What happens in the medullary collecting duct?
only reabsorb H2O (depending on whether or not ADH is present - antidiuretic hormone)
How much sodium is excreted in the urine?
1-2% of Na+ that initially is filtered
What are the types of transport mechanisms across renal epithelial cell membranes?
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
What are the modes of transport in the proximal tubule?
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
What do carbonic anhydrase inhibitors do?
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
What are the carbonic anhydrase inhibitors?
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
What is the basic transport in the thick ascending limb of Henle?
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)
How do loop diuretics work?
- 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.
What is important about the thick ascending loop of henle?
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
What are the loop diuretics and their pharmacokinetics?
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
What are the main clinical uses for loop diuretics and adverse effects?
- 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
what is the basic transport in the distal convoluted tubule?
- reabsorbs 4-8% of filtered Na
- relatively impermeable to water
- site of action for thiazide diuretics
What are the thiazide diuretics?
- 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
What are the pharmacokinetics of thiazide diuretics?
- 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%)
What are the clinical uses and adverse effects of thiazide diuretics?
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
What is the basic transport in the collecting system?
- only 2-5% of Na reabsorption
- most important site for K+ secretion
- site of action for K+ sparing diuretics
What are the potassium-sparing diuretics?
- 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
What are the pharmacokinetics of potassium-sparing diuretics?
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
What are the clinical uses and adverse effects of potassium-sparing diuretics?
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
How does a mineralocorticoid receptor (aldosterone) antagonist work?
- 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
What are the aldosterone antagonists & their pharmacokinetics?
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
What are the clinical uses and adverse effects of aldosterone antagonists?
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
What is the basic transport in the collecting system?
- 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
What are the diuretic sites of action?
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
Proximal Convoluted tubule:
functions, primary transporter, diuretic
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
Proximal Tubule
functions, primary transporter, diuretic
Functions: secretion of most diuretics
Primary transporter: acid and base transporter
diuretic: none
Thin descending limb of henle
functions, primary transporter, diuretic
Functions: passive reabsorption of water
Primary transporter: aquaporins
Diuretic: none
thick ascending limb of henle
functions, primary transporter, diuretic
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
distal convoluted tubule
functions, primary transporter, diuretic
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
cortical collecting tubule
functions, primary transporter, diuretic
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
medullary collecting duct
functions, primary transporter, diuretic
functions: water reabsorption under the control of antidiuretic hormone (ADH)
primary transporter: aquaporins
diuretic: vasopressin antagonists
What are clinical uses of diuretics?
- hypertension
- edema/edematous conditions (e.g. heart failiure, CKD, nephrotic syndrome)
- ascites due to liver cirrhosis
- other conditions (e.g. hypercalemia)
What is edema?
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
What are the types of edema?
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
What are the principles of edema management?
- 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
How is peripheral edema managed?
- 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
How is acute severe edema managed?
- 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.
How is ascites managed?
- 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)
How is efficacy and safety of diuretics monitored?
- daily weight
- inputs (oral and IV) & outputs (urine)
- electrolytes (K+, Na+, Cl-, CO2, Mg2+
- vital signs (blood pressure, HR)
- kidney function (BUN Scr)
