Clinical Use of Diuretics

Review of Anatomy and Physiology Glomerulus -forms ultrafiltrate of plasma

Review of Anatomy and Physiology Proximal Tubule -reabsorbs isosmotically 65-70% of -reclaims all the glucose, amino acids, and bicarbonate Secretes protein bound drugs

Review of Anatomy and Physiology Loop -reabsorbs 15-25% of filtered NaCl -Creates the gradient for the countercurrent multiplier

Review of Anatomy and Physiology Distal Tubule -reabsorbs few percent -fine tunes- volume, osmolarity (ADH), K (aldosterone), acid-base

Location of Diuretic Activity Distal Tubule “High-ceiling diuretics”- HCTZ, Zaroxlyn (metolazone) K-sparing diuretics-amiloride, spironolactone, triamterene Proximal Tubule Acetazolamide Loop Loop diuretics- Lasix, Bumex, Ethacrynic Acid, Torsemide

Loop diuretics 4 loops- furosemide, bumetanide, ethacrynic acid, torsemide Can block a maximum of 20-25% of filtered Na+ Increases the excretion of Ca+ Use therapeutically in cases of hypercalcemia Loop -reabsorbs 15-25% of filtered NaCl -Creates the gradient for the countercurrent multiplier

Distal Tubule Thiazide-type– HCTZ, Chlorthalidone, Zaroxlyn (metolazone), IV form Mild diuretics- even if maximally block– excretion only increased 3-5% Therefore poor choice for edematous states, but excellent for hypertension (where large volume loss isn’t required) Blocks calcium excretion Useful for stone patients Distal Tubule -reabsorbs 3-5% percent -fine tunes the ultimate urine composition- k, acid-base, volume, Calcium

Distal Tubule K-sparing diuretics- amiloride, spironolactone, and triamterene Because 98% of sodium already absorbed, maximal increased excretion of only 1-2% Peri-capillary space (blood) Tubular lumen (urinary space) Na+ Distal Tubule -reabsorbs 3-5% percent -fine tunes the ultimate urine composition- k, acid-base, volume, Calcium K+ Aldosterone sensitive channel =

Distal Tubule Mechanism of Action Spironolactone competitively inhibits aldosterone Distal Tubule Mechanism of Action K-sparing diuretics- amiloride, spironolactone, and triamterene Aldosterone Tubular lumen (urinary space) Peri-capillary space (blood) Na+ K+ Aldosterone sensitive channel --- in the presence of aldosterone the channel is open = Amiloride and triamterene directly block the channel -can use to minimize lithium toxicity

Distal Tubule Diuretics Amiloride Once a day Best tolerated– only mild hyperkalemia Can be used to minimize lithium toxicity- by directly blocking the Na-channel used by lithium to enter the cell and cause DI Picture of periodic table- explain why na and li use the same channel Tubular lumen (urinary space) Peri-capillary space (blood) Na+ K+ Aldosterone sensitive channel --- in the presence of aldosterone the channel is open = Li+

Distal Tubule Diuretics Triamterene Found in Maxzide Direct nephrotoxin- causes crystalluria and cast formation in up to 50% of patients Known cause of interstitial nephritis Approximately 1 case/year at NNMC Tubular lumen (urinary space) Peri-capillary space (blood) Na+ K+ Aldosterone sensitive channel --- in the presence of aldosterone the channel is open =

Distal Tubule Diuretics Aldosterone Spironolactone Long-half life– slow onset and resolution Frequent side effects Gynecomastia (10% ) Ax Tubular lumen (urinary space) Peri-capillary space (blood) Na+ K+ Aldosterone sensitive channel --- in the presence of aldosterone the channel is open =

Other diuretics Mannitol Only diuretic which causes water loss in excess of Na Means only diuretic which causes a dilute urine (specific gravity of <1.010) Therefore significant risk for hypernatremia 2nd to losses of free water ?use to therapeutic advantage in hyponatremia? Theoretical risk with CRI– mannitol is retained causing hyperosmolarity

Time course of diuresis Patient Fallacies “Lasix makes me pee all day”- Wrong, lasix causes increased urine output for approximately 6 hours ( LASt sIX), then urine output actually DECREASES for the remainder of the day.

Time course of diuresis Patient Fallacies “Lasix causes me to make extra urine”- Wrong, after the first three days of diuresis patients are in steady-state. What they drink = what they urinate. Intuititively makes sense. If patients made extra urine everyday, eventually they would have no fluid left in their bodies, turn into dust, and blow away.

Time course of diuresis Why does this occur? Negative feedback loop automatically dampens the diuresis as it progresses. Given a stable dose of lasix, the counter-regulatory hormones eventually balance the lasix and NO FURTHER DIURESIS OCCURS FOR A GIVEN DOSE- input=output Decreased volume, blood pressure, GFR, hormonal activation - increased norepi, renin, angiotensin, aldosterone Lasix - + Diuresis

Time course of diuresis Steady-state implications Assuming stable lasix dose and sodium intake, Weight stable after 72hours (urine output = po intake) Electrolyte abnormalities (if they are going to occur) will occur -this is why you don’t need to check lytes every visit Decreased volume, blood pressure, GFR, hormonal activation - increased norepi, renin, angiotensin, aldosterone Lasix - + Diuresis

Time course of diuresis Patient fallacy #3 Lasix qd can be used as an anti-htn agent Can result in a net increase in volume (especially in the face of high sodium intake) After lasix wears off, kidney then holds on to Na for the next 18 hours Dinner 100meq Na intake LASIX Lunch 100meq Na intake Breakfast 100meq

Time course of diuresis For anti-htn- give BID to TID Prevents the post-lasix sodium retention which would otherwise occur with lunch and dinner Net effect is increased diuresis with improved bp control Dinner 100meq Na intake LASIX LASIX LASIX Lunch 100meq Na intake Breakfast 100meq

Time course of diuresis Why not just increase the am dose? 1. Dose response curve flattens, such that larger doses with minimal increased benefit. But toxicity increases with increasing dose

Time course of diuresis Why not just increase the am dose? 2. Even if higher dose effective, patient unlikely to tolerate such a rapid diuresis Less hypotension risk urinating 200cc/hr x 10hrs vs. 2000cc/hr x 1hr

Diuretic Complications Volume depletion Azotemia Hypokalemia Metabolic Alkalosis Hyponatremia Hyperuricemia Hypomagnesemia

Diuretic Complications Volume depletion Azotemia Hypokalemia Metabolic Alkalosis Hyponatremia Hyperuricemia Hypomagnesemia

Diuretic Complications Volume depletion Azotemia Hypokalemia 50mg HCTZ decreases K an average of 0.4-0.6meq/l Metabolic Alkalosis Hyponatremia Hyperuricemia Hypomagnesemia

Diuretic Complications Volume depletion Azotemia Hypokalemia Metabolic Alkalosis Hyponatremia Hyperuricemia Hypomagnesemia

Diuretic Complications Volume depletion Azotemia Hypokalemia Metabolic Alkalosis Hyponatremia Common in CHF/Cirrhosis Almost all cases 2nd to thiazide diuretic Loops don’t cause because they block the concentration gradient. No gradient, no impairment in free H20 excretion Hyperuricemia Hypomagnesemia

Diuretic Complications Volume depletion Azotemia Hypokalemia Metabolic Alkalosis Hyponatremia Hyperuricemia Due to increased proximal urate absorption associated with hypovolemia Dose related- see graph Hypomagnesemia

Diuretic Complications Volume depletion Azotemia Hypokalemia Metabolic Alkalosis Hyponatremia Hyperuricemia Hypomagnesemia Primarily handled in loop of Henle– therefore loops are etio Thiazides also cause via a 2nd hyperaldosterone state

Diuretic resistance Two important determinants Other determinants Site of action of the diuretic Presence of counterbalancing antinaturic forces (angiotension, aldosterone), a fall in bp Other determinants Rate of drug excretion All loops are highly protein bound Not well filtered. Enter the urine via the proximal tubule secretory pump Higher doses cause higher (initial) levels of sodium excretion

Diuretic resistance Dose response Must reach a threshold amount before any naturesis Once threshold reached, naturesis increased with increasing doses Plateau is reached after which increased doses have no effect Makes sense- once receptor is completely blocked, extra lasix will have no impact Normal subject- max effect is seen with 40 lasix or 1 bumex

Diuretic resistance Dose response Initial aim is to find the effective single dose (on the steep part of the curve) Double the dose until response seen (or a max of 320-400 of oral lasix) Increasing a sub-opt dose to bid will have no effect Higher doses required in: CHF- 2nd to counter-regulatory hormones and decreased absorption Renal failure- 2nd to competition for tubular secretion from retained cations

Diuretic resistance Dose response Initial aim is to find the effective single dose (on the steep part of the curve) Double the dose until response seen (or a max of 320-400 of oral lasix) Increasing a sub-opt dose to bid will have no effect Higher doses required in: CHF- 2nd to counter-regulatory hormones and decreased absorption Renal failure- 2nd to competition for tubular secretion from retained cations

Diuretic resistance Mechanisms of resistance Excess sodium intake Possible to eat more sodium than lasix makes the patients lose Check a 24hr urine sodium level to confirm. Anything over 100meq/day is excessive Decreased or delayed intestinal drug absorption Decreased drug entry into the tubular lumen Increased distal absorption Decreased loop sodium delivery due to low GFR

Diuretic resistance Mechanisms of resistance Excess sodium intake Decreased or delayed intestinal drug absorption Common in CHF/Cirrhosis/Nephrosis Delay in intestinal absorption 2nd to decreased intestinal perfusion, reduced motility, and mucosal edema Explains the preferential response to Bumex or IV lasix Decreased drug entry into the tubular lumen Increased distal absorption Decreased loop sodium delivery due to low GFR

Diuretic resistance Mechanisms of resistance Excess sodium intake Decreased or delayed intestinal drug absorption Decreased drug entry into the tubular lumen Occurs for the same reasons as above Increased distal absorption Decreased loop sodium delivery due to low GFR

Diuretic resistance Mechanisms of resistance Excess sodium intake Decreased or delayed intestinal drug absorption Decreased drug entry into the tubular lumen Increased distal absorption Effect of diuretic is blunted by “downstream” compensation Proximal Diuretic (Acetazolamide)- theoretically should block 60-75%. But actually a poor diuretic 2nd downstream compensation

Diuretic resistance Mechanisms of resistance Excess sodium intake Decreased or delayed intestinal drug absorption Decreased drug entry into the tubular lumen Increased distal absorption Effect of diuretic is blunted by “downstream” compensation Compensation can occur in distal tubule limiting loop effectiveness Loop Diuretic- only blocks 15-20% of sodium reabsorption, but because less downstream tubule to compensate, an effective diuretic

Diuretic resistance Mechanisms of resistance Excess sodium intake Decreased or delayed intestinal drug absorption Decreased drug entry into the tubular lumen Increased distal absorption Effect of diuretic is blunted by “downstream” compensation Distal compensation is overcome by SEQUENTIAL BLOCKING -this is the rational for giving a loop + a thiazide -seen in the usual combination of lasix and Zaroxlyn

Diuretic resistance Mechanisms of resistance HCTZ vs. Zaroxlyn Similar mechanism of action. Zaroxlyn is simply more powerful mg for mg 5mg of Zaroxlyn = 100-200mg HCTZ (approx) Zaroxlyn has a much longer duration of action Allows for biw dosing

Diuretic resistance Nuances of use HCTZ and CRF– still works Ethacrynic acid Torsemide use Bumex nitch– shorter half life Zaroxlyn use Practical points of acetazolamide use