clinical use of diuretics. review of anatomy and physiology glomerulus -forms ultrafiltrate of...
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Clinical Use of Diuretics
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Review of Anatomy and Physiology
Glomerulus
-forms ultrafiltrate of plasma
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Review of Anatomy and Physiology
Proximal Tubule
-reabsorbs isosmotically 65-70% of
-reclaims all the glucose, amino acids, and bicarbonate
Secretes protein bound drugs
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Review of Anatomy and Physiology
Loop
-reabsorbs 15-25% of filtered NaCl
-Creates the gradient for the countercurrent multiplier
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Review of Anatomy and Physiology
Distal Tubule
-reabsorbs few percent
-fine tunes- volume, osmolarity (ADH), K (aldosterone), acid-base
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Location of Diuretic Activity
Proximal Tubule
Acetazolamide Loop
Loop diuretics- Lasix, Bumex, Ethacrynic Acid, Torsemide
Distal Tubule
“High-ceiling diuretics”- HCTZ, Zaroxlyn (metolazone)
K-sparing diuretics-amiloride, spironolactone, triamterene
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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
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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
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Distal Tubule• K-sparing diuretics-
amiloride, spironolactone, and triamterene
• Because 98% of sodium already absorbed, maximal increased excretion of only 1-2%
Distal Tubule
-reabsorbs 3-5% percent
-fine tunes the ultimate urine composition- k, acid-base, volume, Calcium
Tubular lumen (urinary space)
Peri-capillary space (blood)
Na+
K+
Aldosterone sensitive channel
=
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Distal TubuleMechanism of Action
• K-sparing diuretics- amiloride, spironolactone, and triamterene 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
Spironolactone competitively inhibits aldosterone
Aldosterone
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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+
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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
=
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Distal Tubule Diuretics
• Spironolactone– Long-half life– slow
onset and resolution
– Frequent side effects• Gynecomastia (10% )
• Ax
• Ax
Tubular lumen (urinary space)
Peri-capillary space (blood)
Na+
K+
Aldosterone sensitive channel --- in the presence of aldosterone the channel is open
=
Aldosterone
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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
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Time course of diuresis
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0000-06000600-12001200-18001800-2400
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Pre_lasix Total Na
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Patient Fallacies
1. “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.
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Time course of diuresisPatient Fallacies
2. “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.
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Time course of diuresisWhy 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
Lasix +Diuresis
Decreased volume, blood pressure, GFR, hormonal activation
- increased norepi, renin,
angiotensin, aldosterone
-
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Time course of diuresisSteady-state implications
Assuming stable lasix dose and sodium intake,
1. Weight stable after 72hours (urine output = po intake)
2. Electrolyte abnormalities (if they are going to occur) will occur
-this is why you don’t need to check lytes every visit
Lasix +Diuresis
Decreased volume, blood pressure, GFR, hormonal activation
- increased norepi, renin,
angiotensin, aldosterone
-
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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
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Lunch 100meq
Na intake
Dinner 100meq
Na intake
Breakfast 100meq
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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
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Lunch 100meq
Na intake
Dinner 100meq
Na intake
Breakfast 100meq
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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
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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
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Diuretic Complications
• Volume depletion
• Azotemia
• Hypokalemia
• Metabolic Alkalosis
• Hyponatremia
• Hyperuricemia
• Hypomagnesemia
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Diuretic Complications
• Volume depletion
• Azotemia
• Hypokalemia
• Metabolic Alkalosis
• Hyponatremia
• Hyperuricemia
• Hypomagnesemia
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Diuretic Complications
• Volume depletion• Azotemia• Hypokalemia
– 50mg HCTZ decreases K an average of 0.4-0.6meq/l
• Metabolic Alkalosis• Hyponatremia• Hyperuricemia• Hypomagnesemia
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Diuretic Complications
• Volume depletion
• Azotemia
• Hypokalemia
• Metabolic Alkalosis
• Hyponatremia
• Hyperuricemia
• Hypomagnesemia
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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
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Diuretic Complications
• Volume depletion• Azotemia• Hypokalemia• Metabolic Alkalosis• Hyponatremia• Hyperuricemia
– Due to increased proximal urate absorption associated with hypovolemia
– Dose related- see graph
• Hypomagnesemia -0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
Potassium Urate Glucose
Placebo12.5mg25mg50mg100mg
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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
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Diuretic resistance
• Two important 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
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Diuretic resistanceDose 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
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4mg
10m
g40
mg
100m
g40
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NormalCHF
Normal subject- max effect is seen with 40 lasix or 1 bumex
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Diuretic resistanceDose 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
0
5
10
15
20
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30
1mg
4mg
10m
g40
mg
100m
g40
0mg
NormalCHF
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Diuretic resistanceDose 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
0
5
10
15
20
25
30
1mg
4mg
10m
g40
mg
100m
g40
0mg
NormalCHF
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Diuretic resistanceMechanisms 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
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Diuretic resistanceMechanisms 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
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Diuretic resistanceMechanisms 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
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Diuretic resistanceMechanisms 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
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Diuretic resistanceMechanisms 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
Loop Diuretic- only blocks 15-20% of sodium reabsorption, but because less downstream tubule to compensate, an effective diuretic
Compensation can occur in distal tubule limiting loop effectiveness
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Diuretic resistanceMechanisms 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
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Diuretic resistanceMechanisms 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
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Diuretic resistanceNuances of use
• HCTZ and CRF– still works
• Ethacrynic acid
• Torsemide use
• Bumex nitch– shorter half life
• Zaroxlyn use
• Practical points of acetazolamide use