Download Clinical Use of Diuretics

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), acidbase
Location of Diuretic Activity
Distal Tubule
“High-ceiling diuretics”- K-sparing diureticsamiloride,
HCTZ, Zaroxlyn
spironolactone,
(metolazone)
triamterene
Proximal Tubule
Acetazolamide
Loop
Loop diuretics- Lasix,
Bumex, Ethacrynic Acid,
Torsemide
Loop diuretics
Loop
-reabsorbs 15-25% of
filtered NaCl
-Creates the gradient for
the countercurrent
multiplier
• 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
Distal Tubule
Distal Tubule
-reabsorbs 3-5%
percent
-fine tunes the ultimate
urine composition- k,
acid-base, volume,
Calcium
• 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
• K-sparing diureticsamiloride, spironolactone,
and triamterene
• Because 98% of sodium
already absorbed,
maximal increased
excretion of only 1-2%
Peri-capillary
space (blood)
Distal Tubule
Tubular lumen
(urinary space)
Na+
-reabsorbs 3-5%
percent
-fine tunes the ultimate
urine composition- k,
acid-base, volume,
Calcium
K+
= Aldosterone sensitive
channel
Spironolactone
competitively
inhibits
aldosterone
Distal Tubule
Mechanism of Action
Aldosterone
Peri-capillary
space (blood)
• K-sparing diureticsamiloride, spironolactone,
Tubular lumen and triamterene
(urinary space)
Na+
K+
Amiloride and
triamterene directly
block the channel
-can use to minimize
lithium toxicity
= Aldosterone sensitive
channel --- in the presence of
aldosterone the channel is
open
Distal Tubule Diuretics
• Amiloride
Peri-capillary
space (blood)
Tubular lumen
(urinary space)
Na+
Li+
K+
= Aldosterone sensitive
channel --- in the presence of
aldosterone the channel is
open
– 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 tableexplain why na and li use
the same channel
Distal Tubule Diuretics
Peri-capillary
space (blood)
Tubular lumen
(urinary space)
Na+
K+
= Aldosterone sensitive
channel --- in the presence of
aldosterone the channel is
open
• Triamterene
– Found in Maxzide
– Direct nephrotoxincauses crystalluria and
cast formation in up to
50% of patients
– Known cause of
interstitial nephritis
• Approximately 1
case/year at NNMC
Distal Tubule Diuretics
Peri-capillary
space (blood)
Aldosterone
Tubular lumen
(urinary space)
Na+
K+
= Aldosterone sensitive
channel --- in the presence of
aldosterone the channel is
open
• Spironolactone
– Long-half life– slow
onset and resolution
– Frequent side effects
• Gynecomastia (10% )
• Ax
• Ax
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
Pre_lasix
Total Na
90
300
Post-lasix
Total Na
250
300
80
250
250
200
70
60
200
200
150
50
150
150
40
100
30
100
100
20
50
50
50
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Patient Fallacies
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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.
Time course of diuresis
Patient 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.
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
Lasix
+
-
Diuresis
Decreased volume,
blood pressure, GFR,
hormonal activation
- increased norepi,
renin,
angiotensin,
aldosterone
Time course of diuresis
Steady-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
Time course of diuresis
250
– 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
200
150
100
LASIX
• Patient fallacy #3
50
0
0000-0600 0600-1200
Breakfast
100meq
1200-1800
Lunch
100meq
Na intake
1800-2400
Time course of diuresis
100
50
LASIX
150
LASIX
– 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
200
LASIX
• For anti-htn- give BID
to TID
250
0
0000-0600 0600-1200
Breakfast
100meq
1200-1800
Lunch
100meq
Na intake
1800-2400
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
140
120
100
80
60
40
20
0
1mg
10mg
20mg
40mg
80mg 160mg 320mg
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
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Volume depletion
Azotemia
Hypokalemia
Metabolic Alkalosis
Hyponatremia
Hyperuricemia
Hypomagnesemia
Diuretic Complications
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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
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Metabolic Alkalosis
Hyponatremia
Hyperuricemia
Hypomagnesemia
Diuretic Complications
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Volume depletion
Azotemia
Hypokalemia
Metabolic Alkalosis
Hyponatremia
Hyperuricemia
Hypomagnesemia
Diuretic Complications
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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
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Volume depletion
Azotemia
Hypokalemia
Metabolic Alkalosis
Hyponatremia
Hyperuricemia
0.8
0.6
0.4
0.2
0
– Due to increased proximal
urate absorption associated-0.2
with hypovolemia
– Dose related- see graph -0.4
• Hypomagnesemia
-0.6
Potassium Urate Glucose
Placebo
12.5mg
25mg
50mg
100mg
Diuretic Complications
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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
– 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
– Makes sense- once receptor
is completely blocked, extra
lasix will have no impact
30
25
20
Normal
CHF
15
10
5
0
1mg
4mg
10mg
40mg
100mg
400mg
• 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
Normal subject- max effect is seen with 40 lasix or 1 bumex
Diuretic resistance
Dose response
– 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 counterregulatory hormones and
decreased absorption
• Renal failure- 2nd to
competition for tubular
secretion from retained
cations
30
25
20
Normal
CHF
15
10
5
0
1mg
4mg
10mg
40mg
100mg
400mg
• Initial aim is to find the
effective single dose (on
the steep part of the curve)
Diuretic resistance
Dose response
– 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 counterregulatory hormones and
decreased absorption
• Renal failure- 2nd to
competition for tubular
secretion from retained
cations
30
25
20
Normal
CHF
15
10
5
0
1mg
4mg
10mg
40mg
100mg
400mg
• Initial aim is to find the
effective single dose (on
the steep part of the curve)
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
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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
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
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
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HCTZ and CRF– still works
Ethacrynic acid
Torsemide use
Bumex nitch– shorter half life
Zaroxlyn use
Practical points of acetazolamide use