clinical use of diuretics. review of anatomy and physiology glomerulus -forms ultrafiltrate of...

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

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

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%

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

=

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

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

• 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

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

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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.

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.

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

-

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

-

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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Na intake

Dinner 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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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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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

• 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 -0.6

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Potassium Urate Glucose

Placebo12.5mg25mg50mg100mg

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– 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 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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10m

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NormalCHF

Normal subject- max effect is seen with 40 lasix or 1 bumex

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

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NormalCHF

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

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NormalCHF

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

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

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

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

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

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

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

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