09/02/09 Clinical Use Of Diuretics (Ios)

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Edema

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Definition: clinically detectable increase in interstitial volume
typically 10 lb weight gain before clinically evident

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Disease states most commonly associated with generalized edema

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Moderate to Severe Chronic Kidney Disease (CKD)
Heart Failure (HF)
Nephrotic Syndrome
Liver Cirrhosis

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Pathophysiology of Edema (2 models)

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Overflow Model:
primary defect in renal sodium excretion leading to extracellular fluid (ECF) expansion* (chronic or acute)

Underfilling Model:
decreased effective circulating volume -->hypoperfusion of the kidneys-->stimulation of renal Na+ & H2O retention
- kidneys sense that there is a decrease in circulating Na and water such as in HF because the heart is not pumping enough blood

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Peripheral Edema

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Most common type
not severe or life threatening
peda (in feet)l, pretibial or presacral edema
evaluated semiquantitatively as 1+ to 4+ (pitting)

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Anasarca (severe)

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total body edema
not life threatening

dangerous if remove fluid to quickly
very uncomfortable and may impair ability to breath

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Ascites

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peritoneal fluid – peritoneum can store up to 10-20 L fluid

mainly in liver disease
not life threatening

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Pulmonary Edema

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Severe

only form of edema that is dangerous/life-threatening

in disease states such as HF

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Principals of Edema Management

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Treat underlying cause
Dietary sodium restriction (1-2 gm/day) (very key)
Loop Diuretic: (most potent)
drugs of choice
effective at Clcr< 30 ml/min*
Thiazide Diuretics
mild edema or adjunctive therapy
Not effective alone at Clcr< 30 ml/min*
Spironolactone
drug of choice for ascites

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Renal Physiology

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20-25% CO (600-700 ml/min plasma)
goes to the kidneys

20% of plasma (125ml/min =
180L/day ) is filtered by the kidneys

Only 1-2 ml/min (1.5-2.0 L/day) is
eliminated as urine (all the rest is
reabsorbed)

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PCT

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Only 1-2 ml/min (1.5-2.0 L/day) is
eliminated as urine (all the rest is
reabsorbed)

secretes diuretics

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descending loop of henle

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reabsorbs water

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ascending loop of henle

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Reabsorbs:
Na (20-25%)
K+, Cl-, Mg2+, Ca2+

loop diuretics

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DCT

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reabsorbs: Na (3-5%), K, Cl

where thiazides work

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CD

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Secretes: K, H
Reabsorbs: Na, (1-3%), Cl
late CD: reabsorbs water

<1% Na excreted

Where K sparing diuretics work

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Pharmacokinetics Principals

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Reach site of action through tubular lumen (urine)
Actively secreted into the urine by the proximal tubular cells (through either organic acid or base pumps)
Exception: spironolactone & eplerenone enter distal tubular cells via the plasma
Highly protein bound

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What happens when there is too much protein (albumin) in the tubule?

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It binds the diuretic preventing it from working

ususlly protiens are too big to be filtered

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Half life of loop diuretics and dosing

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Furosemide and Bumetanide is short therefore is dosed qd-Q6hrs
torsemide has a longer half life therefore usually dosed qd

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Thiazides half life and dosing

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thiazides have a longer half life therefore they are usually dosed qd

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K sparing half lives and dosing

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Have longer half lives so dosed less frequently

Spironolactone has a short half life however it has an active metabolite with a long half life so is dosed qd

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What loop diuretis have the greatest bioavailbility?

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Furosemide: 50
(10-100)
Bumetanide: 80-100
Torsemide: 80-100

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What thiazide is the only one available iv?

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Chlorothiazide

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Ethacrynic acid

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causes ototoxicty so it is only used in patients with sulfa allergies

loop diuretic

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Relative Potency of Various Diuretics

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Furosemide is the most potent, but Na loss is less when comparing mEq/L. However, there is so mouch more fluid actually being loss so there is more Na and K lost

Thiazides cause more hyponatermia than loops becasue lossing a higher concentration of Na

Thiazides and K sparing loose about equal volumes of fluid whereby loops loose more than doulbe the amount of fluid

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Loop concentration in the urine

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Loop diurectic must reach a threshold concentration to obtain a response

they also have a maximal effective dose-->if give anymore drug the effects are not changed there is just an increase risk of toxicty

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Resistance Issues in the Management of Edema with Diuretics

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Diuretic Resistance
Pharmacokinetic Resistance
Pharmacodynamic Resistance

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Diuretic resistance

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’d pharmacologic response (or ’d diuresis) to a given dose of a diuretic
more common in certain disease states and with chronic administration
In disease states where edema is common

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Pharmacokinetic resistance

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factors that decrease the amount of drug getting to the site of action (can happen with any diuretic)

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Pharmacodynamic resistance

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factors that decrease the response at the site of action
described with loop diuretics

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Pharmacokinetic Issues Leading to Diuretic Resistance (decrease concentration at site of action)

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decreased or slowed absorption of the diuretic:
can lead to a decreased peak conc. at site of action
can be an issue in patients with severe heart failure
decreased serum albumin:
can lead to decreased diuretic delivery to the kidney
can be seen in patients with Nephrotic Syndrome and Chronic Liver Disease
decrease in carrier molecule--> decreases delivery of diuretic to kidney

decreased Renal blood flow
decreased diuretic delivery to the kidney
a possible issue in patients with CKD or HF
increased Organic acids (waste products) competing for the tubular secretion site
decreased diuretic delivery of the diuretic to its site of action
can be seen in patients with CKD
Proteinuria
can lead to increased binding of the diuretic to protein in the urine
can be seen in patients with Nephrotic Syndrome

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Pharmacodynamic Issues Leading to Diuretic Resistance (decrease in response at site of action)

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Braking”: acute adaptive process
Rebound (post-diuretic) sodium retention
Altered concentration-response
2o Na+ re-absorption: chronic adaptive process
(only for loop diuretics)

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Braking

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Decrease in the response to a loop diuretic during acute dosing
Short-term physiological response to prevent excessive sodium and fluid loss
Can occur in anyone receiving a loop diuretic
Management: avoid over aggressive diuresis and intravascular volume loss; remove fluid slowly
the fluid is coming from intersitial space

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Rebound Sodium Retention

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Seen with loop diuretics that have shorter half-lives (furosemide & bumetanide)
Sodium reabsorption can occur after the diuretic concentration falls below the threshold (at the end of the dosing interval)
Can occur at any time in patients who do not adhere to a sodium-restricted diet
Management = give short-acting diuretics 2-3 times a day & maintain sodium restriction

Need to maintain low Na diet or need to increase dose

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Altered Concentration-Response

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Do not get the same response (reduced ability to block sodium reabsorption) even though you have the same or greater diuretic concentration at the site of action
Can be seen in patients with heart failure, Nephrotic Syndrome, and liver cirrhosis
May be due to ’d sodium retention at other tubular sites
Management: give the most effective dose (or maximal effective dose) 2-3 times a day

The maximal effective dose concentration is reduced. Therefore less than 20% of Na reabsorption is being blocked

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Secondary Sodium Reabsorption

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Chronic adaptive process that can occur in anyone receiving loop diuretics long-term

over time DCT tubular adapts be increasing the number of Na channels because the tubules have been exposed to higher concentrations of Na

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Management of Secondary Na Reabsorption

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Combinattion therapy
loop diuretic + thiazide (becasue it works in the DCT

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Pharmacokinetic diuretic resistance and disease states

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Decreased delivery to site of action

Greatest resistance in moderate to severe CKD
HF and nephrotic syndrome does not produce as much resistance

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Pharmacodynamics diuretic resistance and disease states

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altered concentration-response
HF: ++
Moderate to severe CKD: +-
Nephrotic syndrome: +

Rebound Na retention
HF: +
Moderate to severe CKD: +
Nephrotic syndrome: +

Secondary Na reabsorption:
HF: +
moderate to severe CKD: +
nephrotic syndrome: +

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Pharmacodynamic:
Altered concentration-response
management

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Give most effective (or max) dose of loop diuretic bid-tid

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Pharmacokinetic:
decreased delivery to site of action
management

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Give higher doses of diuretics

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Pharmacodynamic:
Rebound Na+ retention
management

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Reinforce dietary sodium restriction + give most effective (or max) dose of loop diuretic bid-tid

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Pharmacodynamic:
Secondary Na+ reabsorption
management

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Combination therapy:
loop + thiazide

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Management of Peripheral Edema

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Usually managed outpatient
Optimize therapies for underlying disease state
Institute dietary sodium restriction
Check for hidden sources of sodium (e.g., meds)
Check for medications which can cause edema
NSAIDs, dihydropyridine calcium channel blockers, thiazolidinedione (TZDs), estrogens
can do more harm if too aggressive with treatment

may need a higher starting dose if HF or kidney impairment

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To manage peripheral edema start with...

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Start with low dose oral loop
e..g., furosemide 20-40 mg orally once daily to twice daily*
Goal = slowly reduce edema
Titrate dose and interval based on response
If patient does not respond as expected, check compliance and look for mechanisms of resistance and treat accordingly

depends on severity of edema and underlying conditions

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Acute Management of Severe Edema

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Typically 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 already on diuretic therapy…
assess compliance with medication and sodium restriction

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acute treatment of severe edema

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Use IV bolus dosing initially (can consider continuous IV infusion)
Dose of loop diuretic will depend on previous dosing history and underlying disease state
Double the initial dose until adequate response* or maximal effective dose for that disease state is reached
Once you find the most effective dose (or maximal dose is reached), give it as often as needed (typically bid to tid)
If the desired response is not achieved usually double the dose

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If a loop is inadequate for management of severe edema

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If loop alone is inadequate, use a combination of loop + thiazide (or k+-sparing diuretic):
if loop is IV, administer oral thiazide 0.5 to 1.0 hr before loop (that way the DCT is blocked before furosemide is given)
Once adequate diuresis has occurred and patient is stable, switch to equivalent oral regimen

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in severe edema what is a good rate of fluid loss?

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2-3 lbs per day initially

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Management of Ascites (Liver Cirrhosis)

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Spironolactone = diuretic of choice due to hyperaldosteronism (blocks aldosterone)
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 spironolactone alone is inadequate, there is a concern for hyperkalemia 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 for K balance
patient can become hyperkalemic
Usual starting dose of oral furosemide is 40 mg daily; oral maximal effective dose = 80 mg
Can administer the loop diuretic more often to improve response (e.g., furo 40 mg po bid)

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Goal fluid loss (ascites without edema)

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~ 500 ml/day (0.5 kg/day)

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Goal fluid loss (ascites with edema)

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~ 1000 ml/day (1.0 kg/day)

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Adverse Effects of Diuresis

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Hypovolemia
Azotemia
 serum creatinine (Scr) &  blood urea nitrogen (BUN)
Electrolyte abnormalities
hypokalemia, hypomagnesemia, hyponatremia
Acid-Base Disorders
metabolic alkalosis or metabolic acidosis
Ototoxicity (rate of IV furosemide < 4mg/min)

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Monitoring (efficacy & safety)

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Daily weight
Inputs (oral and IV) & Outputs (urine)
Electrolytes (K+, Na+, Cl-, CO2, Mg2+)
Vital signs (blood pressure)
Kidney function (BUN, Scr)