• Information
  1. Introduction
  2. Loop Diuretics
  3. Thiazide Diuretics
  4. Potassium Sparing Diuretics
  5. Vasopressin
  6. Combination Diuretics
  7. Acetazolamide
  8. Dopamine
  9. Adenosine Antagonists
  10. Natriuretic Peptides
  11. Effects of Diuretics on Urinary Electrolytes
  12. Diuretic Resistance in CHF

A. Introduction

1. Potent diuretics block sodium (Na+) and chloride (Cl) resorption
   1. Water follows Na (and Cl) and therefore fluid is lost
   2. Many diuretics also block potassium (K+) resorption and can lead to hypokalemia
   3. Magnesium (Mg2+) is often lost leading to hypomagesemia
2. Diuretic properties of different agents in each class are similar
3. Therefore, failed response to one agent in a class suggests cross resistance will occur
4. Non-osmotic diuretics are secreted by the proximal tubule cells
   1. High protein binding (>95%) in blood leads to little glomerular filtration of drug
   2. Good delivery of drug to the proximal tubule is required
   3. Therefore, all diuretics depend on good cardiac function for renal delivery
5. Diuretic Tolerance
   1. There are two major types of tolerance: braking/short term and long term
   2. Braking is decrease in response to a diuretic after the first dose of drug
   3. Braking can be reversed by restoring intravascular volume
   4. Long term administration of loop diuretics leads to redistribution of counter-current salt gradients from loop to more distal regions
   5. Thus, Na+ escaping from the loop is reabsorbed in distal segments of nephron
   6. Thiazides can block this resorption, and are synergistic when combined with loop agent
6. General use of diuretics in critically ill patients with acute renal failure (ARF) is discouraged [3,15]

B. Loop Diuretics [4]

1. Mechanism
   1. Block Na/K/Cl transporter in thick acending Loop of Henle
   2. Prevents both Na+ and K+ resporption
   3. Highly potent diuretic activities
   4. Mechanisms of anti-hypertensive actions are not well understood
   5. Very low doses of these agents have some hypotensive effects without inducing diuresis
2. Other Effects
   1. Potassium wasting
   2. Magnesium wasting
   3. Calcium wasting
   4. Exacerbation of renal insufficiency likely due to intravascular volume depletion
   5. Uricosouric activity (uric acid wasting)
   6. Depletion of thiamine
   7. Some (mild) ototoxicity (increased with ethacrynic acid)
3. Utility
   1. Congestive Heart Failure (CHF)
   2. Acute pulmonary edema
   3. Cirrhotic Ascites - after spironolactone or
   4. Other edematous states including nephrotic syndrome (poor efficacy)
   5. Hypertension (HTN)
   6. Potassium (and Mg2+) supplementation should be given concommitantly
   7. Dose should be increased to maximal of ~200mg furosemide (or equivalent) per day
   8. For intravenous use, poor response to 160-200mg IV furosemide should prompt addition of additional diuretic agent from another class
   9. Metolazone, with both proximal and distal tubule blocking activity, is a good addition to loop diuretics in diuretic-resistant states
   10. Acetazolamide can be added in patients resistant to loop + thiazide combinations
4. Furosemide (Lasix®)
   1. Short acting sulfonamide with onset 30-60 min
   2. 6-8hr duration of action
   3. Also increase renal excretion of K+, Mg2+, Ca2+, and some HCO3-
   4. About 50% is excreted unchanged in urine
   5. Remainder is conjugated to glucuronic acid in kidneys, then secreted
   6. Plasma half-life (t1/2) is prolonged in patients with renal insufficiency
   7. Furosemide of no overall clinical benefit in prevention or treatment of ARF [15]
   8. High dose furosemide associated with ototoxicity in adults [15]
5. Bumetanide (Bumex®)
   1. Sulfonamide, similar onset to furosemide
   2. Bumetanide 1mg ~ Furosemide 40mg
   3. About 50% is metabolized by the liver (t1/2 increased in liver disease)
6. Torsemide (Demadex®) [5]
   1. Sulfa-based loop diuretic approved for HTN and edema
   2. Dose initially 5-10mg po qd
   3. 10mg Torsemide ~ 40mg Furosemide
   4. About 80% is metabolized by the liver (t1/2 increased in liver disease)
   5. Open label study of torsemide versus furosemide suggests torsemide may be preferred in treatment of CHF [5]
7. Ethacrynate (Edecrin®)
   1. Aryloxyacetic acid derivative (no sulfa group)
   2. Short acting similar to furosemide
   3. More ototoxicity than other agents (usually transient)
   4. Least preferred agent overall, but excellent for sulfa-allergic patients
   5. Dose: 50mg po qd (up to 200mg po qd, usually divided doses)
8. Side Effects
   1. Hypokalemia, hypomagnesemia, hyponatremia, hypocalcemia
   2. Calciuria and hyperuricosuria can precipitate kidney stones
   3. Renal insufficiency due to hypovolemia and hypotension can occur
   4. Thiamine depletion
   5. Chronic loop and thiazide diuretics may increase the risk of sudden death in CHF [6]
   6. This likely due to depletion of potassium and magnesium by these agents
   7. Diuretics long term may also deplete thiamine, leading to poorer LV function
9. Serum K+, Na+, Mg2+, Ca2+ MUST always be monitored in patients on diuretics

B. Thiazide Diuretics [2,4]

1. Mechanism
   1. At low dose, reduce blood pressure with minimal diuretic effects
   2. Increase urinary excretion of NaCl and H2O by inhibiting sodium reabsorption
   3. Acts on both the cortical TAL of Henle and the early distal tubules
   4. Increased urinary excretion of K+, Mg2+, and some HCO3-
   5. Reduces excretion of Ca2+ and uric acid
   6. May lead to mild hypercalcemia
   7. Hyperuricemia with gouty attacks may also occur
2. Other Effects
   1. K+ wasting - K+ loss appears to increase risk of primary cardiac arrest
   2. Exacerbation of renal insufficiency through intravascular volume depletion
   3. Uric acid retention - increases serum urate; may precipitate gout
   4. Ca2+ retaining - may lead to hypercalcemia)
   5. Thiamine depletion may also occur (this can exacerbate cardiomyopathy)
   6. Adverse effects on lipid profiles
   7. May increase levels of atherogenic and vascultoxic homocysteine
   8. May have direct vasodilatory responses leading to antihypertensive effects
   9. Current thiazide diuretic use associated with ~50% reduction in risk for hip fracture [14]
3. Thiazides in HTN [8,9,10]
   1. Low dose thiazides reduce overall, stroke, and cardiovascular death rates
   2. Prevents strokes, renal decline and CHF in persons with HTN
   3. Equivalent or superior to ACE inhibitors or calcium blockers in HTN treatment
   4. Often combined with other agents to achieve goal blood pressure
   5. Second line for HTN in patients with chronic angina, diabetes, or gout
   6. Low dose thiazides with electrolyte monitoring should be considered first line in most HTN
4. Hydrochlorothiazide (HCTZ, Hydrodiuril®, Microzide®)
   1. Initial dose is 12.5-25mg po qd
   2. Initial doses higher than 12.5mg qd may cause hypovolemia and light-headedness
   3. Increase to maximal dose 25-50mg po qd
   4. Patients requiring >25mg/day for elevated BP should probably receive second agent rather than increasing to 50mg qd
   5. Excreted unchanged in urine
   6. HCTZ preserves bone mineral density at hip and spine and reduces fracture risks [11]
5. Indapamide (Lozol®)
   1. Primarily metabolized by liver, long t1/2
   2. Dose 2.5-10mg po qd
   3. In persons >80 years old with HTN, indapamide (Lozol®) sustained release ± perindopril reduced all-cause mortality, CVD realed-death, and CHF [33]
6. Metolazone (Diulo®, Zaroxolyn®)
   1. Proximal and distal tubule blocking activities
   2. Very potent with good synergy with loop diuretics
   3. Dose 5-10mg po qd
7. Chlorthalidone - frequently used in HTN, generic, 12.5-50mg in 1-2 doses
8. Other Thiazides
   1. Chlorothiazide (Diuril®) - very short half-life
   2. Trichlormethiazide
   3. Hydroflumethiazide
   4. Polythiazide
9. Use in Fluid Overloaded States
   1. Good first line therapy in mild CHF, generally with creatinine clearances >50mL/min
   2. Combination therapy with loop diuretics for diuretic resistant patients
   3. Except for metolazone, relatively poor single agent therapy in CHF for diuresis
   4. Potassium supplementation should be given concommitantly
   5. Mg2+ levels should be monitored and replaced if needed
10. Use in Hypertension (HTN)

C. Potassium Sparing Diuretics [4]

1. Aldosterone Receptor Blockers [12]
   1. Moderate antihypertensive activity
   2. Effective in severe CHF, often combined with ACE inhibitors (ACE-I; see below)
   3. First line therapy in cirrhosis (where aldosterone levels are very high)
   4. Best for long term use, slower onset of action than other agents (3-5 days)
   5. Spironolactone (Aldactone®): 25mg po bid-tid initially (likely can be given qd; max 450mg/d)
   6. Eplerenone (Inspra®): 50mg po qd to start, up to 100mg po bid
   7. Main risk is hyperkalemia; monitoring is required
   8. Spironolactone dose 25mg maximum in combination with ACE-I or ARB
   9. Spironolactone has higher risk of gynecomastia than eplerenone
   10. Impotence and menstrual disturbances are uncommon with both agents
2. Triampterene (Dyrenium®)
   1. Reduces Na resorption and K+/H+ secretion in collecting tubules
   2. Usually combined with thiazide or loop diuretics to decrease hypokalemia
   3. Metabolized to active agent by liver, then secreted by kidney
3. Amiloride (Midamor®)
   1. Blocks Na+ channels for resorption, and K+/H+ secretion
   2. Acts on distal convoluted tubule and cortical collecting ducts
   3. Completed excreted by the kidney; t1/2 prolonged in renal failure
   4. Can be used to loosen secretions in cystic fibrosis
4. Combining K+ sparing diuretics with ACE inhibitors [24,27]
   1. Combination has high risk of hyperkalemia
   2. Must monitor all electrolytes, particularly K+ levels at least weekly initially
   3. However, maximal angiotensin/aldosterone blockade is obtained with combination therapy
   4. K+ diuretics should not be combined with ACE-I or ARB if creatinine clearance <30mL/min

D. Vasopressin (Antidiuretic Hormone, ADH) Antagonists [25,26]

1. Developed for refractory CHF
2. May have activity in cirrhosis and nephrotic syndrome
3. Block renal free water resorption in collecting ducts with excellent aquaresis
4. Do not lead to potassium losses or blood pressure instability
5. Unclear if V2 selective or V1/2 non-selective antagonists are superior
6. Tolvaptan [30]
   1. Oral, selective vasopressin V2 receptor antagonist
   2. Treatment of euvolemic or hypervolemic hyponatremia (mainly CHF and cirrhosis)
   3. Initial dose is 15mg po qd; increased to 30-60mg daily if necessary based on serum Na+
   4. Showed increased serum Na+ on days 4 and 30 versus placebo
   5. Hyponatremia typically recurred within 7 days of discontinuing drug
   6. Improves most symptoms in acute decompensated CHF [31]
   7. No effect on overall mortality or heart failure morbidity in decompensated CHF [32]
   8. Also being developed in polycystic kidney disease (PKD)
   9. Side effects mainly mechanism based: increased thirst, dry mouth, increased urination
7. Conivaptan (Vaprisol®) [34]
   1. Non-selective V1/2 antagonist
   2. Effective in euvolemic and hypervolemic hyponatremia
   3. Includes SIADH, cirrhosis with ascites, nephrotic syndrome, CHF
   4. FDA approved for intravenous infusions for hyponatremia including SIADH
   5. Potent inhibitor of CYP3A4
   6. Caution with too-rapid correction of hyponatremia, as brain demyelination can occur
8. Other Vasopressin Antagonists
   1. Relcovaptan - selective V1a antagonist for Raynaud's disease, dysmenorrhea, tocolysis
   2. SSR-149415 - selective V1b antagonist for psychiatric disorders
   3. Additional V2 Antagonists: mozavaptan, lixivaptan, satavaptan

E. Combination Diuretics [4]

1. Dyazide®, Maxzide®: triampterene and HCTZ
2. Moduretic®: amiloride HCl and HCTZ
3. Aldactizide®: spironolactone and HCTZ
4. Vasoretic®: enalapril + HCTZ
5. Zesteretic®: lisinopril + HZTZ

F. Acetazolamide (Diamox®)

1. Carbonic Anhydrase Inhibitor. Reduces HCO3- resorption in proximal tubule
2. Note that the tubule sensor for bicarbonate resorption is ~24mM
3. Acetazolamide increases this threshold, leading to bicarbonate losses
4. Can lead to mild hyperchloremic acidosis
5. Used mostly now for artificial dilatation of cerebral vessels
6. Used also for nuclear medicine scanning and in some cases of glaucoma
7. May be given 250-500mg iv for metabolic alkalosis if needed (pH>7.49)

G. Dopamine

1. Sympathomimetic agent acts on dopamine receptor, ß1- and alpha-adrenergic receptors
2. Dopamine <5µg/kg/minute ("Low Dose" or "Renal Range")
   1. Increases renal and mesenteric blood flow in patients with normal renal function
   2. Low dose dopamine has no overall benefit in patients in intensive care units (ICU) [13]
   3. Renal range dopamine will NOT prevent renal deterioration in ICU patients
3. In higher doses, dopamine is a vasopressor, with alpha-adrenergic receptor binding
4. Combination of inotropic levels of dopamine with loop ± thiazide diuretic may be particularly effective in CHF
5. Fenoldopam (Corlopam®) [10]
   1. Selective intravenous DA1 receptor agonist
   2. Vasodilatory and natriuretic effects; may be renal protective
   3. Approved for treatment of hypertensive crisis
   4. Useful in nearly all hypertensive emergencies particularly with renal dysfunction

H. Adenosine Antagonists

1. Aminophyllin is the prototype
2. This is a methylxanthine with diuretic (as well as some bronchodilatory) effects
3. Action on blocking adenosine A1 receptors throughout the kidney
4. Effects of Renal Adenosine Blockade
   1. Renal arteriole vasodilation
   2. Inhibits proximal and distal tubule Na resportion
   3. Blocks justaglomerular feedback mediated vasoconstriction (due to high tubular Na)
   4. Potassium neutral (little or no increase in urine potassium)
5. Not generally used for diuresis due to tachycardic and cardiac vasoconstrictive activity
6. Selective A1-adenosine receptor antagonists are being developed

I. Natriuretic Peptides [16,17]

1. Natrually occurring peptides with renal natriuretic and diuretic activity
   1. Atrial natriuretic peptide (ANP)
   2. B-type or Brain derived natriuretic peptide (BNP; previously BDNP)
   3. C-type natriuretic peptide (CNP)
   4. Guanylin and uroguanylin are related peptides which act in GI tract
   5. Neutral endopeptidase (NEP) degrades all natriuretic peptides [18]
   6. NEP inhibitors can be used to increase levels of natriuretic peptides
2. ANP
   1. Produced primarily by cardiac atria and stored primarily in granules
   2. Production is stimulated by endothelin, arginine vasopressin, and catecholamines
   3. Increased atrial wall tension (increased preload) stimulate secretion
   4. Infusions reduce blood pressure and induce a natriuresis
   5. Mature peptide is a 28 residue C-terminal fragment from a 126 residue precursor
   6. ANP stimulates natriuresis, diuresis, and renal afferent vasodilation
   7. Increased vasodilation can increase glomerular filtration rate (through urodilatin ?)
   8. ANP can block the effects of angiotensin II and may reduce its production
   9. Urodilatin is a unique renal natriuretic peptide with diuretic and natriuretic activity
   10. ANP derivative anaritide did not improve ARF [19]
   11. ANP infusion (0.025µg/kg/min x3 days) in patients with acute MI undergoing reperfusion therapy reduced total creatine kinase and improved left ventricular function [7]
3. Nesiritide (BNP, Natrecor®) [16,20]
   1. Produced primarily by cardiac ventricles, not stored in granules
   2. Originally described in porcine and human brain
   3. Regulated primarily by altering mRNA levels in response to acute and chronic insults
   4. Plasma half-life is greater than ANP
   5. Degraded by plasma neutral endopeptidases
   6. Plasma levels of BNP correlate with death, recurrent MI, CHF, LV dysfunction [21]
   7. Plasma levels <18pg/mL have a negative predictive value of >97% for CHF
   8. In acute coronary syndromes, elevated baseline BNP correlates with poor outcomes [21]
   9. Approved for treatment of decompensated Class IV CHF with dyspnea at rest [20]
   10. Nesiritide lead to reduced wedge pressures and dyspnea at 3 hours compared with nitroglycerin or placebo [22]
   11. May be associated with ~1.7X increased risk of death at 30 days (p~0.06) compared with acutely decompensated patients treated with non-inotrope based therapy [28,29]
   12. May increase mortality in outpatients who receive nesiritide for added diuresis [29]
   13. Vasodilatory and natriuretic activities recommended in patients with suboptimal response to standard diuretics and nitroglycerin
   14. BNP levels may be altered by comorbid conditions and these must be evaluated
4. CNP
   1. There are 22 and 53 residue forms of the peptide hormone
   2. Plasma concentration of CNP is very low
   3. The 22 residue form predominants in CNS, anterior pituitary, kidney, and vascular endothelial cells, and plasma
   4. Synthesized by endothelium
   5. Local vasodilatory and antiproliferative effects on vascular smooth muscle
5. There are three receptors for the natriuretic peptide receptors (A, B, C)
   1. The A receptor binds ANP preferentially to BNP
   2. CNP binds to the B receptor
   3. Receptors A and B are linked to cGMP-dependent signalling
   4. The C receptor is involved in clearance of all three natriuretic peptides
   5. Clearance is also carried out by degradation by plasma neutral endopeptidases
   6. Inhibitors of endopeptidases such as candoxatrilat increase Na+ excretion

J. Effects of Diuretics on Urinary ElectrolytesTable: Urinary Electrolytes and Diuretics

1. Diuretic resistance is very common in advanced (Class III and IV) CHF
2. Mechanisms of Diuretic Resistance
   1. Prerenal azotemia
   2. Increased sodium (Na+) resorption due to counterregulatory hormones
   3. Elevated ACE levels
   4. Elevated aldosterone levels
   5. Elevated antidiuretic hormone (vasopressin)
   6. Reduced delivery of loop diuretics to active site
3. Treatment
   1. Fluid restriction to <1.5L per day is critical
   2. Large doses of IV diuretics used initially
   3. Combination agents are often required in resistance
   4. Spironolactone may be added to loop diuretics for additional efficacy in Class III/IV
   5. Avoid nephrotoxic medications including NSAIDs (including COX-2 specific agents)
   6. Combinations of loop and thiazide diuretics, or metolazone, are usually effective
   7. Metolazone (2.5-10mg/d) is preferred agent since it blocks proximal and distal sites
   8. If spironolactone is used, then K+ levels must be monitored very closely
   9. Acetazolamide may be added, usually for short term, especially when alkalosis present
   10. Tolvaptan, a V2 vasopressin (ADH) selective blocker, increases water loss without hypokalemia or blood pressure loss in acute decompensated CHF [25]

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