Diuretics Flashcards
Furosemide
Loop diuretics selectively inhibit NaCl reabsorption in the thick ascending Loop of Henle by inhibiting the luminal Na+/K+/2Cl- cotransporter (NKCC2). Due to the large NaCl absorptive capacity of the TAL and the fact that the nephron segments past the thick ascending limb do not possess the reabsorptive capacity to rescue the flood of rejectate exiting the thick ascending limb, loop diuretics are the most efficacious diuretic agents currently available, and for this reason, they are sometimes called high-ceiling diuretics.
By inhibiting the reabsorption of NaCl, loop diuretics also diminish the lumen-positive potential that comes from K+ recycling. This positive potential normally drives divalent cation reabsorption in the loop, and by reducing this potential, loop diuretics cause an increase in Mg2+ and Ca2+ excretion.
All loop diuretics increase the urinary excretion of K+ and titratable acid. This effect is due in part to increased delivery of Na+ to the distal tubule (there is enhanced exchange of Na+ for K+ leading to greater excretion of K+), and predisposes the individual to hypokalemia and metabolic alkalosis.
Loop diuretics have also been shown to induce expression of COX-2, which participates in the synthesis of prostaglandins from arachidonic acid. Prostaglandins appear to mediate the diuretic/natriuretic action. The primary effects appear to be alterations in renal hemodynamics with subsequent increases in electrolyte and fluid excretion. In addition furosemide has been shown to increase renal blood flow.
Loop diuretics are used in the management of edema associated with heart failure and hepatic or renal disease; acute pulmonary edema and in the treatment of hypertension (alone or in combination with other antihypertensives). Loop diuretics are not a first line drug in the treatment of hypertension and are normally only indicated when the use of a thiazide is not deemed sufficient.
Furosemide Adverse Effects
Most adverse effects of furosemide occur with high doses, and serious effects are uncommon. The most common adverse effect is fluid and electrolyte imbalance including hyponatremia, hypokalemia, and hypochloremic alkalosis, particularly after large doses or prolonged use.
Ototoxicity: Occasionally can cause ototoxicity that manifests as tinnitus, hearing impairment, deafness, vertigo, and a sense of fullness in the ears. Hearing impairment is usually, but not always, reversible.
Hyperuricemia: Can precipitate gout in some patients.
Acute hypovolemia: Overzealous use of loop diuretics can cause serious depletion of total-body Na+. This may be manifest as hyponatremia and/or extracellular fluid volume depletion associated with hypotension.
K+ Depletion: Increased delivery of Na+ to the distal tubule, particularly when combined with activation of the renin-angiotensin system, leads to increased urinary excretion of K+ and H+, causing a hypochloremic alkalosis. If dietary K+ intake is not sufficient, hypokalemia may develop and this may induce cardiac arrhythmias.
Hypomagnesemia and Hypocalcemia: Evidence suggests that loop diuretics should be avoided in postmenopausal osteopenic women, in whom increased Ca2+ excretion may have deleterious effects on bone metabolism.
Other Effects: Hypersensitivity (for sulfonamide-based diuretics), hyperglycemia, hyperlipidemia, photosensitivity, parasthesias, bone marrow depression, and GI disturbances.
What drugs are Thiazide Diuretics?
Hydrochlorothiazide
Chlorthalidone
Metolazone
Mechanism of Action of Thiazide Diuretics
Thiazides primarily inhibit NaCl reabsorption in the distal convoluted tubule by blocking the Na+/Cl- cotransporter (NCCT).
Thiazides also increase the excretion of K+ and acid by the same mechanisms outlined for loop diuretics. They can also affect calcium handling. Although the thiazides inhibit the reabsorption of sodium, they are able at the same time to increase the reabsorption of calcium. This fall in calcium excretion can be useful in the treatment of recurrent kidney stones due to hypercalciuria. Although thiazides rarely cause hypercalcemia they can unmask hypercalcemia due to other causes (eg, hyperparathyroidism, carcinoma).
Thiazides may also cause a mild magnesuria by a poorly understood mechanism.
Thiazides are used in the management of mild-to-moderate hypertension (either alone or in combination with other antihypertensives); in the treatment of edema due to heart failure; in hypercalciuria; and in the management of premenstrual edema. They are also used off label in the treatment of diabetes insipidus (the antidiuretic effect of thiazides is thought to be the result of an induced sodium deficit. Serum osmolality is reduced and thirst is decreased).
The use of hydrochlorothiazide in the treatment of edema for hepatic cirrhosis has largely been replaced by spironolactone. The use of hydrochlorothiazide in the management of edema in patients with renal dysfunction has largely been replaced by the use of loop diuretics (eg, furosemide).
Thiazides are a preferred choice of first-line antihypertensive drug in black/elderly patients who may not respond as well to treatment with either ACEI’s or ARB’s.
All thiazides can be administered orally and have equal maximum effects, differing only in potency. Due to their long half-lives (~40h) it can take 1-3 weeks to produce a stable drop in blood pressure.
Adverse Effects of Thiazide Diuretics
Hypokalemia: For the same reasons as explained for loop diuretics
Hyponatremia: Have been reports of fatal or near-fatal hyponatremia (has been attributed to inappropriate secretion of ADH). Plasma electrolytes should be monitored.
Volume depletion: Orthostatic hypotension can occur.
Hyperuricemia: Due to the competition for the organic secretory pathway in the proximal tubule by thiazides and uric acid. Can precipitate gout in some patients.
Hypercalcemia: Explained under ‘Mechanism of Action’
Hyperglycemia: Thiazides decrease glucose tolerance, and latent diabetes mellitus may be unmasked during therapy. The mechanism of the impaired glucose tolerance is not completely understood but appears to involve reduced insulin secretion (due to depletion of K+) and alterations in glucose metabolism.
Hyperlipidemia: Thiazides may increase plasma levels of LDL cholesterol, total cholesterol, and total triglycerides (~5-15% increase). These levels may return toward baseline after prolonged use.
Hypersensitivity: The thiazides are sulfonamide derivatives. Photosensitivity or generalized dermatitis occurs rarely. Serious allergic reactions are rare.
Which drugs are Potassium Sparing Diuretics?
AKA Aldosterone Antagonists?
Spironolactone
Eplerenone
Mechanism of Action of Aldosterone Antagonists
Potassium-sparing diuretics prevent K+ secretion by antagonizing the effects of aldosterone at the late distal and cortical collecting tubules. Aldosterone causes retention of salt and water and increases the excretion of K+ and H+ by binding to specific mineralocorticoid receptors. Spironolactone and eplerenone competitively inhibit the binding of aldosterone to its receptors, thus preventing its effects. The clinical efficacy of aldosterone antagonists is a function of endogenous levels of aldosterone. The higher the levels of endogenous aldosterone, the greater are the effects of the antagonists on urinary excretion.
Other actions: Spironolactone has some affinity toward progesterone and androgen receptors, where it acts as an antagonist and thereby induces side effects such as gynecomastia, impotence, and menstrual irregularities. Eplerenone has low affinity for these receptors thus is less likely to produce these effects.
Spironolactone is used primarily in the management of edema associated with excessive aldosterone excretion or with congestive heart failure unresponsive to other therapies. It is also used in hypertension; primary hyperaldosteronism (establishing diagnosis, short-term pre-operative treatment, and long-term maintenance therapy in selected patients); hypokalemia; cirrhosis of the liver accompanied by edema or ascites and nephrotic syndrome.
An important evolving use of spironolactone is in the management of severe HF (NYHA class III-IV) to increase survival and reduce hospitalization when added to standard therapy.
Off-label uses include adjunctive therapy for the treatment of female acne and in the treatment of hirsutism.
Both spironolactone and eplerenone are given orally.
Adverse Effects of Aldosterone Antagonists
Gastric upset and Peptic ulcers: Spironolactone may induce diarrhea, gastritis, gastric bleeding, and peptic ulcers.
Endocrine Effects: Owing to its antagonistic effects at other steroid (androgen) receptors spironolactone may cause gynecomastia, impotence, decreased libido, deepening of the voice and menstrual irregularities.
Hyperkalemia: Unlike most other diuretics, K+-sparing diuretics reduce urinary excretion of K+ and thus can cause mild, moderate or even life-threatening hyperkalemia. These drugs are contraindicated in patients with hyperkalemia and in those at increased risk of developing hyperkalemia either because of disease (eg, chronic kidney disease) or because of administration of other medications (eg, ACEI, ARB or other K+ sparing diuretics).
Hyperchloremic Metabolic Acidosis: By inhibiting H+ secretion in parallel with K+ secretion, the K+-sparing diuretics can cause acidosis.
Other effects: CNS adverse events are rare but include drowsiness, lethargy, ataxia, confusion, and headache.
Eplerenone: Other than hyperkalemia and GI disorders, the rate of adverse events for eplerenone is similar to that of placebo.
Inhibitors of Renal Epithelial Na+ Channels
Which drugs fall under this category? What are their actions and adverse effects?
Potassium Sparing Diuretics – Inhibitors of Renal Epithelial Na+ Channels
Amiloride, and Triamterene
Both amiloride and triamterene cause small increases in NaCl excretion and usually are employed for their antikaliuretic actions to offset the effects of other diuretics (used both in the management of hypertension and heart failure) that increase K+ excretion. Both drugs competitively inhibit the epithelial sodium channels (ENaC) in the late distal tubule and collecting duct thus reducing Na+ reabsorption. Since K+ secretion is coupled with Na+ entry in this segment, these drugs also inhibit K+ secretion.
An advantage to these drugs is that they do not rely on the presence of aldosterone to have their effects.
Triamterene is metabolized in the liver, but renal excretion is a major route of elimination for the active form and the metabolites. Amiloride is eliminated predominantly by urinary excretion of intact drug.
Adverse Effects
Hyperkalemia: For the same reasons as aldosterone antagonists
Hyponatremia: Due to the inhibition of Na+ reabsorption
Triamterene also can reduce glucose tolerance and induce photosensitization and has been associated with interstitial nephritis and renal stones.
Carbonic Anhydrase Inhibitors
Uses
Acetazolamide
Carbonic anhydrase inhibitors potently inhibit both extracellular and intracellular forms of carbonic anhydrase, resulting in the reduction of HCO3- reabsorption in the proximal convoluted tubule. Inhibition of carbonic anhydrase is thus associated with a rapid rise in urinary HCO3- excretion and development of a hyperchloremic metabolic acidosis. Carbonic anhydrase by making H2CO3 provides the protons (H+) required for the activity of the Na+/H+ transporter, thus inhibition of the enzyme results in a reduction in Na+ reabsorption and a mild diuretic action. Because of reduced HCO3- in the glomerular filtrate and the fact that HCO3- depletion leads to enhanced NaCl reabsorption by the remainder of the nephron, the diuretic efficacy of acetazolamide decreases significantly with use over several days.
Acetazolamide is mainly used for pharmacological properties other than its diuretic properties. These include:
Glaucoma: by inhibiting carbonic anhydrase in the eye, acetazolamide decreases the formation of aqueous humor and so decreases intraocular pressure. It is used in the pre-operative management of angle-closure glaucoma, or as an adjunct in the treatment of open-angle glaucoma.
Mountain Sickness: acetazolamide causes the kidneys to excrete bicarbonate. By increasing the amount of bicarbonate excreted in the urine, the blood becomes more acidic. Acidifying the blood stimulates ventilation, which increases the amount of oxygen in the blood. Acetazolamide can thus be used as a prophylaxis for mountain sickness.
Metabolic Alkalosis: can be useful for correcting a metabolic alkalosis, especially an alkalosis caused by diuretic-induced increases in H+ excretion.
Epilepsy: acetazolamide inhibits carbonic anhydrase in the CNS to retard abnormal and excessive discharge from CNS neurons.
Acetazolamide is given orally and is excreted unchanged by secretion in the proximal tubule; therefore, dosing must be reduced in renal insufficiency.
Carbonic Anydrase Inhibitors Adverse Effects
Metabolic Acidosis: Due to chronic reductions in HCO3- stores. Is generally a mild- moderate effect and unlike diuretic action persists as long as the drug is continued
Hyponatremia: Rarely clinically significant
Hypokalemia: Potassium wasting can occur because the increased Na+ presented to the collecting tubule is partially reabsorbed, increasing the lumen-negative electrical potential and enhancing K+ secretion.
Renal Stones: Phosphaturia and hypercalciuria occur during the bicarbonaturic response. Renal excretion of solubilizing factors may also decline with chronic use. Calcium phosphate salts also precipitate in alkaline urine.
Other Effects: Malaise, fatigue, depression, drowsiness, paresthesias can occur following large doses of acetazolamide. Hypersensitivity reactions can also occur.
Osmotic Diuretics
Mannitol
Osmotic diuretics are administered in large enough doses to significantly increase the osmolality of plasma and tubular fluid. By extracting water from intracellular compartments, osmotic diuretics expand the extracellular fluid volume, decrease blood viscosity, and inhibit renin release. They increase the urinary excretion of nearly all electrolytes; including Na+, K+, Ca2+, Mg2+, Cl-, HCO3- and phosphate.
Mannitol is used in the reduction of increased intracranial pressure associated with cerebral edema; the reduction of increased intraocular pressure; the promotion of urinary excretion of toxic substances and as a genitourinary irrigant in transurethral prostatic resection or other transurethral surgical procedures.
Although mannitol is FDA approved for the prevention of acute renal failure and/or promotion of diuresis it is not routinely recommended.
Mannitol must be administered via the intravenous route.
Adverse Effects of Mannitol
Adverse Effects
Extracellular Volume Expansion and Hyponatremia: Mannitol extracts water from cells. Prior to the diuresis, this leads to expansion of the extracellular volume and hyponatremia. Headache, nausea, and vomiting are commonly observed in patients treated with osmotic diuretics.
Tissue Dehydration: Excessive use of mannitol without adequate water replacement can ultimately lead to severe dehydration. As water is extracted from cells, intracellular K+ concentration rises, leading to cellular losses and hyperkalemia.
Contraindications
Mannitol is contraindicated in patients with active cranial bleeding.
Conivaptan
Actions and Adverse Effects?
ADH Antagonists
Conivaptan inhibits the effects of ADH in the collecting tubule by acting as an antagonist at the V1 and V2 receptors. By preventing the effects of ADH the collecting tubule remains impermeable to water and dilute urine is produced.
Conivaptan is used in the treatment of euvolemic and hypervolemic hyponatremia in hospitalized patients. It also has a role in the treatment of SIADH (Syndrome of Inappropriate ADH Secretion). Conivaptan is only used in the management of heart failure when the benefits outweigh the risks as the safety of the agent has not been established.
Conivaptan must be administered intravenously. It is metabolized by and is a potent inhibitor of CYP 3A4.
Adverse Effects
Nephrogenic Diabetes Insipidus: If serum Na+ is not monitored closely. Conivaptan can cause severe hypernatremia and nephrogenic diabetes insipidus.
Infusion site reactions
Atrial fibrillation, GI & electrolyte disturbances
Contraindications
Hypovolemic hyponatremia; Renal failure
