Physiology Review

Background:

•  Body fluid and electrolyte composition are regulated by the kidney-- drugs that interfere with renal transport may be useful in management of clinical disorders.

• Diuretics are drugs which block renal ionic transport, causing diuresis {in increasing urine volume}, often associated with natriuresis{increase in sodium excretion}

• Diuretics often act at different sites of the tubule transport system, at specific membrane transport proteins

• Diuretics that act on specific membrane transport proteins include:

  • loop diuretics

  • thiazides

  • amiloride (Midamor)

  • triamterene (Dyrenium)

• Diuretics may act through:

  • osmotic effects (preventing water reabsorption)-- mannitol

  • enzyme inhibition (carbonic anhydrase inhibitor)-- acetazolamide

  • interaction with hormonal receptors: spironolactone

• Renal physiology and sites of diuretic action:

courtesy of Robert H. Parsons, Ph.D., Rensselaer Polytechnic Institute, used with permission

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• Proximal tubule:

  • Many solutes are reabsorbed in the early portions of the proximal tubule:

    • 85% of filtered sodium bicarbonate

    • 40% of sodium chloride

    • 60% of water

    • nearly all of filtered organic solutes, including glucose and amino acids

      • glucose, amino acids, and other organic solutes are reabsorbed by specific transport systems

• Mechanism of Action: In the proximal tubule, sodium bicarbonate reabsorption can be influenced by carbonic anhydrase inhibitors.

  • Sodium bicarbonate reabsorbed in the proximal tubule depends on the action of sodium/hydrogen exchanger which is found in the luminal membrane of the proximal tubule epithelial cell.

    1. proton secreted into lumen (urine) combine with bicarbonate to form carbonic acid (H₂CO₃)

    2. Carbonic acid is dehydrated by an enzyme carbonic anhydrase which is localized (among other places) on the brush border membrane.

    3. The dehydration products carbon dioxide and water easily move across membranes. Carbon dioxide enters the proximal tubule by diffusion where it is rehydrated back to carbonic acid.

    4. Carbonic acid dissociates back to bicarbonate and the proton (step one)

    5. This cycle depends on carbonic anhydrase

  •  Mechanism of Action: Inhibition of carbonic anhydrase decreases bicarbonate reabsorption in proximal tubule, which in turn decreases water reabsorption

  • Carbonic anhydrase inhibitor: acetazolamide (Diamox)

• In the proximal tubule, water is reabsorbed in direct proportion to salt.

• With a large concentration of impermeant solute, such as glucose or the diuretic mannitol, water reabsorption would decrease for osmotic reasons. (Mechanism for osmotic diuresis)

• Located in the middle third proximal tubule

  • Organic acid secretory system secretes for example:

    • uric acid

    • antibiotics

    • p-aminohippuric acid

• Localized in both early and middle segments of the proximal tubule

  • Organic base secretory system secretes, for example:

    • creatinine

    • procainamide {antiarrhythmic drug}

    • choline

• Organic acid and base transport systems are important in delivery of diuretics to their site of action: luminal side

• Drug interaction: diuretics and probenecid (secretory system inhibitor)

• Thin limb

  • water reabsorption

    • driving force: osmotic -- due to hypertonic medullary fluid

  • no active salt reabsorption, but impermeant solutes (mannitol, glucose) will inhibit water reabsorption {a site of action for osmotic diuretics}

• Thick ascending limb of the loop of Henle: active sodium chloride reabsorption {about 35% of filtered load}--

  • impermeable to water

  • since reabsorption of sodium chloride at this site dilutes the fluid in the tubule, this segment may be referred to as "diluting segment."

  • Reabsorption of sodium chloride in the thick ascending limb is dependent upon the Na/K/2Cl co-transporter.

    1. Loop diuretics block this transporter.

       • furosemide (Lasix)

       • bumetanide (Bumex)

       • ethacrynic acid (Edecrin)

       • torsemide (Demadex)

    2. Normal activity of this transporter and Na/K ATPase results in an increase in intracellular potassium, potassium efflux, and a lumen-positive electrical potential:

    3. This lumen-positive membrane potential provides the driving force for reabsorption of magnesium and calcium cations.

    4. Therefore loop diuretics which inhibit the action of the sodium potassium chloride co-transporter, leading to increase sodium excretion also leads to increased magnesium and calcium loss.

• Distal Convoluted Tubule

  • Properties:

    • impermeable to water

    • sodium reabsorption (about 10% of filtered load) by sodium and chloride co-transporter

    • further dilution of tubular fluids

  • Pharmacological blockade of sodium and chloride co-transporter:

    • thiazide diuretics

    • no potassium recycling; no lumen-positive membrane potential; -- no calcium or magnesium loss by electrical forces

  • Calcium is actively reabsorbed by:

    • an apical calcium channel and

    • Na/Ca exchanger

    • regulated by parathyroid hormone

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• Collecting Tubule

  • Properties:

    • About 2% to 5% of sodium chloride reabsorption

    • Final site for sodium chloride reabsorption -- responsible for final sodium concentration in the urine

    • This site and late distal tubule -- where mineralocorticoids exert their effect

      • Major site of potassium secretion

    • Major sites for sodium, potassium, and water transport

      • principal cells

    • Major site for proton secretion -- intercalated cells

    • Separate sodium and potassium channels:

      • Significant driving force for sodium entry

      •  Na after entering the principal cell is transported to the blood {Na/K ATPase} with potassium translocated to the lumen urine (lumen-negative electrical potential drives chloride back to the blood)

        • Accordingly, delivery of increased sodium to the collecting tubule drives increased potassium efflux

        • Diuretics (acting upstream) that increased delivery of sodium to the collecting tubule will cause potassium loss

        • Delivery of bicarbonate {not readily reabsorbed compared chloride, increasing lumen-negative potentials}, will increase further potassium loss.

        • Diuretic-induced potassium loss, which is clinically important, results from the above mechanisms coupled with enhanced aldosterone secretion due to volume depletion.

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Carbonic Anhydrase Inhibitors

• the Enzyme:

  •  Major location: luminal proximal tubule membrane

  •  Activity: catalyzes dehydration of carbonic acid, H₂CO₃ , required for bicarbonate reabsorption

  •  blockade of carbonic anhydrase activity -- induces a sodium bicarbonate diuresis, reducing body bicarbonate levels

• Carbonic anhydrase inhibitors:

  • unsubstituted sulfonamides (bacteriostatic)

  • alkaline diuresis

  • hyperchloremic metabolic acidosis

  • Prototype: acetazolamide (Diamox)

• Acetazolamide: (Diamox)

  • well-absorbed orally

  • excretion: tubular secretion -- proximal tubule

    •  dose reduction in renal insufficiency

  • At maximal carbonic anhydrase inhibition: 45% inhibition of bicarbonate reabsorption

    •  causes significant bicarbonate loss

    •  hyperchloremic metabolic acidosis

    •  limited effectiveness because:

      • bicarbonate depletion increases sodium chloride reabsorption

    •  reduction in aqueous humor and cerebrospinal fluid production

  • Clinical Application:

    • Glaucoma:

      • decreases rate of aqueous humor production -- leads to a decline in intraocular pressure

      •  most common indication for use of carbonic anhydrase inhibitors

      • Dorzolamide (Trusopf): carbonic anhydrase inhibitor.

        • no diuretic or systemic metabolic effects

        • reduction in intraocular pressure comparable to oral agents

    • Urinary Alkalinization:

      • increased uric acid and cystine solubility by alkalinizing the urine (by increasing bicarbonate excretion)

      • for prophylaxis of uric acid renal stones, bicarbonate administration (baking soda) may be required

    • Metabolic Alkalosis:

      • Results from:

        •  decreased total potassium with reduced vascular volume

        •  high mineralocorticoid levels

        •  These conditions are usually managed by treating the underlying causes; however, in certain clinical settings acetazolamide may assist in correcting alkalosis {e.g. alkalosis due to excessive diuresis in CHF patients}

    • Acute Mountain Sickness:

      • Symptoms: weakness, insomnia, headache, nausea, dizziness {rapid ascension of all of 3000 meters}; symptoms -- usually mild

      •  In serious cases: life-threatening cerebral or pulmonary edema

      • Acetazolamide reduces the rate of CSF formation and decreases cerebral spinal fluid pH.

      • Prophylaxis against acute mountain sickness may be appropriate

    • Other Uses:

      • some role in management of epilepsy

      • hypokalemia periodic paralysis

      • increase urinary phosphate excretion during severe hyperphosphatemia.

  •  Toxicity:

    • hyperchloremic metabolic acidosis

      • due to reduction of body bicarbonate stores

    • renal stones:

      • bicarbonate loss is associated with:

        • phosphaturia

        • hypercalciuria (calcium salts, relatively insoluble at alkaline pH)

    • renal potassium loss:

      • increased sodium bicarbonate in the collecting tubule increases the lumen-negative electrical potential -- enhances potassium excretion

        • counteracted by potassium chloride administration

    • Others:

      • drowsiness, parathesias

      • accumulation in renal failure (CNS toxicity)

      • hypersensitivity reactions

    • Contraindications:

      • hepatic cirrhosis

        • urinary alkalinization will decrease ammonium ion trapping, increasing the likelihood of hepatic encephalopathy.

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Loop Diuretic Drugs

• Introduction

  • Agents include:

    • furosemide (Lasix)

    • bumetanide (Bumex)

    • torsemide (Demadex)

    • ethycrinic acid --no longer in use because of toxicity.

• Mechanism of action:

  • inhibition of NaCl reabsorption in the thick ascending limb of the loop of Henle

    •  inhibit the Na/K/2Cl transport system in the luminal membrane

      1.  reduction in sodium chloride reabsorption

      2.  decreases normal lumen-positive potential (secondary to potassium recycling)

      3.  Positive lumen potential: drives divalent cationic reabsorption (calcium magnesium)

      4.  Therefore, loop diuretics increase magnesium and calcium excretion.

         •  hypomagnesemia may occur in some patients.

         • hypocalcemia does not usually develop because calcium is reabsorbed in the distal convoluted tubule.

           • {in circumstances that result in hypercalcemia, calcium excretion can be enhanced by administration of loop diuretics with saline infusion}

  • Since a significant percentage of filtered NaCl is absorbed by the thick ascending limb of loop of Henle, diuretics acting at this site are highly effective

• Loop diuretics--Properties: rapidly absorbed following oral administration (may be administered by IV)

  • acts rapidly

  • eliminated by a renal secretion and glomerular filtration (half-life -- depend on renal function)

  • co-administration of drugs that inhibit weak acid secretion (e.g. probenecid or indomethacin) may alter loop diuretic clearance.

  • Other effects:

    • Furosemide: increases renal blood flow; blood flow redistribution within the renal cortex

    • Furosemide decreases pulmonary congestion and the left ventricular filling pressure in congestive heart failure (CHF) -- prior to an increase in urine output.

• Clinical Uses:

  • Major uses:

    • acute pulmonary edema

    • acute hypercalcemia

    • management of edema

  • Other uses:

    • hyperkalemia:

      • loop diuretics increase potassium excretion

      • effect increased by concurrent administration of NaCl and water.

    • acute renal failure:

      • may increase rate of urine flow and increase potassium excretion.

      • may convert oligouric to non-oligouric failure {easier clinical management}

      • renal failure duration -- not affected

    •  anion overload:

      • bromide, chloride, iodide: all reabsorbed by the thick ascending loop:

      •  systemic toxicity may be reduced by decreasing reabsorption

        • concurrent administration of sodium chloride and fluid is required to prevent volume depletion

•  Toxicity:

  •  Hypokalemia metabolic alkalosis:

    •  increased delivery of NaCl and water to the collecting duct increases potassium and proton secretion-- causing a hypokalemic metabolic alkalosis

    • in managed by potassium replacement and by ensuring adequate fluid intake

  • Ototoxicity:

    • dose-related hearing loss (in usually reversible)

    • ototoxicity more common:

      •  with decreased renal function

      •  with concurrent administration of other ototoxic drugs such as aminoglycosides

  •  Hyperuricemia:

    • may cause gout

    • loop diuretics cause increased uric acid reabsorption in the proximal tubule, secondary to hypovolemic states.

  •  Hypomagnesemia: loop diuretics cause:

    1. reduction in sodium chloride reabsorption

    2. decreases normal lumen-positive potential (secondary to potassium recycling)

    3. Positive lumen potential: drives divalent cationic reabsorption (calcium magnesium)

    4. Therefore, loop diuretics increase magnesium and calcium excretion.

       • hypomagnesemia may occur in some patients.

       • reversed by oral magnesium administration

  •  Allergic reactions:

    • furosemide: skin rash, eosinophilia, interstitial nephritis(less often)

  • Other toxicities:

    •  Dehydration (may be severe)

    • hyponatremia (less common than with thiazides thought may occur in patients who increased water intake in response to a hypovolemic thirst)

    • Hypercalcemia may occur in severe dehydration and if a hypercalcemia condition {e.g. oat cell long carcinoma} is also present.

Ives, H.E., Diuretic Agents, in: Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 242-259.

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Thiazides

• Introduction:

  • Thiazides inhibit NaCl transport at the distal convoluted tubule

  • Prototypical thiazide:  hydrochlorothiazide

• Properties:

  • Oral administration

  • Secreted by the organic acid secretory system

    • compete with uric acid for secretion {uric acid secretory rates may decline}

  • Differences between thiazides:

    • chlorothiazide (Diuril): less lipid soluble (requires relatively large doses)

    • chlorthalidone (Hygroton): slowly absorbed -- longer duration of action

    • indapamide (Lozol): mainly biliary secretion

  • Mechanism of action:

    • Diuretic action:Inhibition of NaCl reabsorption from the distal convoluted tubule (luminal side)

    • enhance calcium reabsorption in the distal convoluted tubule (unknown mechanism)

      • thiazides infrequently cause hypercalcemia but can unmask hypercalcemia due to other causes such as carcinoma, sarcoidosis, or hyperparathyroidism.

• Clinical Uses:

  • Hypertension

  • Congestive heart failure

  • Nephrolithiasis (due to idiopathic hypercalciuria

  • Nephrogenic diabetes insipidus

•  Toxicity:

  • Hypokalemic metabolic alkalosis and hyperuricemia

  • Impaired carbohydrate tolerance

    • may induce hyperglycemia

      • impaired pancreatic insulin release

      • decreased tissue glucose utilization

      • hyperglycemia may be partially reversed by correcting a hypokalemic state

  • Hyperlipidemia

    • 5% to 15% increase in serum cholesterol and an increase in low-density lipoproteins.

  •  Hyponatremia:

    • Significant adverse effect, occasionally life-threatening

    • Mechanism:

      • hypovolemia-induced increase in ADH

      • reduced renal diluting capacity

      • increased thirst

      • Prevention: decreasing the drug dose or limiting fluid intake

  • Allergic reactions:

    • Thiazides are sulfonamides: cross-reactivity within the group

    • photosensitivity {rare}

    • dermatitis {rare}

    • Extremely rare reactions:

      • hemolytic anemia

      • thrombocytopenia

      • acute necrotizing pancreatitis

  • Other reactions:

    • weakness

    • fatigue

    • paresthesias

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Potassium-Sparing Diuretic Agents

• Introduction:

  • These diuretics inhibit the effects of aldosterone at the cortical collecting tubule and late distal tubule.

  • Mechanisms of action:

    • In the collecting tubule and duct, sodium reabsorption and potassium excretion is regulated by aldosterone.

      • Aldosterone increases potassium secretion by increasing Na/K ATPase activity and sodium and potassium channel activity.

      • Normally, sodium absorption in the collecting tubule results in a lumen-negative electrical force that drives potassium excretion.

      • Aldosterone antagonists interfere with this effect

      •  Aldosterone antagonists act similarly with respect to proton movement, accounting for metabolic acidosis associated with aldosterone antagonists.

    • pharmacologic antagonism at mineralocorticoid receptors { spironolactone (Aldactone)}

    • inhibition of sodium transport through the luminal membrane {triamterene (Dyrenium), amiloride (Midamor)}

    •  Some Potassium-Sparing effects occur with nonsteroidal anti-inflammatory drugs, beta-blockers, converting enzyme-inhibitors, and angiotensin receptor blockers.

• Spironolactone (Aldactone):

  • Synthetic steroid: competitive aldosterone antagonist

    • binds to cytoplasmic mineralocorticoid receptors -- preventing receptor complex translocation to the nucleus

    • also inhibits formation of active metabolite of aldosterone {by inhibiting 5-alpha reductase activity}

  • hepatic inactivation

  • slow onset of action

• Triamterene (Dyrenium):

  • Renal excretion; hepatic metabolism-- extensive metabolism (short half life)

  • Directly blocks Na entry through sodium-specific channels (apical collecting tubule membrane) -- note that since potassium secretion is coupled to sodium entry, potassium secretion {potassium-sparing} is reduced.

• Amiloride (Midamor):

  • Excreted unchanged (urine)

  • Directly blocks Na entry through sodium-specific channels (apical collecting tubule membrane) -- note that since potassium secretion is coupled to sodium entry, potassium secretion {potassium-sparing} is reduced.

•  Clinical Uses:

  • Mineralocorticoid excess:

    • Conn's syndrome (primary hypersecretion)

    • ectopic ACTH production (primary hypersecretion)

    • secondary aldosteronism caused by:

      •  congestive heart failure

      • hepatic cirrhosis

      • nephrotic syndrome

      • conditions that cause renal salt retention with reduced intravascular volume

        • other diuretics may further reduce intravascular volume thus worsening secondary aldosteronism

•  Toxicity:

  •  Hyperkalemia:

    • Potassium-sparing diuretics can cause significant hyperkalemia

    • Factors that increase the likelihood of hyperkalemia:

      • renal disease

      • presence of agents that reduce renin:

        •  beta-blockers

        •   nonsteroidal anti-inflammatory drugs (NSAIDs)

        •   ACE inhibitors

        •   angiotensin receptor blockers

    •  hyperkalemia more likely when potassium-sparing diuretics are used as the only diuretic drug or in the presence of renal insufficiency.

      • given in combination with thiazides, hypokalemia and metabolic alkalosis associated with thiazide use may be balanced by aldosterone antagonists

      • Since thiazide adverse effects may predominate {hyponatremia, metabolic alkalosis}, due to variations in bioavailability, individual dose adjustment of the two drugs may be better.

  • Hyperchloremic Metabolic Acidosis:

    • Acidosis cause by inhibition of proton secretion along with potassium secretion {similar to type IV renal tubular acidosis

  • Gynecomastia:

    •  Endocrine abnormalities associated with synthetic steroids --Spironolactone (Aldactone)

      •  gynecomastia (breast enlargement)

      •  impotence

      •  benign prostatic hyperplasia

  • Acute Renal Failure:

    • Triamterene (Dyrenium) plus indomethacin

  • Kidney Stones:

    • Triamterene (Dyrenium) (poorly soluble) may precipitate in urine, causing renal stones:

•  Contraindications:

  •  may cause severe (potentially fatal) hyperkalemia

  •  potassium supplements should be discontinued prior to administration of aldosterone antagonists

  •  patients with chronic renal insufficiency are at particular risk

  •  hyperkalemia is also more likely to occur or it if beta-blockers or ACE inhibitors are concurrently administered

  •  impairment of hepatic metabolism of triamterene spironolactone may require dose adjustment

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Osmotic Diuretics

• Introduction:

  • Osmotic diuretics cause water to be retained within the proximal tubule and descending limb of loop of Henle (freely permeable to water)

  • Mannitol (Osmitrol) is an example of osmotic diuretic.

  • Clinical Use: mainly used to reduce increased intracranial pressure;

• Osmotic diuretics: properties

  • mannitol (Osmitrol) : not metabolized, freely filtered at the glomerular

  • usually administered by IV; oral administration results in an osmotic diarrhea-- perhaps useful to promote elimination of toxic substances from the GI tract (in conjunction with activated charcoal)

  • urine volume increases with mannitol excretion due to direct osmotic effects

    • sodium reabsorption is reduced because of increased urine flow rates {decreased contact time between urine and tubular epithelial cells}

• Clinical Uses:

  • To increase urine volume:

    • may be used to prevent anuria if the kidney due to hemolysis or rhabdomyolysis is presented with a large pigmented load.

    • when renal hemodynamics are compromised

  • To decrease intracranial or intraocular pressure:

    • Mannitol (Osmitrol) extract water from intracellular compartments, reducing total body water

    • Following IV administration, intracranial pressure falls within 60-90 minutes.

•  Toxicity:

  • Volume expansion effects -- increased extra cellular fluid volume and hyponatremia may cause pulmonary edema, complicating congestive heart failure

  • Headache, nausea, vomiting -- commonly observed

  • Dehydration and hypernatremia:

    • fluid loss leads to significant dehydration and in the absence of adequate fluid replacement leads to hypernatremia.

Ives, H.E., Diuretic Agents, in: Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 242-259.

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Diuretics: antihypertensive properties.

Orally active thiazide drugs have historically been a mainstay of antihypertensive treatment, although present therapy often involves other drugs.   Note the progression of antihypertensive medication;   beginning with a low dosage of either an ACE inhibitor, calcium channel blocker or beta blocker   and proceeding, if needed to add a diuretic   and ultimately additional more powerful drugs, such as centrally acting sympatholytics, peripheral vasodilators or combination. At each step dosages are reviewed and if the patient's hypertension is controlled then therapy may be continued with review for possible removal of medication. Figure adapted from Harrison's "Principles of Internal Medicine, Thirteenth Edition, p. 1128 Reduction in blood pressure is initially due to a reduction in extracellular volume and cardiac output. Long-term antihypertensive effects of thiazides appear due to reduced vascular resistance. The exact mechanism responsible for the reduction in vascular resistance is not known. Thiazides, due to their inhibition of the Na+-Cl- symport system, increase sodium and chloride excretion.(renal synport diagram) Distal Convoluted Tubule:From: Goodman and Gilman's "The Pharmacological Basis of Therapeutics, Ninth Edition   Thiazide diuretics, when used in the management of hypertension, is administered in combination with a potassium-sparing drug. Reduction in the amount of potassium loss can be achieved by: using potassium sparing drugs block Na+ channels in the late distal tubule and collecting duct (amiloride (Midamor) &triamterene (Dyrenium)) Note that amiloride (Midamor) and probably triamterene (Dyrenium) blocks sodium channels in the luminal membrane in the late distal tubule and collecting duct. Such action inhibits the normal movement of Na+ into the cell. Normally, Na+ entry create the net negative luminal charge that results in K+ efflux. By reducing the net negative luminal charge, amiloride (Midamor)/triamterene (Dyrenium) administration help conserve potassium. Therefore, they are called "potassium sparing". Figure adapted from "Goodman and Gillman's The Pharmacological Basis of Therapeutics" Ninth Edition, p. 705 inhibition of aldosterone action ( spironolactone (Aldactone)) Spironolactone is an antagonist of mineralocorticoid receptors (aldosterone-antagonist) . Normally, aldosterone interactions with mineralocoricoid receptors result in synthesis of aldosterone-induced proteins (AIPs). These proteins appear to increase the number or activity of Na+ channels and cause an increase in Na+ conductance. Increased Na+ conductance (with inward movement of Na+) results in a net negative luminal charge favoring K+ loss. Antagonism of the interaction between aldosterone and its receptor by spironolactone conserves K+ (potassium sparing). Figure from Goodman and Gilman's "The Pharmacological Basis of Therapeutics" Ninth Edition, p. 708           inhibition of aldosterone release by ACE inhibitors or angiotensin-receptor blockers

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Clinical uses of diuretics

Carbonic Anhydrase Inhibitor

• Acetazolamide (Diamox)

• Glaucoma:

  • decreases rate of aqueous humor production -- leads to a declining in intraocular pressure

  • most common indication for use of carbonic anhydrase inhibitors

  • Dorzolamide (Trusopf): topical carbonic anhydrase inhibitor.

    •  no diuretic or systemic metabolic effects

    •  reduction in intraocular pressure comparable to oral agents

• Urinary Alkalinization:

  • increased uric acid and cystine solubility by alkalinizing the urine (by increasing bicarbonate excretion)

  • for prophylaxis of uric acid renal stones, bicarbonate administration (baking soda) may be required

• Metabolic Alkalosis:

  • Results from:

    • decreased total potassium with reduced vascular volume

    • high mineralocorticoid levels

    • These conditions are usually managed by treating the underlying causes; however, in certain clinical settings acetazolamide may assist in correcting alkalosis {e.g. alkalosis due to excessive diuresis in CHF patients}

• Acute Mountain Sickness:

  • Symptoms: weakness, insomnia, headache, nausea, dizziness {rapid ascension of all of 3000 meters}; symptoms -- usually mild

  •  In serious cases: life-threatening cerebral or pulmonary edema

  • Acetazolamide (Diamox) reduces the rate of CSF formation and decreases cerebral spinal fluid pH.

  • Prophylaxis against acute mountain sickness may be appropriate

• Other Uses:

  • some role in management of epilepsy

  • hypokalemia periodic paralysis

  • increase urinary phosphate excretion during severe hyperphosphatemia.

Loop Diuretics

• Furosemide (Lasix), bumetanide (Bumex), torsemide (Demadex), ethacrynic acid (Edecrin)

• Major Clinical uses:

  • acute pulmonary edema

  • acute hypercalcemia

  • management of edema

• Other uses:

  •   hyperkalemia:

    •  loop diuretics increase potassium excretion

    •  effect increased by concurrent administration of NaCl and water.

  •  acute renal failure:

    •  may increase rate of urine flow and increase potassium excretion.

    •  may convert oligouric to non-oligouric failure {easier clinical management}

    •  renal failure duration -- not affected

  •  anion overload:

    •  bromide, chloride, iodide: all reabsorbed by the thick ascending loop:

    •  systemic toxicity may be reduced by decreasing reabsorption

      • concurrent administration of sodium chloride and fluid is required to prevent volume depletion

Thiazides

• Hypertension

• Congestive heart failure

• Nephrolithiasis (due to idiopathic hypercalciuria

• Nephrogenic diabetes insipidus

Osmotic Diuretics

Mannitol (Osmitrol)

• To increase urine volume:

  •  may be used to prevent anuria if the kidney due to hemolysis or rhabdomyolysis is presented with a large pigmented load.

  •  when renal hemodynamics are compromised

• To decrease intracranial or intraocular pressure:

  •  Mannitol extract water from intracellular compartments, reducing total body water

  • Following IV administration, intracranial pressure falls within 60-90 minutes.

Potassium Sparing Agents

• Amiloride (Midamor), triamterene (Dyrenium), spironolactone (Aldactone)

• Reduction of potassium loss associated with thiazide or loop diuretic administration

• Mineralocorticoid excess:

  •  Conn's syndrome (primary hypersecretion)

  • ectopic ACTH production (primary hypersecretion)

  • secondary aldosteronism caused by:

    •  congestive heart failure

    •   hepatic cirrhosis

    •   nephrotic syndrome

    •   conditions that cause renal salt retention with reduced intravascular volume

      • other diuretics may further reduce intravascular volume thus worsening secondary aldosteronism

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Adverse Diuretic effects and contraindications

Adverse Effects:  Carbonic Anhydrase Inhibitors (Acetazolamide)

• Toxicity:

  • hyperchloremic metabolic acidosis

    • due to reduction in body bicarbonate stores

  • renal stones:

    • bicarbonate loss is associated with:

      •  phosphaturia

      •   hypercalciuria (calcium salts, relatively insoluble at alkaline pH)

  • renal potassium loss:

    • increased sodium bicarbonate in the collecting tubule increases the lumen-negative and in inelectrical potential -- enhances potassium excretion

      • counteracted by potassium chloride administration

  • Others:

    • drowsiness, parathesias

    • accumulation in renal failure (CNS toxicity)

    • hypersensitivity reactions

  •  Contraindications:

    • hepatic cirrhosis

      • urinary alkalinization will decrease ammonium ion trapping, increasing the likelihood of hepatic encephalopathy.

Adverse Effects:  Loop Diuretics

 Toxicity:

•  Hypokalemia metabolic alkalosis:
  • increased delivery of NaCl and water to the collecting duct increases potassium and proton secretion-- causing a hypokalemic metabolic alkalosis
  • in managed by potassium replacement and by ensuring adequate fluid intake
•  Ototoxicity:
  • dose-related hearing loss (in usually reversible)
  • more common:
    • with decreased renal function
    • with concurrent administration of other ototoxic drugs such as aminoglycosides
•  Hyperuricemia:
  • may cause gout
  • loop diuretics cause increased uric acid reabsorption in the proximal tubule, secondary to hypovolemic states.
•  Hypomagnesemia: loop diuretics cause:
  1. reduction in sodium chloride reabsorption
  2. decreases normal lumen-positive potential (secondary to potassium recycling)
  3. Positive lumen potential: drives divalent cationic reabsorption (calcium magnesium)
  4. Therefore, loop diuretics increase magnesium and calcium excretion.
     • hypomagnesemia may occur in some patients.
     •  reversed by oral magnesium administration
• Allergic reactions:
  • furosemide: skin rash, eosinophilia, interstitial nephritis(less often)
• Other toxicities:
  • Dehydration (may be severe)
  • hyponatremia (less common than with thiazides thought may occur in patients who increased water intake in response to a hypovolemic thirst)
  • Hypercalcemia may occur in severe dehydration and if a hypercalcemia condition {e.g. oat cell long carcinoma} is also present.

Adverse Effects:  Thiazides

Toxicity:

• Hypokalemic metabolic alkalosis and hyperuricemia
• Impaired carbohydrate tolerance
  •  may induce hyperglycemia
    •  impaired pancreatic insulin release
    •   decreased tissue glucose utilization
    •   hyperglycemia may be partially reversed by correcting a hypokalemic state
• Hyperlipidemia
  • 5% to 15% increase in serum cholesterol and an increase in low-density lipoproteins.
• Hyponatremia:
  • Significant adverse effect, occasionally life-threatening
  • Mechanism:
    •   hypovolemia-induced increase in ADH
    •   reduced renal diluting capacity
    •   increased thirst
    •   Prevention: decreasing the drug dose or limiting fluid intake
• Allergic reactions:
  •  Thiazides are sulfonamides: cross-reactivity within the group
  • photosensitivity {rare}
  • dermatitis {rare}
  • Extremely rare reactions:
    • hemolytic anemia
    • thrombocytopenia
    • acute necrotizing pancreatitis
• Other reactions:
  • weakness
  • fatigue
  • paresthesias

Adverse Effects:  Osmotic Diuretics

 Toxicity:

• Volume expansion effects -- increased extra cellular fluid volume and hyponatremia may cause:

  • pulmonary edema, complicating congestive heart failure

• Headache, nausea, vomiting -- commonly observed

• Dehydration and hypernatremia:

  • flow gloss leads to significant dehydration and in the absence of adequate fluid replacement leads to hypernatremia.

Adverse Effects:  Potassium-Sparing Diuretics

•  Toxicity:

  • Hyperkalemia:

    • Potassium-sparing diuretics can cause significant hyperkalemia

    • Factors that increase the likelihood of hyperkalemia:

      • renal disease

      • presence of agents that reduce renin:

        •   beta-blockers

        •   nonsteroidal anti-inflammatory drugs (NSAIDs)

        •   ACE inhibitors

        •   angiotensin receptor blockers

    •  hyperkalemia more likely when potassium-sparing diuretics are used as the only diuretic drug or in the presence of renal insufficiency.

      •  Given in combination with thiazides, hypokalemia and metabolic alkalosis associated with thiazide use may be balanced by aldosterone antagonists

      •  Since thiazide adverse effects may predominate {hyponatremia, metabolic alkalosis}, due to variations in bioavailability, individual dose adjustment of the two drugs may be better.

  • Hyperchloremic Metabolic Acidosis:

    • Acidosis cause by inhibition of proton secretion along with potassium secretion {similar to type IV renal tubular acidosis

  • Gynecomastia:

    •   Endocrine abnormalities associated with synthetic steroids --spironolactone:

      •    gynecomastia (breast enlargement)

      •    impotence

      •    benign prostatic hyperplasia

  • Acute Renal Failure:

    •   triamterene (Dyrenium) plus indomethacin

  • Kidney Stones:

    •  triamterene (Dyrenium) (poorly soluble) may precipitate in urine, causing renal stones:

•  Contraindications:

  • may cause severe (potentially fatal) hyperkalemia

  • potassium supplements should be discontinued prior to administration of aldosterone antagonists

  • patients with chronic renal insufficiency are at particular risk

  • hyperkalemia is also more likely to occur or it if beta-blockers or ACE inhibitors are concurrently administered

  • impairment of hepatic metabolism of triamterene spironolactone may require dose adjustment

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Mechanisms whereby furosemide and thiazides are useful in calcium metabolism disorders management

Role of Diuretics in Calcium Metabolism

• Loop Diuretics & Calcium Metabolism

  • Furosemide (Lasix)

  • Torsemide (Demadex)

  • Bumetanide (Bumex)

• Mechanism of action:

  • Inhibition of NaCl reabsorption in the thick ascending limb of the loop of Henle

    • inhibit the Na/K/2Cl transport system in the luminal membrane

      1. reduction in sodium chloride reabsorption

      2. decreases normal lumen-positive potential (secondary to potassium recycling)

      3.  Positive lumen potential: drives divalent cationic reabsorption (calcium magnesium)

      4.  Therefore, loop diuretics increase magnesium and calcium excretion.

         • hypomagnesemia may occur in some patients.

         • hypocalcemia does not usually develop because calcium is reabsorbed in the distal convoluted tubule.

           •   {in circumstances that result in hypercalcemia, calcium excretion can be enhanced by administration of loop diuretics with saline infusion}

    • Clinical Uses:

      •  Major uses:

        •  acute pulmonary edema

        •  acute hypercalcemia

        •  management of edema

Thiazides & Calcium Metabolism

• Mechanism of action:

  •  Diuretic action:Inhibition of NaCl reabsorption from the distal convoluted tubule (luminal side)

  • enhanced calcium reabsorption in the distal convoluted tubule (unknown mechanism)

    •  thiazides infrequently cause hypercalcemia but can unmask hypercalcemia due to other causes such as carcinoma, sarcoidosis, or hyperparathyroidism.

Thiazides: nephrogenic diabetes insipidus.

• Diabetes insipidus: impaired renal water conservation, caused by:

  •  Inadequate vasopressin secretion (Central or cranial diabetes insipidus)

  • Insufficient kidney response to vasopressin (nephrogenic diabetes insipidus)

  • Induction of diabetes insipidus:

    •  hypercalcemia

    •  hypokalemia

    •   postobstructive renal failure

    •   lithium (incidence: as high as 33%)

    •  demeclocycline (Declomycin)

  • Familial nephrogenic diabetes insipidus: X-linked, typically,recessive)

• Thiazides are central in treatment of nephrogenic diabetes insipidus, reducing urine volume by up to 50%.

• Other drugs:

  • Amiloride: by blocking lithium uptake by the sodium channel in the collecting duct, amiloride is the drug of choice for lithium-induced nephrogenic diabetes insipidus.

• Mechanism of action:

  • Decrease in volume promotes increased proximal tubule reabsorption.

    •  Decreased extracellular fluid volume results in compensatory mechanisms that increase NaCl reabsorption in the proximal tubule -- reducing the volume delivered to the distal tubule.

      •  As a result, less free water is formed and polyuria is decreased

  • Since the effectiveness of thiazide diuretics in treating nephrogenic diabetes insipidus follows the extent of natriuresis, the effectiveness may be enhanced by decreasing sodium intake.

Jackson, E.K. Diuretics In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 685- 713

Jackson, E.K. Vasopressin and Other Agents Affecting the Renal Conservation of Water In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.715-732

Chlorpropamide (Diabinese) and clofibrate (Abitrate, Atromid-S) : Central (Cranial) Diabetes Insipidus

• Diabetes insipidus: impaired renal water conservation, caused by:

  •  inadequate vasopressin secretion (Central or cranial diabetes insipidus)

  • inadequate kidney response to vasopressin (nephrogenic diabetes insipidus)

• Clinical Presentations:

  • Large volumes of dilute (200 mOsm/kg) urine excreted

  • With normal thirst, polydipsia is present

  • By contrast with diabetes mellitus, the urine in diabetes insipidus is tasteless.

  • Central or cranial diabetes insipidus can be discriminated from nephrogenic diabetes insipidus by administration of desmopressin (DDAVP).

    •  Urine osmolality will

      •  increase following desmopressin administration in patients with central diabetes insipidus

      •  have limited effect or no effect in patients with nephrogenic diabetes insipidus.

• Causes of central diabetes insipidus:

  • Head injury (near the pituitary and/or hypothalamus

  • Hypothalamic or pituitary tumor

  • Cerebral aneurysms

  • CNS ischemia

  • CNS infections

  • Central diabetes insipidus: idiopathic or familial

    • familial: autosomal dominant (chromosome 20)

      • point mutations in the signal peptide and VP-neurophysin-- causing defects in synthesis, processing, and preprohoromone transport.

• Treatment:

  • Primary treatment: (antidiuretic peptides): desmopressin (DDAVP)

  • Patients intolerant of desmopressin: chlorpropamide (Diabinese) (oral sulfonylurea)

    • Mechanism of action -- chlorpropramide

      •  potentiates effects of residual, circulating vasopressin (reduces urine volume in more than 50% of patients)

      •   Antidiuretic mechanisms of carbamazepine (Tegretol), clofibrate, chlorpropamide (Diabinese) have not been definitively determined.

  • If polyuria is insufficiently reduced by chlorpropramide, a thiazide diuretic may be added.

  • For short-term management, the combination of carbamazepine (Tegretol) and clofibrate (Abitrate, Atromid-S) will also decreased polyuria in central diabetes insipidus:

    •  Serious, adverse effects associated with prolonged use of this combination are limiting

Jackson, E.K. Vasopressin and Other Agents Affecting the Renal Conservation of Water In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.715-732.

return to Table of Contents

Management of inappropriate secretion of antidiuretic hormone

• Disease of impaired water excretion caused by inappropriate vasopressin secretion, resulting in:
  • hyponatremia
  • hypoosmolality
•  Clinical effects:

• Clinical effects are seen only if excessive fluid intake (in oral or IV) occurs concurrently with inappropriate vasopressin secretion.
• Causes:
  •  malignancies
  • pulmonary disease
  •  CNS injury/diseases
    • trauma
    • infections
    • tumors
  •  surgery
  • drugs {cisplatin, Vinca alkaloids, cyclophosphamide (Cytoxan),chlorpropamide (Diabinese), thiazide diuretics, phenothiazines, carbamazepine (Tegretol), clofibrate, nicotine, narcotics, tricyclic antidepressants}
• Treatment
  • water restriction
  • IV hypertonic saline
  • loop diuretics
  • drugs that reduce the ability of vasopressin to increase water permeability in the renal collecting ducts:demeclocycline (Declomycin)

Jackson, E.K. Vasopressin and Other Agents Affecting the Renal Conservation of Water In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.715-732.

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 Mechanism by which lithium compounds may cause a syndrome like diabetes insipidus

Introduction

• Vasopressin: regulates water conservation

• Synonymous terms: vasopressin: arginine vasopressin (AVP): antidiuretic hormone (ADH)

• Similar peptide: oxytocin-- common vasopressin and oxytocin receptor antagonists

  • binds to myoepithelial cells in the mammary gland (milk ejection) and on uterine smooth muscle cells (uterine contraction)

•  The antidiuretic system consists of:

  • CNS component (vasopressin synthesis, transport, storage, release)

    • supraoptic nucleus (SON)

    • paraventricular nucleus (PVN)

  • Renal collecting duct system

    • epithelial cells -- increased water permeability in response to vasopressin.

• Increased plasma osmolality: increased vasopressin release

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Regulation of vasopressin secretion

•  Osmotic Stimulation of Vasopressin Release

  • CNS structures: osmoreceptive complex

    1.  Osmosensitive: magnocellular neurons (SON, PVN)

    2.  Subfornical organ (SFO) project to SON/PVN

    3.  Organum vasculosum of the lamina terminalis (OVLT) project during clearing directly to SON/PVN

•  Hypovolemic/hypotension stimulation of Vasopressin Release:

  •  Baroreceptors:

    •  Blood volume (filling pressures)--baroreceptors in:

      •  left atrium

      •  left ventricle

      •  pulmonary veins

    •  Arterial blood pressure: baroreceptors -- carotid sinus and aorta

    •  Nerve impulses from baroreceptors are carried:

      •  by the vagus and glossopharyngeal nerves to the nucleus of the solitary tract

      •  to the A1-noradrenergic cells in the caudal ventrolateral medulla

      •  to the SON and PVN

Hormonal Effects

Vasopressin release: stimulation

• Vasopressin release: inhibition:

  • atrial natriuretic peptide

  •  gamma aminobutyric acid (gaba)

  • opioids (dynorphin)

Drug Effects

Lithium Effects:

• Inhibits antidiuretic effect of vasopressin

  • Lithium is used widely for management of bipolar disorder (manic- depressive).

  • Lithium uptake by the sodium channel in the collecting duct, causes lithium-induced nephrogenic diabetes insipidus.

  • Lithium polyuria: normally reversible

  • Mechanism of action:

    • reduces V2 receptor-mediated adenyl cyclase stimulation

•  Often, the antibiotic demeclocycline (Declomycin) reduces the antidiuretic effects of vasopressin (possibly because of reduced cyclic AMP)

Jackson, E.K. Vasopressin and Other Agents Affecting the Renal Conservation of Water In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.715-732.