Basic pharmacology of diuretics

Photo: Scanning electron micrograph of the glomerulus in a human kidney.

From: Widmaier EP. Vander’s Human Physiology: The Mechanisms Of Body Function, 13th Ed. New York, NY: McGraw-Hill Companies, Inc., 2014: 490

Learning Objectives: 1. List major types of diuretics and relate them to their sites of action.

2. List the major applications, toxicities, and the efficacy of thiazides, loop diuretics and potassium-sparing diuretics.

3. Describe two drugs that reduce potassium loss during diuresis.

4. Describe a therapy that will reduce calcium excretion in patients who have recurrent urinary stones.

5. Discuss the principle of force diuresis.

6. Describe drugs for reducing urine volume in nephrogenic diabetes insipidus.

7. Understand the usefulness of altering urine pH by drugs.

8. Discuss the mechanisms by which drugs and chemicals damage the kidney.

9. Understand how to select and prescribe drugs for patients with renal impairment.

Companion: Renal Pharmacology eNotes Marc Imhotep Cray, M.D.

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Some Relevant Drugs: A. Carbonic Anhydrase Inhibitors Acetazolamide dichlorphenamide methazolamide dorzolamide B. Osmotic Diuretics mannitol C. Loop Diuretics furosemide bumetanide torsemide ethacrynic acid Marc Imhotep Cray, M.D.

D. Thiazides chlorthalidone chlorothiazide hydrochlorothiazide metolazone indapamide E. Potassium-sparing diuretics spironolactone eplerenone triamterene amiloride

F. ADH antagonists demeclocycline lithium lixivaptan tolvaptan conivaptan

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Individual Diuretics Topics Outline:      

Mercurial Diuretics Carbonic Anhydrase Inhibitors Thiazide Diuretics Potassium-Sparing Agents Loop (High-Ceiling) Diuretics Osmotic Agents

Marc Imhotep Cray, M.D.

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Mercurial Diuretics Organomercurial agents inhibit active Cl− transport, especially in ascending limb of the Henle loop In acidic conditions, Hg2+ dissociates, binds to, and inhibits sulfhydryl enzymes Na+ reabsorption is thus decreased; more Na+ and Cl− are excreted Because more Na+ is delivered to distal nephron during diuresis, K+ and H+ excretion (sum of urinary NH4 + plus titratable acid − urinary HCO3−) may increase In alkaline conditions, Hg2+ does not dissociate, and patients become refractory to mercurials Marc Imhotep Cray, M.D.

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Mercurial Diuretics (2) Mercurial diuretics (eg, mercaptomerin) are poorly absorbed when taken orally, so an intramuscular route is required  Because of this difficulty and their toxicity (eg, systemic poisoning, cardiac toxicity, hypersensitivity, worsening of renal insufficiency), mercurials are largely obsolete They are sometimes used for CHF, cirrhosis, and portal obstruction because they do not deplete K+

Marc Imhotep Cray, M.D.

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Mercurial Diuretics (3)

Marc Imhotep Cray, M.D.

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014

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Carbonic Anhydrase Inhibitors (CAIs) Capsule Diuretic drugs such as acetazolamide (prototype), dichlorphenamide, methazolamide and dorzolamide inhibit carbonic anhydrase, particularly at proximal convoluted tubule  Carbonic anhydrase normally catalyzes dehydration of carbonic acid (H2CO3) o As a result of CAIs, H+ needed for Na+-H+ exchange is reduced, HCO3− and Na+ reabsorption in proximal tubules is suppressed, and diuresis is promoted Marc Imhotep Cray, M.D.

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Carbonic Anhydrase Inhibitors: Mechanism of Action The enzyme carbonic anhydrase normally helps to make H+ ions available for exchange with sodium and water in proximal tubules CAIs block action of carbonic anhydrase, thus preventing exchange of H+ ions with sodium and water these agents block formation of H+ and HCO3- from CO2 and H2O  end result is that bicarbonate is excreted in urine

Marc Imhotep Cray, M.D.

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Carbonic Anhydrase Inhibitors: Mechanism of Action Inhibition of carbonic anhydrase reduces H+ ion concentration in renal tubules As a result, there is increased excretion of bicarbonate, sodium, water, and potassium Reabsorption of water is decreased and urine volume is increased

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CAIs: Therapeutic Uses  Adjunct agents in long-term management of open-angle glaucoma  Used with miotics to lower intraocular pressure before ocular surgery in certain cases

Also useful in treatment of:  Glaucoma  Edema  Epilepsy  High-altitude sickness Marc Imhotep Cray, M.D.

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CAIs: Therapeutic Uses cont. ď ąAcetazolamide is sometimes used in management of edema secondary to CHF when other diuretics are not effective ď ąCAIs are less potent diuretics than loop diuretics or thiazides ď ąmetabolic acidosis they induce reduces their diuretic effect in 2 to 4 days

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Carbonic Anhydrase Inhibitors: Adverse Effects  hyperchloremic metabolic acidosis (Because of decreased reabsorption of Na+, Na+-K+ exchange increases in distal convoluted tubules)  Drowsiness  Anorexia  Paresthesias  Hematuria  Urticaria  Photosensitivity  Melena Marc Imhotep Cray, M.D.

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CAIs MOA

Marc Imhotep Cray, M.D.

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014

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Thiazide and Thiazide-Like Diuretics hydrochlorothiazide (Esidrix, HydroDIURIL)

chlorothiazide (Diuril) trichlormethiazide (Metahydrin) chlorthalidone (Hygroton) metolazone (Mykrox, Zaroxolyn)

indapamide

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Thiazide Diuretics Capsule  Thiazide (benzothiadiazide) diuretics inhibit Cl− reabsorption, especially in distal portion of ascending limb of Henle loop and proximal portion of distal convoluted tubule  Excretion of Na+, K+, Cl−, and HCO3 − is increased  refractoriness does not develop to diuretic effect  Often used to treat chronic edema and essential hypertension and, less often, nephrosis some forms of diabetes insipidus, and hypercalciuria  Common adverse effects are hypokalemia (K+ supplements are recommended) may lead to alkalosis, and hyperglycemia  Extra caution is needed when these agents are used with digitalis for CHF because of greater digitalis toxicity in conditions of low K+  Because thiazides are excreted via glomerular filtration and tubular secretion they compete with uric acid for tubular secretion result in increase bld uric acid can precipitate gout in at risk persons Marc Imhotep Cray, M.D.

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Thiazide and Thiazide-Like Diuretics: Mechanism of Action Inhibit tubular reabsorption of sodium and chloride ions

Action primarily in ascending loop of Henle and early distal tubule Result: water, sodium, and chloride are excreted Potassium is also excreted to a lesser extent Dilate arterioles by direct relaxation

Drug Effects  Lowered peripheral vascular resistance  Depletion of sodium and water Marc Imhotep Cray, M.D.

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Thiazide Diuretics: Therapeutic Uses Hypertension (one of most prescribed group of agents) Edematous states Idiopathic hypercalciuria Diabetes insipidus Adjunct agents in treatment of CHF and hepatic cirrhosis

Marc Imhotep Cray, M.D.

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Thiazide Diuretics: Adverse Effects Body System CNS

GI

Marc Imhotep Cray, M.D.

Effect Dizziness, headache, blurred vision, paresthesias, decreased libido Anorexia, nausea, vomiting, diarrhea

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Thiazide Diuretics: Adverse Effects Body System GU Integumentary Metabolic

Marc Imhotep Cray, M.D.

Effect Impotence Urticaria, photosensitivity Hypokalemia, glycosuria, Hyperglycemia, Hyperuricemia (gout)

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Thiazide Diuretics MOA

Marc Imhotep Cray, M.D.

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014

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Potassium-Sparing Diuretics Those in clinical use include:  Epithelial sodium channel blockers:  Amiloride  Triamterene Aldosterone antagonists:  Spironolactone  Eplerenone

Marc Imhotep Cray, M.D.

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Potassium-Sparing Agents Capsule Two major categories of K+-sparing diuretic drugs are 1. Na+ channel antagonists (eg, amiloride, triamterene) and 2. Aldosterone receptor antagonists (eg, spironolactone) Amiloride and triamterene inhibit active Na+ reuptake Enhanced Na+ and Cl− excretion disrupts Na+ transport and reduces K+ secretion

They moderately increase Na+, Cl−, and HCO3− excretion when they are used with other diuretics, Na+ excretion increases and K+ is retained Reversible azotemia can occur

Marc Imhotep Cray, M.D.

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K+-Sparing Agents Capsule cont. Triamterene can increase serum uric acid levels, so caution is needed for its use in patients with gout Spironolactone reduces aldosterone-mediated Na+-K+ exchange at distal convoluted tubule which increases Na+ loss while reducing K+ excretion Adverse effects of both types of drugs include hyperkalemia (especially when impaired renal function exists)  Combination therapy with K+-sparing drugs is not advised, but they are often used with other diuretics (eg, thiazides) that K+ excretion to prevent hypoklemia Marcincrease Imhotep Cray, M.D.

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Potassium-Sparing Diuretics: Mechanism of Action Work in collecting ducts and distal convoluted tubules

Interfere with sodium-potassium exchange  Competitively bind to aldosterone receptors Block reabsorption of sodium and water usually induced by aldosterone

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Potassium-Sparing Diuretics: Drug Effects Prevent potassium from being pumped into tubule, thus preventing its secretion

Competitively block aldosterone receptors and inhibit its action

Excretion of sodium and water is promoted Marc Imhotep Cray, M.D.

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Potassium-Sparing Diuretics: Therapeutic Uses  spironolactone and triamterene  Hyperaldosteronism  Hypertension  Reversing potassium loss caused by potassium-depleting drugs (diuretics)  amiloride

 Treatment of CHF

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Potassium-Sparing Diuretics: Adverse Effects Body System

Effect

CNS

Dizziness, headache

GI

Cramps, nausea, vomiting, diarrhea

Other

Urinary frequency, weakness, hyperkalemia

ď ą Spironolactone (also blocks androgenic receptors) gynecomastia, amenorrhea, irregular menses Marc Imhotep Cray, M.D.

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K+-Sparing Diuretics MOA

Marc Imhotep Cray, M.D.

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014

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Loop (High-Ceiling) Diuretics Capsule  Bumetanide, ethacrynic acid, furosemide, torsemide acts mainly on thick ascending limb of the Henle loop  Because they elicit greatest diuresis possible, they are also termed high-ceiling diuretics  They act at luminal nephron surface and inhibit electrolyte reabsorption, with resultant greater Na+, Cl−, K+, Mg2+, and Ca2+ excretion  Inhibition of NaCl reabsorption in Henle loop decreases strength of countercurrent concentrating mechanism and causes greatly increased Marc Imhotep Cray, M.D. urine output

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Loop Diuretics Capsule cont.

Pharmacologic Effects  Bumetanide, furosemide, and torsemide are weak inhibitors of carbonic anhydrase  Ethacrynic acid, which is not a sulfonamide, does not inhibit this enzyme  Refractoriness does not occur

Clinical Use Loop diuretics are used for acute pulmonary edema, edema associated with CHF, cirrhosis, and renal disease

Adverse effects  Fluid and electrolyte imbalances are most common adverse effects  All increase Cl− more than Na+ excretion, which can lead to hypochloremic alkalosis Marc Imhotep Cray, M.D.

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Loop Diuretics: Mechanism of Action ď ąAct directly on ascending limb of loop of Henle to inhibit sodium and chloride reabsorption ď ąIncrease renal prostaglandins, resulting in dilation of blood vessels and reduced peripheral vascular resistance

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Loop Diuretics: Drug Effects  Potent diuresis and subsequent loss of fluid  Decreased fluid volume causes:  Reduced BP  Reduced pulmonary vascular resistance  Reduced systemic vascular resistance  Reduced central venous pressure  Reduced left ventricular end-diastolic pressure  Potassium depletion Marc Imhotep Cray, M.D.

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Loop Diuretics: Therapeutic Uses ď ą Edema associated with CHF or hepatic or renal disease ď ą Less commonly than thiazides, control of hypertension

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Loop Diuretics: Adverse Effects Body System Nervous

Effect Dizziness Headache Ototoxicity (tinnitus) Blurred vision

GI

Nausea/vomiting, diarrhea

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Loop Diuretics: Adverse Effects Body System Hematologic

Effect agranulocytosis, neutropenia, thrombocytopenia

Metabolic

hypokalemia, hyperglycemia, hyperuricemia, hypomagnesemia, metabolic alkalosis

Marc Imhotep Cray, M.D.

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Loop Diuretics MOA

Marc Imhotep Cray, M.D.

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014

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Osmotic Diuretics Capsule Osmotic diuretics (mannitol, glycerol, urea) enter nephron through glomerulus but are poorly reabsorbed along nephron because of their relatively large molecular size

Presence of unabsorbed molecules in tubule lumen creates a concentration (osmotic) gradient across tubular membrane In proximal convoluted tubule, reabsorption of Na+ and water decreases, which produces diuresis without marked changes in Na+ or Cl− excretion Mannitol, agent used most often, is a hexacarbon sugar alcohol that Cray, is given intravenously it is not metabolized Marc Imhotep M.D.

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Osmotic Diuretics Capsule cont. Osmotic diuretics are used to treat  cerebral edema and glaucoma (by reducing cerebrospinal or intraocular fluid pressure)  oliguria and anuria, and  certain phases of acute renal failure (as prophylaxis)

Because osmotic diuretics increase blood volume adverse effects include decompensation in patients with CHF Hyperosmolarity or hyponatremia can occur during therapy of renal failure or cirrhosis Marc Imhotep Cray, M.D.

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Osmotic Diuretics: Mannitol Mechanism of Action Work in proximal tubule Nonabsorbable producing an osmotic effect Pull water into blood vessels and nephrons from surrounding tissues

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Osmotic Diuretics: Drug Effects Reduced cellular edema Increased urine production, causing diuresis Rapid excretion of water, sodium, and other electrolytes, as well as excretion of toxic substances from kidney Reduces excessive intraocular pressure

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Osmotic Diuretics: Therapeutic Uses Used in treatment of patients in early, oliguric phase of ARF To promote excretion of toxic substances Reduction of intracranial pressure Treatment of cerebral edema

Marc Imhotep Cray, M.D.

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Osmotic Diuretics: Adverse Effects  Convulsions  Thrombophlebitis  Pulmonary congestion Also  headaches  chest pains  tachycardia  blurred vision  chills and fever Marc Imhotep Cray, M.D.

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Illust. of where of diuretics act, and how

Marc Imhotep Cray, M.D.

Katzung, Masters, Trevor. Basic and Clinical Pharmacology, 12th ed. New York: McGraw-Hill, 2012

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See next slide for sources and links to additional study tools and resources.

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Sources and further study: eLearning Renal cloud folder tools and resources MedPharm Guidebook: Unit 9 Drugs Used to Affect Renal Function Renal Pharmacology eNotes Clinical Pharmacology Cases 7, 8, & 55 (Learning Triggers) Textbooks Brunton LL, Chabner BA , Knollmann BC (Eds.). Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill, 2011 Katzung, Masters, Trevor. Basic and Clinical Pharmacology, 12th ed. New York: McGraw-Hill, 2012 Mulroney SE. and Myers AK. Netter's Essential Physiology. Philadelphia: Saunders, 2009 Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition.

Philadelphia: Sanders, 2014 Toy E C. et.al. Case Files-Pharmacology Lange 3rd ed. New York: McGraw-Hill 2014.

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