1 Diuretics Xiaoping Du, MD, PhD., Department of Pharmacology Phone: (312) 355 0237; Email: firstname.lastname@example.orgI. Overview 1. Definition: Diuretic agents are drugs that increase renal excretion of water and solutes (mainly sodiumsalt). 2. Purpose of diuretic therapy: Major purposes of diuretic therapy are to decrease fluid volume of the body, and to adjust thewater and electrolyte balance. Diuretics are often used in the management of pathological conditions such as edema (e.g. incongestive heart failure and certain renal diseases) and hypertension. 3. Commonly seen side effects: The most common side effect associated with most diuretics is the distortion of water andelectrolyte balance (such as hypokalemia, hyperkalemia, metabolic alkalosis, acidosis, andhyponatremia). Specific side effects of each diuretic are mainly determined by its mechanism ofaction and conditions of the patient. 4. Mechanisms of action: Most diuretics exert their effects by inhibiting tubular sodium and water reabsorption byepithelial cells lining the renal tubule system. Certain diuretics (such as carbonic anhydraseinhibitors, loop diuretics, thiazide-like diuretics and potassium-sparing diuretics) suppress sodiumand water reabsorption by inhibiting the function of specific proteins that are responsible for (orparticipate in) the transportation of electrolytes across the epithelial membrane; osmotic diureticsinhibit water and sodium reabsorption by increasing intratubular osmotic pressure. Different typesof diuretics may inhibit different transporters in different segments of the tubular system. 5. Different types of diureticsType Example Site of action MechanismCarbonic anhydrase (CA) acetazolamide Proximal tubule inhibition of CAinhibitorsOsmotic Mannitol Loop of Henle (DTL) Osmotic action Proximal tubuleLoop diuretics furosemide Loop of Henle (TAL) inhibition of Na+-K+- 2Cl- symportThiazides hydrochlorothiazide Distal convoluted inhibition of Na+-Cl- tubule symportPotassium-sparing diuretics (1) Na+ channel triamterene, Cortical collecting tubule inhibition of Na+ inhibitors amiloride channel (2) aldosterone spironolactone Cortical collecting tubule inhibition of
2 antagonists aldosterone receptorII. Renal tubule transport mechanisms 1. Basic mechanisms for transmembrane transport of solutes A Active transport a. Primary active transport: Na+-K+ ATPase (sodium pump) in the basolateral membraneof epithelial cells is the major driving force for the transport of solutes in kidney. b. Secondary active transport: Secondary active transport utilizes energy available fromthe transmembrane Na+ gradient established by sodium pump to transport other solutes againsttheir electrochemical gradient. Secondary active transport includes symport (co-transport) whichtransports sodium and other solutes in the same direction, and antiport (counter-transport) whichexchanges movement of sodium for the counter movement of other solutes. B Passive transport a. Convection. b. Simple diffusion. c. Channel-mediated diffusion. d. Carrier-mediated diffusion. 2. Characteristics of different segments of the renal tubule. A. Proximal tubule Proximal tubule reabsorbs 40% of filtered salt and 60% filtered water. Proximal tubule is the major site for sodium carbonate reabsorption (85%), which requiressodium-proton exchanger (antiport) and carbonic anhydrase. Inhibitors of carbonic anhydrase exertdiuretic effects by inhibition of sodium carbonate transport. The proximal tubule is the major site for the secretion of the organic acid and bases to thetubular lumen. This is the mechanism by which most diuretics reach their sites of action. B Loop of Henle Descending thin limb (DTL) of loop of Henle is highly permeable to water but non-permeableto sodium. Water is extracted from DTL by osmotic pressure from the hypertonic medullaryinterstitium. Thick ascending limb (TAL) of loop of Henle actively reabsorbs NaCl and KCl via the Na+-K+-2Cl- symport (35% of salt absorption). TAL is not permeable to water and thus is a urine-dilutingsegment. Active sodium reabsorption at TAL contributes to the hypertonicity in medullaryinterstitium. Loop diuretics inhibit the Na+-K+--2Cl- symport. Na+-K+-2Cl- symport and sodium pump together generate a positive lumen potential thatdrives the reabsorption of Ca++ and Mg++. C. Distal convoluted tubule
3 Distal convoluted tubule absorbs about 10% of NaCl via Na+-Cl- symport, which is a differentprotein from the Na+-K+-2Cl- symport. Thiazides inhibit Na+-Cl- symport. D. Collecting tubule The collecting tubule is the final site for NaCl reabsorption (2-5% NaCl). Sodium reabsorption in thecollecting tubule is regulated byaldosterone. Aldosterone antagonistsexert diuretic effect by inhibitingaldosterone receptor. Sodium reabsorption in thecollecting tubule is mediated by a sodiumchannel, which can be inhibited byamiloride and triamterene. The collecting tubule is the majorsite for K+ secretion. K+ secretion isdriven by a negative lumen potentialestablished by Na+ reabsorption. Drugsthat inhibit Na+ reabsorption in thecollecting tubule thus also inhibit K+secretion. These drugs are called K+-sparing diuretics. Diuretics that act on Tub ule Transp o r t syst emupstream segments of the tubular systemincrease Na+ concentration in the tubularfluid, resulting in increased Na+ absorption in the collecting tubule. These diuretics may thus causeincreased K+ secretion, and hypokalemia. Water permeability in the collecting tubule is regulated by anti-diuretic hormone (ADH).III. Pharmacology of diuretics 1. Carbonic anhydrase (CA) inhibitorsA. Chemistry Sulfonamide derivatives (See the table below). Sulfonamide group (-SO2NH2) is essential for activity.
4 Inhibitors of Carbonic AnhydraseAcetazolamideDichlorphenamideMethazolamideB. Mechanism of action This class of diuretics inhibits carbonicanhydrase in the membrane and cytoplasm of theepithelial cells. The primary site of action is inproximal tubules. Na + In the proximal tubule, Na+-H+ antiport in N a+ ATP K+the apical membrane of epithelial cells transports H CO + H + 3 - H + + HC - O3H + into tubular lumen in exchange for Na+ Na +movement into the cytoplasm. Na + in the CA C Acytoplasm is pumped out to the interstitium by CA In h ib i t o rssodium pump. H+ in the lumen reacts with H O + CO 2 2 H O + CO 2 2HCO3- to form H2CO3. H2CO3 is dehydrated toCO2 and H2O. This reaction is catalyzed bycarbonic anhydrase in the luminal membrane.Both CO2 and H2O can permeate into cells, and Pr o x i al co nvolu t ed t ub u le m Int erst it iumrehydrate to form H2CO3. The rehydration is Lumen epit heli l cell acatalyzed by the cytoplasmic carbonic anhydrase.H2CO3 dissociates to form H+ which is secretedinto lumen, and HCO3- which is transported intointerstitium. Inhibition of anhydrase thus inhibits HCO3- reabsorption. Accumulation of HCO3- inthe tubular lumen subsequently inhibits Na+-H+ exchange and Na+ reabsorption. The increase in sodium concentration in the tubular fluid may be compensated partially byincreased NaCl reabsorption in later segments of the tubule. Thus, the diuretic effect of the carbonicanhydrase inhibitors is mild.C. Clinical indications (i) Glaucoma (ii) Treatment of cystinuria, and enhance excretion of uric acid and other organic acids. (iii) Metabolic alkalosis
5 (iv) Acute mountain sicknessD. Major side effects and toxicity (i) Electrolyte imbalance: Hyperchloremic metabolic acidosis is the most common sideeffect. (ii) Renal stones (iii) Central nerve system effects: drowsiness and paresthesias. (iv) Allergic reactions to sulfonamides such as rash, fever, and interstitial nephritis. 2. Osmotic diureticsA. Chemistry Osmotic DiureticsGlycerinIsosorbideMannitolUrea R, renal excretion; M metabolism; ID, insufficient data.
6B. Mechanism of action Osmotic diuretics are substances to which the tubule epithelial cell membrane has limitedpermeability. When administered (often in a large dosage), osmotic diuretics significantly increasethe osmolarity of plasma and tubular fluid. The osmotic force thus generated prevents waterreabsorption, and also extracts water from the intracellular compartment, expands extracellular fluidvolume and increases renal blood flow resulting in reduced medulla tonicity. The primary sites ofaction for osmotic diuretics are the Loop of Henle and the proximal tubule where the membrane ismost permeable to water.C. Clinical indications (i) To increase urine volume in some patients with acute renal failure caused by ischemia,nephrotoxins, hemoglobinuria and myoglobinuria (test for responsiveness). (ii) Reduction of intracranial pressure before and after neurosurgery and in neurologicalconditions. (iii) Reduction of intraocular pressure before ophthalmologic procedures and during acuteattack of glaucoma.D. Major side effect and toxicity (i) Water and electrolyte imbalance: excessive loss of more water relative to sodium maycause dehydration and hypernatremia. (ii) Expansion of extracellular fluid volume may result in hyponatremia causing centralnerve system symptoms such as nausea, headache, and vomiting. In patients with congestive heartfailure, expansion of extracellular volume may produce pulmonary edema. 3. Loop diuretics A. Chemistry Two major classes of loop diuretics: 1) sulfonamide derivatives such as furosemide,bumetanide and torsemide; and 2) non-sulfonamide loop diuretic such as ethacrynic acid.
7 B. Mechanism of action Loop diuretics inhibit reabsorption of NaCl and KCl by inhibiting the Na+-K+-2Cl- symport inthe luminal membrane of the thick ascending limb (TAL) of loop of Henle. As TAL is responsible forthe reabsorption of 35% of filtered sodium, and there are no significant downstream compensatoryreabsorption mechanisms, loop diuretics are highly efficacious and are thus called high ceilingdiuretics. As the Na+-K+-2Cl- symport and sodium pump together generate a positive lumen potentialthat drives the reabsorption of Ca++ and Mg++, inhibitors of the Na+-K+-2Cl- symport also inhibitreabsorption of Ca++ and Mg++. By unknown mechanisms (possibly prostaglandin-mediated), loop diuretics also have directeffects on vasculature including increase in renal blood flow, and increase in systemic venouscapacitance.
8 C. Major Clinical indications (i) Acute pulmonary edema (ii) Chronic congestive heart failure when diminution of extracellular fluid volume is desirable to Na+ reduce venous and pulmonary edema. Na+ ATP K+ (iii) Treatment of hypertension when patients K+ 2Cl - do not response satisfactorily to thiazide diuretics and anti-hypertensive drugs. K+ (iv) HypercalcemiaL o o p d iu r e t ics N a+ (v) Treatment of hyperkalemia in combination with isotonic NaCl administration. K+ C- l (vi) Used in acute renal failure to increase the C- l urine flow and K+ secretion. + (vii) Treatment of toxic ingestions of bromide, - Ca 2 + Mg2 + fluoride and iodide (with simultaneous saline Lum en T h i k asce n d in g lmb c i Int erst i i m tu administration). epith elal cell i D. Major side effects and toxicity (i) Hypokalemic metabolic alkalosis (ii) Ototoxicity (iii) Hyperuricemia (iv) Hypomagnesemia (v) Allergic reactions 4. Thiazides A. Chemistry Thiazides are also called benzothiadiazides. Thiazides are sulfonamide derivatives. B. Mechanism of action Thiazides inhibit a Na+-Cl- symport in the luminal membrane of the epithelial cells in thedistal convoluted tubule. Thus, Thiazides inhibit NaCl reabsorption in the distal convoluted tubule,and may have a small effect on the NaCl reabsorption in the proximal tubule. Thiazides enhance Ca++ reabsorption in the distal convoluted tubule by inhibiting Na+ entryand thus enhancing the activity of Na+-Ca++ exchanger in the basolateral membrane of epithelialcells. C. Major clinical indications (i) Hypertension. (ii) Edema associated with congestive heart failure, hepatic cirrhosis and renal diseases. (iii) Nephrolithiasis due to hypercalciuria (iv) Nephrogenic diabetes insipidus. D. Major side effects and toxicity (i) Water and electrolyte imbalance is the major side effect.
9 Hypokalemic metabolic alkalosis, and hyperuricemia. Also may cause extracellular volumedepletion, hypotension, hypochloremia, and hypomagnesemia. These effects are similar to thatcaused by loop diuretics. Hypercalcemia. Hyponatremia is more common with thiazides than with loop diuretics. (ii) Thiazides may impair glucose tolerance and hyperglycemia. Hyperglycemia can bereduced when K+ is administered together with thiazides, suggesting that hyperglycemia may berelated to hypokelemia. (iii) Thiazides may cause hyperlipidemia. Plasma LDL, cholesterol and triglycerides areincreased. (iv) Allergic reactions to sulfonamides (v) CNS symptoms and impotence can be seen but not common.
10 DrugBendroflumethiazideChlorothiazideHydrochlorothiazideChlothalidoneIndapamideMetolazoneQuinethazone R, renal ID, insufficient data
11 Lum en Coll ct i g t ubu l e n e Int erst i i m tu N a + Ch a nn e l Pri ncip a l cell in h ib it o rs Na+ Na+ Na+ N a+ A TP A TP Cl - K+ K+ K+ K+T h ia z id e s - AR + Na + Na + A DH- R Ca2 + C a2 + H 2O Cl - - S p ironola c tone + C- l Int ercalat ed cell D i st al co nv o l t e d t u b u l u e Lum en Int erst i i m tu H C O3 - epith elal cell i ATP Cl - H+ Cl -5. Potassium-sparing diuretics (1) Na+ channel inhibitors A. Chemistry Amiloride and triamterene are the only two drugs in this class. Sodium Channel InhibitorsAmiloride Triamterene B. Mechanism of action Amiloride and triamterene inhibit the sodium channel in the luminal membrane of thecollecting tubule and collecting duct. This sodium channel is critical for Na+ entry into cells down
12the electrochemical gradient created by sodium pump in the basolateral membrane, which pumpsNa+ into interstitium. This selective transepithelial transport of Na+ establishes a luminal negativetransepithelial potential which in turn drives secretion of K+ into the tubule fluid. The luminalnegative potential also facilitates H+ secretion via the proton pump in the intercalated epithelial cellsin collecting tubule and collecting duct. Inhibition of the sodium channel thus not only inhibits Na+reabsorption but also inhibits secretion of K+ and H+, resulting in conservation of K+ and H+. C. Major clinical indications (i) Na+ channel inhibitors are mainly used in combination with other classes of diureticssuch as loop diuretics and thiazides in order to enhance Na+ excretion and to counteract K+ wastinginduced by these diuretics. (ii) Pseudo-hyperaldosteronism (Liddles syndrome). (iii) Amiloride is used to treat Lithium-induced nephrogenic diabetes insipidus by blockingLi+ transport into tubular epithelial cells. (iv) Amiloride also inhibits Na+ channel in airway epithelial cells, and is used to improvemucociliary clearance in patients with cystic fibrosis. D. Major side effects and toxicity (i) The major side effect is hyperkalemia. (ii) CNS symptoms such as nausea, vomiting, headache. (iii) Triamterene may reduce glucose tolerance. (iv) Triamterene may induce interstitial nephritis and renal stone. (2) Aldosterone antagonists A. Chemistry Spironolactone is the only available aldosterone antagonist in US. An metabolite ofspironolactone, canrenone, is also active and has a half-life of about 16 hours. B. Mechanism of action
13 Aldosterone, by binding to its receptor in the cytoplasm of epithelial cells in collecting tubuleand duct, increases expression and function of Na+ channel and sodium pump, and thus enhancessodium reabsorption (see " Na+ channel inhibitors" above). Spironolactone competitively inhibits thebinding of aldosterone to its receptor and abolishes its biological effects. C. Major clinical indications (i) Used in combination with loop diuretics and thiazides in treatment of edema andhypertension. Spironolactone enhances Na+ excretion and reduces K+ wasting. (ii) Treatment of primary hyperaldosteronism (such as adrenal adenomas). (iii) Treatment of edema associated with secondary hyperaldosteronism (such as cardiacfailure, hepatic cirrhosis and nephrotic syndrome). Spironolactone is the diuretic of choice inpatients with hepatic cirrhosis. D. Major side effects and toxicity (i) Hyperkalemia (ii) Metabolic acidosis in cirrhotic patients (iii) Due to its steroid structure, Spironolactone may cause gynecomastia, impotence, andhirsutism. (iv) CNS symptoms.