Diuretics

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Diuretics

  1. 1. diuretics
  2. 2. From Knauf & Mutschler Klin. Wochenschr. 1991 69:239-250 70% 20% 5% 4.5% 0.5% Volume 1.5 L/day Urine Na 100 mEq/L Na Excretion 155 mEq/day 100% GFR 180 L/day Plasma Na 145 mEq/L Filtered Load 26,100 mEq/day CA Inhibitors Proximal tubule Loop Diuretics Loop of Henle Thiazides Distal tubule Antikaliuretics Collecting duct Thick Ascending Limb
  3. 3. Principles important for understanding effects of diuretics <ul><li>Interference with Na + reabsorption at one nephron site interferes with other renal functions linked to it </li></ul><ul><li>It also leads to increased Na + reabsorption at other sites </li></ul><ul><li>Increased flow and Na + delivery to distal nephron stimulates K + (and H + ) secretion </li></ul>
  4. 4. <ul><li>Diuretics act only if Na + reaches their site of action. The magnitude of the diuretic effect depends on the amount of Na + reaching that site </li></ul><ul><li>Diuretic actions at different nephron sites can produce synergism </li></ul><ul><li>All, except spironolactone, act from the lumenal side of the tubular cellular membrane </li></ul>Principles important for understanding effects of diuretics
  5. 5. N N SO 2 NH 2 SO 2 NH 2 NH 2 NH 2 NH 2 SO 2 NH 2 Cl Cl SO 2 NH 2 SO 2 NH 2 Cl SO 2 NH 2 N C N SO 2 Prontosil Sulfanilamide p-chlorobenzene sulfonamide 1,3 disulfonamide 6 cholrobenzene Cholrothiazide
  6. 6. THIAZIDE DIURETICS <ul><li>Secreted into the tubular lumen by the organic acid transport mechanisms in the proximal tubule </li></ul><ul><li>Act on the distal tubule to inhibit sodium and chloride transport and result in a modest diuresis </li></ul><ul><li>Increase renal excretion of potassium, magnesium </li></ul><ul><li>Reduce calcium and urate excretion </li></ul><ul><li>Not effective at low glomerular filtration rates </li></ul><ul><li>Impair maximal diluting but not maximal concentrating ability </li></ul>
  7. 7. General Structure of Thiazide Diuretics
  8. 8. Inhibition of high-affinity 3 H-metolazone binding by ions Data from Beaumont et. Al.: Thiazide diuretic drug receptors in rat kidney: identification with 3H]metolazone. Proc. Natl. Acad. Sci. USA 1988, 85:2311-2314. 112±5 Trisodium citrate 118±12 Dipotassium sulfate 152±22 Disodium sulfate 95±5 K acetate 82±5 Na acetate 12±2 KI 25±1 NaI 24±2 NaBr 36±7 Choline chloride 44±2 KCl 20±0.5 NaCl 4±1 LiCl 143±9 NaF % Control Ion
  9. 9. Correlation of the daily clinical doses of thiazide diuretics with their affinity for high-affinity 3 H-metolazone binding sites in rat kidney. Correlation coefficient r=0.7513. From Beaumont et al.: Thiazide diuretic drug receptors in rat kidney: identification with [ 3 H]metolazone. Proc. Natl. Acad. Sci. USA 1988, 85:2311-2314.
  10. 10. Thiazides - Pharmacokinetics <ul><li>Rapid GI absorption </li></ul><ul><li>Distribution in extracellular space </li></ul><ul><li>Elimination unchanged in kidney </li></ul><ul><li>Variable elimination kinetics and therefore variable half-lives of elimination ranging from hours to days. </li></ul>
  11. 11. CLINICAL USES Of THIAZIDES-1 <ul><li>1) HYPERTENSION </li></ul><ul><li>Thiazides reduce blood pressure and associated risk of CVA and MI in hypertension </li></ul><ul><li>they should be considered first-line therapy in hypertension (effective, safe and cheap) </li></ul><ul><li>Mechanism of action in hypertension is uncertain – involves vasodilation that is not a direct effect but a consequence of the diuretic/natriuretic effect </li></ul>
  12. 12. From Birkenhäger, WH: Diuretics and blood pressure reduction: physiological aspects. J. Hyperten. 1990, 8 (Suppl 2) S3-S7. Schematic drawing of temporal changes in mean arterial pressure (MAP), total peripheral vascular resistance (TPR), cardiac output (CO) and plasma volume (PV) during thiazide treatment of a hypertensive subject
  13. 13. From Birkenhäger, WH: Diuretics and blood pressure reduction: physiological aspects. J. Hyperten. 1990, 8 (Suppl 2) S3-S7.
  14. 14. From Birkenhäger, WH: Diuretics and blood pressure reduction: physiological aspects. J. Hyperten. 1990, 8 (Suppl 2) S3-S7.
  15. 15. CLINICAL USES OF THIAZIDES-2 <ul><li>2) EDEMA (cardiac, liver renal) </li></ul><ul><li>3) IDIOPATHIC HYPERCALCIURIA </li></ul><ul><li>condition characterized by recurrent stone formation in the kidneys due to excess calcium excretion </li></ul><ul><li>thiazide diuretics used to prevent calcium loss and protect the kidneys </li></ul><ul><li>4) DIABETES INSIPIDUS </li></ul>
  16. 16. ADVERSE EFFECTS OF THIAZIDES-1 <ul><li>Initially, they were used at high doses which caused a high </li></ul><ul><li>incidence of adverse effects. Lower doses now used cause </li></ul><ul><li>fewer adverse effects. Among them are: </li></ul><ul><li>HYPOKALEMIA </li></ul><ul><li>DEHYDRATION (particularly in the elderly) leading to POSTURAL HYPOTENSION </li></ul><ul><li>HYPERGLYCEMIA possibly because of impaired insulin release secondary to hypokalemia </li></ul><ul><li>HYPERURICEMIA because thiazides compete with urate for tubular secretion </li></ul>
  17. 17. ADVERSE EFFECTS OF THIAZIDES-2 <ul><li>HYPERLIPIDEMIA ; mechanism unknown but cholesterol increases usually trivial (1% increase) </li></ul><ul><li>IMPOTENCE </li></ul><ul><li>HYPONATREMIA due to thirst, sodium lo s loss, inappropriate ADH secretion (can cause confusion in the elderly), usually after prolonged use </li></ul>
  18. 18. <ul><li>Less common problems </li></ul><ul><li>HYPERSENSITIVITY - may manifest as interstitial nephritis, pancreatitis, rashes, blood dyscrasias (all very rare) </li></ul><ul><li>METABOLIC ALKALOSIS due to increased sodium load at the distal convoluted tubule which stimulates the sodium/hydrogen exchanger to reabsorb sodium and excrete hydrogen </li></ul><ul><li>HYPERCALCEMIA </li></ul>ADVERSE EFFECTS OF THIAZIDES-3
  19. 19. LOOP DIURETICS <ul><li>Secreted in proximal tubule by acid mechanisms </li></ul><ul><li>Act on the ascending loop of Henle to inhibit sodium and chloride transport </li></ul><ul><li>Cause a greater natriuresis than thiazides </li></ul><ul><li>Effective at low glomerular filtration rates (as occur in chronic renal failure), where thiazides are ineffective </li></ul><ul><li>Increase potassium, calcium and magnesium excretion </li></ul><ul><li>Decrease urate excretion </li></ul><ul><li>Impair maximal concentrating and diluting capacity </li></ul>
  20. 20. From Martinez-Maldonado, M, and Cordova, HR: Cellular and molecular aspects of the renal effects of diuretic agents. Kidney Int. 1990, 38:632-641.
  21. 21. LOOP DIURETICS <ul><li>Additional non-tubular effects </li></ul><ul><li>1. Renal Vasodilation and redistribution of blood flow </li></ul><ul><li>2. Increase in renin release </li></ul><ul><li>3. Increase in venous capacitance </li></ul><ul><li>These effects mediated by release of prostaglandins from the kidney. </li></ul>
  22. 22. From Brater, DC. Pharmacodynamic considerations in the use of diuretics. Ann. Rev. Pharmacol. Toxicol 1983, 23:45-62.
  23. 23. Loop Diuretics - Pharmacokinetics <ul><li>Rapid GI absorption. Also given i.m. and i.v. </li></ul><ul><li>Extensively protein bound in plasma </li></ul><ul><li>Short half-lives in general </li></ul><ul><li>Elimination: unchanged in kidney or by conjugation in the liver and secretion in bile. </li></ul>
  24. 24. From Brater, DC. Pharmacodynamic considerations in the use of diuretics. Ann. Rev. Pharmacol. Toxicol 1983, 23:45-62.
  25. 25. CLINICAL USES OF LOOP DIURETICS <ul><li>EDEMA due to CHF, nephrotic syndrome or cirrhosis </li></ul><ul><li>Acute heart failure with PULMONARY EDEMA </li></ul><ul><li>HYPERCALCEMIA </li></ul><ul><li>not in widespread use for the treatment of hypertension (except in a few special cases e.g. hypertension in renal disease) </li></ul>
  26. 26. <ul><li>Hypokalemia, metabolic alkalosis, hypercholesterolemia, hyperuricemia, hyperglycemia, hyponatremia </li></ul><ul><li>Dehydration and postural hypotension </li></ul><ul><li>Hypocalcemia (in contrast to thiazides) </li></ul><ul><li>Hypersensitivity </li></ul><ul><li>OTOTOXICITY (especially if given by rapid IV bolus) </li></ul>Adverse Effects of Loop Diuretics similar to thiazides in many respects
  27. 27. Edema: Therapeutic Considerations <ul><li>Therapy is palliative (except with pulmonary edema). </li></ul><ul><li>Need a mild sustained response. </li></ul><ul><li>Specific consideration to potassium homeostasis, i.e. supplement with K-salt or use K-sparing diuretic. </li></ul><ul><li>Therefore, in most cases start with a thiazide. </li></ul><ul><li>If resistant, move to Loop diuretic. </li></ul>
  28. 28. From Brater, DC. Pharmacology of Diuretics. Am. J. Med. Sci. 2000, 319:38-50. FE Na (%)
  29. 29. Conditions treated with Diuretics <ul><li>Edema </li></ul><ul><li>Hypertension </li></ul><ul><li>Nephrogenic Diabetes Insipidus </li></ul><ul><li>Syndrome of Inappropriate ADH Secretion (SIADH) </li></ul><ul><li>To increase or decrease Ca ++ , K + or H + ion excretion. </li></ul>
  30. 30. Diuretic Resistance <ul><li>Compensatory Mechanisms ( RAAS, SNS ) </li></ul><ul><li>Failure to reach tubular site of action </li></ul><ul><li>a - Decreased G.I. absorption </li></ul><ul><li>b - Decreased secretion into tubular lumen </li></ul><ul><li>(e.g. uremia, decreased kidney perfusion) </li></ul><ul><li>c - Decreased availability in tubular lumen </li></ul><ul><li>(e.g. nephrotic syndrome) </li></ul><ul><li>Interference by other drugs ( e.g. NSAID’s ) </li></ul><ul><li>Tubular adaptation ( chronic Loop diuretic use) </li></ul><ul><li>Can Use Combination of Diuretics </li></ul><ul><li>to Induce a Synergistic Effect </li></ul>
  31. 31. Maximum Doses of Loop Diuretics Data from Brater, DC. Pharmacology of Diuretics. Am. J. Med. Sci. 2000, 319:38-50. Oral intravenous Dose of furosemide (mg) Clinical Condition 160 80 Renal Insufficiency 0 < Cl Cr < 50 400 200 Renal Insufficiency Cl Cr < 20 240 120 Nephrotic Syndrome 80 40 Cirrhosis 80-160 40-80 Congestive Heart Failure

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