1. Diuretics

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. Principles important for understanding effects of diuretics Interference with Na + reabsorption at one nephron site interferes with other renal functions linked to it It also leads to increased Na + reabsorption at other sites Increased flow and Na + delivery to distal nephron stimulates K + (and H + ) secretion

4. 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 Diuretic actions at different nephron sites can produce synergism All, except spironolactone, act from the lumenal side of the tubular cellular membrane Principles important for understanding effects of diuretics

6. THIAZIDE DIURETICS

7. NN SO 2 NH 2 NH 2 SO 2 NH 2 Cl SO 2 NH 2 Cl SO 2 NH 2 NC N SO 2 Prontosil Sulfanilamide p-chlorobenzene sulfonamide 1,3 disulfonamide 6 cholrobenzene Cholrothiazide

8. THIAZIDE DIURETICS Secreted into the tubular lumen by the organic acid transport mechanisms in the proximal tubule Act on the distal tubule to inhibit sodium and chloride transport and result in a modest diuresis Increase renal excretion of potassium, magnesium Reduce calcium and urate excretion Not effective at low glomerular filtration rates Impair maximal diluting but not maximal concentrating ability

9. General Structure of Thiazide Diuretics

10. Thiazides - Pharmacokinetics Rapid GI absorption Distribution in extracellular space Elimination unchanged in kidney Variable elimination kinetics and therefore variable half-lives of elimination ranging from hours to days.

11. Actions of diuretics

12. CLINICAL USES Of THIAZIDES-1 1) HYPERTENSION Thiazides reduce blood pressure and associated risk of CVA and MI in hypertension they should be considered first-line therapy in hypertension (effective, safe and cheap) Mechanism of action in hypertension is uncertain – involves vasodilation that is not a direct effect but a consequence of the diuretic/natriuretic effect

13. CLINICAL USES OF THIAZIDES-2 2) EDEMA (cardiac, liver renal) 3) IDIOPATHIC HYPERCALCIURIA condition characterized by recurrent stone formation in the kidneys due to excess calcium excretion thiazide diuretics used to prevent calcium loss and protect the kidneys 4) DIABETES INSIPIDUS

14. ADVERSE EFFECTS OF THIAZIDES-1 Initially, they were used at high doses which caused a high incidence of adverse effects. Lower doses now used cause fewer adverse effects. Among them are: HYPOKALEMIA DEHYDRATION (particularly in the elderly) leading to POSTURAL HYPOTENSION HYPERGLYCEMIA possibly because of impaired insulin release secondary to hypokalemia HYPERURICEMIA because thiazides compete with urate for tubular secretion HYPERCALCEMIA

16. ADVERSE EFFECTS OF THIAZIDES-2 HYPERLIPIDEMIA; mechanism unknown but cholesterol increases usually trivial (1% increase) IMPOTENCE HYPONATREMIA due to thirst, sodium los, inappropriate ADH secretion (can cause confusion in the elderly), usually after prolonged use

17. Less common problems HYPERSENSITIVITY - may manifest as interstitial nephritis, pancreatitis, rashes, blood dyscrasias (all very rare) METABOLIC ALKALOSIS due to increased sodium load at the distal convoluted tubule which stimulates the sodium/hydrogen exchanger to reabsorb sodium and excrete hydrogen ADVERSE EFFECTS OF THIAZIDES-3

18. LOOP DIURETICS

19. Secreted in proximal tubule by acid mechanisms Act on the ascending loop of Henle to inhibit sodium and chloride transport Cause a greater natriuresis than thiazides Effective at low glomerular filtration rates (as occur in chronic renal failure), where thiazides are ineffective Increase potassium, calcium and magnesium excretion Decrease urate excretion Impair maximal concentrating and diluting capacity

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. LOOP DIURETICS Additional non-tubular effects 1. Renal Vasodilation and redistribution of blood flow 2. Decrease in renin release 3. Increase in venous capacitance These effects mediated by release of prostaglandins from the kidney.

22. Loop Diuretics - Pharmacokinetics Rapid GI absorption. Also given i.m. and i.v. Extensively protein bound in plasma Short half-lives in general Elimination: unchanged in kidney or by conjugation in the liver and secretion in bile.

23. From Brater, DC. Pharmacodynamic considerations in the use of diuretics. Ann. Rev. Pharmacol. Toxicol 1983, 23:45-62.

24. CLINICAL USES OF LOOP DIURETICS EDEMA due to CHF, nephrotic syndrome or cirrhosis Acute heart failure with PULMONARY EDEMA HYPERCALCEMIA not in widespread use for the treatment of hypertension (except in a few special cases e.g. hypertension in renal disease)

25. Hypokalemia, metabolic alkalosis, hypercholesterolemia, hyperuricemia, hyperglycemia, hyponatremia Dehydration and postural hypotension Hypocalcemia (in contrast to thiazides) Hypersensitivity OTOTOXICITY (especially if given by rapid IV bolus) Adverse Effects of Loop Diuretics similar to thiazides in many respects

26. Actions of loop diuretics

27. Edema: Therapeutic Considerations Therapy is palliative (except with pulmonary edema). Need a mild sustained response. Specific consideration to potassium homeostasis, i.e. supplement with K-salt or use K-sparing diuretic. Therefore, in most cases start with a thiazide. If resistant, move to Loop diuretic.

29. Conditions treated with Diuretics Edema Hypertension Nephrogenic Diabetes Insipidus Syndrome of Inappropriate ADH Secretion (SIADH) To increase or decrease Ca ++, K + or H + ion excretion.

30. Diuretic Resistance 1.Compensatory Mechanisms ( RAAS, SNS ) 2.Failure to reach tubular site of action a - Decreased G.I. absorption b - Decreased secretion into tubular lumen (e.g. uremia, decreased kidney perfusion) c - Decreased availability in tubular lumen (e.g. nephrotic syndrome) 3.Interference by other drugs ( e.g. NSAID’s ) 4.Tubular adaptation ( chronic Loop diuretic use) Can Use Combination of Diuretics to Induce a Synergistic Effect