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  • 1. 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
  • 2. 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
  • 3.
    • 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
  • 4. 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
  • 5. 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
  • 6. General Structure of Thiazide Diuretics
  • 7. 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
  • 8. 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.
  • 9. 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.
  • 10. 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
  • 11. 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
  • 12. From Birkenhäger, WH: Diuretics and blood pressure reduction: physiological aspects. J. Hyperten. 1990, 8 (Suppl 2) S3-S7.
  • 13. From Birkenhäger, WH: Diuretics and blood pressure reduction: physiological aspects. J. Hyperten. 1990, 8 (Suppl 2) S3-S7.
  • 14. 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
  • 15. 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
  • 16. ADVERSE EFFECTS OF THIAZIDES-2
    • HYPERLIPIDEMIA ; mechanism unknown but cholesterol increases usually trivial (1% increase)
    • IMPOTENCE
    • HYPONATREMIA due to thirst, sodium lo s loss, 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
    • HYPERCALCEMIA
    ADVERSE EFFECTS OF THIAZIDES-3
  • 18. LOOP DIURETICS
    • 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
  • 19. From Martinez-Maldonado, M, and Cordova, HR: Cellular and molecular aspects of the renal effects of diuretic agents. Kidney Int. 1990, 38:632-641.
  • 20. LOOP DIURETICS
    • Additional non-tubular effects
    • 1. Renal Vasodilation and redistribution of blood flow
    • 2. Increase in renin release
    • 3. Increase in venous capacitance
    • These effects mediated by release of prostaglandins from the kidney.
  • 21. From Brater, DC. Pharmacodynamic considerations in the use of diuretics. Ann. Rev. Pharmacol. Toxicol 1983, 23:45-62.
  • 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. 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.
  • 27. From Brater, DC. Pharmacology of Diuretics. Am. J. Med. Sci. 2000, 319:38-50. FE Na (%)
  • 28. 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.
  • 29. Diuretic Resistance
    • Compensatory Mechanisms ( RAAS, SNS )
    • 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)
    • Interference by other drugs ( e.g. NSAID’s )
    • Tubular adaptation ( chronic Loop diuretic use)
    • Can Use Combination of Diuretics
    • to Induce a Synergistic Effect
  • 30. 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