diuretics by Pharma Student

Loop Diuretics Loop of Henle

CA Inhibitors Proximal tubule

Thiazides Distal tubule

5% 70%

Antikaliuretics

Thick Ascending Limb

4.5% Collecting duct

20%

100% GFR 180 L/day Plasma Na 145 mEq/L Filtered Load 26,100 mEq/day

0.5% Volume 1.5 L/day Urine Na 100 mEq/L Na Excretion 155 mEq/day From Knauf & Mutschler Klin. Wochenschr. 1991 69:239-250

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

Principles important for understanding effects of diuretics • 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

NH2

Prontosil

SO2 NH2

NH2 Cl

NH2 SO2NH2

Sulfanilamide

SO2NH2 SO2NH2

p-chlorobenzene sulfonamide

SO2NH2

1,3 disulfonamide 6 cholrobenzene

SO2

Cl Cholrothiazide

N N

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

General Structure of Thiazide Diuretics

Inhibition of high-affinity 3Hmetolazone binding by ions Ion

% Control

NaF

143±9

LiCl

4±1

NaCl

20±0.5

KCl

44±2

Choline chloride

36±7

NaBr

24±2

NaI

25±1

12±2

Na acetate

82±5

K acetate

95±5

Disodium sulfate

152±22

Dipotassium sulfate

118±12

Trisodium citrate

112±5

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.

Correlation of the daily clinical doses of thiazide diuretics with their affinity for high-affinity 3H-metolazone binding sites in rat kidney. Correlation coefficient r=0.7513. From Beaumont et al.: Thiazide diuretic drug receptors in rat kidney: identification with [3H]metolazone. Proc. Natl. Acad. Sci. USA 1988, 85:2311-2314.

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.

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

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 From Birkenh채ger, WH: Diuretics and blood pressure reduction: physiological aspects. J. Hyperten. 1990, 8 (Suppl 2) S3-S7.

From Birkenh채ger, WH: Diuretics and blood pressure reduction: physiological aspects. J. Hyperten. 1990, 8 (Suppl 2) S3-S7.

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

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

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

ADVERSE EFFECTS OF THIAZIDES-3 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

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

From Martinez-Maldonado, M, and Cordova, HR: Cellular and molecular aspects of the renal effects of diuretic agents. Kidney Int. 1990, 38:632-641.

LOOP DIURETICS â&#x20AC;˘ 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.

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

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.

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

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)

Adverse Effects of Loop Diuretics similar to thiazides in many respects

• 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)

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.

FE Na (%)

From Brater, DC. Pharmacology of Diuretics. Am. J. Med. Sci. 2000, 319:38-50.

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.

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. NSAIDâ&#x20AC;&#x2122;s) 4. Tubular adaptation (chronic Loop diuretic use) Can Use Combination of Diuretics to Induce a Synergistic Effect

Maximum Doses of Loop Diuretics Clinical Condition

Dose of furosemide (mg) intravenous

Oral

160

200

400

Cirrhosis

120 40

240 80

Congestive Heart Failure

40-80

80-160

Renal Insufficiency 0 < ClCr < 50 Renal Insufficiency ClCr < 20 Nephrotic Syndrome

Data from Brater, DC. Pharmacology of Diuretics. Am. J. Med. Sci. 2000, 319:38-50.