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/LNa Excretion 155 mEq/day

100%GFR 180 L/day

Plasma Na 145 mEq/LFiltered Load 26,100 mEq/day

CA InhibitorsProximal tubule

Loop DiureticsLoop of Henle

ThiazidesDistal tubule

Antikaliuretics

Collecting duct

Thick Ascending Limb

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

• 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

N NSO2

NH2

SO2NH2NH2

NH2

NH2

SO2NH2Cl

Cl

SO2NH2

SO2NH2

Cl

SO2NH2

N CN

SO2

Prontosil

Sulfanilamide

p-chlorobenzene sulfonamide

1,3 disulfonamide 6 cholrobenzene

Cholrothiazide

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

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

KI 12±2

Na acetate 82±5

K acetate 95±5

Disodium sulfate 152±22

Dipotassium sulfate 118±12

Trisodium citrate 112±5

Inhibition of high-affinity 3H-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.

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

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

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

From Birkenhäger, 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 highincidence 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

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

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

• Additional non-tubular effects1. Renal Vasodilation and

redistribution of blood flow2. Increase in renin release3. 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)

• 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

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.

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

FE Na (%)

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 Resistance1. Compensatory Mechanisms (RAAS, SNS)2. Failure to reach tubular site of action

a - Decreased G.I. absorptionb - 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

Clinical Condition Dose of furosemide (mg)intravenous Oral

Renal Insufficiency 0 < ClCr < 50 80 160

Renal Insufficiency ClCr < 20 200 400

Nephrotic Syndrome 120 240Cirrhosis 40 80

Congestive Heart Failure 40-80 80-160

Maximum Doses of Loop Diuretics

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