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5%
Antikaliuretics Thick Ascending Limb
70%
4.5%
Collecting duct
100%
GFR 180 L/day Plasma Na 145 mEq/L Filtered Load 26,100 mEq/day
20%
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
Prontosil
NH2 NH2
SO2 NH2
NH2
SO2NH2
Sulfanilamide
Cl
p-chlorobenzene sulfonamide
SO2NH2
SO2NH2
Cl SO2NH2
1,3 disulfonamide 6 cholrobenzene
SO2NH2
Cl
Cholrothiazide
SO2 N N C
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
LiCl
NaCl KCl Choline chloride
41
200.5 442 367
NaBr
NaI KI Na acetate K acetate Disodium sulfate Dipotassium sulfate Trisodium citrate
242
251 122 825 955 15222 11812 1125
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.
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 Birkenhger, WH: Diuretics and blood pressure reduction: physiological aspects. J. Hyperten. 1990, 8 (Suppl 2) S3-S7.
From Birkenhger, WH: Diuretics and blood pressure reduction: physiological aspects. J. Hyperten. 1990, 8 (Suppl 2) S3-S7.
From Birkenhger, WH: Diuretics and blood pressure reduction: physiological aspects. J. Hyperten. 1990, 8 (Suppl 2) S3-S7.
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
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.
From Brater, DC. Pharmacodynamic considerations in the use of diuretics. Ann. Rev. Pharmacol. Toxicol 1983, 23:45-62.
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)
FE Na (%)
From Brater, DC. Pharmacology of Diuretics. Am. J. Med. Sci. 2000, 319:38-50.
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. NSAIDs)
Oral
160
80
200
120 40
400
240 80
40-80
80-160
Data from Brater, DC. Pharmacology of Diuretics. Am. J. Med. Sci. 2000, 319:38-50.