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Transcript of diuretics
diuretics
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 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
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 Resistance
1. 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 120 240
Cirrhosis 40 80Congestive 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.