Loop Diuretics
Loop of Henle
CA Inhibitors
Proximal tubule
Thiazides
Distal tubule
5%
Antikaliuretics
70%
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
N
N
NH2
Cl
NH2
SO2NH2
Sulfanilamide
SO2NH2
SO2NH2
p-chlorobenzene
sulfonamide
Cl
SO2NH2
SO2NH2
1,3 disulfonamide
6 cholrobenzene
SO2
Cl
N
Cholrothiazide
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
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
KI
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 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.
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
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.
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. NSAID’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
Renal Insufficiency
0 < ClCr < 50
80
160
Renal Insufficiency
ClCr < 20
200
400
120
40
240
80
40-80
80-160
Nephrotic Syndrome
Cirrhosis
Congestive Heart
Failure
Data from Brater, DC. Pharmacology of Diuretics. Am. J. Med. Sci. 2000, 319:38-50.