LOOP DIURETICS

At a glance.
Classification
Mechanism of action
Pharmacokinetics
Uses and indications
Adverse effects
Diuretic braking

Classification of diuretics
MECHANISM OF ACTION

The diuretics are

generally divided into four major classes, which are distinguished
by the site at which they impair sodium reabsorption :

LOOP DIURETICS : act in the thick ascending limb of the

loop of Henle
THIAZIDE TYPE DIURETICS: in the distal tubule and connecting
segment (and perhaps the early cortical collecting tubule)
POTASSIUM SPARING DIURETICS: in the aldosterone-sensitive
principal cells in the cortical collecting tubule
ACETAZOLAMIDE AND MANNITOL: act at least in part in the
proximal tubule

PRIMARY SITES OF DIURETIC ACTION

 To appreciate how diuretics act, it is first necessary to review the

general mechanism by which sodium is reabsorbed. Each of the

sodium-transporting cells contains Na-K-ATPase pumps in the
basolateral membrane.
These pumps perform two major functions: they return reabsorbed
sodium to the systemic circulation; and they maintain the cell sodium
concentration at relatively low levels.
The latter effect is particularly important, since it allows filtered sodium

to enter the cells down a favorable concentration gradient via carriermediated transport.
Each of the major nephron segments has one or more unique sodium

entry mechanisms and the ability to specifically inhibit this step explains
the nephron segment at which the different classes of diuretics act.

Loop of Henle Transport

Collecting tubule transport

Distal Tubular transport

 The site of action within the nephron is a major determinant of

diuretic potency. Most of the filtered sodium is reabsorbed in the

proximal tubule (about 60 to 65 percent) and the loop of Henle
(20 percent).
As a result, it might be expected that a proximally acting diuretic,
such as the carbonic anhydrase inhibitor acetazolamide, could
induce relatively large losses of sodium and water.
However, this does not occur since almost all of the excess fluid
delivered out of the proximal tubule can be reabsorbed more
distally, particularly in the loop of Henle and to a lesser degree
the distal tubule.
Transport in these segments is primarily flow-dependent,
varying directly with the delivery of chloride .

LOOP DIURETICS
Furosemide
Bumetanide
Torsemide
Ethacrynic acid

 When administered at maximum dosage, the loop diuretics, furosemide,

bumetanide, torsemide, and ethacrynic acid, can lead to the excretion of

up to 20 to 25 percent of filtered sodium.
They act in the medullary and cortical aspects of the thick ascending

limb, including the macula densa cells in the early distal tubule. At each of
these sites, sodium entry is primarily mediated by a Na-K-2Cl carrier in
the luminal membrane that is activated when all four sites are occupied .
. The loop diuretics appear to compete for the chloride site on this carrier,

thereby diminishing net reabsorption.

Inhibition of an isoform of this cotransporter in the inner ear is thought to

be responsible for the ototoxicity that is rarely seen with high dose
intravenous loop diuretic therapy.

 Loop diuretics also have important effects on renal

calcium handling.
The reabsorption of calcium in the loop of Henle is
primarily passive, being driven by the electrochemical
gradient created by NaCl transport and occurring through
the paracellular pathway .
As a result, inhibiting the reabsorption of NaCl leads to a
parallel reduction in that ofcalcium, thereby increasing
calcium excretion.
A potential concern is that the calciuric response can lead
to kidney stones and/or nephrocalcinosis.

PHARMACOKINETICS
FUROSEMIDE:
Half-life elimination : 30- 120 ,min( normal renal function),

9 hrs ( in ESRD).
Absorption: 60-80%(PO)
Bioavailability : 47-64% (PO)
Protein bound: 91-99%
Vd : 0.2 l /Kg
Metabolism : liver (10%)
Duration :iv -2 hr
PO- 6-8 hr

 Onset :
initial effect :30-60 min9PO), 5 min (iv)
Max effect: less than 15 min9 iv), 1-2 hr (PO)

Clinical uses
Edematous conditions
CCF Acute decompensated heart failure and chronic

heart failure
Cirrhosis
Nephrotic Syndrome
Idiopathic Edema
Hypertension

Maximum effective dosage

ADVERSE EFFECTS
Hyperuricemia
Hypokalemia
Hypomagnesemia
Hypocalcemia
Glucose intolerance
Vertigo ,tinnitus
Hearing impairment
Anorexia ,nausea, diarrhoea
Weakness ,muscle cramps
Hypotension
Hypersensitivtiy reactions

DIURETIC BRAKING PHENOMENON

1st dose of diuretic provides a good diuresis
Within 1 week the body wt stabilises and the excretion no

longer exceeds intake

Effect of dietary salt intake on braking phenomenon
Post diuresis salt retention
Persist upto 2 weeks of abrupt cessation of loop diuretic
therapy
Contraction alkalosis

Mechanism
Increased Na Cl Reabsorption at the distal sites
RAAS and Sympathetic nervous system activity increased
Reduced Na Cl delivery to frusemide site of action
Limited Inhibition of frusemide
Hypertrophy of DCT and CD

Cl might be low in Alkalosis

Glycosylation of bumetanide sensitive co transporter

Strategies to decrease Diuretic Braking

Restrict dietary salt intake
Another class of diuretic
Multiple daily dosing of diuretic with prolonged action
Do not stop diuretic action abruptly
Prevention/ reversal of metabolic alkalosis

HUMORAL AND NEURONAL MODULATORS OF

THE RESPONSE TO DIURETICS
RAAS
Eicasonoids PGE2
AVP
Catecholamines and symphathetic nervous system

DIURETIC RESISTANCE
Inadequate clearance of edema despite a full dose of

diuretic
Diuretic dose must be above the natriuretic threshold

Causes of diuretic resistance

Approach to management of Diuretic resistance

DIURETIC COMBINATIONS
Loop diuretic and thiazides Syngergistic
Loop Diuretics/ Thiazides + Distal Potassium sparing

diuretics

CLINICAL USES OF DIURETICS

Edematous conditions
CCF Acute decompensated heart failure and chronic

heart failure
Cirrhosis
Nephrotic Syndrome
Idiopathic Edema

Clinical and bichemical characteristics and responses

in patients with nephrotic syndrome

 Non Edematous cconditions

AKI
Type IV RTA
Hypercalcemia
Hypercalcemia
Nephrolithiasis
Osteoporosis
Diabetes Insipidus

ADVERSE EFFECTS OF DIURETIC

FLUID AND ELECTROLYTE ABNORMALITIES
ECF Volume depletion and azotemia
Hyponatremia
Hypokalemia
Hyperkalemia
Hypomaagnesemia
Hypercalcemia
Acid base changes

METABOLIC COMPLICATIONS ASSOCIATED

WITH DIURETIC USE
Hyperglycemia
Hyperuricemia
Hyperlipidemia

Other Adverse Effects

Impotence
Ototoxicity
Pregnancy hazards
Vitamin Defeciency
Drug allergy
Malignancy
Adverse drug Interactions

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