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Loop Diuretics

Loop diuretics are also known as high ceiling diuretics or Na+K+2Cl- cotransporter inhibitors.

Loop diuretics act at the ascending thick limb. The ascending thick limb has the greatest capacity to reabsorb NaCl.

Why called high ceiling diuretics??

Where dose is on x-axis while Na+ excretion is on y-axis.

Maximum response is called ceiling effect. As loop diuretics have highest ceiling so called high ceiling diuretics.

Chemistry

Sulphonamide and carboxylic acid derivatives except ethacrynic acid (phenoxy acetic acid derivative).

Pharmacokinetics

Can be absorbed orally.

  1. Torsemide takes 1 hour to reach peak levels. Duration of action is 4-6 hours.
  2. Frusemide takes 2-3 hours to reach peak levels. Duration of action is shorter, 2-3 hours.

Site of action is within the lumen of nephron. They reach the site of action partly by filtration and mostly by active tubular secretion. After I/V injection, they produce dieresis within minutes.

Mechanism of action

1.      Site of action is the ascending thick limb.
2.      Reach the site of action by active tubular secretion in S2 segment.
3.      Normal physiology

Greater K+ leads to extrusion leading to greater positivity, which pumps K+ by transcellular pathway along with Mg++ and Ca++.

4.      Ionic Changes

Na+ and K+ are not reabsorbed and positive potential does not develops. They indirectly lead to decreased Mg++ and Ca++ reabsorption. Na+, K+ and Cl- are excreted along with Ca++, Mg++. Chronic use may lead to

  1. hypomagnesemia
  2. hypokalemia.

But hypocalcaemia does not develop because calcium is reabsorbed by distal convoluted tubule by separate mechanism.

5.      Hemodynamic changes

Hemodynamic changes are probably prostaglandin mediated, producing vasodilatation. Redistribution of blood occurs, mainly in the kidneys. Intra renal blood flow increases under the action of loop diuretics. Venous return to the heart decreases, secondary to vasodilatation. Decrease in pulmonary congestion occurs, as well as decrease in left ventricular filling and decreased work load (preload). This effect is seen before any diuretic effect and is separate form it.

Indications

Acute pulmonary edema and CCF

Acute pulmonary edema is an emergency and the patient may die within minutes. Loop diuretics are used along with morphine and oxygen therapy. Loop diuretics are given I/V and are effective within minutes. They produce two types of effects:

  1. PG mediated (decrease left ventricular filling pressure and pulmonary congestion)
  2. Diuretic effect (reduce blood volume)

Pulmonary edema might be a complication of CCF but CCF, itself is different. Loop diuretics are effective in CCF as they decrease work load, as heart is not pumping enough blood,

If CCF is secondary to hyperaldosteronism (nephritic syndrome, cirrhosis, CCF) it puts extra pressure on heart.

Hypertension (emergency)

Loop diuretics are effective within minutes. Thiazide diuretics are better for long standing hypertension.

Loop diuretics decrease the blood volume and Na+ load, decreasing the neural activity along with Ca++ levels, while increasing the vasodilatation.

Torsemide has short duration of action.

Hypercalcemia

Used in emergency. Hypercalcemia might occur due to:

  1. chronic renal failure
  2. vitamin D excess
  3. hyperthyroidism
  4. tumors like carcinoma
  5. breast and lung cancer
  6. ectopic parathyroid hormone
  7. milk alkali syndrome (overuse of NSAIDS or increased ingestion of milk)

These conditions can be treated by loop diuretics. They reduce the reabsorption of Ca++, but by themselves, do not produce hypocalcaemia because:

  1. Separate mechanism is present in distal tubules
  2. Volume depletion leads to activation of mechanism in proximal tubules to reabsorb Ca++

If combined with infusion of 0.9% NaCl, can lead to increased excretion of Ca++. In this case there is no volume depletion. Although some calcium is still reabsorbed, Ca++ excretion does take place.

 Refractory Edema

Loop diuretics are most efficacious in mobilizing the fluid.

 Hyperkalemia

In emergency, K+ excretion can be increased by

  1. insulin therapy, which increases K+ entry into cells
  2. Loop diuretics, which increase K+ excretion by increased Na+ excretion and increased load of Na+ at distal tubule.

Hypovolemia must not develop, so are combined with 0.9% NaCl.

 Acute Renal Failure

(Due to toxins or pigments overload)

Normally acute renal failure resolves automatically. Hemodialysis or peritoneal dialysis may be used. If secondary to hemolysis, loop diuretics can be used I/V as test drug. It can convert oliguric phase to non oliguric phase, which is helpful in excretion of K+. Loop diuretics do not shorten the duration of disease, but are still helpful.

 Halide Overdosage

Halides are reabsorbed at ascending thick limb, just like Cl-. Their reabsorption is also blocked, as are also univalent ions. In cases of poisoning due to these ions, loop diuretics can be given along with 0.9% NaCl.

 Adverse Effects

Hypokalemic metabolic alkalosis

Greater the load of Na+ entering nephron, more Na+ is reabsorbed and more K+ is excreted, so called hypokalemic metabolic alkalosis.

Ototoxicity

Main complaint is the fullness of ear, tinnitus, hearing loss and disturbance of ionic balance of endolymph. As Na+K+2Cl- is present in internal ear, so ionic balance is also disturbed, leading to ototoxicity.

Ethacranic acid is mostly ototoxic. If combined with amino glycosides, more ototoxic effects are seen.

Hyperuricemia

a. Same mechanism is present in S2 for loop diuretics and uric acid. Competitive inhibition of tubular secretion leads to hyperuricemia.
b. Volume depletion leads to increased reabsorption of uric acid, which may precipitate gout

As loop diuretics are used for hypertension and in CCF, basic investigations of uric acid levels must be done prior to starting the treatment.

Hypomagnesemia

No separate mechanism is present for Mg++, the levels of which decrease by long term usage. This might be a risk factor in cardiac arrhythmias.

Allergic Reactions

Suphonamids are notorious for allergic manifestations. Ethacranic acid is associated with far less allergic effects.

Other Adverse Effects:

Loop diuretics may also lead to:

  1. Hyperglycemia
  2. Disturbance of lipid levels ( increased LDL and decreased HDL)
Caution:
a. Cross – reactivity with sulphonamides

Loop diuretics cross react with sulphonamides. If person is hypersensitive, doctor should refrain from giving loop diuretics.

b. Hepatic Cirrhosis

If liver is not functioning, hypoproteinemia and decreased plasma oncotic pressure occurs, leading to exudation of fluid and development of edema or ascitis, known as third space hypovolemia.

As a result kidneys perceive hypovolemia and increase renin secretion. In this condition, aldosterone antagonists are preferred. Sometimes loop diuretics may be combined. But overuse is counter productive, as will lead to decreased volume and decreased blood flow to liver, worsening liver functions.

c. CCF

If heart is not pumping enough blood, salt and water retention occurs. Blood volume has to be decreased. If it is reduced too much, it decreases venous return. Overaggressive therapy might be harmful.

Drug Interactions:
  1. As causes hypokalemia, in patients taking digoxin chances of cardiac arrhythmias are increased.
  2. NSAIDS (aspirin) can blunt the action of loop diuretics by blocking the PG mediated effects.
  3. If combined with amino glycosides, ototoxicity might occur.
  4. Synergistic effects occur when combined with K+ sparing diuretics or thiazide diuretics, which increases their efficacy.

Increased efficacy with K+ sparing diuretics occurs in two ways:
a. Loop diuretics act on ascending thick limb, while K+ sparing diuretics on collecting tubule, different site of action enhances the effect.
b. Loop diuretics are associated with hypokalemia; K+ sparing diuretics spare K+.

Thiazide diuretics act at distal tubule, when combined leads to increased efficacy.

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