Clinical pharmacology: loop diuretics (furosemide, torsemide, bumetanide, ethacrynic acid)

1. Loop
diuretics
Domina Petric, MD

2. Introduction
Loop diuretics selectively inhibit NaCl reabsorption in
the thick ascending limb of Henle´s loop (TAL).
TAL has large NaCl absorptive capacity.
Diuretic action of loop diuretics is not limited by
development of acidosis.
These drugs are the most efficacious diuretic agents
currently available.

3. Chemistry
• Furosemide, ethacrynic acid!
• Bumetanide and torsemide are sulfonamide loop diuretics.
• Ethacrynic acid is a phenoxyacetic acid derivative
containing an adjecent ketone and methylene group.
• The methylene group forms an adduct with the free
sulfhydryl group of cysteine.
• The cysteine adduct appears to be an active form of the
drug.
• Organic mercurial diuretics also inhibit salt transport in the
TAL, but are toxic.

4. Pharmacokinetics
• The loop diuretics are rapidly absorbed.
• They are eliminated by the kidney by glomerular
filtration and tubular secretion.
• Absorption of oral torsemide is 1 hour and that of
furosemide 2-3 hours.
• Oral absorption is nearly as complete as with
intravenous administration.
• The duration of effect for furosemide is 2-3 hours
and of torsemide 4-6 hours.

5. Pharmacokinetics
• Half-life depends on renal function.
• Loop agents act on the luminal side of the tubule.
• Their diuretic activity correlates with their
secretion by the proximal tubule.
• NSAIDs and probenecid compete for weak acid
secretion in the proximal tubule.
• Simultaneous administration of loop diuretics and
NSAIDs result in reduction in the secretion of loop
diuretics.

6. Pharmacodynamics
• Loop diuretics inhibit the luminal Na+/K+/2Cl-
transporter (NKCC2) in the TAL of Henle´s loop.
• These agents reduce the reabsorption of NaCl and
diminish the lumen-positive potential that comes
from K+ recycling.
• Loop diuretics cause an increase in Mg2+ and Ca2+
excretion.
• Prolonged use can cause significant
hypomagnesemia.

7. Pharmacodynamics
• Loop diuretics do not generally cause hypocalcemia
because vitamin D-induced intestinal absorption and
parathyroid hormone-induced renal reabsorption of
Ca2+ can be increased.
• In disorders that cause hypercalcemia, Ca2+ excretion
can be enhanced by treatment with loop diuretics
combined with saline infusions.
• Loop diuretics induce expression of cyclooxygenase 2
(COX-2) which participates in the synthesis of
prostaglandins from arachidonic acid.

8. Pharmacodynamics
• PGE2 inhibits salt transport in the TAL and participates in
the renal actions of loop diuretics.
• NSAIDs can interfere with the actions of loop diuretics by
reducing prostaglandin synthesis in the kidney.
• This interference is significant in patients with nephrotic
syndrome or hepatic cirrhosis.
• Furosemide increases renal blood flow via prostaglandin
actions on kidney vasculature.
• Furosemide and ethacrynic acid reduce pulmonary
congestion and left ventricular filling pressures in
heart failure.

9. Typical dosages of loop diuretics
Drug Total daily oral dose
Bumetanide 0,5-2 mg
Ethacrynic acid 50-200 mg
Furosemide 20-80 mg
Torsemide 5-20 mg

10. Clinical indications
The most important are ACUTE PULMONARY
EDEMA, OTHER EDEMATOUS CONDITIONS
AND ACUTE HYPERCALCEMIA.
Other indications are hyperkalemia, acute
renal failure and anion overdose.

11. Edematous states
• Reduction of peripheral or pulmonary edema that has
accumulated as a result of cardiac, renal or vascular
disease, that reduce blood flow to the kidney.
• This reduction is sensed as insufficient effective arterial
blood volume, which leads to salt and water retention.
• Excessive diuretic therapy may compromise the effective
arterial blood volume and reduce the perfusion of vital
organs.
• The use of diuretics to mobilize edema requires careful
monitoring of the patient´s hemodynamic status.

12. Hyperkalemia
Loop diuretics can significantly
enhance urinary excretion of
potassium.
This response is enhanced by
simultaneous NaCl and water
administration.

13. Acute renal failure
• Loop agents can increase the rate of urine flow and enhance
potassium excretion in acute renal failure.
• They can not prevent or shorten the duration of renal failure.
• If a large pigment load has precipitated acute renal failure, loop
agents may help to flush out intratubular casts and ameliorate
intratubular obstruction.
• Loop agents can worsen cast formation in myeloma and light
chain nephropathy: increased distal Cl- concentration enhances
secretion of Tamm-Horsfall protein.
• This protein aggregates with myeloma Bence Jones proteins.

14. Anion overdose
Loop diuretics are useful in treating toxic
ingestions of bromide, fluoride and iodide, which
are reabsorbed in the TAL.
Saline solution must be administered to replace
urinary losses of Na+ and to provide Cl-.
This is important to avoid extracellular
fluid volume depletion.

15. Toxicity
Hypokalemic metabolic alkalosis
Ototoxicity
Hyperuricemia
Hypomagnesemia
Allergic and other reactions

16. Hypokalemic metabolic alkalosis
• By inhibiting salt reabsorption in the TAL, loop
diuretics increase sodium delivery to the
collecting duct.
• Increased delivery leads to increased secretion
of potassium and hydrogen ions by the duct:
hypokalemic metabolic alkalosis.
• This toxicity is a function of the magnitude of
the diuresis and can be reversed by potassium
replacement and correction of hypovolemia.

17. Ototoxicity
Dose-related hearing loss
is usually reversible.
It is most common in patients who
have diminished renal function or who
are receiving simultaneously other
ototoxic agents (for example,
aminoglycoside antibiotics).

18. Hyperuricemia
Loop diuretics can cause hyperuricemia and
precipitate attacks of gout.
This is caused by hypovolemia-associated
enhancement of uric acid reabsorption in the
proximal tubule.
It may be prevented by using lower doses to avoid
development of hypovolemia.

19. Hypomagnesemia
Magnesium depletion is a consequence
of the chronic use of loop agents.
It occurs most often in patients with
dietary magnesium deficiency.
It can be reversed by administration of
oral magnesium preparations.

20. Allergic and other reactions
All loop diuretics, except ethacrynic acid, are
sulfonamides:
• skin rash
• eosinophilia
• interstitial nephritis
This toxicity usually resolves rapidly after drug
withdrawal.
Allergic reactions are much less common with
ethacrynic acid.

21. Allergic and other reactions
• Henle´s loop is indirectly responsible for water
reabsorption by the downstream collecting duct.
• Loop diuretics can cause severe dehydration.
• Hyponatremia is less common than with the thiazides.
• Patients who increase water intake in response to
hypovolemia-induced thirst can become severly
hyponatremic.
• Loop agents can cause hypercalciuria, which can lead to
mild hypocalcemia and secondary hyperparathyroidism.

22. Allergic and other reactions
Loop agents can have the
opposite effect, hypercalcemia,
in volume-depleted patients
who have another cause for
hypercalcemia: metastatic
breast or squamous cell lung
carcinoma.

23. Contraindications
Furosemide, bumetanide and torsemide may
exhibit allergic cross-reactivity in patients
sensitive to other sulfonamides, but it is
very rare.
Overzealous use of any diuretic is
dangerous in hepatic cirrhosis, borderline
renal failure and heart failure.

24. Literature
•Katzung, Masters, Trevor.
Basic and clinical
pharmacology.