Loop diuretics

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

1. Loop
diuretics
Domina Petric, MD

2. Introduction
LoopdiureticsselectivelyinhibitNaClreabsorptionin
thethickascendinglimb ofHenle´s loop(TAL).
TAL has large NaCl absorptive capacity.
Diuretic action of loop diuretics is not limited by
development of acidosis.
Thesedrugsare themost efficaciousdiureticagents
currentlyavailable.

3. Chemistry
•Furosemide, ethacrynicacid!
•Bumetanideandtorsemideare sulfonamideloopdiuretics.
•Ethacrynicacidis a phenoxyaceticacidderivative
containinganadjecentketoneandmethylenegroup.
•Themethylenegroupformsanadductwiththefree
sulfhydrylgroupofcysteine.
•Thecysteineadductappearsto beanactiveformofthe
drug.
•Organicmercurialdiureticsalsoinhibitsalttransport inthe
TAL, but are toxic.

4. Pharmacokinetics
•Theloopdiureticsare rapidlyabsorbed.
•Theyare eliminatedbythekidneybyglomerular
filtrationandtubularsecretion.
•Absorptionoforaltorsemideis 1 hourandthatof
furosemide2-3 hours.
•Oralabsorptionis nearlyas completeaswith
intravenousadministration.
•Thedurationofeffectfor furosemideis 2-3 hours
andoftorsemide4-6 hours.

5. Pharmacokinetics
•Half-lifedependson renalfunction.
•Loopagentsacton theluminalside ofthetubule.
•Theirdiureticactivitycorrelateswiththeir
secretionbytheproximaltubule.
•NSAIDsandprobenecidcompetefor weakacid
secretionintheproximaltubule.
•Simultaneousadministrationofloopdiureticsand
NSAIDsresultinreductioninthesecretionofloop
diuretics.

6. Pharmacodynamics
•LoopdiureticsinhibittheluminalNa
+
/K
+
/2Cl
-
transporter (NKCC2) intheTAL ofHenle´s loop.
•TheseagentsreducethereabsorptionofNaCland
diminishthelumen-positivepotentialthatcomes
fromK
+
recycling.
•LoopdiureticscauseanincreaseinMg
2+
andCa
2+
excretion.
•Prolongeduse cancausesignificant
hypomagnesemia.

7. Pharmacodynamics
•Loopdiureticsdo notgenerallycausehypocalcemia
becausevitamin D-inducedintestinalabsorptionand
parathyroidhormone-inducedrenalreabsorptionof
Ca
2+
canbeincreased.
•Indisordersthatcausehypercalcemia, Ca
2+
excretion
canbeenhancedbytreatmentwithloopdiuretics
combinedwithsalineinfusions.
•Loopdiureticsinduceexpressionofcyclooxygenase2
(COX-2)whichparticipatesinthesynthesisof
prostaglandinsfromarachidonicacid.

8. Pharmacodynamics
•PGE
2inhibitssalttransport intheTAL andparticipatesin
therenalactionsofloopdiuretics.
•NSAIDscaninterferewiththeactionsofloopdiureticsby
reducingprostaglandinsynthesisinthekidney.
•Thisinterferenceis significantinpatientswithnephrotic
syndromeor hepaticcirrhosis.
•Furosemideincreasesrenalbloodflowviaprostaglandin
actionson kidneyvasculature.
•Furosemideandethacrynicacidreducepulmonary
congestionandleftventricularfillingpressuresin
heartfailure.

9. Typicaldosagesofloopdiuretics
Drug Total dailyoraldose
Bumetanide 0,5-2 mg
Ethacrynicacid50-200 mg
Furosemide 20-80 mg
Torsemide 5-20 mg

10. Clinicalindications
Themost importantare ACUTE PULMONARY
EDEMA, OTHER EDEMATOUS CONDITIONS
AND ACUTE HYPERCALCEMIA.
Otherindicationsare hyperkalemia, acute
renalfailureandanion overdose.

11. Edematousstates
•Reductionofperipheralor pulmonaryedemathathas
accumulatedas a resultofcardiac, renalor vascular
disease, thatreducebloodflowto thekidney.
•Thisreductionis sensedas insufficienteffectivearterial
bloodvolume, whichleadsto saltandwaterretention.
•Excessivediuretictherapymaycompromisetheeffective
arterialbloodvolumeandreducetheperfusionofvital
organs.
•Theuse ofdiureticsto mobilizeedema requirescareful
monitoringofthepatient´s hemodynamicstatus.

12. Hyperkalemia
Loopdiureticscansignificantly
enhanceurinaryexcretionof
potassium.
Thisresponseis enhancedby
simultaneousNaClandwater
administration.

13. Acuterenalfailure
•Loopagentscanincreasetherate ofurine flowandenhance
potassiumexcretioninacuterenalfailure.
•Theycannotpreventor shortenthedurationofrenalfailure.
•Ifa largepigment loadhasprecipitatedacuterenalfailure, loop
agentsmayhelpto flushoutintratubularcastsandameliorate
intratubularobstruction.
•Loopagentscanworsencastformationinmyelomaandlight
chainnephropathy: increaseddistalCl
-
concentrationenhances
secretionofTamm-Horsfallprotein.
•Thisprotein aggregateswithmyelomaBenceJonesproteins.

14. Anion overdose
Loop diuretics are useful in treating toxic
ingestions of bromide, fluoride and iodide, which
are reabsorbed in the TAL.
Salinesolutionmust beadministeredto replace
urinarylossesofNa
+
andto provide Cl
-
.
Thisis importantto avoidextracellular
fluid volumedepletion.

15. Toxicity
Hypokalemic metabolic alkalosis
Ototoxicity
Hyperuricemia
Hypomagnesemia
Allergicandotherreactions

16. Hypokalemicmetabolicalkalosis
•ByinhibitingsaltreabsorptionintheTAL, loop
diureticsincreasesodiumdeliveryto the
collectingduct.
•Increaseddeliveryleadsto increasedsecretion
ofpotassiumandhydrogenionsbytheduct:
hypokalemicmetabolicalkalosis.
•Thistoxicityis a functionofthemagnitude of
thediuresisandcanbereversedbypotassium
replacementandcorrectionofhypovolemia.

17. Ototoxicity
Dose-relatedhearingloss
is usuallyreversible.
Itis most commoninpatientswho
havediminishedrenalfunctionor who
are receivingsimultaneouslyother
ototoxicagents(for example,
aminoglycosideantibiotics).

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.
Itmaybepreventedbyusinglowerdosesto avoid
developmentofhypovolemia.

19. Hypomagnesemia
Magnesium depletion is a consequence
of the chronic use of loop agents.
It occurs most often in patients with
dietary magnesium deficiency.
Itcanbereversedbyadministrationof
oralmagnesiumpreparations.

20. Allergicandotherreactions
Allloopdiuretics, exceptethacrynicacid, are
sulfonamides:
•skinrash
•eosinophilia
•interstitialnephritis
Thistoxicityusuallyresolvesrapidlyafterdrug
withdrawal.
Allergicreactionsare muchlesscommonwith
ethacrynicacid.

21. Allergicandotherreactions
•Henle´s loopis indirectlyresponsiblefor water
reabsorptionbythedownstreamcollectingduct.
•Loopdiureticscancauseseveredehydration.
•Hyponatremiais lesscommonthanwiththethiazides.
•Patientswhoincreasewaterintakeinresponseto
hypovolemia-inducedthirstcanbecomeseverly
hyponatremic.
•Loopagentscancausehypercalciuria, whichcanleadto
mildhypocalcemiaandsecondaryhyperparathyroidism.

22. Allergicandotherreactions
Loopagentscanhavethe
oppositeeffect, hypercalcemia,
involume-depletedpatients
whohaveanothercausefor
hypercalcemia: metastatic
breastor squamouscelllung
carcinoma.

23. Contraindications
Furosemide, bumetanide and torsemide may
exhibit allergic cross-reactivity in patients
sensitive to other sulfonamides, but it is
very rare.
Overzealoususe ofanydiureticis
dangerousinhepaticcirrhosis, borderline
renalfailureandheartfailure.

24. Literature
•Katzung, Masters, Trevor.
Basicandclinical
pharmacology.