What engineer,

wishing to regulate the composition of the internal environmnt of the body

on which depends the function of every bone, gland, muscle, and nerve,
would devise a scheme that operated by throwing the whole thing out 16 times a day and re
ly on grabbing from it, as it fell to earth, only those
precious elements which he wanted to keep?
Homer Smith, From Fish to Philosopher

History
As the philosophizing physiologist, Homer Smith, noted, the kidney filters the
extra cellular fluid volume across the renal glomeruli an average of 16 times a
day, and the renal nephrons precisely regulate the fluid volume of the body and
its electrolyte content via processes of secretion and reabsorption.
Disease states such as hypertension, heart failure, renal failure, nephrotic synd
rome, and cirrhosis may disrupt this balance. (Goodman & Gilman's The
Pharmacological Basis of Therapeutics, 2011)
Diuretics increase the rate of urine flow and Na+ excretion and are used to
adjust the volume and/or the composition of body fluids. Furosemide increases
the delivery of solutes out of the loop of Henle.
Around the year 1960 loop diuretics (furosemide, ethacrynic acid and
bumetanide) were developed. These block the Na+-K+-2Cl cotransport system
in the ascending limb and inhibit Na+, Cl and K+ entering the tubular cell. Loop
diuretics are highly efficacious, and for this reason, are called high-ceilingdiuretics.
Introduction
The basic urine-forming unit of the kidney is the nephron, which consists of a
filtering apparatus, the glomerulus, connected to a long tubular portion that
reabsorbs and conditions the glomerular ultrafiltration. Normally the flux of
Na+, Cl and K+ from the lumen into the epithelial cells in the thick ascending
limb is mediated by a Na+-K+-2Cl symporter. This symporter captures free
energy in the Na+ electrochemical gradient established by the basolateral Na+
pump and provides for uphill transport of K+ and Cl into the cell. (Pacifici,
2013)

Pharmacokinetics
Furosemide is a white to off-white odorless crystalline powder. It is practically
insoluble in water, sparingly soluble in alcohol, freely soluble in dilute alkali
solutions and insoluble in dilute acids.
Absorption
Furosemide is more rapidly absorbed from the oral solution (50 minutes) than
from the tablet (87 minutes); peak plasma levels and area under the plasma
concentration-time curves do not differ significantly.
ln healthy subjects, the bioavailabilty of furosemide ranges from 60 to 69%; but
in end-stage renal failure its availabilty is reduced to 43-46%. Food does not
alter bioavailability, although the rate of absorption is decreased.

Metabolization
Furosemide is metabolized by human livers microsomes and binds covalently
to proteins. About 99% of furosemide is bound to plasma proteins, almost
exclusively to albumin. Plasma concentrations ranging from 1 to 400 g/mL are
91 to 99% bound in healthy individuals. The unbound fraction averages 2.3 to
4.1% at therapeutic concentrations. However, they are secreted efficiently by
the organic acid transport system in the proximal tubule, and thereby gain access
to their binding sites on the Na+-K+-2Cl symport in the luminal membrane of
the thick ascending limb.
Two-compartment models are most often used to describe the kinetics of
furosemide. The half-time of the -phase averages 10-15 min and that of the phase, 47-90 min. The onset of diuresis following oral administration is within
1 hour. The peak effect occurs within the first or second hour. The duration of
diuretic effect is 6 to 8 hours. The apparent volume of distribution at steady
state is approximately 190 ml/kg.
Excretion
The plasma clearance of furosemide is 2.2-3.0 ml/min per kg. Glucuronide
conjugate is the only well documented metabolite of furosemide in man.
Approximately 65% of furosemide is excreted unchanged in urine, and the
remainder is conjugated to glucuronic acid in the kidney, 20% of furosemide is
eliminated by renal glucuronidation; it has been suggested that the remaining
25-30% may be secreted into the gut in unchanged and/or conjugated form.
Pharmacodynamics
Na -K -2Cl symporters are an important family of transport molecules found
in many secretory and absorbing epithelia. Studies demonstrated that Na+-K+2Cl symporters are of two varieties (Kaplan et al., 1996).
The "absorptive" symporter is expressed only in the kidney, is regulated by
cAMP/PKA
(Obermller
et
al.,
1996Plata
et
al.,
1999).
The "secretory" symporter is a "housekeeping" protein that is expressed widely
in epithelial cells, is localized to the basolateral membrane.
The affinity of loop diuretics for the secretory symporter is
somewhat less than for the absorptive symporter. A model of Na+-K+-2Cl
symporter has been proposed based on ordered binding of ions to the symporter
(Lytle et al., 1998).
Inhibitors of Na+-K+-2Clsymport bind to the Na+-K+-2Clsymporter in the
thick ascending limb and block its function, bringing salt transport in this
segment of the nephron to a virtual standstill. The molecular mechanism by
+

which this class of drugs blocks the Na+-K+-2Cl symporter is unknown, but
evidence suggests that these drugs attach to the Cl binding site located in the
symporter's transmembrane domain (Isenring and Forbush, 1997).
Inhibitors of Na+-K+-2Cl symport also inhibit Ca2+ and Mg2+ reabsorption in
the thick ascending limb by abolishing the transepithelial potential difference
that is the dominant driving force for reabsorption of these cations.
Indications
Edema
Its indicated in adults and pediatric patients for the treatment of edema
associated with congestive heart failure, cirrhosis of the liver, and renal disease,
including the nephrotic syndrome. Is particularly useful when an agent with
greater diuretic potential is desired.
Dose:
Adults Single initial dose of 20 to 80 mg. If needed, the same dose can be
administered 6 to 8 hours later or the dose may be increased. It may be raised
by 20 or 40 mg and given not sooner than 6 to 8 hours after the previous dose
until the desired diuretic effect has been obtained. The individually determined
single dose should then be given once or twice daily (eg, at 8 am and 2 pm).
The dose may be carefully titrated up to 600 mg/day in patients with clinically
severe edematous states.
Geriatric patients - In general, dose selection for the elderly patient should be
cautious, usually starting at the low end of the dosing range.
Pediatric patients - The usual initial dose is 2 mg/kg body weight, given as a
single dose. If the diuretic response is not satisfactory after the initial dose,
dosage may be increased by 1 or 2 mg/kg no sooner than 6 to 8 hours after the
previous dose. Doses greater than 6 mg/kg body weight are not recommended.
For maintenance therapy in pediatric patients, the dose should be adjusted to the
minimum effective level.
Hypertension
Oral furosemide may be used in adults for the treatment of hypertension alone
or in combination with other antihypertensive agents.
Dose:
Adults - The usual initial dose is 80 mg, usually divided into 40 mg twice a day.
Dosage should then be adjusted according to response. If response is not
satisfactory, add other antihypertensive agents.
Geriatric patients - In general, dose selection and dose adjustment for the
elderly patient should be cautious, usually starting at the low end of the dosing
range.
3

Contraindications
Contraindications to the use of loop diuretics include severe Na+ and volume
depletion, hypersensitivity to sulfonamides (for sulfonamide-based loop
diuretics), and anuria unresponsive to a trial dose of loop diuretic.
Interactions
Drug interactions may occur when loop diuretics are co-administered with:
aminoglycosides, carboplatin, paclitaxel and several other agents (synergism of
ototoxicity) anticoagulants (increased anticoagulant activity) digitalis
glycosides
(increased
digitalis-induced
arrhythmias)
lithium
(increased
plasma
levels
of
lithium)
Propranolol
(increased plasma levels of propranolol) Sulfonylureas (hyperglycemia)
Cisplatin
(increased
risk
of
diuretic-induced
ototoxicity)
NSAIDs (blunted Diuretic response and salicylate toxicity when given with
high doses of salicylates) probenecid (blunted diuretic response)
thiazide diuretics (synergism of diuretic activity of both drugs leading to profo
und diuresis) amphotericin B (increased potential for nephrotoxicity and
toxicity and intensification of electrolyte imbalance).
Adverse effect
The most common adverse effects of furosemide are fluid and electrolyte
imbalance, including hypnatraemia, hypokalaemia and hypochloraemic
alkalosis. Hyperuricaemia is relatively common, and a variety of uncommon
adverse reactions have been reported. Signs of volume depletionand
hypokalaemia have been reported in several studies. Rare adverse effects
reported in patients receiving furosemide include skin rash, thrombocytopenia,
gynaecomastia, temporary hearing impairment and hepatic coma in cirrhotic
patients.
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Bibliography
-Pacifici, G. (2013). Clinical Pharmacology of Furosemide in Neonates: A
Review. Pharmaceuticals, 6(9), 1094-1129. doi:10.3390/ph6091094
-Maron B.A., Rocco T.P. (2011). Chapter 28. Pharmacotherapy of Congestive
Heart Failure. In Brunton L.L., Chabner B.A., Knollmann B.C. (Eds), Goodman
& Gilman's The Pharmacological Basis of Therapeutics, 12e. Retrieved May
05,
2015
from
http://accessmedicine.mhmedical.com/content.aspx?bookid=374&Sectionid=4
1266235.
-INTERNATONAL AGENCY FOR RESEARCH ON CANCER,. (1990).
Pharmaceutical Drugs. IARC MONOGRAHS ON THE EVALUATION OF
CARCINOGENIC RISKS TO HUMANS, 50, 277-291. Retrieved from
http://monographs.iarc.fr/ENG/Monographs/vol50/mono50-18.pdf
-FDA U.S. Food and Drug Administration,. (2010). Lasix (furosemide) tablets
label
(www.accessdata.fda.gov/drugsatfda_docs/label/2010/016273s061lbl.pdf).
-Mens-sexual-tablets.com,. (2015). #1 OFFICIAL PHARMACY! - BUY ED
PILLS. Retrieved 11 May 2015, from http://mens-sexual-tablets.com/diureticsmedicine-usa.html
-Health-lab.net,. (2015). furosemide | Health-lab.net. Retrieved 11 May 2015,
from http://health-lab.net/diuretics/furosemide.html