Furosemide
FUROSEMIDE
International Programme on Chemical Safety
Poisons Information Monograph 240
Pharmaceutical
1. NAME
1.1 Substance
Furosemide
1.2 Group
Diuretics (C03)/ High ceiling diuretics (C03C)/
Sulfonamides, plain (C03CA)
1.3 Synonyms
Frusemide (BAN); Furosemidum; LB-502;
Fursemide;
1.4 Identification numbers
1.4.1 CAS number
54-31-9
1.4.2 Other numbers
RTECS:CB2625000
1.5 Main brand names, main trade names
Monocomponent products:
Aluzine; Aquarid; Arcanamide; Diural; Diurolasa; Dryptal;
Durafurid; Frumax; Frusetic; Frusid; Fumarenid; Furix;
Furo-basan; Furo-Puren; Furorese; Fusid; Hydrex; Hydro-rapid;
Impugan; Lasiletten, Lasilix; Lasix; Novosemide; Oedemex;
Puresis;Ruseyde; Seguril; Sigasalur; Uremide; Urex; Uritol;
Vesix;
Combination products
Betasemid; Diaphal; Diumide-K Continuous; Diumid+K; Diutrix;
Duraspiron Comp; Fluss 40; Fru-Co; Frumil; Frusene; Furesis
Comp; Furospir; Hydrotrix
Lasikal; Lasilactone; Lasipressin; Lasitone; Lasix+K;
Lasix-Reserpin; Lasoride; Logirene; Nortensin; Osyrol;
Spiro-D-Tablinen; Spirofur; Terbolan
1.6 Manufacturers; Importers
Australia: Hoechst; Protea
Canada: Hoechst; Horner; Novopharm
Eire: Hoechst; Napp
France: Hoechst; Rorer
Germany: Azupharma; Brenner-Efeka; Bristol; Durachemie;
Hexal; Hoechst; Klinge-Nattermann; Medice; Rorer; Sanorania;
Siegfried; Winthrop
Netherlands: Hoechst; ICN
Italy: Hoechst; Lepetit; Scharper
South Africa: Arcana; Hoechst; Lennon; Rolab; Schwulst
Spain: Alter; Lasa; Hoechst
Sweden: A.L.; Benzon; Dumex; Hoechst
Switzerland: Hoechst; Mepha; Mundipharma; Schonenberger;
United Kingdom: Askbourne; Asta Medica; Berk; CP
Pharmaceuticals; Cox; DDSA Pharmaceuticals; Evans; Fisons;
Hoechst; Kerfoot; Norton; Rorer; Unimed
United States of America: Hoechst
2. SUMMARY
2.1 Main risks and target organs
Overdoses of diuretics are uncommon and infrequently
serious. Problems most frequently involve chronic
overmedication or poor monitoring and/or lack of anticipation
of drug interactions or not compensating for concomitant
hepatic or renal dysfunction. Main toxic effects are on the
kidneys with diuresis of water; sodium; and potassium leading
most frequently to a hyponatremic; hypokalemic; and
hypochloremic dehydration. More caution is warranted with
patients at higher risk for abnormal renal function including
patients with any renal disease; diabetes mellitus; and
borderline fluid and/or electrolyte status. In a hospital-
based study of adverse reactions to medications there was a
21% rate of adverse affects to frusemide with most common
ones being hypovolemia; hyperuricemia; and hypokalemia which
for the most part were mild; but the rate and severity
increased with increasing daily doses.
2.2 Summary of clinical effects
Patients with either acute or chronic overdosage with
frusemide may show signs of dehydration with thirst;
lethargy; confusion; poor skin turgor; and prolonged
capillary refill time; but may have a paradoxical continued
diuresis. Electrolyte abnormalities will include
hyponatremia; hypokalemia; and hypochloremia and in larger
ingestions may lead to further deterioration in mental
status; seizures; electrocardiographic abnormalities; and
arrhythmias. Prior renal insufficiency will lead to more
toxicity at a given dose. Hypokalemia may lead to muscular
weakness; hyporeflexia; and contribute to hypochloremic
metabolic alkalosis (the so-called "volume contraction
metabolic alkalosis").
Cardiac arrhythmias may occur due to potassium deficiency
and/or coexistent hypomagnesemia. Gastrointestinal bleeding
has been reported in patients taking frusemide; especially if
renal insufficiency is present. Abuse or overdose may result
in pancreatitis. Hyperglycemia; hyperuricemia; and
hyperlipidemia may occur with acute overdose or in chronic
use or abuse. Hypersensitivity reactions such as rash;
photosensitivity; thrombocytopenia; and pancreatitis are
rare.
2.3 Diagnosis
The diagnosis of a frusemide overdose (acute or
chronic) should be considered in the patient with an
unexplained hypovolemia specifically with concurrent
hyponatremia; hypokalemia; and hypochloremia; especially if
the patient has a paradoxical diuresis. Patients most likely
to have access to frusemide include ones with congestive
heart failure; renal or hepatic insufficiency or other
edematous states; or patients who may be taking it
surreptitiously (eg. bulimics). Measurement of frusemide
levels is not useful in clinical management.
2.4 First aid measures and management principles
Since the complications of an overdose of strictly
frusemide are relatively rare; invasive or noxious
interventions such as syrup of ipecac or gastric lavage are
probably not warranted in most cases. Gastrointestinal
decontamination with activated charcoal is probably warranted
if the patient presents within 1 to 2 hours post-ingestion
with an especially large ingestion or with complicating
underlying diseases. Cathartics should be withheld in face
of pre-existent dehydration. There is no role for enhanced
elimination. Intervention should be targeted at replacing
any fluid and electrolyte abnormalities initially with
intravenous isotonic crystalloid solutions. There is no
specific antidote. Serum electrolytes including serum
bicarbonate are warranted. For hypotension; vigorous fluid
hydration is necessary before resorting to vasopressors; and
invasive monitoring with at least a central venous pressure
monitor is recommended.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Synthetic
3.2 Chemical structure
Chemical names:
4-Chloro-N-furfuryl-5-sulphamoylanthranilic acid
5-(Aminosulfonyl)-4-chloro-2-[(2-furanylmethyl) amino]benzoic
acid.
4-Chloro-N-(2-furylmethyl)-5-sulfamoylanthranilic acid.
Molecular formula: C12H11ClN2O5S
Molecular weight: 330.7
(Reynolds, 1993; Budavari, 1996)
3.3 Physical properties
3.3.1 Colour
White or slightly yellow.
3.3.2 State/form
Solid-crystals
Solid-powder
3.3.3 Description
Odourless.
Practically insoluble in water; very slightly soluble
in chloroform; soluble in alcohol; slightly soluble in
ether; freely soluble in acetone; dimethylformamide;
methyl alcohol and solutions of alkali hydroxides.
pKa 3.9 (20°C)
(Reynolds, 1993)
3.4 Other characteristics
3.4.1 Shelf-life of the substance
No data available.
3.4.2 Storage conditions
Protect from light
Store at a temperature between 15 to 30°C.
(McEvoy; 1995)
4. USES
4.1 Indications
4.1.1 Indications
Diuretic
High-ceiling diuretic
Sulfonamide;
plain;
high-ceiling diuretic
4.1.2 Description
Oedema associated with congestive heart
failure; and pulmonary; renal and hepatic
disorders.
Oedema in patients unresponsive to thiazide
diuretics.
Renal insufficiency.
Hypertension (either as the sole drug or as an adjunct
to other antihypertensives).
Severe hypercalcaemia (to promote urinary calcium
excretion)
(Reynolds, 1993).
4.2 Therapeutic dosage
4.2.1 Adults
Oral
Oedema:
20 to 600 mg daily; depending on the severity.
Hypertension:
40 to 80 mg daily.
Chronic renal insufficiency:
250 mg (increased every 4 hours to a total dose of up
to 2 g in 24 hours).
Parenteral
Oedema:
20 to 50 mg by intramuscular or slow intravenous
injection.
Pulmonary oedema:
40 to 80 mg intravenously.
Oliguria in acute or chronic renal failure:
250 mg to 1 g by slow intravenous infusion.
(Reynolds 1993)
4.2.2 Children
Oral
1 to 3 mg/kg bodyweight daily.
Parenteral
0.5 to 1.5 mg/kg bodyweight up to a maximum of 20 mg
daily.
(Reynolds; 1993)
4.3 Contraindications
Known hypersensitivity to frusemide (Physician's Desk
Reference, 1995) or sulfonamides (TGA, 1991).
Contraindicated in patients with anuria; or in patients with
renal failure; when caused by nephrotoxic or hepatotoxic
drugs (Reynolds, 1993).
Should not be used in patients in renal failure associated
with coma (Reynolds, 1993; TGA, 1991).
Contraindicated in pre-comatose states associated with
hepatic cirrhosis (Reynolds, 1993).
5. ROUTES OF EXPOSURE
5.1 Oral
This is the most commonly used route of entry. Tablets
and liquid forms are available.
5.2 Inhalation
Not relevant.
5.3 Dermal
Not relevant.
5.4 Eye
Not relevant.
5.5 Parenteral
The intramuscular and intravenous routes are used.
5.6 Other
Not relevant
6. KINETICS
6.1 Absorption by route of exposure
Oral
Rapidly absorbed after ingestion (Moffat, 1986). Extent of
availability (i.e. the percentage of an oral dose that
reaches the arterial blood in an active form to produce
pharmacological actions) is 61% (Gilman et al., 1990).
6.2 Distribution by route of exposure
Protein binding in the plasma is 98.8%; the volume of
distribution is 0.11 L/kg (Gilman et al., 1990; Moffat,
1986).
Frusemide crosses the placenta and is found in human milk
(Briggs et al., 1994; McEvoy, 1995).
6.3 Biological half-life by route of exposure
The serum half-life in therapeutic doses is 92 minutes;
increasing in patients with uremia; congestive heart failure
and cirrhosis as well as in the neonate and aged patients.
(Gilman et al., 1990). In such patients the half-life may be
extended to 20 hours (Moffat, 1986).
6.4 Metabolism
It would appear that frusemide glucuronide is the only
or at least the major biotransformation metabolite in man
(TGA, 1991; Physician s Desk Reference, 1995). 2-amino-4-
chloro-5-sulfamoylanthranilic acid has been reported in some
studies but not in others; and is thought to be an analytical
artifact (Moffat, 1986).
6.5 Elimination and excretion
Oral
Total systemic clearance of drug from is 2 mL/min/kg in
adults (Gilman et al., 1990; Moffat, 1986) decreased in
uraemia; neonates and heart failure (Moffat, 1986). Sixty six
per cent (66%) of the administered dose is excreted unchanged
in the urine of a healthy young adult (Gilman et al., 1990).
The percentage excreted in urine of cystic fibrosis patients
is reduced.
Intravenous
Up to 90% of the dose is excreted in the urine; principally
as the unchanged drug and up to 14% of the dose as a
glucuronide conjugate (Moffat, 1986). About 69 to 97% of this
excreted amount is eliminated in the urine in the first 4
hours (McEvoy, 1995).
Six (6) to 18% of a dose is eliminated via the faeces in
healthy patients and increases to about 60% in patients with
renal failure (Moffat, 1986).
Intramuscular
80% of a dose is excreted in urine within 24 hours; with 69
to 97% of this amount being excreted in the first 4 hours
(McEvoy, 1995).
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
7.1.1 Toxicodynamics
Details of the mechanism by which excess
potassium is lost during frusemide therapy are set out
in 7.1.2.
Frusemide diuresis increases the excretion of sodium;
chloride; potassium; hydrogen; calcium; magnesium;
ammonium and bicarbonate (McEvoy, 1995). The depletion
of these electrolytes is a major cause of toxicity
effects.
For example; low potassium (and chloride) levels
increase the cardiac toxicity of digitalis (TGA,
1991). Excessive loss of hydrogen; potassium and
chloride may cause metabolic acidosis (McEvoy,
1995).
A hypotensive reaction may occur from decreased plasma
volume; following excessive diuresis (McEvoy, 1995).
7.1.2 Pharmacodynamics
The exact mode of action of frusemide has not
been fully defined (McEvoy, 1995). Frusemide primarily
inhibits sodium and chloride absorption in the thick
ascending limb of the loop of Henle. (Gilman et al.,
1990; Thomas & Altman, 1987).
The action of frusemide is best seen in the context of
the mechanism of reabsorption of salts (NaCl in
particular) and water; particularly the different
points at which reabsorption takes place within the
renal tubule. According to Thomas & Altman (1987)
frusemide acts by reducing the osmotic pull around the
thin descending limb through inhibiting the active
transport mechanism of salt escaping via the wall of
the thick ascending limb. This action reduces
reabsorption of salt (NaCl) and hence the
concentration of salt around the thin descending limb
is also reduced. This in turn reduces the amount of
water reabsorbed out of the thin descending limb; with
the result that more water is excreted as urine.
A consequence of this inhibition of the re-uptake of
NaCl in the ascending limb is that more NaCl than
normal reaches the distal convoluted tubule and the
collecting duct. At both these points Na+ is
reabsorbed by active transport and the Cl- is left in
the tubule. The negative Cl- then attracts positive K+
and H+ ions from the surrounding tissue. These ions
remain in the fluid; passing into the bladder and are
lost in the urine. Hence frusemide is a potassium
depleting diuretic.
Frusemide is an inhibitor of carbonic anhydrase but
the effect is not strong enough to contribute to
proximal diuresis except at very large doses. The
diuretic effects of frusemide are independent of the
acid-base balance of the patient (McEvoy, 1995).
Frusemide initially increases renal blood flow without
increasing the filtration rate; particularly after
intravenous injection; with consequent reduction of
fluid and electrolyte reabsorption in the proximal
tubule; which in turn leads to decreased renal blood
flow. (Gilman et al., 1988)
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
Acute
Life threatening hyperkalemia and reversible
renal failure occurred in an elderly male
taking captopril concomitantly with frusemide
(Chan & Critchley, 1992).
Acute rhabdomyolysis and myoglobinuria due to
hypokalaemia occurred in a 74-year-old male
taking frusemide (Shintani et al., 1991).
Severe anaphylactic reaction to frusemide
involving urticaria; angioedema and
hypotension occurred in an adult 5 minutes
after receiving intravenous frusemide
(Hansbrough et al., 1987)
Chronic
Frusemide abuse (400 mg daily) was associated
with severe hyponatraemia and central pontine
myelinolysis (Copeland, 1989).
Surreptitious self-administration of
frusemide over 6 years resulted in
calcification of the renal medulla (Tajiri et
al., 1981).
7.2.1.2 Children
Acute
Nephrocalcinosis and nephrolithiasis occurred
in 5 children after treatment with frusemide
(Alon et al., 1994). Stafstrom et al. (1992)
also reported nephrocalcinosis in premature
infants being treated with frusemide.
Cholelithiasis in infants was caused by
frusemide (Randall et al., 1992).
Tachycardia following a high dose intravenous
regimen for frusemide (Wilson et al.,
1991).
Renal calcifications were encountered in
premature infants when given frusemide at a
dose of 2 mg/kg/day for 12 days (Hufnagle et
al., 1982).
Chronic
Frusemide-induced renal calcifications in low
birth weight infants may lead to glomerular
and tubular dysfunction in the long-term
(Downing et al., 1992; Ezzedeen et al, 1988)
7.2.2 Relevant animal data
LD50 (oral) rat >1000 mg/kg
LD50 (oral) mouse >1000 mg/kg
LD50 (oral) dog >1000 mg/kg
Intravenous values for the same test animal species
were one to two thirds lower. (Physician's Desk
Reference, 1995)
Chronic administration to rats at a dose of 50 mg/kg
has caused tubular degeneration in the kidneys.
Calcification and damage to the renal parenchyma
occurred in a subchronic study in dogs at 10 mg/kg
(McEvoy, 1995).
7.2.3 Relevant in vitro data
No data available.
7.3 Carcinogenicity
No carcinogenic studies on frusemide have been
undertaken (Physician's Desk Reference, 1995).
7.4 Teratogenicity
Developmental studies have been conducted in mice; rats
and rabbits. An increase in the incidence and severity of
hydronephrosis (distention of the renal pelvis and
occasionally the ureters) was seen in a mouse study and one
of three rabbit studies (Physician's Desk Reference, 1995;
McEvoy, 1995). In the absence of other data; such as the
doses administered; incidence in historical controls and the
no-effect-level; no conclusions can be drawn from this
information.
7.5 Mutagenicity
No mutagenicity tests on frusemide have been undertaken
(Physician's Desk Reference, 1995).
7.6 Interactions
Cephalosporin antibiotics
Frusemide may enhance the nephrotoxic effects of this class
of antibiotic; e.g. cephalothin (Reynolds; 1993).
Aminoglycoside antibiotics
Frusemide can enhance the ototoxic effects of this class of
antibiotic e.g. kanamycin; streptomycin; gentamicin
(Reynolds, 1993; Rybak, 1982).
Antihypertensive drugs
Frusemide enhances the hypotensive effects of
antihypertensives; particularly in combination with ACE
inhibitors such as captopril (Reynolds, 1993; Chan &
Critchley, 1992).
Antiepileptics
Antiepileptic drugs have been shown to reduce the diuretic
effect of frusemide to 51 to 68% of that achieved in healthy
subjects (Reynolds, 1993).
Indomethacin
Indomethacin decreases the diuretic; natriuretic and
antihypertensive effects of frusemide (Hansten, 1985; Shinn,
1988).
Chloral hydrate
Intravenous administration of frusemide to patients with
acute coronary disease and taking chloral hydrate has been
associated with uneasiness; diaphoresis; hot flushes and
hypertension (Hansten, 1985; Shinn, 1988;) Chloral hydrate
if used 24 hours prior to frusemide use may lead to a
reaction characterised by diaphoresis; flushing; uneasiness;
and hypertension (Malach et al., 1975; Pevonka et al., 1977).
Clofibrate
Frusemide and clofibrate may cause muscular pains and
stiffness and increased diuresis in patients with
hypoalbuminemia (Hansten, 1985).
Antidiabetic agents
The hypoglycaemic effect of insulin or oral antidiabetic
drugs may be reduced when frusemide is given concomitantly
(McEvoy, 1995).
Corticosteroids
Clinical observations indicate that this combination results
in severe potassium depletion; particularly in patients with
inadequate potassium intake (Hansten, 1995).
Tubocurarine
Limited evidence suggests that frusemide may enhance the
neuromuscular blockade effect of tubocurarine and
succinylcholine (Hansten, 1985; Physician's Desk Reference,
1995).
Lithium
Hansten (1985) quotes several cases where the evidence is
limited to show that concurrent treatment with lithium and
frusemide may reduce the clearance of lithium. McEvoy (1995)
also reports this interaction and suggests that if both drugs
are given concomitantly; the patient should be hospitalized
and dosing carefully monitored.
Digoxin
Frusemide may deplete potassium to a low level where the
sensitivity of the myocardium is increased and digoxin
toxicity may occur (TGA, 1991).
7.7 Main adverse effects
Hypovolemia was seen as the main adverse (dose-related)
effect associated with frusemide in a hospital drug
surveillance program involving 123 patients with a total of
177 adverse reactions with frusemide. Hypovolemia occurred in
85 cases (Lowe et al,1979).
The excessive dehydration which may occur in geriatric
patients and in patients with chronic heart disease (with
long-term sodium restriction); who are being treated with
frusemide; may give rise to hypovolaemia and consequential
serious complications such as circulatory collapse and
potentially fatal vascular thromboses and/or emboli. In rare
instances; death has occurred; following parenteral
administration of frusemide (McEvoy, 1995).
8. TOXICOLOGICAL/TOXINOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
8.1 Material sampling plan
8.1.1 Sampling and specimen collection
8.1.1.1 Toxicological analyses
8.1.1.2 Biomedical analyses
8.1.1.3 Arterial blood gas analysis
8.1.1.4 Haematological analyses
8.1.1.5 Other (unspecified) analyses
8.1.2 Storage of laboratory samples and specimens
8.1.2.1 Toxicological analyses
8.1.2.2 Biomedical analyses
8.1.2.3 Arterial blood gas analysis
8.1.2.4 Haematological analyses
8.1.2.5 Other (unspecified) analyses
8.1.3 Transport of laboratory samples and specimens
8.1.3.1 Toxicological analyses
8.1.3.2 Biomedical analyses
8.1.3.3 Arterial blood gas analysis
8.1.3.4 Haematological analyses
8.1.3.5 Other (unspecified) analyses
8.2 Toxicological Analyses and Their Interpretation
8.2.1 Tests on toxic ingredient(s) of material
8.2.1.1 Simple Qualitative Test(s)
8.2.1.2 Advanced Qualitative Confirmation Test(s)
8.2.1.3 Simple Quantitative Method(s)
8.2.1.4 Advanced Quantitative Method(s)
8.2.2 Tests for biological specimens
8.2.2.1 Simple Qualitative Test(s)
8.2.2.2 Advanced Qualitative Confirmation Test(s)
8.2.2.3 Simple Quantitative Method(s)
8.2.2.4 Advanced Quantitative Method(s)
8.2.2.5 Other Dedicated Method(s)
8.2.3 Interpretation of toxicological analyses
8.3 Biomedical investigations and their interpretation
8.3.1 Biochemical analysis
8.3.1.1 Blood, plasma or serum
"Basic analyses"
"Dedicated analyses"
"Optional analyses"
8.3.1.2 Urine
"Basic analyses"
"Dedicated analyses"
"Optional analyses"
8.3.1.3 Other fluids
8.3.2 Arterial blood gas analyses
8.3.3 Haematological analyses
"Basic analyses"
"Dedicated analyses"
"Optional analyses"
8.3.4 Interpretation of biomedical investigations
8.4 Other biomedical (diagnostic) investigations and their
interpretation
8.5 Overall interpretation of all toxicological analyses and
toxicological investigations
Sample collection
Levels of diuretics are rarely available or clinically
useful; with the possible exception of alleged use or abuse
in patients that present with unexplained fluid and/or
electrolyte abnormalities or in suspected Munchausen syndrome
or Munchausen-by-proxy patients. If necessary; these levels
would be checked in a routine serum collection.
Biomedical analysis
Analysis should be targeted to the expected electrolyte
abnormalities including sodium; potassium; chloride; and
bicarbonate measurements in the mildly to moderately ill
patient. Blood gas analysis may be necessary in the more
severely ill patient or when one needs to more precisely
define the acid-base disturbance that may be present. In
more chronic use or abuse or in patients with muscular
weakness or arrhythmias; magnesium and calcium levels may be
necessary to define their depletion and guide replenishment.
If drug abuse of any kind is suspected; a general urine drug
screen may be indicated.
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
Oral ingestion is the usual means of exposure
outside of a health care facility. The clinical
effects are the same as those described in Section
2.2.
9.1.2 Inhalation
Not relevant.
9.1.3 Skin exposure
There is no appreciable dermal absorption.
9.1.4 Eye contact
There is no appreciable absorption or local
irritation.
9.1.5 Parenteral exposure
Frusemide is used intravenously in acute volume
overload states but would not be available outside of
a health care facility. The clinical effects are the
same as those described in Section 2.2.
9.1.6 Other
Not relevant.
9.2 Chronic poisoning
9.2.1 Ingestion
As in acute poisoning.
9.2.2 Inhalation
Not relevant.
9.2.3 Skin exposure
As in acute poisoning.
9.2.4 Eye contact
As in acute poisoning.
9.2.5 Parenteral exposure
As in acute poisoning.
9.2.6 Other
Not relevant.
9.3 Course; prognosis; cause of death
The great majority of acute overdoses; especially in
otherwise healthy individuals are benign and with simple
symptomatic care should have an excellent outcome. Patients
that are on chronic therapy and presenting with complications
thereof may have a worse prognosis especially if not
recognized by the clinician. Long-term therapy with
diuretics must be monitored closely. Patients on long-term
therapy who present with acute problems should be
specifically evaluated for volume status and electrolyte and
acid-base abnormalities including metabolic alkalosis.
Patients that present with arrhythmias or seizures that are
on diuretics should be rapidly evaluated for hyponatremia;
hypokalemia; and hypomagnesemia. Patients that present with
unexplained fluid or electrolyte abnormalities should be
evaluated for possible diuretic abuse. Prognosis should also
be excellent in these patients if these potential
abnormalities are quickly evaluated and treated according to
severity. Treatment should be based on the patient's
condition and not strictly on the amount ingested.
Deaths; though rare; do occur; not directly from the drug;
but complications in its use or abuse; namely arrhythmias and
seizures from electrolyte abnormalities or cardiac or renal
dysfunction secondary to volume depletion.
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
Frusemide may cause postural hypotension and
syncope (particularly in conjunction with hypotensive
drugs) because of its transient but potent vasodilator
properties (Dukes, 1988). Arrhythmias may result from
hypokalemia but are usually not life-threatening
unless digoxin is also being administered and are
self-limited with potassium replenishment. Myocardial
function may be impaired due to hypovolemia in
patients with marginal function who require high
ventricular loading pressures. There was a series of
three pediatric post-operative cardiac patients that
developed SVT during frusemide infusion resulting in
large fluid and electrolyte shifts (Wilson et al.,
1991). Hypomagnesemia may also be a major contributor
to these ventricular arrhythmias. Hypomagnesemia
decreases intramyocardial magnesium content which is a
necessary cofactor in the sodium-calcium-ATPase pump
(Reyes et al., 1984). Use of frusemide in premature
neonates may increase the risk of patent ductus
arteriosus (McEvoy, 1995).
9.4.2 Respiratory
No known effects.
9.4.3 Neurological
9.4.3.1 Central Nervous System (CNS)
May be manifested as lethargy and
generalized weakness. There may be seizures
due to hyponatremia. Vertigo; headache;
xanthopsia; blurred vision and paresthesias
have been reported (McEvoy, 1995).
9.4.3.2 Peripheral nervous system
May demonstrate hyporeflexia due to
hypokalemia.
9.4.3.3 Autonomic nervous system
There are no known effects.
9.4.3.4 Skeletal and smooth muscle
There may be muscle weakness in both
skeletal and smooth muscle due to
hypokalemia. There is a report of
rhabdomyolysis in a patient with symptomatic
hypomagnesemia secondary to surreptitious
frusemide use and a report of rhabdomyolysis
secondary to hypokalemia due to frusemide use
(Shintani et al., 1991; Brucato et al.,
1993).
9.4.4 Gastrointestinal
Oral ingestion may cause nausea; vomiting;
cramping; diarrhea and constipation (McEvoy, 1995).
There have been reports of GI bleeding in patients
taking frusemide especially with concurrent renal
insufficiency. Chronic use or abuse may result in
pancreatitis which may been immune-mediated and may be
associated with hyperlipidemia (Call et al., 1977).
An increased incidence of neonatal cholelithiasis has
been reported in newborns treated with TPN and
frusemide (Randall et al., 1992; Callahan et al.,
1982).
9.4.5 Hepatic
Frusemide may induce hepatic coma in patients
with pre-existing liver failure by an unknown
mechanism (Dukes, 1988).
9.4.6 Urinary
9.4.6.1 Renal
Excessive diuresis and dehydration
may cause a transient decrease in glomerular
filtration rate and elevation of serum BUN.
Incorrect or unmonitored use may exacerbate
underlying renal insufficiency due to a
multitude of conditions including diabetes
mellitus; chronic hypertension; cystic kidney
disease; collagen vascular disease;
radiocontrast nephropathy; or gout (Weinstein
et al., 1992). Nephrocalcinosis and
nephrolithiasis has been frequently reported
in premature infants treated with frusemide
in the neonatal ICU for congestive heart
failure or pulmonary disease (Alon et al.,
1994; Downing et al., 1992; Ezzedeen et al.,
1988). Urinary bladder spasms; frequency and
flank pain have been reported (McEvoy, 1995).
9.4.6.2 Other
May lead to urinary incontinence in
the elderly and urinary retention in patients
with prostatism (Dukes 1988).
9.4.7 Endocrine and reproductive systems
Frusemide may induce hypoglycaemia or
glycosuria and in rare cases has been reported to have
precipitated diabetes mellitus (McEvoy, 1995; TGA,
1991).
Rare cases of inappropriate antidiuretic hormone
secretion syndrome (IADHS) involving severe potassium
loss have been reported (Dukes, 1988). Hyperglycemia
may result with acute or chronic use or overdose and
is usually self-limited.
9.4.8 Dermatological
May lead to bullous lesions when used in high
doses in patients with pre-existing renal failure
(Goldfrank, 1994). Bullous hemorrhagic eruption
manifested as a prominent purpuric eruption with
multiple tense subepidermal bullae (Guin, 1980). Other
reports of bullous reactions associated with frusemide
use appear in the literature. Purpura;
photosenstivity; rash; urticaria; pruritis; erythema
multiforme; exfoliative dermatitis; and necrotizing
angiitis have been reported (McEvoy, 1995).
9.4.9 Eye; ear; nose; throat: local effects
High dose frusemide especially if given rapidly
intravenously may result in significant ototoxicity
including tinnitus; and temporary or irreversible
deafness (Dukes, 1988; Reynolds, 1993; McEvoy, 1995;
Brown et al., 1991; David and Hitzig, 1971; Gallagher
and Jones, 1979; Rybak, 1982); and was associated
with neonatal sensorineural hearing loss in patients
that received it in the nursery even after controlling
for all other known risk factors (Brown et al.,
1991).
9.4.10 Haematological
Rare immune-mediated thrombocytopenia has been
reported (Duncan et al., 1981). Agranulocytosis;
anemia; hemolytic anemia; leukopenia; and neutropenia
have been reported McEvoy; 1995; Dukes; 1988).
9.4.11 Immunological
There have been rare reports of
hypersensitivity reactions (Goldfrank, 1994).
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
Chronic use has resulted in a
hypochloremic/hypokalemic metabolic alkalosis
and can be seen to a lesser degree in acute
overdose (Laudignon et al., 1989).
9.4.12.2 Fluid and electrolyte disturbances
Acute or chronic use or abuse can
result in dehydration due to free water and
electrolyte loss. Electrolyte abnormalities
may include hyponatremia; hypokalemia; and
hypochloremia. To a lesser degree and usually
on a more chronic basis significant
hypomagnesemia and hypocalcemia may result.
There has been a report of life-threatening
hyperkalemia in a patient being treated
concurrently with frusemide and an
angiotensin converting enzyme inhibitors and
potassium supplements (Chan et al.,
1992).
Hypokalaemia was seen as a prominent adverse
(dose-related) effect associated with
frusemide in a hospital drug surveillance
program involving 123 patients with a total
of 177 adverse reactions with frusemide.
Hypokalaemia occurred in 21 cases. (Lowe et
al., 1979). Furosemide does not promote
reabsorption of calcium in the distal tubule
and may cause transient hypercalcaemia in
adults. In premature infants it may cause
secondary hyperparathyroidism causing
skeletal calcium loss with excretion rates 10
to 20 times those of normal children. This
effect has caused renal calcification (Dukes,
1988; Reynolds, 1993).
9.4.12.3 Others
Hyperuricaemia has been associated
with frusemide therapy; with precipitation of
gouty attacks and the need for treatment
(Dukes, 1988). Hyperuricaemia was seen as the
main adverse (dose-related) effect associated
with frusemide in a hospital drug
surveillance program involving 123 patients
with a total of 177 adverse reactions with
frusemide. Hyperuricaemia occurred in 54
cases. (Lowe et al., 1979). Hyperuricemia
and hyperlipidemia may result following
chronic use. There is a case report of
initiation of gouty tophi in an elderly
patient recently started on frusemide
(Wordsworth et al., 1985).
9.4.13 Allergic reactions
There are rare true allergic reactions
reported to frusemide. One case report documented
anaphylaxis to intravenous frusemide with a positive
skin test to it and to a related sulfonamide compound
(Hansbrough et al., 1987).
9.4.14 Other clinical effects
Salicylates share competitive renal excretory
sites with frusemide so concomitant use may increase
salicylate levels (Goldfrank, 1994).
Frusemide may decrease the effects of oral
antidiabetic medications and insulin by increasing the
blood glucose level (Dean et al., 1991).
The resulting hypokalemia may exacerbate underlying
digoxin toxicity.
Diuretics may also enhance the toxicity of lithium
(Hurtig et al., 1974).
There may be decreased GI absorption of frusemide when
it is taken concurrently with phenytoin (Fine et al.,
1977).
9.4.15 Special risks
As noted above special risks with frusemide
use or overdose exist in patients with pre-existing
renal disease or fluid and/or electrolyte
abnormalities. Excess ototoxicity will be seen in
patients taking other ototoxins (eg. aminoglycosides).
There is documented placental transfer of frusemide;
at least during the peripartum period; with equal cord
and maternal levels 8 hours after an oral dose; with
more diuresis and higher potassium levels in urine in
the newborns (Beerman et al., 1978). Frusemide is
classified by the FDA as a Category C in pregnancy:
"only given after risks to the fetus are considered;
animal studies have shown adverse reactions; no human
studies available" (Briggs et al., 1990). As with all
diuretics; it is not recommended for the treatment of
toxemia. Frusemide is secreted in breast milk but no
adverse effects have been reported in breast-fed
infants (Briggs et al., 1990).
9.5 Other
None identified.
10. MANAGEMENT
10.1 General principles
Since diuretic overdoses are usually benign; aggressive
decontamination procedures are not warranted. Treatment is
symptomatic in nature and is directed at correcting any fluid
and/or electrolyte abnormalities. More aggressive management
may be necessary in the patient with underlying abnormalities
including renal insufficiency; fluid and/or electrolyte
abnormalities; myocardial dysfunction; or taking other
potentially toxic medications such as digoxin or an
aminoglycoside antibiotics; or in patients with chronic
overuse or abuse. The aggressiveness of treatment must be
targeted to the severity of toxicity and the underlying acute
or chronic nature of the ingestion.
10.2 Life supportive procedures and symptomatic/specific treatment
Life supportive measures are usually not necessary and
may only be needed in potentially life-threatening
arrhythmias seen with hypokalemia (especially with concurrent
digoxin use) and with seizures secondary to hyponatremia;
both fairly rare complications. Symptomatic treatment is
directed at fluid/electrolyte repletion; initially with
intravenous isotonic crystalloid solutions. Depending on the
severity of volume depletion; this can be administered
initially as rapid boluses in the range of 1 to 2 L in the
adult patient or 10 to 20 mL/kg in the pediatric patient.
Further repletion should be based on clinical response to the
first bolus and definitive blood chemistry analysis. Care
must be taken in bolusing patients with underlying renal or
cardiac insufficiency that may make them more prone to fluid
overload and pulmonary edema.
In cases of severe hyponatremia resulting in seizures;
attention must be made to assess the patient's airway;
breathing; and circulation status. Seizures should be
controlled with standard anticonvulsant therapy.
Arrhythmias associated with hypokalemia usually are not
malignant and will respond to judicious potassium
replacement. If arrhythmias are life-threatening in nature;
and while replenishing potassium; the usual ventricular
antiarrhythmic agents are utilized. In the chronic use or
abuse of diuretics; hypomagnesemia may contribute to
ventricular arrhythmias especially torsades de pointe and
replacement therapy in an urgent manner may terminate these
arrhythmias without resorting to potentially toxic
medications. The dose would be magnesium sulfate 2 to 4 g
intravenously diluted to 100 to 250 mL over 15 to 30 minutes
(40 to 80 mg/kg for pediatric patients; suitably
diluted).
10.3 Decontamination
Since these ingestions are usually benign or are
associated with hypovolemia; specific measures such as
inducing vomiting or administering cathartics are
contraindicated. If the patient presents early; certainly in
less than 2 hours; and with a large ingestion or has
underlying cardiac; renal; or hepatic insufficiency; then a
dose of activated charcoal is probably indicated. Activated
charcoal administered 5 minutes after frusemide ingestion
greatly decreased absorption (Neuvonen et al., 1988); but
administration one hour after ingestion was no better than
administration of water alone (Kivisto and Neuvonen, 1990).
Certainly; in otherwise normal children with a limited acute
accidental ingestion; no Gastrointestinal decontamination is
warranted.
10.4 Enhanced elimination
There is no role for enhanced elimination.
10.5 Antidote treatment
10.5.1 Adults
There is no antidote for any of the diuretics.
10.5.2 Children
There is no antidote for any of the diuretics.
10.7 Management discussion
Since these ingestions are usually benign with rare
serious complications and the treatment is only supportive
and symptomatic; there are no controversies in the management
and no identification of research needs.
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
A 31 year old male had a syncopal episode five hours
after ingestion of 160 mg of frusemide; and recovered without
sequellae after hydration. A 25 year old female developed
syncope; nausea; vomiting; and dizziness; and hyponatremia
and hypokalemia after taking 200 mg orally daily for three
days and also fasting (Niezgoda et al., 1989).
12. Additional information
12.1 Specific preventive measures
For children; the usual preventive measures (eg. child-
proof caps and anticipatory guidance from primary care
givers) should decrease the incidence of accidental
ingestions. In adults; intentional overdoses are rarely a
significant problem; but chronic or surreptitious use needs
to be carefully considered and/or monitored to decrease
morbidity from frusemide use.
12.2 Other
No data available.
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14. AUTHOR(S); REVIEWER(S); DATE(S) (INCLUDING UPDATES); COMPLETE
ADDRESS(ES)
Authors: Dr Craig R. Warden; MD
Dr Jefferey L. Burgess; MD
Washington Poison Center
155 NE 100th St.; Suite 400
Seattle WA 98125
USA
Date: 10 October 1995
Peer Review: Berlin; Germany; October 1995
Editor: Dr M. Ruse (July, 1997)