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Furosemide

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Main brand names, main trade names
   1.6 Manufacturers; Importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/form
      3.3.3 Description
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Storage conditions
4. USES
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF EXPOSURE
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination and excretion
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
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
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological 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
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course; prognosis; cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central Nervous System (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye; ear; nose; throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic/specific treatment
   10.3 Decontamination
   10.4 Enhanced elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.7 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
12. Additional information
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S); REVIEWER(S); DATE(S) (INCLUDING UPDATES); COMPLETE ADDRESS(ES)
    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 (20C)
    
                    (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 30C.
    
                    (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)
    


    See Also:
       Toxicological Abbreviations