Frusemide

OVERVIEW

• frusemide is a loop diuretic, known as furosemide in North America
• cost in NZ$: 250mg IV $8.99, 20mg IV 59 cents, 40mg tablets 1 cent

INDICATIONS

Diuretic used in settings such as:

• fluid overload
• ARDS
• congestive heart failure
• AKI
• Hypercalcaemia (requires rehydration first)

PRESENTATION AND ADMINISTRATION

Oral

• Tablets: Diurin 40mg tablets (off white), Diurin 500mg tablets (off white)
• Oral Solution: Lasix oral solution 10mg/ml

Intravenous

IV formulations available are:

1. Frusemide injection 20mg/2ml solution
2. Lasix high dose infusion 250mg in 25ml with 1000mg of mannitol as a stabilising agent

• Administer doses of up to 80mg by slow IV injection over 2-5 minutes
• For infusion doses of up to 5mg/hr use low dose infusion mixture of 40mg in 40ml of compatible IV fluid; for infusion doses of greater than 5mg/hr use high dose infusion mixture with undiluted Lasix high dose infusion (ie 250mg in 25ml or 500mg in 50ml)
• Rate of infusion should not exceed 4mg/min
• Compatible with the following IV fluids:
  • Normal saline, Hartmann’s
  • Note: glucose solutions are unsuitable
• Store at room temperature; protect from light
• Dilutions in compatible IV fluid are stable for 24 hours at room temperature – discard if not used within 24 hours. Do not use if solutions have a yellow colour or contain crystal deposits

DOSAGE

• PO:
  Usual dosage from 10mg daily to 80mg three times a day
• IV:
  Dosage is highly individualised. 5mg may be sufficient to cause significant diuresis in the frusemide naïve patient. Doses of 100mg/hr by infusion may be required in those with significant renal impairment.

Renal failure and renal replacement therapy

• Dose in renal impairment [GFR (ml/min)]
  <10: dose as in normal renal function; increased doses may be required
  10-20: dose as in normal renal function; increased doses may be required
  >20-50: dose as in normal renal function
• Dose in renal replacement therapy
  CAPD: not indicated
  HD: not indicated
  CVVHDF: rarely indicated; increased doses may be required

Paediatrics

• IV/ PO:
  Usually, 0.5-1mg/kg 6 hourly to four times a day.
  IV infusion: 50mg/kg in 50ml of normal saline at 0.1-1 mg/kg/hr (i.e 0.1-1ml/hr)

CLINICAL PHARMACOLOGY

• Frusemide is a potent diuretic that inhibits the absorption of sodium and chloride in the proximal and distal tubules and the loop of Henle

PHARMACOKINETICS

• Absorption:
  Poor oral bioavailability (possibly due to the poor solubility of the compound, site-specific absorption, presystemic metabolism and/or other unknown mechanisms). Diuretic effect onset is within 1 hour following oral administration and the peak effect occurs within 1-2h. The duration of action is 4-6h (up to 8h).
  Following IV administration diuresis occurs within 30 min and duration of action is~ 2h.
• Distribution: highly bound to plasma proteins, almost exclusively to albumin. Although the drug is insoluble in water and favours partitioning into fatty tissue, the high degree of plasma protein binding restricts the apparent volume of distribution at steady-state to values within a multiple of 2 to 5 times the plasma volume
• Metabolism: a small fraction is metabolised by the liver
• Elimination: 2/3 renal (by both glomerular filtration and proximal tubular secretion), 1/3 biliary (as faeces)

DRUG INTERACTIONS

• Frusemide may increase the ototoxic potential of aminoglycoside antibiotics, especially in the presence of impaired renal function. Except in life-threatening situations, avoid this combination.
• Lithium generally should not be given with diuretics because they reduce lithium’s renal clearance and add a high risk of lithium toxicity.
• Allergy to sulfa drugs

ADVERSE REACTIONS

• Gastrointestinal System Reactions:
  Pancreatitis, jaundice (intrahepatic cholestatic jaundice), anorexia, oral and gastric irritation, cramping, diarrhea, constipation, nausea, and vomiting.
• Systemic Hypersensitivity Reactions:
  Systemic vasculitis, interstitial nephritis, and necrotizing angiitis.
• Central Nervous System Reactions:
  Tinnitus and hearing loss, paresthesia, vertigo, dizziness, headache, blurred vision, and xanthopsia.
• Hematologic Reactions:
  Aplastic anemia (rare), thrombocytopenia, agranulocytosis (rare), hemolytic anemia, leukopenia, and anemia.
• Dermatologic-Hypersensitivity Reactions:
  Exfoliative dermatitis, erythema multiforme, purpura, photosensitivity, urticaria, rash, and pruritus.
• Cardiovascular Reaction:
  Orthostatic hypotension may occur and be aggravated by alcohol, barbiturates or narcotics.
• Other Reactions:
  Hyperglycemia, glycosuria, hyperuricemia, muscle spasm, weaknesses, restlessness, urinary bladder spasm, thrombophlebitis, and fever.

EVIDENCE

• The primary role of diuretics in the critically ill is in adjusting overall fluid balance. ARDSNet investigators found that a conservative strategy of fluid management (due to fluid restriction and/or diuretics) improved lung function and shortened the duration of mechanical ventilation and intensive care without increasing nonpulmonary-organ failures.
• In critically ill patients with acute renal failure, there is no evidence to suggest that the use of loop diuretics reduces mortality, reduces length of ICU or hospital stay, or increases the recovery of renal function.
• Co-administration of albumin with furosemide may help overcome diuretic resistance in hypoalbuminemic patients (modest effect suggested in meta-analysis)
• Furosemide by continuous infusion in the recovery phase of hemofiltration-dependent acute kidney failure did increase urinary volume and sodium excretion but did not lead to a shorter duration of renal failure or more frequent renal recovery.

References and Links

• Bagshaw SM, Delaney A, Haase M, Ghali WA, Bellomo R. Loop diuretics in the management of acute renal failure: a systematic review and meta-analysis. Crit Care Resusc. 2007 Mar;9(1):60-8. PMID: 17352669.
• Bagshaw SM, Bellomo R, Kellum JA. Oliguria, volume overload, and loop diuretics. Crit Care Med. 2008 Apr;36(4 Suppl):S172-8. PMID: 18382190.
• Ho KM, Power BM. Benefits and risks of furosemide in acute kidney injury. Anaesthesia. 2010 Mar;65(3):283-93. PMID: 20085566.
• Kitsios GD, Mascari P, Ettunsi R, Gray AW. Co-administration of furosemide with albumin for overcoming diuretic resistance in patients with hypoalbuminemia: a meta-analysis. J Crit Care. 2014 Apr;29(2):253-9. PMID: 24268626. [Free Full Text]
• Mehta R L, Pascual M T, Soroko S. et al. Diuretics, mortality, and nonrecovery of renal function in acute renal failure. JAMA 2002;288(20):2547-53. [PubMed]
• National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, deBoisblanc B, Connors AF Jr, Hite RD, Harabin AL. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006 Jun 15;354(24):2564-75. PMID: 16714767.
• Uchino S, Doig G S, Bellomo R. et al. Beginning and Ending Supportive Therapy for the Kidney (B.E.S.T. Kidney) Investigators. Diuretics and mortality in acute renal failure. Crit Care Med2004;32(8):1669-77. [PubMed]
• Worthley LI. “I gave her a litre of saline and then some frusemide to ‘kick’ the kidneys along”. Crit Care Resusc. 2004 Mar;6(1):71-2. PMID: 16563109.