About Furosemide 

Furosemide is widely recognised and used clinically in veterinary medicine as a loop diuretic and is the core diuretic recommended in ACVIM MMVD consensus protocols (Keene et al., 2019). 

Furosemide has a vasodilatory effect that precedes diuresis and may confer its immediate benefit in patients with volume overload (Abbott and Kovacic, 2008).  

Furosemide Pharmacology 

A sulfamoyl-anthranilic acid derivative is a rapid-onset high-ceiling loop diuretic. Furosemide increases nephron filtration volume and impairs sodium, chlorine, and water re-absorption. Potassium excretion increases with dose (Abbott and Kovacic, 2008; Adin et al., 2017, 2003; Berg and Loew, 1977; Cohen et al., 1976; Ding et al., 2016; Harada et al., 2015; Hori et al., 2010, 2007; Lee et al., 1986; Ochoa et al., 2006; Raisbeck et al., 1983; Sayer et al., 2009; Scruggs and Rishniw, 2013; Uechi et al., 2003). 

Other Roles:  Furosemide demonstrates a wide spectrum of pharmacologic activity. 

• Furosemide can be inhaled to relieve dyspnea in patients with bronchospasm (Abbott and Kovacic, 2008). 

• Furosemide shows promise as an adjunct to antiseizure therapy to help control epilepsy, status epilepticus, and acute ischemic damage related to seizures (Abbott and Kovacic, 2008). 

UK Formulations

• Injection: 50 mg/ml Solution for Injection

• Tablets: 10 mg, 20 mg, 40 mg tablets

• Oral Liquids: 20 mg/5 ml Oral Solution and 10mg/ml Oral Solution

Sole Use

• Chronic Diuretic monotherapy in the management of cardiac failure should be avoided, as patients receiving diuretics alone may deteriorate more rapidly than those receiving other treatment modalities.

Multimodal Use

• We recommend following ACVIM and similar consensus guidelines for disease staging and the use of Furosemide in MMVD-related canine heart failure.  This usually involves additional Pimobendan.  Additional medications may differ during stabilisation and maintenance of MMVD Stage C, which is detailed within this monograph. 

Treatment Goals 

To maintain patient comfort at each stage of MMVD and prolong the length and quality of life of MMVD patients at each ACVIM stage.

Assessing any improved quality of life of patients with MMVD receiving Furosemide currently relies upon a subjective, case-by-case judgement; however, there is a clear case for a future focus on the cost and quantity of beneficial quality-adjusted life years (QALYs) achieved through specific Furosemide protocols (Cohen et al., 2018; Neumann et al., 2018, 2016; Neumann and Cohen, 2018; Neumann and Kim, 2023; P Neumann and Cohen, 2015). 

• Organ Level: Treatment aims to reduce oedema and ascites, improve cardiac function in canine patients with MMVD, and slow, halt, or reverse the progression and stage of MMVD.

• Patient Level: The treatment objective is to increase the quality and quantity of survival time for patients with MMVD and to slow, halt or reverse the disease progression. 

• Client level:  The goal of treatment is to offer a value-for-money increase in beneficial quality-adjusted life years (QALYs)  to clients with dogs experiencing MMVD.

Treatment End Point 

• The duration of treatment is unlimited and so usually lifelong until death or euthanasia (Keene et al., 2019).

Therapeutic Monitoring

Renal function, hydration status and serum electrolytes status should be monitored (Serum electrolytes, BUN, creatinine, SDMA +/- glucose if diabetic):

• When treatment is commenced

• 24-48h post commencement

• 24-48h post-dose adjustment

• If adverse events occur.

Additionally, patients will benefit from regular physical assessments covering. Heart rate and quality, respiratory rate and effort (resting and sleeping), blood pressure, signs associated with oedema, thirst, urine output and weight.

Efficacy Profile

Furosemide is an effective high ceiling small animal loop diuretic (Abbott and Kovacic, 2008; Adin et al., 2017, 2003; Berg and Loew, 1977; Cohen et al., 1976; Ding et al., 2016; Harada et al., 2015; Hori et al., 2010, 2007; Lee et al., 1986; Ochoa et al., 2006; Raisbeck et al., 1983; Sayer et al., 2009; Scruggs and Rishniw, 2013; Uechi et al., 2003).

Several studies compare its action to torasemide which is not available as an injectable product in the UK at time of writing (Hori et al., 2007; Uechi et al., 2003).

• Potency: Torsemide is 10 to 20 times more potent as a loop diuretic than Furosemide.

• Bioavailability: Torsemide has higher bioavailability and a longer duration of action than Furosemide, with reduced comparative calciuresis and kaliuresis.

Adverse Effects

• Azotaemia: Elevations in BUN and creatinine are seen. Long-term outcomes do not show that azotaemic qualities have detrimental patient effects.

• Dehydration: Due to the diuretic action of furosemide, there may be hemoconcentration and impairment of circulation.

• Electrolyte Derangement: Electrolyte deficiency (including hypokalemia & hyponatremia) and dehydration may occur with prolonged treatment.

Sulphonomide Sensitivity: Cross-reactivity to sulfonamides is possible.

Contraindications

• Circulatory Compromise: Do not use Furosemide in hypovolaemia, hypotension or dehydration.

• Compromised Cardiac Output: A marked reduction in cardiac output can occur in animals with severe pulmonary disease, hypertrophic cardiomyopathy, pericardial or myocardial disorders, cardiac tamponade and severe hypertension.

• Electrolyte Derangement: Do not use Furosemide where there is known or suspected electrolyte deficiency. Do not use it in the presence of anuria, depleted electrolytes, or significant dehydration.

• Excessive Dose: Do not use 40 mg tablets in patients weighing less than 4 kg.

• Excessive Water Access: Therapeutic efficacy may be impaired by increased drinking water intake. Water intake should be restricted during treatment where the animal's condition permits.

• Hypersensitivity: Do not use in cases of hypersensitivity to furosemide, sulfonamides, or excipients.

• Interactive Medications:  Monitoring plasma potassium levels is advisable during prolonged combined therapy treatment with Cardiac Glycosides. Potassium supplements may be necessary. Allergic reactions have been associated with the use of Sulphonamides. Do not use concurrently with Aminoglycoside antimicrobials. Do not use concurrently with Cephalosporin antimicrobials.

• Nephropathy: Do not use in animals with acute glomerular nephritis, renal failure with anuria, or electrolyte deficiency disease.

Reproductive Safety

• Pregnancy Avoid Use. Furosemide crosses the placenta. Embryotoxic effects (foetal urinary tract malformation) were seen in trials with laboratory animals at maternally non-toxic doses. However, some UK products are authorised for use during reproduction and lactation (SPC data).

• Lactation: Avoid Use. Furosemide is excreted in milk and may affect nursing offspring. However, some UK products are authorised for use during reproduction and lactation  (SPC data).

• Male Fertility: Avoid Use. The effects are unknown  (SPC data).

• Female Fertility: Avoid Use. The effects are unknown (SPC data).

Neonates: Avoid Use. The effects are unknown (SPC data).

Overdose

• Acute: Dehydration. electrolyte and water imbalances. This may present as depressed mentataion, akinesia,  seizures, and cardiovascular collapse.

• Chronic: Typically electrolyte derrangements such as hypokalamia are seen.

Potential Interactions

• Anti-Arrhythmic Medications (including Amiodarone and Sotalol): Increased risk of cardiac toxicity because of Furosemide-induced hypokalaemia. Antagonism of effects of Lidocaine, Tocainide or Mexiletine possible.

• Anti-Diabetic Medications: Antagonism of hypoglycaemic effects.

• Anti-Hypertensive Medications: Enhanced hypotensive effect possible with all types. Concurrent use with ACE inhibitors or Angiotensin II receptor antagonists can result in marked falls in blood pressure; Furosemide should be stopped or the dose reduced before starting an ACE inhibitor or Angiotensin II receptor antagonists. Increased risk of first-dose hypotension with post-synaptic alpha-blockers (e.g. Prazosin). Enhanced hypotensive effect with Phenothiazines.

• Antihistamines: Hypokalaemia with increased risk of cardiac toxicity.

• Antimicrobials: Increased risk of ototoxicity with Aminoglycosides, Polymixins or Vancomycin. Increased risk of nephrotoxicity with Aminoglycosides or Cefaloridine. Increased risk of hyponatraemia with Trimethoprim.

• Anxiolytics and Hypnotics: Enhanced hypotensive effect of some agents.

• Cardiac Glycosides: Increased risk of cardiac toxicity (because of Furosemide-induced hypokalaemia and electrolyte disturbances, including hypomagnesaemia).

• Corticosteroids: Increased risk of hypokalaemia, sodium retention and possible antagonism of diuretic effect.

• Cytotoxics: Increased risk of nephrotoxicity and ototoxicity with platinum compounds/Cisplatin.

• NSAIDs: Increased risk of nephrotoxicity (especially with pre-existing hypovolaemia/dehydration. Indometacin and Ketorolac may antagonise the effects of Furosemide.

• Oestrogens: Diuretic effect antagonised.

• Other diuretics: Possible severe additive effect. Increased risk of hypokalaemia with Thiazide diuretics. Contraindicated concurrently with some potassium-sparing diuretic products (e.g. Amiloride/ Spironolactone) - increased risk of hyperkalaemia.

• Potassium Salts: Contraindicated due to significant risk of hyperkalaemia.

• Salicylates: Effects potentiated by Furosemide. Salicylic toxicity is increased.

• Sympathomimetics: Increased risk of hypokalaemia with high doses of beta2 sympathomimetics.

• Tetracyclines: Increased risk of azotaemia.

• Torsades de pointes: Increased risk of cardiac toxicity when used alongside drugs that prolong Q-T interval because of Furosemide-induced hypokalaemia and other electrolyte disturbances.

• Vasodilators: Enhanced hypotensive effect possible, e.g. with Hydralazine.

Alternative Products 

Other Diuretics

• Amiloride

• Hydrochlorothiazide

• Spironolactone

• Torasemide

Alternative Protocols

• VCI recommends the ACVIM protocols for MMVD. Where additional material is identified, it supplements existing ACVIM consensus protocols.