Loop Diuretics

Synonyms: high ceiling diuretics

Loop diuretics are powerful and rapid-acting diuretics. They have more than twice the potency of thiazides and four times the potency of amiloride.¹ Their prime use is in the treatment of heart failure, both acute left ventricular and chronic heart failure. They provide symptom relief but are not thought to alter disease course. In Europe, almost 90% patients with heart failure receive them, despite underprescribing of other evidence-based medication (ACEIs and β-blockers).²

Loop diuretics licensed in the UK are:

1. Furosemide (frusemide)
2. Bumetanide
3. Torasemide

No one loop diuretic has been shown to be more efficacious than another in treating cardiac failure. Bumetanide tends to be used in patients who are allergic or resistant to furosemide. Torasemide has a longer duration of action so is sometimes used in the treatment of hypertension.
Bumetanide and torasemide are better absorbed than furosemide - on average 80-100% absorption compared to 50% with furosemide so may be more effective where absorption is an issue, for example, with an acutely oedematous gut.³

Mode of action

• Na⁺/K⁺/Cl^--transporter blockade - loop diuretics block the Na⁺/K⁺/Cl^--transporter in the thick ascending loop of Henlé. This inhibits salt and water reabsorption.^4,5 Compared to thiazides, loop diuretics result in greater urine formation and relatively less urinary sodium and potassium loss.¹ Additionally, furosemide has some action at both the proximal and distal tubules, while bumetanide has exhibited indirect effects on the proximal tubule. Torasemide exerts no action at the proximal tubule, and this may account for its decreased kaliuresis.
• Extrarenal effects - loop diuretics acutely increase venous capacitance and systemic vascular resistance and chronically decrease cardiac preload.¹
• Pharmacokinetics - onset of action occurs within an hour of oral administration with a peak between 1-2 hours and is over within 3-4 hours so that twice daily dosing is possible without interfering with sleep.^4,5 With IV administration, peak effect occurs within 30 minutes and is complete by approximately 4 hours. IV furosemide can be given as intermittent boluses or as a continuous infusion (e.g. after cardiac surgery⁶ or in acute congestive cardiac failure⁷).
• Resistance - over time, resistance to loop diuretics may develop and those on long term diuretics may need their regular dose increased to get the same effect and require very high doses when they present acutely compared to the diuretic naive patient.⁸

• Oedema - loop diuretics are most commonly used to provide symptom-relief in heart failure.⁹There is little evidence that loop diuretics significantly alter disease progression or improve mortality but they do appear to improve individual's exercise capacity.⁷
• Oliguria due to renal failure - loop diuretics are sometimes used to provoke a diuresis in a well-hydrated patient with acute oliguria in a hospital setting. However, evidence for clinical benefit is poor although it may still benefit certain subsets of patients (e.g. post cardiac surgery or those acutely unwell with falciparum malaria) in combination with inotropes.^10,11,12
• Hypertension - compared to other diuretics, loop diuretics are rarely used for the treatment of hypertension. Only torasemide is licensed - the other loop diuretics having too short duration of action to offer good blood pressure control.

(see individual drugs for full list)

• Hypovolaemia
• Dehydration
• Severe hypokalaemia or hyponatraemia
• Renal failure with anuria⁴
• Pre-comatose states associated with liver cirrhosis⁴

(see individual drugs for full list)

• Risk of hypotension through rapid intravascular volume depletion.
• Hypokalaemia - particular care needed in those where hypokalaemia may have severe consequences e.g. patients taking digoxin or other anti-arrhythmics.
• Hepatic insufficiency.
• Prostatic hypertrophy or other cause of impaired micturition - over rapid diuresis may trigger urinary retention.
• Pregnancy - toxicity shown in animal studies with torasemide.
• Breast feeding - furosemide may inhibit lactation.

(see individual drugs for full list)

• Ototoxicity - especially with rapid, high-dose infusions in the context of renal failure
• Electrolyte disturbances - hypokalaemia, hyponatraemia, hypochloremic alkalosis
• Gastrointestinal disturbance
• Hyperuricaemia and gout
• Raised plasma cholesterol and triglycerides
• Hyperglycaemia (though less commonly than with the thiazides)
• Rashes
• Postural hypotension
• Photosensitivity
• Bone marrow suppression
• Loss of bone mineral density in older men¹³

• ACE Inhibitors - increased risk of first dose hypotension when starting ACEI therapy after prior treatment with diuretics.¹⁴ This may be profound where the patient has been on a high dose of loop diuretic. Temporary withdrawal of the loop diuretic may reduce the risk but may also cause severe rebound pulmonary oedema. It may be appropriate for these patients to be started on an ACEI under specialist supervision. Those on lower doses may be started in the community but care should be taken (advise to take first dose lying down in bed) and a very low dose of ACEI should be given initially.
• Aminoglycosides, polymyxins and vancomycin - increased risk of ototoxicity.
• Lithium - increased risk of toxicity.
• Theophylline - increased risk of hypokalaemia.

• Repeat serum electrolytes within a week of starting a loop diuretic⁹ and clinically review patient. The aim is to offer a dose that relieves symptoms without causing the patient to become dehydrated. There are large individual differences in dose requirement.¹⁵
• Titrate dose of diuretic to clinical effect and check U & Es on a weekly basis until treatment is stable.¹⁶ The tendency of loop diuretics to produce hypokalaemia is frequently offset by the co-prescription of ACEIs, ARBs or spironolactone. The frequency of bloods and clinical reviews should be based on the patient's condition, potency of the diuretic and risk of complications. Once stable, six-monthly should suffice unless there is any change in therapy, intercurrent illness or worsening renal impairment.⁹
• Daily weights can help monitor fluid loss with cardiac oedema or ascites. With ascites, aim for a weight reduction of no more than 0.5 kg/day.⁸
• The effect of the loop diuretic wears off rapidly (due to their short half-lives - one hour for bumetanide, three to four hours for torasemide) and the kidneys immediately start to retain compensatory sodium chloride. Sodium restriction can be used to counter this effect.³
• Use the lowest dose possible to control symptoms: doses of more than 80 mg daily of furosemide and 2 mg bumetanide daily are rarely required and specialist input should be sought if higher doses appear to be needed.¹⁶
• Compliance - many patients find that diuresis interferes with their daily activity. Discuss with the patient to find the most convenient time to take their diuretic (not necessarily first thing in the morning).

• Strategies for dealing with diuretic resistance:¹⁷
  • Altering dose - either increasing the dose or decreasing the dose interval.
  • Use of IV bolus or continuous infusion, overcoming absorption problems.
  • Combination therapy - typically using a diuretic with action at an additional site e.g. thiazide or acetazolamide.³ Due to the increased risk of side-effects, synergistic dual therapy is usually initiated by or under the advice of a specialist.¹⁶
• The dose of a loop diuretic required to control chronic heart failure is a prognostic indicator.¹⁸

• Inadequate response to therapy
• Poor tolerance of drugs
• Deteriorating renal function

• Explain indication for use of diuretic (or “water tablet”).
• Explain frequency of initial monitoring and how blood tests/reviews will be arranged and followed-up.
• Diuretics usually make people need to pass urine more frequently. Ask your patient about difficulty getting to the toilet in time or problems with sleep or interrupted day-time activities.
• Side-effects such as impotence should be mentioned since patients may not volunteer these themselves.
• Advise that some OTC medications such as NSAIDs may interact with their diuretic and patients should check with pharmacists/their doctor before taking additional medicines.