Diuretics, loop

Key examples

• Furosemide
• Bumetanide

 

Common indications

1. For relief of breathlessness in acute pulmonary oedema in conjunction with oxygen and nitrates.
2. For symptomatic treatment of fluid overload in chronic heart failure.
3. For symptomatic treatment of fluid overload in other oedematous states, e.g. due to renal disease or liver failure, where they may be given in combination with other diuretics.

 

Mechanisms of action

• As their name suggests, loop diuretics act principally on the ascending limb of the loop of Henle, where they inhibit the Na+/K+/2Cl−co-transporter. This protein is responsible for transporting sodium, potassium and chloride ions from the tubular lumen into the epithelial cell. Water then follows by osmosis. 
• Inhibiting this process has a potent diuretic effect. In addition, loop diuretics have a direct effect on blood vessels, causing dilatation of capacitance veins. 
• In acute heart failure, this reduces preload and improves contractile function of the ‘overstretched’ heart muscle. Indeed, this is probably the main benefit of loop diuretics in acute heart failure, as illustrated by the fact that the clinical response is usually evident before a diuresis is established.

 

Important adverse effects

• Water losses due to diuresis can lead to dehydration and hypotension. Inhibiting the Na+/K+/2Cl− co-transporter increases urinary losses of sodium, potassium and chloride ions. Indirectly, this also increases excretion of magnesium, calcium and hydrogen ions. You can therefore associate loop diuretics with almost any low electrolyte state (i.e. hyponatraemia, hypokalaemia, hypochloraemia, hypocalcaemia, hypomagnesaemia and metabolic alkalosis). A similar Na+/K+/2Cl− co-transporter is responsible for regulating endolymph composition in the inner ear. At high doses, loop diuretics can affect this too, leading to hearing loss and tinnitus.

 

Warnings

• Loop diuretics are contraindicated in patients with severe hypovolemia or dehydration. 
• They should be used with caution in patients at risk of hepatic encephalopathy (where hypokalaemia can cause or worsen coma) and those with severe hypokalaemia and/or hyponatraemia. 
• Taken chronically, loop diuretics inhibit uric acid excretion and this can worsen gout.

 

Important interactions

• Loop diuretics have the potential to affect drugs that are excreted by the kidneys. For example, lithium levels are increased due to reduced excretion. 
• The risk of digoxin toxicity may also be increased, due to the effects of diuretic-associated hypokalaemia. 
• Loop diuretics can increase the ototoxicity and nephrotoxicity of aminoglycosides.