2.9 Diuretics

Diuretics

For this topic you will need to revise the anatomy and physiology of the renal system as you will need this knowledge to understand the focus this week which is on diuretics and their uses in clinical practice.

Revision of Anatomy and Physiology of the Renal System

An understanding of renal anatomy and physiology is critical to your understanding of the action of drugs that affect the renal system such as diuretics. You are already familiar with this system but as you progress through this week’s work, you may want to refer back to the following sections to ensure you have a good understanding. The most important renal system anatomical and physiological concepts you may want to revise from your anatomy and physiology text [Tortora, GJ., Derrickson, B., Burkett, B., Peoples, G., Dye, D., Cooke, J., et al. Principles of anatomy and physiology. Second Asia-Pacific ed. Queensland, Australia: John Wiley & Sons; 2019] are:

• Blood and nerve supply of the kidneys (Page 1459–1461 of above text)
• The nephron (Page 1461-1467 of above text)
• Glomerular Filtration Rate (P1470-1473 of above text)
• Renalautoregulation of GFR.
• Neuralregulation of GFR.
• Hormonalregulation of GFR.
• Principles of tubular reabsorption and secretion. (Page 1473-1476 of above text)
• Reabsorption and secretion in the proximal convoluted tubule. (Page 1476-1479 of above text)
• Reabsorption in the nephron loop. (Page 1479-1481
• Reabsorption in the early distal convoluted tubule. (Page 1481 of above text)
• Reabsorption and secretion in the late distal convoluted tubule and collecting duct. (Page1481 of above text)
• Homeostatic regulation of tubular reabsorption and tubular secretion. (Page 1481-1485 of above text)
• Production of dilute and concentrated urine. (Page 1485-1491 of above text)

Introduction to Diuretics

Of the four types, osmotic diuretics such as mannitol are the most potent and one of the least commonly used. The two most commonly used diuretic classes in Australia are loop diuretics (i.e. frusemide) and thiazide diuretics (hydroclorothiazide). Diuretics are used for hypertension and a broad range of conditions that require fluid load reduction such as cirrhosis, partial renal failure and oedema, symptomatic management of congestive heart failure and other conditions that result in peripheral oedema.

All diuretics modify renal function to reduce the reabsorption of water from the filtrate via the common mechanism of increasing sodium excretion in the filtrate.

Loop Diuretics

Of the 3 available loop diuretics frusemide, bumetanide and etacrynic acid – frusemide is the most commonly used agent. Loop diuretics are a moderately potent diuretic second only to osmotic diuretics. They are all relatively short acting lasting about 4-6 hours. Their potency results from their site of action on the nephron – that site being the thick ascending loop of Henle. Loop diuretics are used for conditions that require fluid load reduction but unlike thiazide diuretics are not used in the management of hypertension.

Loop diuretics are actively secreted into the lumen via the proximal tubule. In the Loop of Henle, they inhibit the Na⁺/K⁺/2Cl^– cotransporter reducing sodium reabsorption (see figure below). As water follows sodium, the increased sodium concentration in the filtrate reduces the osmotic gradient reducing water movement back into the interstitial space surrounding the nephron (and eventually the blood). Loop diuretics are so potent because the Loop of Henle is the major site of sodium reabsorption – accounting for between 15-25% of sodium and chloride reabsorption normally.

Loop diuretics are also sometimes called potassium-wasting diuretics. This is because of the nature of the symporter the loop diuretics block and the normal movement of ions (sodium and potassium) from the filtrate to the blood. When frusemide (or other loop diuretics) block the Na⁺/K⁺/Cl^– symporter, water reabsorption is reduced and the excretion of sodium is increased. So too is the loss of potassium in the filtrate.

Loop diuretics are well absorbed from the GIT and have good oral bioavailability. They are commonly given by mouth but can also be administered in IV form.

Side Effects of Loop Diuretics

Frusemide and other loop diuretics can cause electrolyte disturbances (calcium, potassium, sodium, chloride, magnesium loss) though this is dose related. Other common side effects include postural hypotension, dehydration, dizziness, rash and metabolic alkalosis (H⁺ is lost in the filtrate also due to loop diuretic effect). They can also precipitate gout (they decrease excretion of uric acid) and cause ototoxicity. Ototoxicity is uncommon in normal doses but can occur when administered with other ototoxic drugs.

Unlike other diuretics, loop diuretics are high-ceiling diuretics. This means they are effective over a very broad range of doses and the greater the dose given, the greater the effect. This is useful in renal impairment. Though like all drugs, the higher the dose, the higher the risk of side effects – particularly sodium and potassium loss and ototoxicity.