Loop Diuretics Pharmacology!

Loop Diuretics Pharmacology

Diuretics are drugs that promote diuresis; a process that leads to increased production of urine. The purpose of every diuretic is to promote water loss.

There are many other different types of diuretic such as thiazide diuretics, potassium-sparing diuretics, and osmotic diuretics. Here though, we focus on loop diuretics. Loop diuretics achieve their diuretic effect by acting on the ascending limb of the loop of Henle; a part of the nephron named after the acclaimed German physician and anatomist, Friedrich Gustav Jakob Henle (1809-1885).

Examples of loop diuretics include:

• Furosemide
• Bumetanide
• Ethacrynic acid
• Torsemide

Over the course of this guide, we review their mechanism of action, side effects, and drug interactions. We also take some time to review important clinical pharmacology that pharmacy students are expected to know. Now, though, we will learn about what loop diuretics are used to treat.

Loop diuretics are used in the treatment of conditions such as:

• Chronic heart failure – treating symptoms of edema accumulation.
• Hypertension – fluid build-up leads to high blood pressure. However, loop diuretics are not first-line treatment options for this indication. Instead, thiazide diuretics are used first-line.
• Pulmonary edema – loop diuretics are used to relieve breathlessness. They are often used alongside other treatment options, such as oxygen and nitrates.
• Liver / renal dysfunction – treating fluid build-up associated with these conditions.

Edema is the common thread that weaves its way through each indication. Edema refers to the accumulation of fluid in certain parts of the body. The more fluid build-up, the more “swelling” manifests (the word “edema” takes its name from the Greek to mean “swelling”).

With these indications in mind, let’s learn more about the mechanism of loop diuretics; how they manage to promote diuresis and eliminate edematous states.

Mechanism of action

If you’re unfamiliar with the basic physiology of the nephron, we recommend taking a few moments to learn more about the structure and function of this feature. The four basic functions of the nephron include:

• Filtration
• Reabsorption
• Secretion
• Excretion

Knowing these processes is essential to properly understand how diuretics work.

Loop diuretics act on the thick ascending limb of the loop of Henle. Along this limb, loop diuretics inhibit a protein responsible for sodium, potassium, and chloride transport – a protein called the Na⁺/K⁺/2Cl^– transporter.

More specifically, loop diuretics compete with the Cl^– site of the transporter – reducing the reabsorption of the above ions – with water following by osmosis. It’s this water loss that generates the therapeutic potential of loop diuretics.

However, loop diuretics also work by a secondary mechanism – namely, dilatation of capacitance veins; an effect which reduces preload and enhances the contractile ability of cardiac muscle.

Both effects – water elimination and vasodilation – combine to generate the therapeutic potential of loop diuretics.

Side effects

Loop diuretics are associated with their own range of potential side effects.

Common side effects of loop diuretics include:

• Hypotension
• Hypokalemia
• Hypocalcemia
• Dehydration
• Hyperglycemia
• Electrolyte loss
• Dizziness
• Faintness
• Elevated serum creatinine concentration

Because the endolymph of the inner ear is regulated by a similar transporter as that found in the nephron, loop diuretics impact electrolyte balance in the ear and lead to tinnitus, vertigo, and deafness. This typically occurs when loop diuretics are used at high doses or for prolonged periods.

Clinical Pharmacology

When we talk about the clinical pharmacology of loop diuretics, we must consider the following factors:

• Loop diuretics are contraindicated in patients with dehydration or severe hypovolemia.
• Loop diuretics may impact other drugs eliminated via the kidney. For example, loop diuretics increase the risk of lithium and digoxin toxicity.
• Loop diuretics increase the risk of ototoxicity and nephrotoxicity in patients taking aminoglycosides.
• Loop diuretics should be used with caution in patients with hepatic encephalopathy – a condition in which hypokalemia can worsen coma.
• Similarly, caution is warranted in patients with pre-existing hypokalemia and hyponatremia etc.
• Taken over the long-term, loop diuretics can reduce the excretion of uric acid and worsen gout.
• Due to hypokalemia, loop diuretics increase the risk of arrhythmias; a risk potentiated if these drugs are taken with antipsychotics, such as amisulpride.
• Loop diuretics are counseled to be taken early, to prevent nocturia.
• Loop diuretics are classified as pregnancy category C – meaning that “risk is not ruled out”.
• Due to the risk of hypokalemia, drugs such as furosemide are available in combination products with the potassium-sparing drug, amiloride (Co-amilofruse).
• Loop diuretics, when combined with an NSAID and an ACE inhibitor, constitute the “triple whammy effect” in which there is a heightened risk of kidney failure.
• Ethacrynic acid is the only member of the loop diuretic drug class which is not a “sulfa drug”. Therefore, ethacrynic acid is not contraindicated in patients with sulfa allergies. Ethacrynic acid is also associated with a comparably higher rate of gastrointestinal toxicity effects compared to other loop diuretics.

That concludes our review of loop diuretics pharmacology. Check back to our pharmacy blog soon for more of the must-know facts about drugs and medicines!