Diuretics: Renal Function and Clinical Use

• Diuretics affect renal function.

Characteristics of Diuretic Agents

• Diuretic efficacy order: loop diuretics > thiazide diuretics > K+-sparing diuretics.

Combined Therapy

• Loop diuretics + thiazide diuretics have a synergistic effect.
  • Not recommended for outpatient use due to hemodynamic changes and hypokalemia.
• K+-sparing diuretics + (loop diuretics / thiazide diuretics) can manage hypokalemia.

Effects of Diuretic Agents

• Increased fluid excretion.

Use in Oedematous State

• Used in conditions like heart failure, kidney disease, and liver diseases.
• Reduces peripheral or pulmonary oedema WITHOUT significantly decreasing blood volume.
• Excessive diuresis can further compromise effective arterial blood volume, leading to decreased vital organ perfusion.

Use in Non-Oedematous State

• Lowers hypertension.
• Treats hypercalciuria/hypercalcemia.
• Reduces polyuria.

Effects of Diuretic Agents - Loop Diuretics

• Examples: Furosemide, Bumetanide (sulfonamide), Ethacrynic acid (phenoxyacetic acid derivative).
• Inhibits Na/K/2Cl cotransporter in the thick ascending loop of Henle.
• Decreases Na, Cl reabsorption into the interstitium.
• Enhances renal excretion of water and Na+, reducing salt retention.
• Increases K and H⁺ loss in the collecting duct because Na builds up in the filtrate.
• Promotes sodium reabsorption in the collecting duct via open channels by diffusion.
• Na entry activates the Na/K pump on the basolateral side.
• Decreases magnesium and calcium reabsorption.

Clinical Use - Loop Diuretics

• Used to treat oedema by increasing Na excretion and reducing salt retention, benefiting heart failure and kidney disease patients.
• Increases systemic venous capacitance and causes vasodilation, decreasing venous return and LV filling.
• Reduces venous and pulmonary congestion in heart failure and pulmonary oedema.
• Treats hypertension, especially in renal insufficient or resistant hypertension patients.
• Limited use due to post-diuretic Na reabsorption.

Adverse Effects - Loop Diuretics

• Hypokalemia: can cause pro-arrhythmia, which can be reversed by K replacement or less Na intake.
• Hyponatremia: can lead to ECF depletion.
  • Water leaves the blood, causing hypotension, reduced GFR, circulatory collapse, thromboembolic episodes, hepatic encephalopathy.
• Hypomagnesemia: can cause pro-arrhythmia.
• Hypocalcemia: less common as it is compensated by Vit.D / PTH reabsorption. Deleterious effects on bone in postmenopausal in those
• Hyperuricemia from increased reabsorption in the PCT, potentially causing gout.
• Hyperglycemia.
• Hyperlipidemia.
• Metabolic alkalosis from H+ loss, which can be reversed by K replacement.
• Ototoxicity (mainly with Ethacrynic acid), due to electrolyte transport inhibition in the inner ear is mostly reversible, and least likely with oral administration.
• Sulfonamide-related allergy (except Ethacrynic acid).

Effects of Diuretic Agents - Thiazide-like Diuretics

• Examples: Hydrochlorothiazide, Chlorthalidone.
• Inhibits the Na/Cl cotransporter in the distal convoluted tubule (DCT).
• Na+, Cl− reabsorption is inhibited into interstitium.
• Increases Calcium reabsorption.

Thiazide: Clinical uses

• Treats oedema, though less effective than loop diuretics.
  • Ineffective when GFR<30, since Na+ is reabsorbed mainly in PCT.
• Treats hypertension.
  • Reduces blood pressure by 10-15 mmHg.
  • Has an additive effect with other antihypertensives.
    • Inexpensive.
    • Longer acting with a slightly safer profile: can be administered once daily, well-tolerated for chronic use, and few contraindications.

Thiazide: Adverse effects (similar to loop diuretics):

• Hypokalemia
• Metabolic alkalosis
• Hyponatremia
• Hypomagnesemia
• Hyperuricemia (less effect – safer)
• Hypercalcemia: can be masked by hyperparathyroidism.
• Hyperglycemia: reduces insulin secretion by hyperpolarizing pancreatic beta cells
  • Reduced tissue utilization of glucose.
  • Greater risk of diabetes in thiazide than loop diuretics.
• Hyperlipidemia
• Sulfonamide-related allergy

Effects of Diuretic Agents - Potassium Sparing Diuretics

• Examples: Amiloride; Aldosterone antagonists: Spironolactone, Eplerenone.
• Amiloride
  • Inhibits Na+ influx and K+ efflux in the collecting tubule.
  • Potassium sparing.

Potassium Sparing: Clinical uses

• Combined therapy with other diuretics.
• Not effective as a sole agent in treatment of oedema/hypertension
• Reduces K+ secretion by other diuretics

Potassium Sparing: Adverse effects

• Hyperkalemia
  • Pro-arrhythmia
  • Reversed by thiazide
  • Enhanced in renal diseases or RAAS inhibitors
    • Beta blockers
    • Nonsteroidal anti-inflammatory drugs
• Metabolic acidosis: due to hyperkalemia

Effects of Diuretic Agents: Aldosterone antagonists

• Example drugs: Spironolactone & Eplerenone.

MOA

• Aldosterone antagonists: antagonize the mineralocorticoid receptor, prevent aldosterone action; thereby:
  • Reducing Na+ reabsorption
  • Reducing Potassium excretion

Aldosterone antagonists: Clinical uses

• Treats hyperaldosteronism: reduces refractory oedema associated with secondary aldosteronism, heart failure, hepatic cirrhosis, nephrotic syndrome.

Aldosterone antagonists: Adverse effects

• Gynecomastia, impotence, menstrual irregularities (only with Spironolactone)
• Spironolactone: antagonist for androgen and progesterone receptors

Resistance to Loop Diuretics

• Reduced renal blood flow (e.g., in renal failure or induced by drugs)
  • Decreases delivery of diuretics to the kidneys
  • Accumulation of endogenous organic acid
  • Reduced active transport of diuretics at the proximal tubule.
• Drug interaction:
  • Inhibition of prostaglandin production (e.g., by non-steroidal anti-inflammatory drugs).
  • Competes for organic acid transport system in the proximal tubule (e.g., probenecid).
• Increased proximal tubular Na+ reabsorption (e.g., in hepatic cirrhosis, nephrotic syndrome or heart failure):
  • Decreases delivery of Na+ to the loop of Henle.

RAAS Inhibitors

ACE Inhibitors

• Drugs include Captopril, enalapril, lisinopril, quinapril.
• Reduces the formation of Ang II (from Ang I).

ARBs

• Drugs include Losartan, valsartan.
• Inhibits the actions of Ang II: functions as a selective antagonist of type I angiotensin receptor Does not affect type II receptors (AT2 receptors may lead to vasodilatation, with additional benefit or bradykinin release, leading to angioedema).

Clinical Use- ACEi and ARBs

• Treats hypertension.
• Treats heart failure.
• Treats oedema.

Adverse Effects

• Severe hypotension.
• Acute renal failure.
• Hyperkalemia (especially with K+-sparing diuretics).
• Risk for foetal hypotension, renal failure, or malformation.
• Dry cough (ACE inhibitors).
• Angioedema.
  • ACE inhibitors increase levels of bradykinin.

Insufficiency

• Interrupts the Negative feedback action of Ang II.
• Blocks action of Ang II.
• Increase renin release from JG cells.
• Countercats ACEi and ARBS.
  • Can be reversed by renin inhibitors.

Renin Inhibitors

• Drugs: Aliskiren.
• Decreases activity of renin
  • Leads to decreased vasoconstriction and decreased peripheral vascular resistance.
  • Leads to decreased fluid retention and therefore also decreased edema.
  • Decreased vascular and cardiac remodeling helps improve survival.

Renin Inhibitors: Adverse effects

• Acute renal failure.
• Hyperkalemia (caution with K+-sparing diuretics).
• Risk of fetal hypotension, renal failure, or malformation (contraindicated during pregnancy).

Renin Inhibitors: Insufficiency

• Alternative mechanisms for aldosterone production.
• Can be reversed by aldosterone antagonists.