Drugs and Membrane Transporters

Drugs and Membrane Transporters: Renal Transport Systems

• Renal transport systems are essential for drug action and side effects.
• Loop diuretics, thiazide diuretics, and potassium-sparing diuretics are discussed as examples.

Learning Objectives

• Students will understand the site of action, mechanism of action, and side effects of loop diuretics.
• Students will understand the site of action, mechanism of action, and side effects of thiazide diuretics.
• Students will understand the site of action, mechanism of action, and side effects of potassium sparing diuretics.

Further Readings

• Medical Physiology, 3rd Edition, Chapter 35, Transport of Sodium and Chloride, pp 1111-1116.
• Rang and Dale's Pharmacology, 10th edition, Chapter 29, The Kidney and Urinary System, pp 402-412.

Site and Mechanism of Action

• Diuretic: Site of Action: Mechanism of Action
• Osmotic diuretics: Proximal tubules: Inhibition of water and Na+ reabsorption
• Carbonic anhydrase inhibitors: Proximal tubules: Inhibition of bicarbonate reabsorption
• Loop diuretics: Loop of Henle (thick ascending limb): Inhibition of Na+, K+ and Cl- reabsorption
• Thiazide diuretics: Early distal tubule: Inhibition of Na+ and Cl- co-transport
• K+ sparing diuretics: Late distal tubule / Collecting Duct: Inhibition of Na+ reabsorption

Loop Diuretics

• Example drugs: furosemide, bumetanide
• Act on the chloride-binding site, inhibiting the Na+/K+/2Cl- co-transporter (NKCC2) in the thick ascending loop of Henle.
• This reduces Na+ and Cl- reabsorption.
• 25% of filtered Na+ reabsorbed in the thick ascending limb.
• Inhibition of NKCC2 increases ion concentration in the tubule and decreases surrounding interstitial hypertonicity.
• Reduced water reabsorption into the blood.

Thiazide Diuretics

• Example drugs: hydrochlorothiazide, chlorothiazide, bendroflumethiazide
• Used to treat high blood pressure and other conditions.
• Act by inhibiting Na+ and Cl- reabsorption in the distal convoluted tubules.
• Also increase Ca2+ reabsorption in the distal tubule.

Potassium-Sparing Diuretics

• Aldosterone antagonists (e.g., spironolactone, eplerenone): Block aldosterone's effect to reduce Na+ reabsorption and K+ secretion.
• Na+ channel inhibitors (e.g., amiloride, triamterene): Block ENaC, inhibiting Na+ reabsorption and reducing K+ secretion.

Thiazide Diuretic Contraindications

• Contraindications: Hypotension, Gout, Renal failure, Lithium therapy, Hypokalemia, Worsening diabetes.
• Thiazides reduce uric acid clearance, raising uric acid levels in the blood.
• Chronic administration can cause hyperglycemia.
• Thiazides cause potassium loss, while conserving calcium.

Potassium Loss With Thiazides

• The kidney is good at conserving Na+.
• Thiazides initially prevent Na+ conservation, but a more vigorous attempt is later made to conserve Na+.
• Potassium loss action of thiazides is mediated by increased aldosterone secretion (aids potassium loss).
• Hypochloraemic alkalosis accompanies potassium loss due to loss of Cl-.
• Potassium loss is a concern.

Digoxin Toxicity

• Digoxin is an inhibitor of the Na+/K+ ATPase pump.
• Increased intracellular Na+ results from decreased Na+/K+ ATPase pump activity.
• This, in turn, reduces the effectiveness of the Na+/Ca2+ exchanger.
• Increased intracellular calcium results.
• Depolarization occurs (due to disturbed cardiac rhythm at high doses).

Adverse Effects of K+ Sparing Diuretics

• Hyperkalemia: Potassium supplements should not be co-prescribed.
• Use with caution with drugs such as ACE inhibitors that increase blood potassium levels (risk of cardiac arrhythmias).

Explore the renal transport systems related to drug actions and side effects in this quiz. Dive into loop diuretics, thiazide diuretics, and potassium-sparing diuretics, understanding their mechanisms and effects. Gain insights from essential readings in Medical Physiology and Pharmacology.