Medical Pharmacology Chapter 26:  Renal Pharmacology

Physiology Review

• Background

  • Body fluid and electrolyte composition are regulated by the kidney

    • Drugs that interfere with renal transport may be useful in management of clinical disorders.

  • Diuretics are drugs which block renal ionic transport, causing diuresis {an increase in urine volume}, often associated with natriuresis (increase in sodium excretion)

  • Diuretics often act at different sites of the tubule transport system, at specific membrane transport proteins

  • Diuretics that act on specific membrane transport proteins include:

    • Loop diuretics

    • Thiazides

    • Amiloride (Midamor)

    • Triamterene (Dyrenium)

  • Diuretics may act through:

    • Osmotic effects (preventing water reabsorption) such as mannitol

    • Enzyme inhibition (carbonic anhydrase inhibitor) such as acetazolamide

    • Interaction with hormonal receptors, for example, spironolactone

• Renal physiology and sites of diuretic action

  • courtesy of Robert H. Parsons, Ph.D., Rensselaer Polytechnic Institute, used with permission

  • "The glomerular capillaries are very leaky about 400 times as high as most other capillaries and produce a filtrate that is similar to blood plasma except the it is devoid of proteins and cellular elements. The glomerular filtration rate (GFR) is effected by the same forces as other capillaries: GFR = Kf X (Pc -Pb - PiG +PiB) where Kf = Filtration coefficient Pc = Glomerular hydrostatic pressure Pb = Bowman's capsule hydrostatic pressure PiG = Glomerular capillary colloidal osmotic pressure PiB = Bowman's capsule colloidal osmotic pressure " courtesy of Robert H. Parsons, Ph.D., Rensselaer Polytechnic Institute, used with permission

     

• Proximal tubule

  • Many solutes are reabsorbed in the early portions of the proximal tubule:

    • 85% of filtered sodium bicarbonate

    • 40% of sodium chloride

    • 60% of water and

    • Nearly all of filtered organic solutes, including glucose and amino acids.

      • Glucose, amino acids, and other organic solutes are reabsorbed by specific transport systems

• Sodium Bicarbonate and the Proximal Tubule

  • Mechanism of Action: In the proximal tubule, sodium bicarbonate reabsorption can be influenced by carbonic anhydrase inhibitors.

    • Sodium bicarbonate reabsorbed in the proximal tubule depends on the action of sodium/hydrogen exchanger which is found in the luminal membrane of the proximal tubule epithelial cell.

      1. proton secreted into lumen (urine) combine with bicarbonate to form carbonic acid (H₂CO₃)

      2. Carbonic acid is dehydrated by an enzyme carbonic anhydrase which is localized (among other places) on the brush border membrane.

      3. The dehydration products carbon dioxide and water easily move across membranes. Carbon dioxide enters the proximal tubule by diffusion where it is rehydrated back to carbonic acid.

      4. Carbonic acid dissociates back to bicarbonate and the proton (step one)

      5. This cycle depends on carbonic anhydrase

    •  Mechanism of Action: Inhibition of carbonic anhydrase decreases bicarbonate reabsorption in proximal tubule, which in turn decreases water reabsorption

    • Carbonic anhydrase inhibitor: acetazolamide (Diamox)

  • In the proximal tubule, water is reabsorbed in direct proportion to salt.

  • With a large concentration of impermeant solute, such as glucose or the diuretic mannitol, water reabsorption would decrease for osmotic reasons. (Mechanism for osmotic diuresis)

   

• Organic Acid Secretory System

  • Located in the middle third proximal tubule

    • Organic acid secretory system secretes for example:

      • Uric acid

      • Antibiotics

      • Para-aminohippuric acid

• Organic Base Secretory System

  • Localized in both early and middle segments of the proximal tubule

    • Organic base secretory system secretes, for example:

      • Creatinine

      • Procainamide {antiarrhythmic drug}

      • Choline

  • Organic acid and base transport systems are important in delivery of diuretics to their site of action: luminal side

  • Drug interaction: diuretics and probenecid (secretory system inhibitor)

• Loop of Henle

  • Thin limb

    • Water reabsorption

      • Driving force is osmotic, due to the hypertonic medullary fluid.

    • No active salt reabsorption, but impermeant solutes (mannitol, glucose) will inhibit water reabsorption. 

      • This is a site of action for osmotic diuretics.

  • Thick ascending limb of the loop of Henle: active sodium chloride reabsorption, about 35% of filtered load.

    • Impermeable to water

    • Since reabsorption of sodium chloride at this site dilutes the fluid in the tubule, this segment may be referred to as "diluting segment."

    • Reabsorption of sodium chloride in the thick ascending limb is dependent upon the Na/K/2Cl co-transporter.

      1. Loop diuretics block this transporter. 

         1. Examples of loop diuretics include:

            1. Furosemide (Lasix)

            2. Bumetanide (Bumex)

            3. Ethacrynic acid (Edecrin)

            4. Torsemide (Demadex)

      2. Normal activity of this transporter and Na⁺/K⁺ ATPase results in an increase in intracellular potassium, potassium efflux, and a lumen-positive electrical potential:

         1. This lumen-positive membrane potential provides the driving force for reabsorption of magnesium and calcium cations.

         2. Therefore loop diuretics which inhibit the action of the sodium potassium chloride co-transporter, leading to increase sodium excretion also leads to increased magnesium and calcium loss.

• Distal Convoluted Tubule

  • Properties:

    • Impermeable to water

    • Sodium reabsorption (about 10% of filtered load) by sodium and chloride co-transporter

    • Further dilution of tubular fluids

  • Pharmacological blockade of sodium and chloride co-transporter:

    • Thiazide diuretics

    • No potassium recycling; no lumen-positive membrane potential; -- no calcium or magnesium loss by electrical forces

  • Calcium is actively reabsorbed by:

    • aAn apical calcium channel and

    • Na⁺/Ca²⁺ exchanger and

    • Is regulated by parathyroid hormone

• Collecting Tubule

  • Properties:

    • About 2% to 5% of sodium chloride reabsorption

    • Final site for sodium chloride reabsorption -- responsible for final sodium concentration in the urine

    • This site and late distal tubule represent the location where mineralocorticoids exert their effect

      • Major site of potassium secretion

    • Major site for sodium, potassium, and water transport

    • Major site for proton secretion is the intercalated cells

    • Separate sodium and potassium channels:

      • Significant driving force for sodium entry

      •  Na⁺ after entering the principal cell is transported to the blood using the Na⁺/K⁺ ATPase driven transporter, with potassium translocated to the lumen urine.

        • The lumen-negative electrical potential drives chloride back to the blood.

          • Accordingly, delivery of increased sodium to the collecting tubule drives increased potassium efflux.

          • Diuretics (acting upstream) that increased delivery of sodium to the collecting tubule will cause potassium loss.

          • Delivery of bicarbonate which is not readily reabsorbed compared to chloride and thus increases lumen-negative potentials, will increase further potassium loss.

          • Diuretic-induced potassium loss, which is clinically important, results from the above mechanisms coupled with enhanced aldosterone secretion due to volume depletion.