Medical Pharmacology Chapter 26:  Renal Pharmacology

Diuretic Therapy in Hypertension

• Diuretics: Antihypertensive properties

  • Two main classes of diuretics are used in mangement of hypertension: thiazides and potassium sparing drugs.

  • Objective: pharmacological alteration of sodium load.

  • A reduction in sodium leads to reduced intravascular volume and a blood pressure reduction.

  • Thiazide diuretics cause an inhibition of NaCl transport in the Distal Convoluted Tubule (DCT).

    • Nephron Anatomy

      Anatomy of the Nephron: From: Guyton's Textbook of Physiology, Ninth Edition

• Orally active thiazide drugs have historically been a mainstay of antihypertensive treatment, although present therapy often involves other drugs.

   

  • Note the progression of antihypertensive medication; Beginning with a low dosage of either an ACE inhibitor, calcium channel blocker or beta blocker And proceeding, if needed to add a diuretic And ultimately additional more powerful drugs, such as centrally acting sympatholytics, peripheral vasodilators or combination. At each step dosages are reviewed and if the patient's hypertension is controlled then therapy may be continued with review for possible removal of medication. Figure adapted from Harrison's "Principles of Internal Medicine, Thirteenth Edition, p. 1128

     

  • Reduction in blood pressure is initially due to a reduction in extracellular volume and cardiac output.

    • Long-term antihypertensive effects of thiazides appear due to reduced vascular resistance. The exact mechanism responsible for the reduction in vascular resistance is not known.

    • Thiazides, due to their inhibition of the Na⁺-Cl^- symport system, increase sodium and chloride excretion.

      • Distal Convoluted Tubule:From: Goodman and Gilman's "The Pharmacological Basis of Therapeutics, Ninth Edition

    • Thiazide diuretics, when used in the management of hypertension, is administered in combination with a potassium-sparing drug.

      • Reduction in the amount of potassium loss can be achieved by:

        • Using potassium sparing drugs block Na⁺ channels in the late distal tubule and collecting duct (amiloride (Midamor)  and triamterene (Dyrenium))

         

        • Note that amiloride (Midamor) and probably triamterene (Dyrenium) blocks sodium channels in the luminal membrane in the late distal tubule and collecting duct. Such action inhibits the normal movement of Na+ into the cell. Normally, Na+ entry create the net negative luminal charge that results in K+ efflux. By reducing the net negative luminal charge, amiloride (Midamor)/triamterene (Dyrenium) administration help conserve potassium. Therefore, they are called "potassium sparing". Figure adapted from "Goodman and Gillman's The Pharmacological Basis of Therapeutics" Ninth Edition, p. 705

           

      • Inhibition of aldosterone action (spironolactone (Aldactone):

        • Spironolactone is an antagonist of mineralocorticoid receptors (aldosterone-antagonist) . Normally, aldosterone interactions with mineralocoricoid receptors result in synthesis of aldosterone-induced proteins (AIPs). These proteins appear to increase the number or activity of Na+ channels and cause an increase in Na+ conductance. Increased Na+ conductance (with inward movement of Na+) results in a net negative luminal charge favoring K+ loss. Antagonism of the interaction between aldosterone and its receptor by spironolactone conserves K+ (potassium sparing). Figure from Goodman and Gilman's "The Pharmacological Basis of Therapeutics" Ninth Edition, p. 708