Renal-Kidney Pharmacology and Physiology

Chapter 20:  Renal Pharmacology

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Physiology Review

Background:

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

 

Sodium Bicarbonate and the Proximal Tubule

 

Organic Acid Secretory System

Organic Base Secretory System

 

Carbonic Anhydrase Inhibitors

 

Loop Diuretic Drugs

Ives, H.E., Diuretic Agents, in: Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 242-259.

Thiazides

Thiazides and Related Sulfonamide Diuretics

bendroflumethazide

benzthiazide

chlorothiazide

chlorthalidone

hydrochlorothiazide

hydroflumethiazide

indapamide

methyclothiazide

metolazone

polythiazide

quinethazone

trichlomethiazide

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Potassium-Sparing Diuretic Agents

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Osmotic Diuretics

Ives, H.E., Diuretic Agents, in: Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 242-259.

 

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)

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.(renal synport diagram)

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:

  • 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

  • inhibition of aldosterone release by ACE inhibitors or angiotensin-receptor blockers

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Clinical uses of diuretics

Carbonic Anhydrase Inhibitor

Loop Diuretics

Thiazides

bendroflumethazide

benzthiazide

chlorothiazide (Diuril)

chlorthalidone (Hygroton)

hydrochlorothiazide (HCTZ, Esidrix, HydroDIURIL)

hydroflumethiazide

indapamide (Lozol)

methyclothiazide

metolazone (Zaroxolyn, Mykrox)

polythiazide

quinethazone

trichlomethiazide

Osmotic Diuretics

Mannitol (Osmitrol)

Potassium Sparing Agents

 

Diuretic-Other Drug Interactions
cardiac glycosides oral hypoglycemics aminoglycoside antibiotics
oral anticoagulants uricosuric drugs non-steroidal anti-inflammatory drugs

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Adverse Diuretic effects and contraindications

Adverse Effects:  Carbonic Anhydrase Inhibitors (Acetazolamide)

Adverse Effects:  Loop Diuretics

 Toxicity:

Adverse Effects:  Thiazides

Toxicity:

Adverse Effects:  Osmotic Diuretics

 Toxicity:

Adverse Effects:  Potassium-Sparing Diuretics

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Mechanisms whereby furosemide and thiazides are useful in calcium metabolism disorders management

Role of Diuretics in Calcium Metabolism

 

Thiazides & Calcium Metabolism

 

Thiazides: nephrogenic diabetes insipidus.

Jackson, E.K. Diuretics In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 685- 713

Jackson, E.K. Vasopressin and Other Agents Affecting the Renal Conservation of Water In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.715-732

 

Chlorpropamide (Diabinese) and clofibrate (Abitrate, Atromid-S) : Central (Cranial) Diabetes Insipidus

Jackson, E.K. Vasopressin and Other Agents Affecting the Renal Conservation of Water In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.715-732.

 

Management of inappropriate secretion of antidiuretic hormone

Jackson, E.K. Vasopressin and Other Agents Affecting the Renal Conservation of Water In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.715-732.

 Mechanism by which lithium compounds may cause a syndrome like diabetes insipidus

Introduction

 

Regulation of vasopressin secretion

Hormonal Effects

Drug Effects

Lithium Effects:

Jackson, E.K. Vasopressin and Other Agents Affecting the Renal Conservation of Water In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.715-732.

 

Diuretics

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