Diuretic

Diuretic Agents Renal Tubule Transport Mechanisms .

Proximal Tubule

85 % NaHCO3 40 % NaCl 60 % water organic solutes glucose amino acids

Mechanisms of organic acid (A) and organic base (B) secretion in the proximal tubule. A: uric acid, p-aminohippuric acid, diuretics, antibiotics B: creatinine, procainamide, choline

Basic Pharmacology of Diuretic Agents

Carbonic Anhydrase Inhbitors Sodium bicarbonate reabsorption Na+/H+ exchanger Na+/K+ ATPase Carbonic anhydrase

Acetazolamide 1. Chemistry

Sulfanilamide (antimicrobial drug): metabolic acidosis, alkaline urine Dichlorphenamide: increased ratio of NaCl excretion relative to NaHCO3

2. Pharmacodynamics Carbonic anhydrase inhibitor 1) bicarbonates depletion bicarbonate diuresis 2) metabolic acidosis hyperchloremic Na reabsorbed, K secreted 3) aqueous humor 4) cerebrospinal fluid

3. Clinical Indications 1) glaucoma: topical analog: dorzolamide, brinzolamide 2) urinary alkalinization: uric acid. cystine, aspirin 3) metabolic alkalosis 4) acute mountain sickness 5) other uses epilepsy hyperphosphatemia

4. Toxicity 1) hyperchloremic metabolic acidosis 2) renal stone calcium salts: insoluble at alkaline pH 3) renal potassium wasting collecting tubule: 4) other toxicities: renal failure drowsiness, paresthesias 5. Contraindications hepatic cirrhosis: NH4+

Loop Diuretics 1. Thin descending limb water reabsorption osmotic diuretics 2. Thick ascending limb diluting segment loop diuretic

Thick ascending limb Na+/K+/2Cl- cotransport Na+/K+ ATPase K-selective channel

1. Chemistry sulfonamide der: furosemide bumetanide Phenoxyacetic acid der. Ethacrynic 2. Pharmacokinetics 1) glomerular filtration renal secretion 2) act on luminal side 3) indomethacin, probenecid inhibit weak acid secretion

3. Pharmacodynamics 1) NaCl reabsorption↓ 2) K+ recycling 3) hypomagnesemia 4) hypocalcemia (-) hypercalcium (+ saline) 5) potassium wasting: hypokalemic alkalosis 5) direct vascular effect renal blood flow↑ venous capacitance↑ ⇒left ventricular filling pressure↓ ⇒pulmonary congestion ↓ PG synthesis

4. Clinical Indication 1) edematous states: 2) hyperkalemia 3) severe hypercalemia 4) acute renal failure 5) anion overdose: bromide, iodide 5. Toxicity 1) hypokalemic metabolic alkalosis enhance the renal secretion of K+ and H+ 2) ototoxicity

3) hyperuricemia enhancement of uric acid reabsorption 4) hypomagnesemia 5) allergic reactions: sulfonamide moiety 6) other toxicities: severe dehydration hypovolemia ⇒water intake↑ ⇒ hyponatremic 6. Contraindication: sensitive of sulfonamides, overzealous: hepatic cirrhosis, renal failure, congestive heart failure

Thiazides neutral Na+ and Cl- cotransport Na+/Ca+2 exchanger apical Ca channel

Parathyroid hormone

1. Chemistry benzothiazides organic acid 1) sulfonamide group 2) thiazide-like agents: indapamide 2. Pharmacokinetics 1 duration > loop diuretics 1) uric acid secretory↓

3. Pharmacodynamics 1) NaCl transport system↓ 2) Ca reabsorption↑ Na ↓ ⇒ Na+/Ca+2 exchange ↑ Ca channel 3) hypercalcemia (-) 4) hyperparathyroidism hypercalcemia 5) hypercalciuria ⇓ treatment of kidney stone 4) PG

4. Clinical indications 1) hypertension: blood volume↓, vascular resistance ↓ 2) congestive heart failure 3) nephrolithiasis 4) nephrogentic diabetes insipidus 5. Toxicity 1) hypokalemic metabolic alkalosis and hyperuricemia 2) impaired carbohydrate tolerance 3) hyperlipidemia 4) hyponatremia: life-threatening 5) allergic reaction 6) other toxicities: impotence 6. Contraindications: overzealous use

Potassium-Sparing Diuretics Aldosterone: enhance K+ secretion

1. Chemistry & Pharmacokinetics 1) spironolactone: steroid der. antagonist to aldosterone slow onset and offset of action 2) triamterene amiloride blocking the Na channel

2. Pharmacodynamics 1) spironolactone: aldosteron antagonist Na channel and Na+/K+ ATPase 2) ACE inhibitor aldosterone secretion 3) Triamterene and Amiloride Na+ entry PG K+ secretion↓ H+ secretion ↓⇒acidosis

3. Clinical Indications 1) combine a thiazide 2) mineralocorticoid excess a) primary hypersecretion b) secondary aldosteronism congestive heart failure, hepatic cirrhosis, nephrotic syndrome 4. Toxicity 1) hyperkalemia: combination of thiazide 2) hyperchloremic metabolic acidosis 3) gynecomastia 4) acute renal failure 5) kidney stone: triamterene 5. Contraindication: oral K+ administration, renal insufficiency, beta-blockers, ACE inhibitors: K+ ↑

Agents That Alter Water Excretion Osmotic diuretics: Mannitol 1) Pharmacokinetics a) poorly absorbed: osmotic diarrhea b) parenteral: without tubular reabsorption or secretion

2. Pharmacokinetics a) proximal tubule descending limb of the loop of Henle b) hypernatremia 3. Clinical indications a) to increase urine volume b) reduction of intracranial and intraocular pressure 4. Toxicity a) extracellular volume expansion (hyponatremia) b) dehydration and hypernatremia

Antidiuretic Hormone Agonists Vasopressin and desmopressin pituitary diabetes insipidus

ADH Antagonists Li+ and demeclocycline Pharmacodynamics reduce the formation of cAMP in the response to ADH Clinical Indication a) syndrome of inappropriate ADH secretion (SIADH) b) other causes of elevated ADH effective circulating blood volume↓ Toxicity a) nephrogenic diabetes insipidus b) renal failure c) other demeclocycline should be avoided in patients with liver

Diuretic Combinations Loop agents and Thiazides additive diuretic response Potassium-sparing diuretics and Loop Agents or thiazides hypokalemia

Clinical Pharmacology of Diuretic Agents Edematous States 1) Cngestive heart failure 2) Kidney disease 3) Hepatic cirrhosis 4) Idiopathic edema Nonedematous State 1) hypertension 2) Nephrolithiasis 3) hypercalcemia 4) diabetes insipidus

OBJECTIVES 1. List five major types of diuretics and relate them to

their sites of action. 2. Describe two drugs that reduce potassium loss during sodium diuress. 3. Describe a therapy that will reduce calcium excretion in patients who have recurrent urinary stones 4. Describe a treatment for severe hypercalcemia in a patient with advanced carcinoma. 5. Describe a method for reducing urine volume in nephrogenic diabetes insipidus. 6. List the major applications and the toxicities of thiazides, loop diuretics, and potassium-sparing diuretics.