Ass. Prof. Dr. Naza M. Ali Lec. 11-12 G2 19 May 2019 G1 22 May 2019 Diuretic Agents Ass. Prof. Dr. Naza M. Ali Lec. 11-12 G2 19 May 2019 G1 22 May 2019

Outlines Normal Regulation of Fluid and Electrolytes The Nephron Major Segments of The Nephron Diuretics and Classification Multiple Choice Examples

Normal Regulation of Fluid and Electrolytes About 16 -20 % of the blood plasma entering the kidneys is filtered from the glomerular capillaries into the Bowman capsule. The filtrate, normally free of proteins and blood cells, does contain most LMWT plasma components in approximately the same concentrations as are found in the plasma.

Like glucose, sodium bicarbonate, amino acids, and electrolytes, such as Na+ , K+ , Cl–. The kidney regulates the ionic composition and volume of urine by: the active reabsorption or secretion of ions and/or the passive reabsorption of water at five functional zones

The Nephron PCT The descending loop of Henle The ascending loop of Henle DCT The collecting tubule and duct

Sites of transport of solutes and water along the nephron

Major Segments of the Nephron

Diuretics: Any substance which increase urine and solute excretion. It often change its pH as well as the ionic composition of the urine and blood. Classification 1. Carbonic anhydrase inhibitors / PCT 2. Loop diuretics / TAL 3. Thiazide / DCT 4. K- sparing diuretics / CCT 5. Drugs that modify water excretion

Major locations of ion and water exchange in the nephron, showing sites of action of the diuretic drugs.

Proximal Convoluted Tubule _ HCo3 reabsorption is initiated by the action of Na + /H + exchange (via NHE3). Which allow Na + to enter the cell from the tubular lumen in exchange for a proton H+ from inside the cell Carbonic Anhydrase (CA)

1. Carbonic Anhydrase Inhibitors/ CAI Acetazolamide/ Sulfonamide derivatives Effects: Normally, carbonic anhydrase catalyzes the dehydration of H2CO3 to CO2 at the luminal membrane & rehydration of CO2 to H2CO3 in the cytoplasm The major renal effect is bicarbonate diuresis (NaHCO3 is excreted)

Body bicarbonate is depleted, and metabolic acidosis results. CAI blunt NaHCO3 reabsorption and cause diuresis are well absorbed after oral administration. Diuresis is apparent within 30 minutes, is maximal at 2 hours, and persists for 12 hours after a single dose.

Clinical Indications Glaucoma Mountain sickness C. Urinary Alkalinization D. Metabolic Alkalosis E. Other Uses

Glaucoma: Is to reduce the elevated intraocular pressure Decreases the production of aqueous humor, by blocking carbonic anhydrase in the ciliary body of eye. It is useful in the chronic treatment of glaucoma. Topical, dorzolamide and brinzolamide Have the advantage of not causing any systemic effects.

Mountain sickness: Can be used in the prophylaxis of acute mountain sickness among healthy, physically active individuals who rapidly ascend above 10,000 feet. Acetazolamide given nightly for 5 days before the ascent prevents the weakness, breathlessness, dizziness, nausea, and cerebral as well as pulmonary edema characteristic of the syndrome.

D. Other Uses used as adjuvants in the treatment of epilepsy useful in treating patients with CSF leakage (By reducing the rate of CSF formation and intracranial pressure) CAI can significantly slow the rate of CSF leakage) Protect against Acute Mountain Sickness

Toxicity A. Drowsiness and parasthesias B. Metabolic Acidosis C Toxicity A. Drowsiness and parasthesias B. Metabolic Acidosis C. Renal Stone/ alkalization of urine may precipitation of calcium salts, enhanced stone formation D. Renal Potassium Wasting E. Cross-allergy

Thick Ascending Limb NKCC2 is the primary transporter in the luminal membrane. Because k+ is pumped into the cell from both the luminal & basal sides, an escape route must be provided. This occurs into the lumen via a potassium-selective channel. Because the potassium diffusing through these channels is not accompanied by an anion, a net positive charge is set up in lumen. This positive potential drives the reabsorption of Ca+ ² and Mg +² Target loop diuretics

2. Loop Diuretics: Sulfonamide derivative :Furosemide, Bumetanide, Torsemide Not a sulfonamide derivative forms: Ethacrynic acid Inhibit co-transport of sodium, potassuim chloride ( inhibit NKCC2)

Effects Selectively inhibit NaCl reabsorption in the TAL Diuresis effects: Na+ , K+, 2Cl-, Mg+², Ca+² excretion The diluting ability of the nephron is reduced because loop of Henle is the site of significant dilution of urine. So Ca +2 excretion increase

Loop diuretics have highest efficacy in mobilizing Na+ and Cl – from the body Loop diuretics have potent pulmonary vasodilating effects PG are important in maintaining glomerular filtration Drugs such as NSAIDs , which inhibit PG synthesis, the efficacy of loop diuretics decrease

Loop diuretics Oral and parentéral preparation Duration: short acting 4 hr Clinical Indications Acute pulmonary edema, other edematous conditions Hypertension Acute hypercalcemia Hyperkalemia, acute renal failure useful in treating toxic ingestion of bromide, fluoride & iodide which are reabsorbed in TAL

Toxicity A. Hypokalemic Metabolic Alkalosis B. Ototoxicity C. Hyperuricemia D. Allergic

Distal Convoluted Tubule NCC is the primary sodium and chloride transporter in the luminal membrane. Calcium is reabsorbed under control of parathyroid hormone thus calcium must be transported via the sodium –calcium exchanger back into the blood. (R, parathyroid hormone [PTH] receptor.)

Thiazide-like analogs Chlorthalidone Indapamide Metolazone 3. Thiazides Chlorothiazide Hydrochlorothiazide Thiazide-like analogs Chlorthalidone Indapamide Metolazone All of them have sulfonamide group

The thiazide derivatives act mainly in the ascending loop of Henle and the distal tubule to decrease the reabsorption of Na+ , by inhibition of a Na+ /Cl– co-transporter on the luminal membrane of the tubules

Oral, duration of action 6-12 h All thiazides are secreted by the organic acid secretory system in the proximal tubule and compete with the secretion of uric acid by that system. decrease uric acid secretion elevate serum uric acid level

Effects In full doses, thiazides produce moderate but sustained sodium and chloride diuresis. Reduction in the transport of sodium and promote sodium –calcium exchange . As a result reabsorption of calcium from urine is increased ( the opposite effect of loop diuretics). Reduce blood pressure Inhibition of renal PG synthesis will reduces the efficacy of thiazides

Clinical Indications (1) hypertension, (2) heart failure, (3) Primary hypercalciuria, (4) nephrogenic diabetes insipidus.

Toxicity A. Hypokalemic, Metabolic Alkalosis ,Hyperuricemia B Toxicity A. Hypokalemic, Metabolic Alkalosis ,Hyperuricemia B. Hyperlipidemia C. Hyponatremia D. Allergic Reactions E. Hyperglycemia in diabetic patients due to both impaired pancreatic release of insulin and diminished tissue utilization of glucose.

Cortical Collecting Tubule / CCT Final segment of nephron is the Last tubular site for sodium reabsorption and is controlled by Aldosterone The reabsorption of sodium occur via channels not transporter epithelial sodium channel (ENaC) Accompanied by equivalent loss of K+ or H+ (R, aldosterone receptor.) Collecting tubule is the primary site of acidification of the urine and last site of potassium excretion

4. Potassium – sparing diuretics Aldosterone antagonist / Steroid derivative Spironolactone Eplenerone Slow onset & offset of action 24 -72h Reduce Na + absorption

Aldosterone Antagonist Non-Aldosterone Antagonists Potassium – Sparing Diuretics Aldosterone Antagonist (Steroid Derivative) Non-Aldosterone Antagonists Spironolactone Eplenerone Amiloride Triamterene

Antagonizes aldosterone at intracellular cytoplasmic receptor sites. Spironolactone Antagonizes aldosterone at intracellular cytoplasmic receptor sites. The spironolactone-receptor complex is inactive. it prevents translocation of the receptor complex into the nucleus of the target cell, it cannot bind to DNA. This results in a failure to produce proteins that are normally synthesized in response to aldosterone.

These mediator proteins normally stimulate the Na+/K+ exchange sites of the collecting tubule. Thus, a lack of mediator proteins prevents Na+ reabsorption and, therefore, K+ and H+ secretion. Potassium absorption (and K + secretion) at this site is regulated by aldosterone

Clinical Indication Hyperaldosteronism, Hepatic edema Treatment of potassium wasting cause by chronic therapy with thiazide and loop diuretics Adverse effects: Hyperkalemia, Spironolactone can cause endocrine abnormality (gynecomastia and antiandrogenic effects).

B. Nonaldosterone antagonists: Amiloride Triamterene Have duration 12-24h directly interfere with Na+ entry through the epithelial Na+ channels So block Na+ transport channel , decrease Na+ entry , decrease K+ secretion Toxicity A. Hyperkalemia B. Metabolic Acidosis

5. Drugs that modify water excretion A. Osmotic diuretics The proximal tubule and descending limb of Henle’s loop are freely permeable to water . Mannitol Mannitol is poorly absorbed by the GI tract, For systemic effect, mannitol must be given IV Mannitol is not metabolized and is excreted by glomerular filtration within 30–60 minutes

Clinical Indications A. Increase of Urine Volume B. Reduction of Intracranial and Intraocular Pressure Mannitol can reduce brain volume and intracrainal pressure by osmotically extracting water from tissue into blood. A similar effect occur in the eye. Toxicity . Extracellular Volume Expansion . Dehydration, Hyperkalemia, and Hypernatremia . Hyponatremia

B. Antidiuretic Hormone Drugs that modify water Excretion A. Osmotic Diuretics B. Antidiuretic Hormone Mannitol Urea ADH Agonists Vasopressin Desmopressin ADH Antagonist Conivaptan

B. Antidiuretic hormone Agonists & Antagonists: ADH Agonists: Vasopressin Desmopressin ADH Antagonists: Conivaptan

ADH Agonists: ADH facilitates water reabsorption from the collecting tubule by activation of V2 receptor which stimulate adeynylyl cyclase via Gs Increase cAMP cause insertion of additional aquaporin AQP2 water channels into luminal membrane in this part of the tubule. Reduce urine volume & increase its concentration. are used in the treatment of pituitary diabetes insipidus. Toxicity : large water load may cause hyponatremia.

Collecting Duct Above, low water permeability exists in the absence of antidiuretic hormone (ADH). Below, in the presence of ADH, aquaporins are inserted into the apical membrane, greatly increasing water permeability. AQP2, apical aquaporin water channel AQP3,4, basolateral aquaporin water channel V2 , vasopressin V2 receptor.

ADH Antagonists: Conivaptan ADH antagonists oppose the actions of ADH on V2 receptor use in the syndrome of inappropriate ADH secretion, when water restriction has failed to correct the abnormality.

Electrolyte changes by diuretics Agents NaCl NaHCo3 K + Body PH CAI ↑ ↑↑↑ Acidosis Loop ↑↑↑↑ ----------- Alkalosis Thiazide ↑↑ K+ sparing ------------ ↓

Choose the ONE best answer. 18.1  An elderly patient with a history of heart disease is brought to the emergency room with difficulty breathing. Examination reveals that she has pulmonary edema. Which treatment is indicated? A. Acetazolamide. B. Chlorthalidone. C. Furosemide. D. Hydrochlorothiazide. E. Spironolactone. 18.2  A group of college students is planning a mountain climbing trip to the Andes. Which would be appropriate for them to take to prevent mountain sickness? A thiazide diuretic such as hydrochlorothiazide. An anticholinergic such as atropine. A carbonic anhydrase inhibitor such as acetazolamide. A loop diuretic such as furosemide. A β-blocker such as metoprolol.

18. 3 An alcoholic male has developed hepatic cirrhosis 18.3 An alcoholic male has developed hepatic cirrhosis. To control the ascites and edema, which should be prescribed? A. Acetazolamide. B. Chlorthalidone. C. Furosemide. D. Hydrochlorothiazide. E. Spironolactone. 18.4 A 55-year-old male with kidney stones has been placed on a diuretic to decrease calcium excretion. However, after a few weeks, he develops an attack of gout. Which diuretic was he taking? A. Furosemide. B. Hydrochlorothiazide. C. Spironolactone. D. Triamterene. E. Urea. 18.5 A 75-year-old woman with hypertension is being treated with a thiazide. Her blood pressure responds well and reads at 120/76 mm Hg. After several months on the medication, she complains of being tired and weak. An analysis of the blood indicates low values for which of the following? A. Calcium. B. Glucose. C. Potassium. D. Sodium. E. Uric acid.

Correct answer = C. Correct answer = E. Correct answer = B.