Prof. Hanan Hagar Pharmacology Department DIURETICS Part 1 Prof. Hanan Hagar Pharmacology Department

Diuretics Are drugs that increase renal excretion of sodium and water resulting in increase in urine volume. Most diuretics act by interfere with the normal sodium handling by the kidney.

Sites of action for diuretics Target molecules for diuretics are specific membrane transport proteins in renal tubular epithelial cells (transporters).

Classification of diuretics Carbonic Anhydrase Inhibitors Loop Diuretics Thiazides Potassium-Sparing Diuretics Osmotic Diuretics

SITES OF ACTION OF DIURETICS

kidney Nephron is the unit of the kidney It is classified structurally and functionally into different zones Glomerulus Proximal convoluted tubule Descending loop of Henle Ascending loop of Henle Distal convoluted tubule Collecting duct

FUNCTION OF THE KIDNEY Kidney is responsible for regulation of fluids and electrolytes. Kidney do its function through three processes Glomerular filtration Passive tubular re-absorption Active tubular secretion

Regulation of fluids and electrolytes

Sites for solutions and water transport along the nephron

Glomerular filtration: 16-20 % of blood entering the kidney is filtered Filtrate contains water, glucose, amino acids, sodium bicarbonates, organic solutes and electrolytes (sodium, potassium, chloride).

Responsible for re-absorption of all glucose, amino acids Proximal convoluted tubules: Responsible for re-absorption of all glucose, amino acids organic solutes electrolytes as sodium chloride (NaCl)(66% of Na) sodium bicarbonate (NaHCO3,85%) Potassium (K+, 66 %)

PCT is the site of organic acids or bases secretory systems Proximal convoluted tubule (PCT): HCO3- is reabsorbed by action of enzyme carbonic anhydrase (luminal membrane of proximal tubular cells). Water (passively following salts to maintain osmolarity in tubular fluids (60%). PCT is the site of organic acids or bases secretory systems

carbonic anhydrase Lumen Blood Luminal membrane Basolateral membrane

organic acids or bases secretory systems Organic base secretory system responsible for secretion of bases into luminal fluid e.g. choline and creatinine Organic acid secretory system responsible for secretion of acids into luminal tubular fluid e.g. uric acid, NSAIDs, antibiotics and diuretics.

Descending loop of Henle In thin descending loop of Henle : water is re-absorbed by osmotic forces in hypertonic medullary interstitium (counter current mechanism)

Ascending loop of Henle Is impermeable to water In thick ascending loop of Henle (TAL) is responsible for active re-absorption of Na, K and Cl (25-30% Na) via transport system in luminal membrane called Na+/ K+ / 2Cl- co-transporter TAL is called the diluting segment Ca and Mg enter the interstitial fluid via paracellular pathway

Ascending loop of Henle

Distal convoluted tubule (DCT) Is impermeable to water Responsible for active re-absorption of NaCl (10%) via transport system Na/Cl transporter in luminal membrane Ca2+ actively reabsorbed via apical Ca channel and Na+/Ca2+ exchanger in basolateral membrane

Distal convoluted tubules (DCT)

Collecting tubule Principal cells are responsible for re-absorption of Na (in exchange for K via Na/K-ATPase) and water Aldosterone receptors located in the principle cells influence Na re-absorption and K secretion Intercalated cells affect H secretion Water re-absorption (anti-diuretic hormone, ADH).

COLLECTING TUBULES (CT)

COLLECTING TUBULES (CT)

Sodium Excretion Regulation Nephron Segment Filtered Na+ reabsorbed Na+ Transporter Proximal CT 60-70% Na+- H+ transporter Ascending Loop of Henle 20-30% Na+-K+-2Cl- transporter Distal CT 5-10% Na+-Cl- transporter Cortical Collecting Tubules 5% Aldosterone Na+ channel ADH

Site of action of diuretics transporter Function segment Carbonic anhydrase inhibitors Na/H transporter, Carbonic anhydrase enzyme Re-absorption of 66% Na, K, Ca, Mg, 100% glucose and amino acids; 85% NaHCO3 Proximal convoluted tubules None Acid & base transporter Secretion and re-absorption of organic acids and bases Proximal Straight Tubules Loop diuretics Na/K/2Cl transporter Active reabsorption 25% Na, K, Cl Secondary reabsorption Ca, Mg Thick ascending loop Thiazide diuretics Na and Cl cotransporter Active tubular reabsorption of 5%Na, Cl, Ca Distal convoluted tubules K-sparing diuretics Na channels K & H transporter Na reabsorption K & H secretion Collecting tubules

Diuretics

Carbonic Anhydrase Inhibitors Acetazolamide – dorzolamide Mechanism of action: Inhibits carbonic anhydrase (CA) enzyme in PCT thus interferes with NaHCO3 re-absorption and causes diuresis. CA is required for reversible reaction, in which CO2 +H2O ↔ H2CO3

Blood Lumen Basolateral membrane Luminal membrane

Carbonic Anhydrase Inhibitors

Pharmacological actions: ↑ urinary excretion of bicarbonate, sodium, potassium “alkaline diuresis” Metabolic acidosis. ↑ urinary phosphate excretion. Weak diuretics. Decreases after several days (self-limiting as the blood bicarbonate falls).

Carbonic anhydrase inhibitors

Pharmacokinetics: given orally once a day. Onset of action is rapid (30 min). Duration of action (12 h). Excreted by active secretion in proximal convoluted tubules forming alkaline urine

Therapeutic uses: Open angle glaucoma (↓ IOP by reducing aqueous humor formation via blocking carbonic anhydrase in ciliary body of eye). As prophylactic therapy, in acute mountain sickness (to decrease CSF and pH of brain).

Therapeutic uses: Urinary alkalinization to enhance renal excretion of acidic substances (uric acid and cysteine in cystinuria). Epilepsy (decrease cerebrospinal fluid, CSF). Hyperphosphatemia Metabolic alkalosis

Adverse effects: Hypokalemia (potassium loss). Metabolic acidosis. Renal stone formation (calcium phosphate stones). Hypersensitivity reactions

Dorzolamide Is a carbonic anhydrase inhibitor Used topically for treatment of increased intraocular pressure in open-angle glaucoma. no diuretic or systemic side effects (Why?).

LOOP DIURETICS High Ceiling diuretics The most efficacious diuretics Efficacy: High 25-30% natriuresis Drugs as Furosemide - torsemide Bumetanide - Ethcrynic acid

LOOP DIURETICS Mechanism: inhibit Na+ / K+ / 2 Cl- co-transporter in the luminal membrane of the thick ascending loop of Henle (TAL). inhibit Ca++ and Mg ++ re-absorption.

Has fast onset of action (suitable for emergency) Pharmacokinetics Given orally or I. V. Has fast onset of action (suitable for emergency) Have short duration of action. Excreted by active tubular secretion of weak acids into urine (compete with uric acid for renal secretory system).

Ascending loop of Henle

Ascending loop of Henle

Pharmacological effects: ↑ urinary excretion of Na+ , K,+ Ca++ and Mg ++ ↑ urine volume ↑ renal blood flow.

Uses: are drug of choice for emergency situations as: Acute pulmonary edema Edema associated with heart failure, nephrotic syndrome Acute hyperkalaemia. Acute hypercalcemia

Adverse effects : Hypokalemia (dietary K supplementation or K-sparing diuretics). Metabolic alkalosis. Acute Hypovolemia, postural hypotension

Adverse effects : Hyponatraemia. Hypomagnesaemia Hyperuricemia (increase gouty attack). Ototoxicity (risk increased if combined with aminoglycosides) Allergic reactions