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  1. 1. DiureticsSpecial focus onhydrochlorthiazide
  2. 2. Topics for discussion Renal pathology Diuretics Thiazides
  3. 3. Renal pathology& pharmocology
  4. 4. Renal Pathology Kidneys: Represent 0.5% of total body weight, but receive ~25% of the total arterial blood pumped by the heart Each contains from 1-2 million nephrons:  Glomerulus  Proximal convoluted tubule  Loop of Henle  Distal convoluted tubule
  5. 5. Renal Pharmacology  Renal processes Functions  Filtration - glomerulus  Clean extracellular  Reabsorption fluid and maintain ECF  Tubular secretion volume and composition  In 24 hours the kidneys reclaim:  Acid-base balance  ~ 1,300 g of NaCl  Excretion of wastes  ~ 400 g NaHCO3  ~ 180 g glucose and toxic substances  almost all of the 180 L of water that entered the tubules
  6. 6. Renal Pharmacology Blood enters the glomerulus under pressure This causes water, small molecules (but not macromolecules like proteins) and ions to filter through the capillary walls into the Bowmans capsule This fluid is called nephric filtrate  Not much different from interstitial fluid Nephric filtrate collects within the Bowmans capsule and flows into the proximal tubule: Here all of the glucose and amino acids, >90% of the uric acid, and ~60% of inorganic salts are reabsorbed by active transport  The active transport of Na+ out of the proximal tubule is controlled by angiotensin II.  The active transport of phosphate (PO4)3- is regulated (suppressed by) the parathyroid hormone. As these solutes are removed from the nephric filtrate, a large volume of the water follows them by osmosis:  80–85% of the 180 liters deposited in the Bowmans capsules in 24 hours As the fluid flows into the descending segment of the loop of Henle, water continues to leave by osmosis because the interstitial fluid is very hypertonic:  This is caused by the active transport of Na+ out of the tubular fluid as it moves up the ascending segment of the loop of Henle In the distal tubules, more sodium is reclaimed by active transport, and still more water follows by osmosis.
  7. 7. Diuretics
  8. 8. Diuretics Diuretics are drugs which increase urine excretion mainly by ↓ reabsorption of salts and water from kidney tubules General clinical uses:  Hypertension  Oedema of heart, renal, and liver failure  Pulmonary oedema  ↑ intracranial pressure (Mannitol)  ↑ Intraocular pressure=Glaucoma ( CA inhibitors)
  9. 9. Diuretics – main types Loop Diuretics  Frusemide, Torasemide Potassium Sparing Diuretics:  Spiranolactone, Eplerenone, Triamterene, amiloride Osmotic diretics  Mannitol Carbonic anhydrase inhibitors Thiazides
  10. 10. Diuretic- applications Hypercalcemia (Furosemide=Frusemide) Idiopathic hypercalciuria (Thiazides) Inappropriate ADH secretion (Furosemide) Nephrogenic diabetes insipidus  Basicknowledge of renal physiology particularly salt and water movements (absorption, reabsorption and secretion) and cotransporter systems is mandatory.
  11. 11. Diuretics – what are they? Diuretics are considered 1st line therapy for most hypertensive patients  They are effective, relatively safe and cheap  Accumulating evidence proves that diuretics, particularly thiazides decrease the risk of cardiovascular disease, fatal and nonfatal MI and stroke.
  12. 12. Diuretics - MOA Diuretics act simply by increasing urine output → ↓ plasma and stroke volume →↓ CO → ↓ BP The initial ↓ CO leads to an ↑ in peripheral resistance but with chronic use extra cellular fluid and plasma volume return to normal and peripheral resistance ↓ to values lower than those observed before diuretic therapy Thiazide diuretics also are believed to have direct vasodilating effect
  13. 13. Diuretics – Common Thiazides Thiazides and Thiazide Like Diuretics = Low to moderate efficacy diuretics  Hydrochlorothiazide  Chlorthiazide  Chlorthalidone  Indapamide  Metolazone
  14. 14. Diuretics – Rare Thiazides Bendroflumethiazide Hydroflumethiazide Methyclothiazide Polythiazide Benzthiazide Quinethazone Trichlormethiazide **All are usually given orally (Chlorthiazide could be given IV); they differ in potency, DOA and t½
  15. 15. ThiazidesSpecial focus onhydrochlorthiazide
  16. 16. Diuretics –Thiazides Inhibition of Thiazide sensitive Na+/Cl- transporter in distal convoluted tubule, thus inhibiting Na+ reabsorption → ↑ Na+, K+, Cl-, HCO3- and H2O excretion They lead to about 5-10% loss of filtered Na+ ↑ in dose will not lead to further increase in diuretic effect ( low ceiling ) Thiazides are ineffective in patients with impaired renal function or patients with GFR
  17. 17. Diuretics –Thiazides Thiazides ↑ Ca++ reabsorption Thiazides have little carbonic anhydrase inhibitory effect Thiazides have a direct vasodilating effect ( Indapamide has been observed for its pronounced vasodilating effect) Thiazides ↓ response of blood vessels to NE
  18. 18. Diuretics – Common Thiazides Widely used Thiazides are Hydrochlorothiazide and Chlorthalidone and Thiazide kinetics are as follows:  Usually given orally  Strongly bind to plasma albumin  Excreted via the kidney by a specific secretory mechanism (not filtered) (small fraction biliary excretion) Thiazides are highly effective in lowering BP when combined with other antihypertensive agents (synergistic effect )
  19. 19. Diuretics –Thiazides Side effects of Thiazides:  Weakness  Muscle cramps  Erectile dysfunction  Hyperglycemia  Hypercalcemia  Pancreatitis  Hyperlipidemia ( ↑ LDL; ↑ TG’s )  Hypokalemia and hypomagnesemia  The most frequent and dangerous side effect which could lead to muscle weakness and serious cardiac arryhthmias
  20. 20. Diuretics – Thiazides Patients at high risk of hypokalemia are those with:  LVH  Previous history of MI  Previous history of cardiac arrhythmias, or  Patients who are on digoxin therapy Hyperuricemia → could precipitate Gout  The effect of thiazides on blood uric acid is dose dependent…Low doses → Hyperuricemia  Large doses → ↓ uric acid reabsorption →↓ uric acid blood levels.
  21. 21. Diuretics – Thiazide clinical uses Hypertention Oedema of CHF, Liver cirrhosis, etc Nephrogenic diabetes insipidus Hypercalciuria Available as 12.5 mg. / 25 mg. tablets Combined with: A. Ace Inhibitors / ARBs B. Beta blockers C. Calcium channel blockers, if present along with A & B.