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
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
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.
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)
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.
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.
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
Diuretics – Common Thiazides Thiazides and Thiazide Like Diuretics = Low to moderate efficacy diuretics Hydrochlorothiazide Chlorthiazide Chlorthalidone Indapamide Metolazone
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
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
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
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 )
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
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.
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.