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Premium member Presentation Transcript PowerPoint Presentation: Dr.Rakesh Chintalapudi, M.D., D.A., Asst.Professor – King George Hospital, Visakhapatnam –Andhra Pradesh-INDIA mail id : firstname.lastname@example.org D i u r e t i c sPowerPoint Presentation: Diuretic: substance that promotes the excretion of urine caffeine, yerba mate, nettles, cranberry juice, alcohol Natriuretic: substance that promotes the renal excretion of Na+Functions of the Urinary System: Filtration of the blood Occurs in the glomerulus of the kidney nephron Contributes to homeostasis by removing toxins or waste Functions of the Urinary SystemPowerPoint Presentation: Reabsorption of vital nutrients, ions and water Occurs in most parts of the kidney nephron Contributes to homeostasis by conserving important materialsPowerPoint Presentation: Secretion of excess materials Assists filtration in removing material from the blood Contributes to homeostasis by preventing a build-up of certain materials in the body such as drugs, waste,etc.PowerPoint Presentation: Activation of Vitamin D Vitamin D made in the skin is converted to Vitamin D3 by the kidney Active Vitamin D (D3) assists homeostasis by increasing calcium absorption from the digestive tractPowerPoint Presentation: Secretion of excess materials Assists filtration in removing material from the blood Contributes to homeostasis by preventing a build-up of certain materials in the body such as drugs, waste,etc.PowerPoint Presentation: Release of Erythropoietin by the kidney Erythropoietin stimulates new RBC production New RBC’s assist homeostasis by insuring adequate Oxygen and Carbon Dioxide transportPowerPoint Presentation: Release of Renin by the kidney Renin stimulates the formation of a powerful vasoconstrictor called Angiotensin II Angiotensin II assists homeostasis by causing vasoconstriction which increases blood pressurePowerPoint Presentation: Release of Prostaglandins Prostaglandins dilate kidney blood vessels Dilated blood vessels contribute to homeostasis by maintaining blood flow in the kidneysPowerPoint Presentation: Secretion of H +and reabsorption of HCO3- Eliminates excess hydrogen ions and conserves buffer material such as bicarbonate Contributes to homeostasis by controlling acid / base conditions in body fluidsPhysiology of Urine Formation: Physiology of Urine Formation Volume and Composition of Urine formed is determined by : 1. Glomerular Filtration 2. Tubular Reabsorption 3. Active Tubular Secretion.PowerPoint Presentation: Urine excretion = filtration rate – reabsorption rate (2) + secretion rate (3) Urine Formation 1 3 2 2 1 3G F R: G F R Amount of filtrate formed by both kidneys together in unit time is called GFR. Average adult GFR is about 125 ml/min. or 180 L/day Entire plasma volume is only about 3 ltrs., whereas the GFR is about 180 l/day the entire plasma can be filtered and processed about 60 times each day. High GFR allows the kidneys to precisely and rapidly control the volume and composition of the body fluids, so also the toxic products in the body.PowerPoint Presentation: GFR is 180 liters per day and the urine output is only 1.5 to 2 ltrs. That clearly shows that Reabsorption is a major quantitative activity that is taking place. Here Diuretics act as mainly Inhibiting the reabsorption of water and also some minerals along with it as an obligation will be delivered out as increased urine output. Most of the diuretics are Natriuretics and Kaliuretics.PowerPoint Presentation: 180 Liters 1.5 to 2 Liters MORE URINE DIURETICPowerPoint Presentation: Juxtamedullary nephron functions Bowman's capsule: filtering Proximal tubule: recovery of nutrients Loop of Henle: generation of a salt gradient Distal tubule: further ion recovery Collecting duct: generation of hypoosmotic or hyperosmotic urineTubular Reabsorption & Secretion in different parts of Nephron: Tubular Reabsorption & Secretion in different parts of NephronPowerPoint Presentation: 100% GFR 180 L/day Plasma Na 145 mEq/L Filtered Load 26,100 mEq/day CA Inhibitors Proximal tubule 70% Thiazides Distal tubule Loop Diuretics Loop of Henle 20% 4.5% Antikaliuretics Collecting duct Thick Ascending Limb 5% 0.5% Volume 1.5 L/day Urine Na 100 mEq/L Na Excretion 155 mEq/dayPowerPoint Presentation: 70% 20% 4.5% 0.5% Volume 1.5 L/day 100% GFR 180 L/day Plasma Na 145 mEq/L Filtered Load 26,100 mEq/day 5%PowerPoint Presentation: H2O Na+ HCO3- K+ Glucose Amino acids Chlorides 65 to 70 % TUBULAR REABSORPTION P C TPowerPoint Presentation: TUBULAR SECRETION 1.H+ 2.Metabolic wastes Urea creatinine 3.Drugs Penicillin Salicylates H+ + HCO3- H2CO3 H2CO3 CO2 + H2O ( Carbonic Anhydrase Enzyme ) P C TPowerPoint Presentation: Mechanisms involved in Reabsorption and Secretion 1.Paracellular Transport 2.Active Transport 3.Pinocytosis 4.Passive Reabsorption a . Primary Active Transport b. Secondary Active Trans. ( CO TRANSPORT) SECONDARY ACTIVE SECRETION ( Na+ K+ Counter Transport ) P C TPowerPoint Presentation: 1Na+ / 2 Cl- / 1K+ T P C A SYMPORTER is an integral membrane protein that is involved in movement of two or more different molecules or ions across a phospholipid membrane such as the plasma membrane in the same direction, and is therefore a type of COTRANSPORTER Na+/K+/2Cl- symporter in the loop of Henle in the renal tubules of the kidney transports 4 molecules of 3 different types; a sodium ion (Na+), a potassium ion (K+) and two chloride ions (2Cl-).PowerPoint Presentation: An ANTIPORTER (also called exchanger or COUNTER- TRANSPORTER ) is an integral membrane protein which is involved in secondary active transport of two or more different molecules or ions (i.e. solutes) across a phospholipid membrane such as the plasma membrane in opposite directions. Na+---H+ Counter TransportTubular Reabsorption & Secretion in Loop H: Tubular Reabsorption & Secretion in Loop H Permeable to Solutes Impermeable to Water Permeable to Water Thin Desc. Loop Thin Asc. Loop Thick Asc. LoopPowerPoint Presentation: THIN DESC.LOOP THICK ASCD. LOOP SIMPLE DIFFUSION 20 % OF WATER REABSORPTION OF 25 % OF SOLUTES Na+ K+ Cl- HCO3- Ca++ Mg++ 1 Na+-2Cl- 1K+ TPC Active Na+ K+ ATPase Pump Na+-- H+ Counter Transport Impermeable to Water 1. Na+ Reabsorption 2. Paracellular Reabsorption of Na+ K+ Mg++ Ca++ 3. Na+ H+ COUNTER Transport 4.Reabsorption of Na + into interstitiumPowerPoint Presentation: RENAL TUBULAR INTERSTITIUM LUMEN Na+ K+ Cl- TPC Na+ H+ Na+ K+ PARACELLULAR DIFFUSION Na+ K+ Mg++ Ca++ Cl- +8 mVPowerPoint Presentation: Paracellular reabsorption of Cations like Mg++--Ca++--Na+--K+ Na+ - H+ Counter Current Multiplier in Thick Asc. Loop Thick Asc. Loop is totally impermeable to water, lost most of the solute and remains in a very diluted filtrate. Then it enters, in DCT as very diluted filtrate for necessary concentration of urine depending upon the REQUIREMENTS of the Body.Early DCT: Early DCT Absorbs most of the ( 5 %) of the Na+ K+ Cl-,and virtually impermeable to Water. For this reason, it is referred to as the diluting segment because it also dilutes the tubular fluid.( Similar to Thick Asc. LH) Na+ Cl- COTRANSPORTER moves into cell. Chloride diffuses out of cell, through chloride channels. Na+ K + ATPase COUNTER pump transport Na+ out and K+ in.D C T: D C T Early DCT Late DCT Na+ Cl- LUMEN K+ Na+ Cl- THIAZIDESLate Distal Tubule Cortical Collecting Tubule: Late Distal Tubule Cortical Collecting Tubule Principal cells reabsorb Na+ ( through Na+ channels) and Water from Lumen, secrete K+ into Lumen By N+-K+ ATPase Pump Site for action of K Sparing diuretics Intercalated cells secrete H+ Reabsorb HCO3-(H+ transport is by H+ ATPase mechanism) Production of H+ is by CA (CO2 + H2O H+ + HCO3- ) Secretion of H+ is in exchange for HCO3-(ONE FOR ONE) INTERCALATED CELLS PRINCIPAL CELLSLate DCT cortical CT: Late DCT cortical CT PRINCIPAL CELLS INTERCALATED CELLS K+ H+ Na+ K+ H2O Na + K+ ATPase Pump Na+ K+ Na + K+ ATPase Pump H2O Na+ K+ Cl- POTASSIUM SPARING DIURETICS Na+ CHANNEL BLOCKERS HCO3+ ALDOSTERONE Stimulation of’ Na+ reabsorption K+ Secretion Na+ K+Medullary Collecting Duct: Medullary Collecting Duct Although the Medullary collecting ducts reabsorb less than 10 % of the filtered water and sodium, it is the final site for processing the urine, therefore plays a role in determining the final urine output of water and solutes.PowerPoint Presentation: 1.Action of ADH 2.Permeability to Urea. 3.Has a role in Acid-Base regulation as it secretes H+ ionsPowerPoint Presentation: COUNTER CURRENT MULTIPLIER FOR BUILDING UP MEDULLARY CONCENTRATION GRADIENT VASA PRAEVIA ACTING AS COUNTER CURRENT EXCHANGER (maximizes the rate of exchange).PowerPoint Presentation: DiureticsCeiling Effect: Ceiling Effect Ceiling effect of a drug refers to the dose beyond which there is no additional effect . Higher doses do not provide any additional effect but may increase the likelihood of side effects as well as the cost of treatment.PowerPoint Presentation: Dose of Diuretic that Achieves a Ceiling [Diuretic] in the Tubular Lumen. Said Differently Dose of Diuretic that Yields a Near-Maximal Diuretic Response. CONCEPT OF CEILING DOSEPowerPoint Presentation: EFFECT < Ceiling Effect Ceiling Effect Ceiling Effect ACTUAL DOSE < Ceiling Dose Ceiling Dose > Ceiling Dose CONCEPT OF CEILING DOSEPowerPoint Presentation: Exceeding Ceiling Dose Yields: Pointless, and possibly harmful, to exceed ceiling dose of diuretic!! No Additional Effect Possible Adverse Effects CONCEPT OF CEILING DOSEPowerPoint Presentation: High Ceiling ( loop) diuretics Medium Ceiling Diuretics Minimal Ceiling DiureticsClassification of Diuretics: Classification of Diuretics Carbonic anhydrase inhibitors Loop diuretics Osmotic diuretics Potassium-sparing diuretics Thiazide and thiazide-like diureticsCarbonic anhydrase inhibitors : Carbonic anhydrase inhibitors Acetazolamide : limited uses as diuretic prototype carbonic anhydrase inhibitor developed from sulfanilamide (caused metabolic acidosis and alkaline urine)PowerPoint Presentation: inhibits carbonic anhydrase in renal proximal tubule cells carbonic anhydrase catalyzes formation of HCO3- and H+ from H2O and CO2 inhibition of carbonic anhydrase decreases [H+] in tubule lumen less H+ for for Na+/H+ exchange increased lumen Na+, increased H2O retentionPowerPoint Presentation: CA blocks Na+ HCO3- reabsorption H+ HCO3- SECRETION REABSORPTION Na+ H+ CA HCO3- present in eyePowerPoint Presentation: used to treat chronic open-angle glaucoma aqueous humor has high [HCO3-] acute mountain sickness prevention and treatment metabolic alkalosis sometimes epilepsy mostly used in combination with other diuretics in resistant patients Therapeutic Uses :Side effects: Side effects rapid tolerance increased HCO3- excretion causes metabolic acidosis drowsiness fatigue CNS depression paresthesia (pins and needles under skin) nephrolithiasis (renal stones) K+ wastingThiazide Diuretics: active in distal convoluted tubule Chlorothiazide (prototype) Hydrochlorothiazide Chlorthalidone Metolazone Thiazide DiureticsMechanism of Action: Mechanism of Action inhibit Na+ and Cl- transporter in distal convoluted tubules increased Na+ and Cl- excretion weak inhibitors of carbonic anhydrase, increased HCO3- excretion increased K+/Mg2+ excretion decrease Ca2+ excretionD C T: D C T Early DCT Late DCT Na+ Cl- LUMEN K+ Na+ Cl- THIAZIDESPharmacokinetics: Pharmacokinetics orally administered poor absorption onset of action in ~ 1 hour wide range of T 1/2 amongst different thiazides, longer than loop diuretics free drug enters tubules by filtration and by organic acid secretionTherapeutic Uses: Therapeutic Uses hypertension congestive heart failure hypercalciuria: prevent excess Ca2+ excretion to form stones in ducts osteoperosis nephrogenic diabetes insipidus treatment of Li+ toxicitySide effects: Side effects hypokalemia increased Na+ exchange in CCD volume-contraction induced aldosterone release hyponatremia hyperglycemia diminished insulin secretion elevated plasma lipids hyperuricemia hypercalcemiaOsmotic Diuretics: do not interact with receptors or directly block renal transport activity dependent on development of osmotic pressure Mannitol (prototype) Urea Glycerol Isosorbide Osmotic DiureticsMechanism of Action: osmotic diuretics are not reabsorbed increases osmotic pressure specifically in the proximal tubule and loop of Henle prevents passive reabsorption of H2O osmotic force solute in lumen > osmotic force of reabsorbed Na+ increased H2O and Na+ excretion Mechanism of ActionTherapeutic Uses: Mannitol drug of choice: non-toxic, freely filtered, non-reabsorbable and non-metabolized administered prophylatically for acute renal failure secondary to trauma, CVS disease, surgery or nephrotoxic drugs short-term treatment of acute glaucoma infused to lower intracranial pressure Urea, glycerol and isosorbide are less efficient. (orally administered) Therapeutic UsesMannitol: Mannitol It is a Sugar, administered intravenously To be effective, administered in large doses Not suitable as a diuretic in CHF, as it does not draw water from ECF, rather intra cellularly. Available 10 % 20 % 100ml 350 ml 500ml vials.Side Effects: increased extracellular fluid volume cardiac failure pulmonary edema hypernatremia hyperkalemia secondary to diabetes or impaired renal function headache, nausea, vomiting Side EffectsLoop Diuretics: active in “loop” of Henle Furosemide (prototype) Bumetanide Torsemide Ethacrynic acid Loop DiureticsLOOP DIURETICS: Onset of action: roughly 30 minutes with PO, 5 minutes with IV Duration: 6 hours La sts Six Hours = LASIX LOOP DIURETICS Representative Example: Furosemide (Most Popular Commercial Name)Site of Action: Site of ActionPowerPoint Presentation: RENAL TUBULAR INTERSTITIUM LUMEN Na+ K+ Cl- TPC Na+ H+ Na+ K+ PARACELLULAR DIFFUSION Na+ K+ Mg++ Ca++ Cl- +8 mV THICK ASCENDING LOOP LOOP DIURETICSPowerPoint Presentation: 1Na2Cl1K TPC is necessary for: Dilution of Tubular Filtrate Establishing the Hypertonic Medullary Interstitium Providing the concentration gradient by which water is reabsorbed from the collecting duct (urinary concentration)PowerPoint Presentation: Decrease sodium reabsorption Impairs the generation of a Medullary gradient Thus… Impairs urine dilution Impairs urine concentrationPowerPoint Presentation: Blocking NaK2Cl causes: Impaired dilution No concentration gradient Increased free water excretionLoop Diuretics: Loop Diuretics Na K Cl Na K Calcium LUMENLoop Diuretics: Loop Diuretics Na K Cl Na K Calcium Loop Diuretics: Increase excretion of CalciumLoop Diuretics: Loop Diuretics Collecting Duct Na Na Na Na K The increase in Na delivery to the Collecting Duct causes an increase in the exchange of Na for secretion of K/H+ HDiuretics: Diuretics LASIX Quick onset of diuresis Good for acute volume overload Increases urinary calcium excretion Used to treat hypercalcemia (Malignancy, Hyperparathyroidism) Increases urinary excretion of potassium and hydrogen ions Used to treat acute hyperkalemia 3 Reasons to like your loop diureticDiuretics: Diuretics LASIX Excessive diuresis can lead to volume depletion and ARF/hypotension/CV collapse 3 Reasons to think twice DiuresisDiuretics: Diuretics LASIX Excessive diuresis can lead to volume depletion and ARF/hypotension/CV collapse 3 Reasons to think twice DiuresisDiuretics: Diuretics LASIX Excessive diuresis can lead to volume depletion and ARF/hypotension/CV collapse Can exacerbate calcium based kidney stones Can cause hypokalemia, metabolic alkalosis 3 Reasons to think twiceTherapeutic Uses: Therapeutic Uses 1.Edema-cardiac – renal - hepatic 2.Acute pulmonary edema ( LVF) 3.Cerebral edema – Mannitol 4.Hypertension – CHF – CRF - Thiazides 5.Fluid overload (Blood transfusion) 6.Hypercalcaemia renal calcium stones.K-Sparing Diuretics: K-Sparing Diuretics 1. Aldosterone Antagonists Representative Example: Spironolactone Site of Action: Cortical Collecting Duct Mechanism: Competes with aldosterone receptor Pharmacokinetics: Can take between 10-48 hours to reach maximal efficacyLate DCT cortical CT: Late DCT cortical CT PRINCIPAL CELLS INTERCALATED CELLS K+ H+ Na+ K+ H2O Na + K+ ATPase Pump Na+ K+ Na + K+ ATPase Pump H2O Na+ K+ Cl- POTASSIUM SPARING DIURETICS Na+ CHANNEL BLOCKERS HCO3+ ALDOSTERONE Stimulation of’ Na+ reabsorption K+ Secretion Na+ K+K-Sparing Diuretics: K-Sparing Diuretics Collecting Duct Na Na Na Na K Aldosterone is the mineralocorticoid which promotes Na reabsorption by increasing the number of Na channels (ENaC) on the luminal surface and the number of Na-K pumps on the basolateral surface AldoK-Sparing Diuretics: K-Sparing Diuretics Collecting Duct Na Na Na Na Aldosterone is the mineralocorticoid which promotes Na reabsorption by increasing the number of Na channels (ENaC) on the luminal surface and the number of Na-K pumps on the basolateral surface Aldo Spironolactone is an aldosterone antagonist, thus preventing sodium reabsorption and K excretion KK Sparing Diuretics: K Sparing Diuretics Despite being a weaker diuretic, aldosterone antagonists have a greater effect in cirrhotics than lasix! Cirrhotic patients have a poor response to lasix due to their low albumin state and reduced tubular secretion. Aldosterone antagonists do not require secretion into the tubular lumen, and thus may remain effective despite marginal renal perfusion in the context of cirrhosisK-sparing Diuretics: K-sparing Diuretics 2. ENaC Blockers Representative Example: Amiloride, Triamterene Site of action: Cortical collecting duct Mechanism: Blocks ENaC channels Pharmacokinetics: Half-life = 3-5 hours Spares potassium by decreasing the lumen-negative gradient that drives the expulsion of K/H into the lumenK-Sparing Diuretics: K-Sparing Diuretics Collecting Duct Na Na Na Na Amiloride and Triamterene directly block the ENaC channel Aldo This makes amiloride an ideal agent for the treatment of patient’s with Liddles Syndrome, in which there is an abundance of “active” ENaC channels expressed in the CCD K KSpironolactone: Spironolactone Prevent K loss caused by other diuretics in: Hypertension Refractory edema Heart failure Primary aldosteronism Hirsutism due to P C O D. Edema – especially edema in CirrhoticsPowerPoint Presentation: Dose orally administered (100 mg/day) Spironolactone / thiazide preparation (aldactazide) 25 or 50 mg of each drug in equal ratio.PowerPoint Presentation: Hyperkalemia - avoid excessive K supplementation when patient is on Spironolactone. Androgen like effects due to it steroid structure Gynecomastia GI disturbances Side EffectsTriamterene and Amiloride: Non-steroid in structure. (It is not a Aldosterone Antagonists) Triamterene and AmilorideTherapeutic uses: Eliminate K wasting effects of other diuretics in: Edema Hypertension Amiloride – Lithium induced Diabetes Insipidus. Therapeutic usesK-Sparing Diuretics: K-Sparing Diuretics Collecting Duct Li Li Li Li Li Certain drugs (trimethoprim, pentamidine) may have mild diuretic effects due to their ability to block reduce the number of open ENaC channelsToxicity: Hyperkalemia. Avoid K+ supplementation Drug interaction - do not use in combination with spironolactone since the potassium sparing effect is greater than additive Caution with ACE inhibitors Reversible azotemia (triamterine) Triamterene nephrolithiasis. 1 in 1500 patients ToxicityNon Diuretic Uses of Diuretic Drugs: Non Diuretic Uses of Diuretic Drugs HTN (hydrochlorothiazide) Idiopathic calcium urolilthiasis (hydrochlorothiazide) Diabetes insipidus (hydrochlorothiazide) Glaucoma (Acetazolamide) Mountain sickness (Acetazolamide) Hirsutism (Spironolactone)Thank You: Thank You You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.