Diuretics. Diuretics Agents that promote natriuresis (salt loss) and diuresis (water loss) Used to treat hypertension and fluid retention

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Diuretics Slide 2 Diuretics Agents that promote natriuresis (salt loss) and diuresis (water loss) Used to treat hypertension and fluid retention Slide 3 Salt & Water Balance 2/3 ICF 1/3 ECF What causes edema? Plasma Interstitium 1. Edema is a manifestation of an increase in the interstitial fluid compartment of the body Slide 4 Salt & Water Balance 2/3 ICF 1/3 ECF What causes edema? Plasma Interstitium 1. Edema is a manifestation of an increase in the interstitial fluid compartment of the body When water is added to the system, it distributes evenly: 2/3 to the ICF, 1/3 to the ECF Isotonic fluid, however, stays in the ECF Slide 5 Salt & Water Balance 2/3 ICF 1/3 ECF ISOTONICISOTONIC What causes edema? Plasma Interstitium BP Edema 1. Edema is a manifestation of an increase in the interstitial fluid compartment of the body Slide 6 Salt & Water Balance 2/3 ICF 1/3 ECF ISOTONICISOTONIC What causes edema? Plasma Interstitium 1. Edema is a manifestation of an increase in the interstitial fluid compartment of the body Slide 7 Salt & Water Balance What causes edema? 1. There is a change in capillary hemodynamics favoring the movement of fluid from the vascular to interstitial space Increased Hydrostatic Pressure Decreased Oncotic Pressure Increased Capillary Permeability Slide 8 Diuretics Diuretics have profound clinical implications They allow physicians to manipulate salt and water excretion in impaired states of volume/solute regulation Like all great therapeutic interventions, they have the potential to make patients better, and, when not considered carefully, the potential to make patients worse Slide 9 Diuretics Act primarily by inhibiting Na channels in the renal tubular system To reach the tubular lumen, these drugs must be Ingested and absorbed Ingested and absorbed Effectively circulated Effectively circulated Secreted into the renal tubular lumen Secreted into the renal tubular lumen Bound to the target transporter Bound to the target transporter Slide 10 Question 1 All of the following are potential obstacles in the diuretics migration from pill bottle to apical transporter EXCEPT: A. Low Albumin States A. Low Albumin States B. Pt non compliance B. Pt non compliance C. Renal Failure C. Renal Failure D. All of these are obstacles to effective diuresis D. All of these are obstacles to effective diuresis Slide 11 Question 2 In patients with nephrotic syndrome, oral diuretics: A. Are not effective, since these patients have volume retention due to low albumin states and not salt retention A. Are not effective, since these patients have volume retention due to low albumin states and not salt retention B. Are absorbed more efficiently in the gut B. Are absorbed more efficiently in the gut C. May bind albumin in the urine instead of their targeted apical transporters C. May bind albumin in the urine instead of their targeted apical transporters D. Are unable to reach the apical transporters due to impaired glomerular permeability D. Are unable to reach the apical transporters due to impaired glomerular permeability Slide 12 Regulation of Urine Content ADH Slide 13 Diuretics Slide 14 Diuretics Are all diuretics pretty much the same? Well, they all cause people to pee Well, they all cause people to pee But recognize the difference based on the channels being blocked But recognize the difference based on the channels being blocked Favorite test questions focus on Why is one diuretic better than another in a particular context? Favorite test questions focus on Why is one diuretic better than another in a particular context? Slide 15 Diuretics ClassSiteEffectUse Side Fx Thiazides Loop K Sparing Other Slide 16 Diuretics LOOP DIURETICS Representative Example: Furosemide (Lasix) Onset of action: roughly 30 minutes with PO, 5 minutes with IV Duration: 6 hours LASIX = Lasts Six [Hours] Slide 17 Diuretics LOOP DIURETICS Representative Example: Furosemide (Lasix) Site of Action: NaK2Cl transporter in the Thick Ascending Limb Slide 18 Loop Diuretics Decrease sodium reabsorption Impairs the generation of a medullary gradient Thus Impairs urine dilution Impairs urine dilution Impairs urine concentration Impairs urine concentration Slide 19 Regulation of Urine Content ADH NaK2Cl is necessary for: 1.Dilution of Tubular Filtrate 2.Establishing the Hypertonic Medullary Interstitium 3.Providing the concentration gradient by which water is reabosrbed from the collecting duct (urinary concentration) Slide 20 Effect of Lasix ADH Blocking NaK2Cl causes: 1.Impaired dilution 2.No concentration gradient 3.Increased free water excretion LASIXLASIX Impaired dilution Slide 21 Lasix: Lets see that one more time Slide 22 Diluting and Concentrating Slide 23 TAL Distal Tubule Collecting Duct Medullary Interstitium Slide 24 Loop Diuretics Decrease sodium reabsorption Impairs the generation of a medullary gradient Thus Impairs urine dilution Impairs urine dilution Impairs urine concentration Impairs urine concentration Slide 25 Loop Diuretics Na K Cl Na K Calcium Slide 26 Loop Diuretics Na K Cl Na K Calcium Loop Diuretics: Increase excretion of Calcium Slide 27 Loop Diuretics Collecting Duct Na K The increase in Na delivery to the Collecting Duct causes an increase in the exchange of Na for secretion of K/H+ H Slide 28 Diuretics LASIX Quick onset of diuresis Quick onset of diuresis Good for acute volume overload Increases urinary calcium excretion Increases urinary calcium excretion Used to treat hypercalcemia (Malignancy, Hyperparathyroidism) Increases urinary excretion of potassium and hydrogen ions Increases urinary excretion of potassium and hydrogen ions Used to treat acute hyperkalemia 3 Reasons to love your loop diuretic Slide 29 Diuretics LASIX Excessive diuresis can lead to volume depletion and ARF/hypotension/CV collapse Excessive diuresis can lead to volume depletion and ARF/hypotension/CV collapse 3 Reasons to think twice Diuresis Slide 30 Diuretics LASIX Excessive diuresis can lead to volume depletion and ARF/hypotension/CV collapse Excessive diuresis can lead to volume depletion and ARF/hypotension/CV collapse 3 Reasons to think twice Diuresis Slide 31 Diuretics LASIX Excessive diuresis can lead to volume depletion and ARF/hypotension/CV collapse Excessive diuresis can lead to volume depletion and ARF/hypotension/CV collapse Can exacerbate calcium based kidney stones Can exacerbate calcium based kidney stones Can cause hypokalemia, metabolic alkalosis Can cause hypokalemia, metabolic alkalosis 3 Reasons to think twice Slide 32 Diuretics ClassSiteEffectUse Side Fx Thiazides Loop K Sparing Other TAL NaK2Cl Impairs dilution and concentration Acute overload, edema, Ca/K serum K, Met Alkalosis, Volume Depletion, U Ca Slide 33 Diuretics THIAZIDE DIURETICS Representative Example: Hydrochlorothiazide (HCTZ) Onset of action: roughly 2 hours Duration: 6-12 hours Factoid: In April of 2005, Hydrochlorothiazide was nominated as one of the most intimidating medication names. Less effective at GFR < 40 Slide 34 Diuretics THIAZIDE DIURETICS Representative Example: Hydrochlorothiazide (HCTZ) Site of Action: Distal Convoluted Tubule Factoid: In April of 2005, Hydrochlorothiazide was nominated as one of the most intimidating medication names. Effect: HCTZ impairs urinary dilution, increases Na excretion in the urine Slide 35 Regulation of Urine Content Slide 36 HCZT Slide 37 Regulation of Urine Content ADH HCZT Thiazide Diuretics: 1.Impair Dilution, leading to excretion of salt and water 2.Do not disrupt the concentrating mechanism Slide 38 Question 3 Why are patients on thiazides more prone to hyponatremia than those on loop diuretics? A. Thiazides provide greater natriuretic effect than loop diuretics A. Thiazides provide greater natriuretic effect than loop diuretics B. Trick question: They both equally predispose patients to hyponatremia B. Trick question: They both equally predispose patients to hyponatremia C. Loop diuretics impair renal urine concentration and dilution, whereas thiazides impair only urine dilution C. Loop diuretics impair renal urine concentration and dilution, whereas thiazides impair only urine dilution D. By increasing delivery of salt to the collecting duct, thiazide diuretics increase the drive for free water absorption, leading to hyponatremia D. By increasing delivery of salt to the collecting duct, thiazide diuretics increase the drive for free water absorption, leading to hyponatremia Slide 39 Diuretics How do I choose between a loop diuretic and a thiazide diuretic? Similarities: Both will make you pee Both can result in hypokalemia and metabolic alkalosis Both can be used for edema and HTN Slide 40 Diuretics How do I choose between a loop diuretic and a thiazide diuretic? Differences: LoopThiazide Concentration/Dilution Impairs both; greater free water excretion Impairs dilution only; more prone to Na Potassium Greater kaliuretic effect; better for Tx of K Less kaliuresis Calcium Increases Ca excretion; better for Tx of Ca Ca reabsorption; better for folks with Ca stones Unique Superpowers Better in renal failure; Relieves resp distress Inexpensive; First line agent for HTN Slide 41 Diuretics ClassSiteEffectUse Side Fx Thiazides Loop K Sparing Other TAL NaK2Cl Impaired dilution and concentration Acute overload, edema, Ca/K serum K, Met Alkalosis, Volume Depletion, U Ca DCT Na/Cl cotrnsprt Impaired dilution Edema, HTN, Ca stones Hyponatremia, serum K, Met Alkalosis, Volume Depletion Slide 42 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 efficacy Factoid: If Peter Griffin (Family Guy) was on a diuretic it would probably be spironolactone, which would account for his gynecomastia Slide 43 K-Sparing Diuretics Collecting Duct Na K Ald