Understanding Diuretics in Clinical Pharmacology

1. Leki moczopędne Maciej Niewada Clinical and Experimental Pharmacology Email: mniewa@amwaw.edu.pl

2. Diuretics Critical group of drugs used to adjust the composition of plasma electrolytes and/or volume of circulating fluids in various disorders affecting large population. Edema That accompanies CHF, renal failure, liver failure (cirrhosis). Hypertension Reduce blood volume (increase H2O excretion). Reduce Na+reabsorption (increase Na+ excretion).

3. Terms Diuretic: includes diuresis and natriuresis. Diuresis: increased urine flow.Natriuresis: increased sodium excretion. Na+ Sodium (Natrium) K+ Potassium (Kalium) - Hyperkalemia (increased K+ in blood) - Hypokalemia (reduced K+ in blood) Acidosis - Acids Alkalosis - Bases (Alkaline)

4. Terms Osmosis:the passage of water or another solvent across a semi-permeable membrane into a compartment that has a higher concentration of solutes; this tends to regulate the concentration of solutes in the two compartments Osmotic pressure:the pressure created when water flows by osmosis through a semi-permeable membrane into a chamber containing a high concentration of solutes. Hypo/Hyper tonic:any solution that has a lower/higher osmotic pressure than another solution (i.e. has a lower/higher concentration of solutes than another solution).

5. Functions of the Kidneys Major function of kidneys is the formation of urine. Regulation of the volume of extracellular fluid. Regulation of ion concentration (electrolyte homeostasis, pH of body fluids). Excretion of nitrogenous waste products of metabolism (urea, creatinin) Nephron (basic unit of the kidney) allows formation of urine. Glomerular Filtration Glomerulus consists of a specialized spherical tuft of capillaries enclosed in an epithelial cell capsule which empties tubular fluid into the nephron tubular system. Serves as “sieve” for plasma through fenestrated endothelium & podocytes. Filtration rate is affected by renal blood flow (afferent/efferent renal arterioles). Small molecules are freely filtered. Large ones no. 130-150 liters/day. Approx 10 x volume of extracellular fluid, 60 x plasma. Large proportion must be reabsorbed. Tubular Reabsorption Active transport of electrolytes and other solutes from lumen of tubules, to peritubular fluid (blood). H2O is likely to be reabsorbed by osmotic processes. Tubular Secretion Organic acids and bases secreted. Mainly in proximal tubule.

6. Tubular Reabsorption 5 4 1 3 2 1 4 2 3 Water Permeability None Variable High Major site (2/3) of Na+ and H2O reabsorption. Bicarb. Reabsorption. Carbonic Anhydrase Inhibitors. Isotonic Impermeable to H2O. 25% Na+ reabsorb. Fluid becomes hypotonic. Loop Diuretics. Impermeable to H2O. 5% Na+ reabsorb. Active Ca++ reabsorption. Thiazides. “Fine-tuning” of electrolyte balance. Final site of Na+ reabsorb. K+ excretion (correl to amt. Na+ reabs). Controlled by Aldosterone. Potassium Sparing. Thin descending Limb of Henle Proximal Convoluted Tubule & Thin Descending Limb. Osmotic Diuretics. Hypertonic

7. Natrecor - hormon natriuretyczny rekomendowany do rejestracji przez FDA Wskazania: • krótkotrwałe wlewy dożylne w zaostrzeniu niewydolności serca J Am Coll Cardiol 1999 Jul;34(1):155-62

8. General Na+/H2O reabsorption Na+ Na+ Channel ATP K+ Na+ Symport Na+ X- Na+ Antiport H+ Transcellular H2O Paracellular H2O Interstitium (Blood) Lumen (Urine) Renal Epithelial Cell Basolateral Cell Membrane Apical Cell Membrane

9. - W kanaliku bliższym, końcowej części kanalika dalszego (dystalnego) i początkowej części kanalika zbiorczego jony sodowe są wymieniane na jony potasowe i wodorowe, które przechodzą do światła kanalika.- W niedoborze potasu wzrasta wydalanie jonów wodorowych; w ten sposób powstaje zasadowica metaboliczna w hipokaliemii

10. Proximal Convoluted Tubule Major site of Na+ and H2O reabsorption (as much as 2/3 reabsorbed); blocked by ANF Major site of bicarbonate (HCO3-) reab. Fluid stays isotonic. Driving force for Na+ reabsorption is Na+/ATPase pump at basement membrane of tubular cell. Na+ reabsorption is performed by Na+/H+ exchanger. Conservation of HCO3-is accomplished through CA at luminal surface. NaHCO3 Sodium Bicarbonate HCO3-Bicarbonate H2CO3 Carbonic Acid

11. Loop DiureticsLoop of Henle ThiazidesDistal tubule CA InhibitorsProximal tubule 5% Antikaliuretics Thick Ascending Limb 70% 4.5% Collecting duct 20% 100%GFR 180 L/day Plasma Na 145 mEq/LFiltered Load 26,100 mEq/day 0.5% Volume 1.5 L/dayUrine Na 100 mEq/L Na Excretion 155 mEq/day From Knauf & Mutschler Klin. Wochenschr. 1991 69:239-250

12. I.Leki modyfikujące transport kanalikowy • 1. O wysokiej efektywności (Do 25 -30%) zwane inaczej diuretykami pętlowymi • a) pochodne sulfonamidowe (furosemid, torasemid, bumetanid, piretanid) • b) pochodne kwasu fenoksyoctowęgo (kwas etakrynowy) • c) związki organiczne rtęci - diuretyki rtęciowe (mersalyl) • 2. O umiarkowanej efektywności (do 15%) zwane również diuretykami korowego odcinka pętli nefronu • a) pochodne benzotiadiazyny czyli tiazydy moczopędne (chlorotiazyd, hydrochlorotiazyd) • b) związki tiazydopodobne (chlortąlidon, indapamid, klopamid) • C) antagoniści wazopresyny • 3. O miernej efektywności (<5%) • a)środki moczopędne oszczędzające potas (spironolakton, triamteren, amilorid) • b) inhibitory anhydrazy węglanowej (acetazolamid) • II.Inne leki moczopędne • 1. diuretyki osmotyczne (mannitol) • 2. środki pochodzenia roślinnego

13. Na+ ATP K+ Proximal Convoluted Tubule Lumen (Urine) Renal Epithelial Cell Na+/ATPase pump keeps i.Na+ low. Na+/H+ exchanger reabsorbs Na+ and secretes H+ in lumen. H+ ions combine w/ filtered HCO3- to form H2CO3. H2CO3 is dehydrated w/ CA to H2O and CO2. H2O and CO2 cross membrane and are rehydrated w/ CA to H2CO3. H2CO3 dissociates to H+ and HCO3- providing another H+ to be used in Na+/H+ exchanger and allows regenerated HCO3- to be reabsorbed in plasma. Na+ HCO3- H+ HCO3- H+ H2CO3 H2CO3 CA CA CO2 H2O CO2 H2O Cl - Base -

14. Na+ ATP K+ Proximal Convoluted Tubule CA Inhibitors Acetazolamide Inhibit enzyme CA. Decrease availability of H+ for Na+/H+ exchanger. Na+ secreted with HCO3-. Decreased H2O and CO2 formation in lumen. High tolerance develops (not used as diuretics or antihypertensives). Increased HCO3-excretion Acidosis. Alkalinize urine (attn. renal stones form). Tx. Metabolic acidosis., epilepsy, Prevent acute mt. Sickness (Δ pressure may cause respiratory alkalosis). Tx. High intraocular pressure (glaucoma), because aqueous humor has high bicarb. Hyperphosphatemia Loss of appetite, drowsiness, confusion (CA in CNS). Hepatic encephalopathy (due to increased plasma ammonia). Sulphonamide derivative Lumen (Urine) Renal Epithelial Cell Na+ HCO3- H+ HCO3- H+ H2CO3 H2CO3 CA CA CO2 H2O CO2 H2O Cl - Base -

15. Thick Ascending Limb Impermeable to H2O, but 25-35%Na+ reabsorption. Driving force for Na+ reabsorption is Na+/ATPase pump at basement membrane of tubular cell. Na+ reabsorption is performed by Na+/K+/2Cl-co-transport. RECYCKLING OF Na+ produces osmotic gradient – fluid becomes hypotonic.

16. Na+ ATP K+ Thick Ascending Limb Lumen (Urine) Renal Epithelial Cell Na+/ATPase pump keeps i.Na+ low. Na+/K+/2Cl- cotransporter reabsorbs. Great buildup of i.K+ (coming from lumen and interstitium). Result: backward diffusion of K+ into lumen, creating net + charge in lumen. This + charge causes electrostatic repulsion with + ions, encouraging absorption of + ions Mg++, Ca++. Na+ K+ 2Cl- K+ K+ (+) Cl- Mg ++ Ca++ H2O

17. Na+ ATP K+ Thick Ascending Limb Loop Diuretics Compete with Cl- for a binding site on the Na+/K+/2Cl- cotransporter. Block transporter. Prevent Na+ reabsorption (increase secretion). Impermeable to H2O so no great changes in H2O reabsorption at this site, but increased luminal Na+ prevents H2O reabsorption in collecting duct. Increased Na+ in collecting duct will increase K+ and H+ excretion. Therefore induce hypokalemia and metabolic alkalosis(used tx. hyperkalemia). Decreased Na+ and Cl- reabsorption & K+ excretion prevents absorption of Ca++ and Mg++ (electrical gradient). May be used to tx. Hypercalcemia (do not induce hypocalcemia as Ca++ is absorbed in distal c. t.) . Hypomagnesemia. Hypochloremia. Hyponatremia and/or dehydration. Hyperuricemia (excess uric acid in blood, gout). Ototoxicity; more severe with use of ototoxic antibiotics (e.g. aminoglycosides) unknown mech. Lumen (Urine) Renal Epithelial Cell Na+ K+ 2Cl- K+ K+ (+) Cl- Mg ++ Ca++ H2O

18. Thick Ascending Limb Loop Diuretics Induce dilation of venous system and renal vasodilation - increase in renal flow (prob. mediated by prostaglandings). Increases glomerular filtration. Fall in left ventr. press. Edema. Pulmonary and others (CHF, cirrhosis). Antihypertensives, esp. in patients w/ impaired renal function. NSAIDS decrease diuretic effects (block prostaglandins). Probenecid inhibits secretion of drugs & decreases diuretic action. Short latency of action onset (20 min). Very efficacious “high ceiling”. May impair glucose tolerance (hyperglycemia). Attn. patients with diabetes melliuts. Symptoms secondary to electrolyte imbalance; hypokalemia may exacerbate some. Ethacrynic Acid (Edecrin) Not sulfonamide derivative. V. ototoxic. Oral use; salt for i.v. use. Furosemide (Lasix) Sulfonamide derivative. Prescribed v. commonly. Bumetanide (Bumex) Sulfonamide derivative. V. potent (40x lowed doses than furosemide enough). Torsemide (Demadex) Sulfonamide derivative. Newer, longer lasting. Allergies to sulfonamides

19. Distal Convoluted Tubule Impermeable to H2O, but Na+ reabsorption continues (5-10%). Site of active Ca++ reabsorption (regulated by parathyroid hormone). Driving force for Na+ reabsorption is Na+/ATPase pump at basement membrane of tubular cell. Na+ reabsorption is performed by Na+/Cl- co-transport.

20. Na+ ATP K+ Distal Convoluted Tubule Lumen (Urine) Renal Epithelial Cell Na+/ATPase pump keeps i.Na+ low. Na+/Cl- cotransporter reabsorbs. Ca++ reabsorption occurs (regulated by parathyroid hormone). Once inside the cell, Ca++ is absorbed via Na+/Ca++ exchanger. Na+ Cl- Na+ Ca++ Ca++ H2O

21. Na+ ATP K+ Distal Convoluted Tubule Thiazides Lumen (Urine) Renal Epithelial Cell Compete with Cl- for a binding site on the Na+/Cl- cotransporter. Block transporter. Prevent Na+and Cl- reabsorption (increase secretion). Impermeable to H2O so no great changes in H2O reabsorption at this site, but increased luminal Na+ prevents H2O reabsorption in collecting duct. Increased Na+ in collecting duct will increase K+ and H+ excretion. Therefore induce hypokalemia and metabolic alkalosis. Decreased Na+ reabsorption increases Ca++ reabsorption (electrical gradient). Renal stones. May help tx. of Osteoporosis. Hypomagnesemia (unknown mechanism). Hypochloremia. Hyponatremia and/or dehydration. Hyperuricemia (excess uric acid in blood). Hyperlipidemia; increase LDL cholesterol. Na+ Cl- Na+ Ca++ Ca++ H2O

22. Distal Convoluted Tubule Thiazides Moderately potent diuretics (most salts have already been absorbed, only 5-10% Na+ reabsorbed here). Most commonly prescribed class of diuretics. Antihypertensives (mild-moderate). Increase efficacy of other antihypertensive agents, esp. ACE inhibitors. CHF (loop diuretics are drug of choice). Most drugs are benzothiazides (shortened to thiazides), some are sulfonamides. NSAIDS decrease diuretic effects. Probenecid inhibits secretion of drugs. May impair glucose tolerance (hyperglycemia). Attn. patients with diabetes melliuts. Symptoms secondary to electrolyte imbalance; hypokalemia may exacerbate some. Allergy to sulfonamides (many drugs are sulfonamide derivatives). Chlorthiazide (Diuril, Hygorton) Hydrocholrothiazide (Esidrex) Chlorthalidone (Hygroton) Metolazone (Mykrox, Zaroxolyn) Indapamide (Lozol)

23. Mechanism of action of the paradoxical effect of thiazide diuretics on diabetes insipidus

24. Collecting Tubule Final site of electrolyte adjustment (“fine-tuning” of ion secretion). Only 2-5% Na+ reabsorption. Major site of K+ excretion. 2 types of cells Principal cells: Na+, K+, H2O transport. Intercalated cells: H+ transport. Driving force for Na+ reabsorption is Na+/ATPase pump at basement membrane of tubular cell. Na+ and K+ transport is performed by Na+ and K+ channels. Regulated by Aldosterone.

25. Na+ ATP K+ Collecting Tubule Lumen (Urine) Renal Epithelial Cell Na+/ATPase pump keeps i.Na+ low. Passive influx of Na+ (channels). To lesser extent efflux K+ (channels). Drive for Na+ influx higher than K+ efflux. Negative charge builds in lumen pushes Cl- out, and K+ in. The more Na+ delivered in, the more K+ goes out. Aldosterone stimulates production of Na+/ATPase pump, Na+ channels, K+ channels. ADH regulates (increases) H2O permeability. Na+ R Aldosterone K+ R H2O ADH H2O Channel Molecules Cl- H+ Cl- ATP HCO3-

26. Na+ ATP K+ Collecting Tubule K+ sparing Lumen (Urine) Renal Epithelial Cell Inhibit Na+ reabsorption (therefore indirectly K+ excretion). Channel blockers/Aldosterone antagonists. Decreased Na+ reabsorption decreases H2O reabsorption. Diuretic activity weak (most salts have already been absorbed only 3% Na+ reabsorbed here). Used in combination with loop diuretics or thiazides for tx. hypertension. Decreased Na+ reabsorption (lumen negative) will decreases K+excretion (potassium sparing). Correct Hypokalemia induced w/ other diuretics. Hyperkalemia (life threatening). Decrease H+ secretion. Metabolic Acidosis. Glucose intolerance/Hyperglycemia. Na+ R Aldosterone K+ R H2O ADH H2O Channel Molecules Cl- H+ Cl- ATP HCO3-

27. Collecting Tubule K+ sparing Spironolactone (Aldactone, Alatone) GenPrototype of aldosterone antagonist. Needs to be metabolized to carnenone to have K+ sparing activity (i.e. is a prodrug). Generally ineffective if used alone as antihypertensive agent. UseIn combination w/ loop diuretic or thiazide for hypertension. Correct hypokalemia induced by other agents. Liver cirrhosis (drug of choice). Hyperaldosteronism. Edema (CHF, cirrhosis, nephrotic syndrome). MOA Competitive aldosterone antagonist. Binds to intracell. aldosterone receptors (mineralocorticoid receptors). (Aldo. stimulates facilitates Na+ reabsorption and K+ and H+ excretion). SE Most serious: Hyperkalemia (serum K+ should be monitored regularly). Metabolic acidosis (aldo. Stimulates H+ secretion from intercalated cells). Hyperglycemia (impairs insulin release & utilization glucose). Gynecomastia in men (prob. binding of carnenone to androgen receptors). Hirsutism & menstrual irregularities (it’s a steroid).

28. Collecting Tubule K+ sparing Triamterene (Dyrenium, Maxzide) GenWeak folic acid antagonist (prob. for cirrhosis in patients). Generally ineffective if used alone as antihypertensive agent. UseIn combination w/ loop diuretic or thiazide for hypertension & Edema. Correct hypokalemia induced by other agents. MOA Blocks Na+ channel of principal cells. Reduces Na+ conductance. SE Most serious: Hyperkalemia (serum K+ should be monitored regularly). Nausea, vomiting, leg cramps, dizziness. Glucose intolerance. Kidney stones (triamterene is poorly soluble and may precipitate in urine forming kidney stones). Megaloblastic anemia in patients w/ cirrhosis. Photosensitization. Interacts w/ indomethacin; may induce acute renal failure. Amiloride (Midamor) More potent (10x lower doses than triamterene). Not associated w/ kidney stones.

29. Proximal Tubule & Thin Descending Limb Osmotic Diuretics These segments of tubule are highly permeable to H2O. Osmotic agent not transported (reabsorbed) causes water to be retained, promoting diuresis. Do not interact w/renal transport mechanism (inert drugs - osmotic pressure changes). Increases extracell.fluid by attracting H2O from intracell. (intraocular, intracranial). Decrease blood viscosity & renin release (reflex sympathetic), causing vasodilation. Vasodilation may involve prostaglandins. Used as diureticsbut not antihypertensives. Reduce intraocular pressure (short term tx. Glaucoma). Reduce intracranial pressure. May cause pulmonary edema(extract H2O from intracell. compt. expanding extracell. fluid volume. Initially increase blood volume. Increase work load heart & complicate CHF. Dehydration, headache, nausea, vomiting.

30. Proximal Tubule & Thin Descending Limb Osmotic Diuretics Mannitol (Osmitrol) Osmotic agent of choice. Not absorbed. Not absorbed orally. Must be given i.v. Causes initial increase in BV (pulls from intracell. to extracell.) May induce diarrhea if given orally. Isosorbide (Ismotic) Less efficient beacuse penetrates cellular membranes - absorbed. May be given orally.

31. POTAS W DIECIE 50 – 150 mEq/dobę POTAS WEWNĄTRZKOMÓRKOWY Ogółem 4200 mEq Stężenie 150 mEG/L POTAS ZEWNĄTRZKOMÓRKOWY Ogółem 65 mEq Stężenie 3.5 – 5.3 mEq/L 50 – 150 mEq/dobę K+ KANALIK ZBIORCZY 800 mEq/dobę K+ K+ FILTRACJA KŁĘBKOWA 180 L/dobę osocza 800 mEq/dobę K+ KANALIK PROKSYMALNY NEFRONU KANALIK PROKSYMaALNY NEFRONU WYDALANIE Z MOCZEM 50 – 150 mEq/dobę

32. Potas:- działa jak „diuretyk”, zmniejsza objętość osocza poprzez hamowanie resorbcji sodu w cewkach proksymalnych - wpływa na aktywność układu renina-angiotensyna-aldosteron i zmniejszanie oddziaływania angiotensyny na receptory w naczyniach krwionośnych, nadnerczach i nerkach- rozszerza naczynia krwionośne poprzez pobudzanie sodowo-potasowej-ATPazy w komórkach mięśni gładkich i w adrenergicznych zakończeniach nerwowych- oddziaływuje na centralne i obwodowe mechanizmy regulujące ciśnienie tętnicze krwi. - Dieta bogata w potas może dodatkowo obniżać ciśnienie tętnicze poprzez relaksację mięśni gładkich naczyń krwionośnych i bezpośrednie zmniejszanie oporu naczyń obwodowych.