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- 2. Diuretics • Physiology ofnephron - renal tubular function • Mechanisms of action of particular type of diuretics Classification of diuretics: • Inhibitors of Na+/K+/Cl- symport (loop diuretics, high-ceilling diuretics) • Inhibitors of Na+/Cl- symport (thiazides and thiazide-like diuretics) • Inhibitors of carbonic anhydrase • Osmotic diuretics • Inhibitors of renal epithelial Na+ channels (K+ - sparing diuretics) • Antagonists of mineralocorticoid receptors (aldosterone antagonists, K+ - sparing diuretics) Presentation plan
- 3. Detail: “Blood Flowin the Nephron” by Phil Schatz. License: CC BY 4.0 GFR indicates the volume of primary urine filtered in the glomerulus per time unit. It is 85 – 135 ml/min in healthy kidneys.
- 4. Nephrons and Vessels Detail:“Nephrons and Vessels” by Phil Schatz. License: CC BY 4.0
- 7. Renal handling ofmajor minerals. The semipermeable GBM allows passage of proteins that have molecular weights lower than albumin (68,000 daltons). Almost all proteins reaching the proximal tubule are reabsorbed, and the final urine contains less than 150 mg of protein per 24 hours.
- 8. Production of hyperosmotic and hypo-osmoticurine under the influence of ADH. A, Diuresis in the presence of high serum antidiuretic hormone (ADH). B, Diuresis in the absence of ADH. The thicker, dotted line indicates impermeability to water. P−, phosphate.
- 9. Sodium handling by thekidneys. Most of the sodium filtered in the glomeruli is reabsorbed, and less than 1% is excreted in the urine. ANH, atrial natriuretic hormone.
- 10. Potassium handling bythe kidneys.
- 11. Carbonic anhydrase Carbonic anhydrase(CA) forms bicarbonate (HCO3−) from the CO2, which has diffused into the cytoplasm of tubular cells. Bicarbonate then returns into the blood to serve as a buffer. This interchange is linked to the flux of sodium (Na+) and potassium (K+) mediated by an Na+/K+ ATPase
- 12. The juxtaglomerular apparatusThe cutaway sections show 1. the granular renin-containing cells around the afferent arteriole 2. the macula densa cells in the distal convoluted tubule. The inset shows the general relationships between the structures. DT, distal tubule; G, glomerulus.
- 13. Transport processes inthe proximal convoluted tubule The main driving force for the absorption of solutes and water from the lumen is the Na + -K + -ATPase in the basolateral membrane of the tubule cells. Many drugs are secreted into the proximal tubule
- 14. Reabsorption of fluidand solute in the kidney Filtered/day Excreted/day b Percentage reabsorbed Na + (mmol) 25,000 150 99+% K + (mmol) 600 90 93+% Cl − (mmol) 18,000 150 99+% HCO 3 − (mmol) 4900 0 100% Total solute (mosmol) 54,000 700 87% H 2 O (L) 180 ~1.5 99+%
- 15. Diuretics Acting Directlyon Cells of the Nephron Most diuretics with a direct action on the nephron act from within the tubular lumen and reach their sites of action by being secreted into the proximal tubule (spironolactone is an exception). Diuretics Acting Directly on Cells of the Nephron The main therapeutically useful diuretics act on the: • thick ascending loop of Henle • early distal tubule • collecting tubules and ducts Mechanisms of ion absorption at the apical margin of the tubule cell: (1) Na + /H + exchange; (2) Na + /K + /2Cl − co-transport; (3) Na + /Cl − co-transport; (4) Na + entry through sodium channels. Sodium is pumped out of the cells into the interstitium by the Na + -K + -ATPase in the basolateral margin of the tubular cells (not shown).
- 16. Drug effects onrenal tubular ion transport (A)Bicarbonate ion reabsorption in the proximal convoluted tubule, showing the action of carbonic anhydrase inhibitors. (B)Ion transport in the thick ascending limb of Henle loop, showing the site of action of loop diuretics, namely the Na + /K + /2Cl – co-transporter (C 1 ) . Chloride ions leave the cell through basolateral chloride channels by an electroneutral K + /Cl – co- transporter (C 2 ) which are also present in the distal tubule.
- 17. Drug effects onrenal tubular ion transport (C) Salt transport in the distal convoluted tubule, showing the site of action of thiazide diuretics, namely the Na + /Cl – co- transporter (C 3 ) . (D) Actions of hormones and drugs on the collecting tubule. • The cells are impermeable: 1. to water in the absence of antidiuretic hormone (ADH) 2. to Na + in the absence of aldosterone. Aldosterone acts on: • a nuclear receptor within the tubule cell • membrane receptors
- 18. Diuretic X causes: •Hyponatriemia,hypokaliemia
- 19. Hypokaliemia Hypokalemia manifests as •severe cardiac arrhythmias (e.g. torsade de pointes), • skeletal muscle weakness, • constipation, and even intestinal paralysis, • urinary retention (due to weakening of the bladder muscles) • neurological disorders (paraesthesia, nervous hyperactivity or apathy)
- 20. Hyperkaliemia Hyperkalemia reduces theresting potential of cell membranes, which impairs the generation and propagation of stimuli. The dysfunction of myocytes and neurocytes is manifested by: • weakness or paralysis of skeletal muscles, • weakened tendon reflexes, • arrhythmias (bradycardia, asystole, ventricular fibrillation), • reduced stroke volume, • impaired sensation (paraesthesia) • disturbances of consciousness
- 21. Na+ K+ loops severe hypokalemia Mechanism ofaction Inhibition of Na+/K+/Cl- symport in thick ascending limb of the loop of Henle.
- 22. Pharmacological actions: • ↑excretion of Na + (diuretic effect up to 35%), Cl-, K +, Ca2 +, Mg2 +, HCO3-, phosphates • excretion of uric acid • ↑ RBF and GFR • ↑ renin release • ↑ the volume of the venous capacitance LOOP DIURETICS
- 23. LOOP DIURETICS -indications: • chronic congestive heart failure • acute pulmonary edema • chronic renal failure - reducing fluid overload • acute renal failure - maintenance of GFR • edema due to ascites (hepatic insufficiency) • nephrotic syndrome Lumen
- 24. LOOP DIURETICS -indications • treatment of arterial hypertension - acute and chronic • forced diuresis (poisoning with substances excreted by the kidneys) • hypercalcemia - a constant infusion of NaCl is necessary to maintain the increased excretion of Ca • hyperkalemia • life-threatening hyponatremia
- 25. Examples: sulfonamide- based: furosemide bumetanide phenoxyacetic acid derivative: ethacrinicacid, sulfonylurea torsemide
- 26. Loop diuretics •Dehydration and dyselecrolithemia •Thrombosis •Hypochloraemicalkalosis •Ototoxicity •Hyperuricemia •Hyperglycemia and hyperlipidemia Contraindications: •Hyponatraemia, hypokalemia •Dehydration -severe volume depletion •Allergy to sulfonamides •Irreversible anuria Side effects:
- 27. Dose–response curves for furosemide and hydrochlorothiazid showing differencesin potency and maximum effect ‘ceiling’. Note that these doses are not used clinically.
- 28. Diuretic causes: •Hyponatriemia, hypokaliemia •Hypocalcemia,hypomagnesemia •Metabolic alkalosis •Hyperuricemia •Ototoxicity
- 29. How diuretic effectshould be monitored? Every day – by body weight measure The goal: the loss of 1% of body weight usually 0.5-1.0 kg/24h How diuretics (especially diuretic X) should be administered? Once a day (orally or i.v. bolus)? Twice a day (orally or i.v. bolus)? As a continous infusion?
- 30. Loop diuretic– mechanismof action?
- 31. • A 56-year-oldpatient suffered from recurring headaches accompanied by increased blood pressure (mean 170/100). The doctor diagnosed arterial hypertension and decided to start treatment with a diuretic. • Which diuretic did he choose?
- 32. Thiazides Lumen Thiazides Mechanism of action Inhibition of Na+/Cl-symport in renal distal convoluted tubule.
- 33. Diuretic causes: • Hyponatremia,hypokalemia, hypercalcemia • Metabolic alkalosis • Glucose intolerance, hiperlipidemia • Hyperuricemia
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- 35. Thiazides diuretic effect -diuretic effect up to 15% influence on the excretion of electrolytes and compounds: • ↑ Na +, K +, Mg2 +, Cl-, • Ca2 +, uric acid other activities: • GFR - by stimulation of tubulo-glomerular feedback • vascular arterial bed expansion - systemic resistance - RR (arterial blood pressure decreases)
- 36. Thiazides Indications • arterial hypertension •heart failure Indications like loop diuretics except of : (because of enhanced Ca 2+ reabsorption and reduced GFR) • nephrolithiasis • osteoporosis • nephrogenic diabetes insipidus • Br (bromine) intoxication
- 37. Thiazides Side effects • waterand electrolyte disturbances • hyperglycemia and hyperlipidemia • impotence • neurological and gastrointestinal symptoms, • blood dyscrasias (inappropriate synthesis coagulation factors by the liver) •Contraindications: • hyponatremia, • severe volume depletion, • anuria, • diabetes mellitus, • hyperlipidemia, • renal insufficiency
- 38. The patient withCOPD (chronic obstructive pulmonary disease) developed metabolic alkalosis. Which diuretic can be used in this patient?
- 39. Carbonic anhydrase inhibitors– mechanism of action? What is the main therapeutic indication for CAI? Patient with chronic obstructive pulmonary disease (COPD) suffers from metabolic alkalosis.
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- 41. Diuretic causes: •Metabolic acidosis •Hyponatremia,hypokalemia, hypophosphatemia
- 42. Carbonic anhydrase inhibitors Pharmacologicalaction: • ↑ urinary HCO3- excretion, ↑ urine pH, • in blood - metabolic acidosis (hyperchloraemic) • ↑ Na + (5%) and K + excretion • ↑ phosphates excretion • production of HCO3- in aqueous humor (watery fluid in the eyeball) • CNS pH (metabolic acidosis) • reduction of gastric acid secretion
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- 44. Carbonic anhydrase inhibitors Indications: •glaucoma •urinealkalization •metabolic alkalosis •mountain sickness •severe hyperphosphatemia •hypo- and hyperkalemic periodic paralysis, •epilepsy
- 45. Carbonic anhydrase inhibitors Sideeffects: sulfonamide-like • allergy • bone-marrow depression, • renal lesions, • drowsiness and paresthesias, • calculus formation Contraindications: •liver failure – hepatic encephalopathy •severe acidosis •hyponatremia and hypokalemia
- 46. • In 40-yearsold patient with massive bleeding from GI tract, urine production decreased significantly and creatinine level increased. What are main therapeutic indications for mannitol? Osmotics– mechanism of action? Examples: urea mannitol glycerin
- 47. Osmotic diuretics Mechanism ofaction • disribution of water into the vascular space due to their osmotic effect • the water is excreted in the urine Activity along the whole nephron The major sites of action are: • the proximal tubule • the loop of Henle
- 48. Osmotic diuretics Pharmacological profile Generalfeatures: • Freely filtered at the glomerulus • Undergo limited reabsorption Pharmacological action • volume depletion • increased excretion of almost all electrolytes • decreased blood viscosity • increased RBF and GFR Indications: • acute renal insufficiency, intoxications, • cerebral edema – prophylaxis
- 49. Osmotic diuretics Contraindications: • left-ventricularcardiac insufficiency, • chronic renal insufficiency, • irreversible anuria Adverse effects: •dehydration and dyselectrolitemia • pulmonary edema •hyponatremia •trombosis or pain in site of injection - urea •hepatic failure •hyperglycemia - glycerin
- 50. • Patient withascites requires diuretic therapy.
- 51. Diuretic causes: • Hyponatremia,hyperkalemia • Metabolic acidosis • Delayed action
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- 53. Antagonists of mineralocorticoidreceptors K+ – sparing diuretics Spironolactone and eplerenone Indications: •edema and hypertension to prevent hypokalemia (in combination with other diuretics) •edema associated with secondary aldosteronism • hypertension in the course of Conn's syndrome • prevention of left ventricular remodeling in HF •prevention of post-infarction fibrosis
- 54. Antagonists of mineralocorticoidreceptors K+ – sparing diuretics Pharmacological profile •mild influence on blood volume, ↓excretion of K+, H+, Ca2+, Mg2+ , uric acid, •metabolic acidosis Contraindications: •pregnancy, •lactation Adverse effects: •hyperkalemia •diarrhea • gastric bleeding Spironolactone • gynecomastia, • impotence, •decreased libido, •hirsutism, • deepening of the voice, •menstrual irregulations,
- 55. Amyloride, triamterene -potassium-sparingdrugs Inhibitors of renal epithelial Na+ channels Mechanism of action • Inhibition of renal epithelial Na+ channels in: • distal convoluted tubule • collecting duct system Pharmacological profile • slight effect on fluid volume • ↓excretion of : K+, H+, Ca2+, Mg2+, uric acid • metabolic acidosis
- 56. Amyloride, triamterene -potassium-sparingdrugs Inhibitors of renal epithelial Na+ channels Contraindications: • hypersensitivity • anuria • renal insufficiency Adverse effects: • hyperkalemia, • GI disturbances • Triamterene • folic acid antagonist • reduces glucose tolerance • interstitial nephritis and nephrolithiasis Indications: • edema • hypertension (only in combination with thiazides or loop diuretics) • cystic fibrosis – amyloride • lithium- induced diabetes insipidus
- 57. Potassium-sparing drugs Inhibitors ofrenal epithelial Na+ channels amyloride, triamterene
- 60. Diuretic effect isdependent on activity of hormonal mechanisms
- 62. •A 77-years oldpatient with chronic cardiac insufficiency requires treatment with diuretic.
- 63. Resistance to diureticse.g in the course of HF •GI edema decreases diuretics absorption in about 70% - administer higher doses orally or give diuretic i.v. - combine furosemide with thiazide to promote diuretic effect (thiazide 1h before furosemide) -combine furosemide with spironolactone to prolonge furosemide activity, to prevent hypokalemia and to inhibit myocardium remodeling -check albumins concentration – hypoalbuminemia decreases diuretics secretion into the tubules
- 64. • Pulmonary edemawas recognized in 68-years old patient.
- 65. •A 60-years oldpatient with chronic renal insufficiency (GFR about 10 ml/min) requires diuretic. Resistance to diuretics e.g in the course of CRI • Adequate GFR and sodium load – check body volume and exclude hypovolemia • Use high and very high doses of furosemide 500 mg per dose • Use i.v. bolus 1-2 mg/kg and infusion 0,1 – 1 mg/kg/h
- 66. Antidiuretic hormone -vasopressin
- 67. Syndrome of inapropriateADH secretion - SIDAH A complex of symptoms caused by an excessive amount of vasopressin (ADH) in the blood in relation to plasma osmolality, with a normal circulating blood volume. Causes: • brain damage (injuries, tumors, operations, inflammations, psychoses), • lung diseases (inflammations, tuberculosis, pleural empyema, asthma), • neoplasms (lung cancer, gastrointestinal cancer, prostate cancer; thymomas, serotonin-secreting neuroendocrine neoplasms), • right heart failure, • drugs (painkillers, psychotropic, diuretic, cytostatic)
- 68. Syndrome of inapropriateADH secretion - SIDAH The pathomechanism of SIADH is complex; • tumors can induce ectopic ADH production, • in non-neoplastic diseases (eg, lungs), ADH secretion is stimulated by hypoxia. Excess ADH causes increased water retention with normal Na + excretion, resulting in : • hyponatraemia, • plasma hypoosmolality • high urine osmolality
- 69. ADH Antidiuretic hormoneantagonists conivaptan tolvaptan demeclocycline lithium
- 70. Antidiuretic Hormone Antagonists Conivaptanand tolvaptan • conivaptan blocks both V 1A and V 2 receptors, • tolvaptan is V 2 selective • The V 2 receptors are coupled with insertion of aquaporin channels in the apical membranes of the renal collecting ducts, leading to reabsorption of water (antidiuretic effect). • By activating these receptors, antidiuretic hormone helps maintain plasma osmolality in the normal range. • Antagonism of V 2 receptors by conivaptan and tolvaptan causes free water excretion or aquaresis, and the drugs are called aquaretics. Side effects: • Dehydration, hypokalemia, orthostatic hypotonia Symptoms: • relative hyponatremia • decreased plasma osmolality < 280 mOsm/kg • increased urine osmolality > 150 mOsm/kg • weakness • CNS symptoms: • depression • coma • seizures Syndrome of inapropriate ADH secretion - SIDAH
- 71. Antidiuretic Hormone Antagonists demeclocycline, lithium reduce cAMP formation in response to ADH in collecting tubule and interfere with cAMP Pharmacological profile: •inhibit the effect of ADH secretion Indications: SIADH
- 72. Antidiuretic Hormone Antagonists demeclocycline, lithium Contraindications: • demeclocycline – liver failure, • lithium – hypothyroidism, renal insufficiency Adverse effects: • nephrogenic diabetes insipidus, severe hypernatremia, acute renal failure, lithium – mental obtundation, cardiotoxicity, thyroid dysfunction, leukocytosis
- 73. Summary DIURETICS • Normally <1%of filtered Na + is excreted. • Diuretics increase the excretion of salt (NaCl or NaHCO 3-) and water. • Loop diuretics, thiazides and K + -sparing diuretics are the main therapeutic drugs. • Loop diuretics (e.g. furosemide ) cause copious urine production. They inhibit the Na + /K + /2Cl − co-transporter in the thick ascending loop of Henle. They are used to treat heart failure and other diseases complicated by salt and water retention. Hypovolaemia and hypokalaemia are important unwanted effects.
- 74. Summary Thiazides have asmaller diuretic effect than loop diuretics. • They inhibit the Na + /Cl − co-transporter in the distal convoluted tubule. • They are used to treat hypertension, working partly through an indirect vasodilator action. • Erectile dysfunction is an important adverse effect. • Hypokalaemia and other metabolic effects (e.g. hyperuricaemia, hyperglycaemia) can occur, especially with high doses.
- 75. Summary Potassium-sparing diuretics: • actin the distal nephron and collecting tubules; • they are • weak diuretics but effective in some forms of hypertension and heart failure • can prevent hypokalaemia caused by loop diuretics or thiazides • canrenone, the active metabolite of spironolactone and eplerenone compete with aldosterone for its receptor. • amiloride and triamterene act by blocking the sodium channels controlled by aldosterone's protein mediator.
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- 77. Diuretics Acting Directlyon Cells of the Nephron Mechanisms of ion absorption at the apical margin of the tubule cell: (1) Na + /H + exchange; (2)Na + /K + /2Cl − co- transport; (3)Na + /Cl − co- transport; (4)Na + entry through sodium channels. Sodium is pumped out of the cells into the interstitium by the Na + -K + -ATPase in the basolateral margin of the tubular cells (not shown).
- 78. Review Questions Loop diureticsare used in conjunction with dietary salt restriction and often with other classes of diuretic, in the treatment of salt and water overload associated with the following examples : 1. cirrhosis of the liver complicated by ascites 2. nephrotic syndrome 3. renal failure 4. acute pulmonary oedema 5. chronic heart failure
- 79. Review Questions CLINICAL USESOF THIAZIDE DIURETICS. Which example is uncorrect: 1. Hypertension 2. Mild heart failure (loop diuretics are usually preferred) 3. Severe resistant oedema (together with loop diuretics) 4. To prevent recurrent stone formation in idiopathic hypercalciuria 5. Nephrogenic diabetes insipidus 6. Decreased GFR
- 80. Review Questions CLINICAL USESOF THIAZIDE DIURETICS Which example is uncorrect: 1. Hypertension 2. Mild heart failure (loop diuretics are usually preferred) 3. Severe resistant oedema (together with loop diuretics) 4. To prevent recurrent stone formation in idiopathic hypercalciuria 5. Nephrogenic diabetes insipidus 6. Decreased GFR
- 81. Review Questions Spironolactone oreplerenone is used in the following situations except of: • heart failure , to improve survival • primary hyperaldosteronism (Conn’s syndrome) • resistant essential hypertension • secondary hyperaldosteronism caused by hepatic cirrhosis complicated by ascites • the only one diuretic in pulmonary edema
- 82. Review Questions Spironolactone oreplerenone is used in the following situations except of: • heart failure , to improve survival • primary hyperaldosteronism (Conn’s syndrome) • resistant essential hypertension • secondary hyperaldosteronism caused by hepatic cirrhosis complicated by ascites • as the only one diuretic in pulmonary edema
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- 84. Aldosterone antagonists =Spironolactone and eplerenone
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- 91. References 1. Rang &Dale's Pharmacology, 9th Edition2020, Elsevier Books 2. Brenner and Stevens' Pharmacology, Elsevier Books, 2017
Editor's Notes
- #13 The juxtaglomerular apparatus. The cutaway sections show the granular renin-containing cells around the afferent arteriole, and the macula densa cells in the distal convoluted tubule. The inset shows the general relationships between the structures. DT, distal tubule; G, glomerulus.
- #14 Transport processes in the proximal convoluted tubule. The main driving force for the absorption of solutes and water from the lumen is the Na + -K + -ATPase in the basolateral membrane of the tubule cells. Many drugs are secreted into the proximal tubule (see Ch. 10 ). (Redrawn from Burg, 1985. Brenner, B.M., Rector, F.C. (eds). In: The Kidney, third ed., Philadelphia: WB Saunders, pp 145–175.)
- #19 Loop diuretics Loop diuretics are the most powerful diuretics , capable of causing the excretion of 15%–25% of filtered Na + . Their action is often described – in a phrase that conjures up a rather uncomfortable picture – as causing ‘torrential urine flow’. The main example is furosemide ; bumetanide and torasemide are alternative agents. These drugs act on the thick ascending limb, inhibiting the Na + /K + /2Cl − carrier in the lumenal membrane by combining with its Cl − binding site.
- #71 Antidiuretic Hormone Antagonists Conivaptan and tolvaptan are nonpeptide antagonists of antidiuretic hormone (arginine vasopressin). Conivaptan blocks both V 1A and V 2 receptors, whereas tolvaptan is V 2 selective. The V 2 receptors are coupled with insertion of aquaporin channels in the apical membranes of the renal collecting ducts, leading to reabsorption of water (antidiuretic effect). By activating these receptors, antidiuretic hormone helps maintain plasma osmolality in the normal range. Antagonism of V 2 receptors by conivaptan and tolvaptan causes free water excretion or aquaresis, and the drugs are called aquaretics. Conivaptan and tolvaptan are approved for treating euvolemic and hypervolemic hyponatremia (low serum sodium concentration) in hospitalized patients, but they are contraindicated in hypovolemic hyponatremia. Conivaptan is given as an intravenous infusion, usually for 4 days, and typically increases free water clearance by 3800 mL and serum sodium concentration by 6.5 mEq/L. Almost 70% of patients achieve a normal serum sodium concentration of 135 mEq/L after 4 days of conivaptan therapy. Tolvaptan is a newer orally administered drug for treating hyponatremia. Conivaptan and tolvaptan are extensively metabolized by CYP3A4 and should not be given with potent 3A4 inhibitors. Conivaptan and tolvaptan may increase serum levels of midazolam, simvastatin, and other drugs metabolized by 3A4. The most common adverse reactions reported with conivaptan are infusion site reactions.
- #75 DIURETICS • Normally <1% of filtered Na + is excreted. • Diuretics increase the excretion of salt (NaCl or NaHCO 3 ) and water. • Loop diuretics, thiazides and K + -sparing diuretics are the main therapeutic drugs. • Loop diuretics (e.g. furosemide ) cause copious urine production. They inhibit the Na + /K + /2Cl − co-transporter in the thick ascending loop of Henle. They are used to treat heart failure and other diseases complicated by salt and water retention. Hypovolaemia and hypokalaemia are important unwanted effects. • Thiazides (e.g. bendroflumethiazide ) have a smaller diuretic effect than loop diuretics. They inhibit the Na + /Cl − co-transporter in the distal convoluted tubule. They are used to treat hypertension, working partly through an indirect vasodilator action. Erectile dysfunction is an important adverse effect. Hypokalaemia and other metabolic effects (e.g. hyperuricaemia, hyperglycaemia) can occur, especially with high doses. • Potassium-sparing diuretics: – act in the distal nephron and collecting tubules; they are weak diuretics but effective in some forms of hypertension and heart failure, and they can prevent hypokalaemia caused by loop diuretics or thiazides. – canrenone, the active metabolite of spironolactone and eplerenone compete with aldosterone for its receptor. – amiloride and triamterene act by blocking the sodium channels controlled by aldosterone's protein mediator.