1. Diuretics Martin Sterba, PharmD. PhD. Associate professor Department of Pharmacology, LFHK UK 2015, Dentistry

2. Drugs increasing excretion (volume) of urine (diuresis) –Most of them have very significant natriuretic properties – i.e, they increase urinary Na + excretion (but NOT all) –They act from the luminal site of the tubules to block the ion transporting molecules Some of them have also significant extrarenal effects –Therapeutically useful - vasodilating effects (direct/indirect) –Adverse effects – e.g., metabolic Diuretics

3. Acetazolamide Osmotic diuretics Loop diuretics - furosemide Thiazides Aldosterone antagonists ADH antagonists Functional description of the nephron upraveno podle Katzung's Pharmacology: Examination and Board Review. McGraw-Hill/Appleton & Lange; 6th edition (August 6, 2001) 50-65 % 15-25 % 4-8 % 2-5 %

4. Diuretics Carbonic anhydrase inhibitors Thiazides Loop diuretics Potassium-sparing diuretics Osmotic diuretics

5. Proximal tubule Acetazolamide Proximální tubulus Lumen Modified according to Katzung's Pharmacology: Examination and Board Review. McGraw-Hill/Appleton & Lange; 6th edition (August 6, 2001)

6. Acetazolamide Inhibitor of the carbonic acid anhydrase Inhibits bicarbonate reabsorption in the proximal tubule  bicarbonate loss via urine - ↑ pH urine within 0.5-2h and persists 12h –Result: hyperchloremic metabolic acidosis Diuretic (natriuretic) effect is limited –compensated within the distal parts of the nephron –decrease of the effect within few days of the treatment Indication –Glaucoma treatment (shorter treatment, before surgery) carbonic acid anhydrase is also in the ciliary body to control secretion of the bicarbonate and Na into the aqueous humor acetolazamide decreases the intraocular humor production  decreases intraocular pressure –Local glaucoma treatment - dorzalamide –Alkalization of the urine – e.g., in cysteinuria (excretion facilitation)

7. Acetazolamide – adverse reactions Metabolic acidosis –Predictable loses of the HCO 3 - stores - limitation for both long term safety and efficacy of the treatment Nephrolithiasis –higher concentration of the salts and their lower solubility in the alkaline environment Potassium vasting resulting into the hypokalemia Contraindications – hepatic encephalopathy – alkalization of the urine  lower NH 4 excretion which may further contribute to the hyperammoneamia and hepatic encephalopathy in patients with cirrhosis

8. Loop diuretics FurosemideTorasemide Etoziline, ethacrynic acid

9. Loop of Henle Furosemide LumenVzestupné raménko Henleovy kličky Modified according to Katzung's Pharmacology: Examination and Board Review. McGraw-Hill/Appleton & Lange; 6th edition (August 6, 2001)

10. Loop diuretics 1. Renal effects (within 10 min after i.v. administration, but quite short-term effect: furosemide 2-3 h) a)Inhibition of Na + /K + /2Cl - re-uptake b)Decrease the lumen-positive potential that comes from K+ recycling  decreased reabsorption divalent cations, resulting into the hypocalcaemia a hypomagnesaemia a)Increased prostaglandin synthesis – improved renal perfusion 2. Extrarenal effects –Vasodilation (venous system) – important in i.v. treatment of acute pulmonary oedema, it can overtake the urinary effects - incompletely understand mechanisms –Decreased preload and filling pressures in RV and later also in LV – important in HF –Decreased pulmonary congestion/oedema

11. Loop diuretics Pharmacokinetics Oral administration (quite good absorption) I.V. in urgent cases High plasma protein binding Renal elimination – GF (limited) + tubular secretion Effect duration – quite short (2-3 h furosemide), torasemide is longer (4-6h) and it has an active metabolite Tubular secretion can be decreased by the competition with other drugs ( e.g., NSAID)

12. Loop diuretics indications Acute pulmonary edema – i.v. treatment Active tubular secretion makes it useful even in shock-like states CHF (esp. with signs of blood congestion) –Decreased Na + retention, intravascular volume and preload and reduction of edema, improve symptoms! Other diseases with fluid/sodium retention and edema E.g. In the liver disease associated with ascites etc. Acute renal failure – useful even when Cl cr is below 30 ml/min. –For prevention of Na/fluid retention with oliguria/anuria Esp. When edema and/or hypokalemia occur –For flush-out of intratubular casts arising from hemolysis or rhabdomyolysis Hyperkalemia Hypertension – only when associated with renal/heart failure (see further)!

13. Loop diuretics adverse reactions Hypokalemia – hypokalemic metabolic alkalosis –↓ Na reabsorption in the Loop  ↑ Na concentrations in collecting tub.  ↑ reabsorption, but in exchange for K +  K + wasting (H + ) –Increased risk of potentially fatal ventricular arrhythmias –Prevention – low NaCl diet, K + compensation (KCl) or combination with K + sparring diuretics (see below) Hypomagnesemia – predictable, esp. in patients with dietary deficit Hypocalcemia Hypovolemia (diuresis up to 4 L/24 h), dehydration, hypotension Ototoxicity Hyperuricemia and gout precipitation – also attributable to hypovolemia Allergic reactions – sulfonamide moiety - skin rashes, eosinophilia, exceptionally interstitial nephritis - skin rashes, eosinophilia, exceptionally interstitial nephritis

14. Loop diuretics contraindications Electrolyte imbalance, hypotension –hyponatremia, hypokalemia, hypochloremic alkalosis, hypotension Hypersensitivity to furosemide –cross-hypersensitivity with sulfonamides

15. Distal tubule Lumen Thiazide s Accrding to Katzung's Pharmacology: Examination and Board Review. McGraw-Hill/Appleton & Lange; 6th edition (August 6, 2001)

16. Thiazides HydrochlorothiazideChlorthalidone Indapamide and metipamide –All the drugs are actively secreted into the tubule and act in the distal tubule

17. Thiazides – sulfonamide structure - indapamide and metipamide have a different structure All of them can be given orally All of them can be given orally –daily treatment, long treatment Different T 1/2, –hydrochlorothiazide (12h) others (>24h) All of them are secreted actively by tubular secretion Indapamide and metipamide are mainly excreted by the liver, but sufficient amount can get into the kidney Thiazide diuretics structure and pharmacokinetics

18. Thiazides pharmacodynamics 1. Renal effects –Inhibition of Na + reabsorption in the distal tubule → decreased Na retention and intravascular volume → decreased Na retention and intravascular volume –natriuretic and diuretic effects are less pronounced than those of loop diuretics!!! –increased Ca 2+ reabsorption 2. Extrarenal effects –Decreased preload and consequently also afterload –After few weeks (2-3) the PVR gradually decreases –Indapamide and metipamide have also direct vasodilating effects

19. Arterial hypertension Chronic heart failure (rather milder forms) Might be useful in patient with osteoporosis Thiazide diuretics Indications

20. Thiazide diuretics adverse effects Hypokalemia and metabolic alkalosis –the same mechanism and prevention as previously, less severe, dose ! Impaired glucose tolerance –Link to hypokalemia which may decrease insulin secretion?! Dose and correction! Dyslipidemia – increased total cholesterol and LDL, potentially triglycerides Hyperuricemia – competition for secretion transporters with uric acid (prevention/correction with allopurinol) Hyponatremia, hypovolemia Allergic reaction –sulfonamide structure, skin rashes, very rarely hemolytic anemia Low doses used in hypertension (e.g., 6.25/12.5-25mg/day) –still good therapeutic response along with much less complications

21. Collecting tubuleLumen Amiloride Spironolactone Potassium-sparring diuretics Modified according to Katzung's Pharmacology: Examination and Board Review. McGraw-Hill/Appleton & Lange; 6th edition (August 6, 2001)

22. Potassium-sparing diuretics SpironolactoneEplerenoneAmilorideTriamterene

23. PD effects: –Decreased Na + reabsorption in the collecting tubule with slightly increased natriuresis –Decreased K + secretion (excretion) into the lumen of the collecting tubule Overall diuretic effect – relativity small PK –Amiloride – p.o., slower onset of action –Spironolactone – short T 1/2, but its active metabolite is responsible for most of the drug´s effects –Eplerenon – once daily, p.o., no active metabolites

24. Potassium-sparing diuretics indications In combination with other diuretics –To effectively prevent K + wasting (hypokalemia) –Superior alternative to long term KCl supplementation (it is not as practical, poor compliance) –It should be discouraged to combine both approaches Spironolactone and eplerenone –Primary and secondary hyperaldosteronism (e.g., induced by liver cirrhosis) – to prevent excessive Na + and extravascular fluid retention –Chronic heart failure – moderate to severe forms In addition to other drugs Improve symptoms and prognosis Prevent and regress pathological remodeling of the heart and vessels

25. Potassium-sparing diuretics adverse effects Hyperkalemia – –dose dependent –very likely to develop in combination with other drugs with antialdosterone effects –It is very likely to develop in combination with other drugs with antialdosterone effectsACE-inhibitors,beta-blockers –K + supplementation! Spironolactone –gynecomastia, menstrual disorders etc (much less in eplerenon )

26. Osmotic diuretics Mannitol 10-20% solution Osmotically active agent without any specific pharmacological action Non-reabsorbable osmotically active agents –Hydrophilic - administered i.v. Indications –Enhance water excretion without loss of Na + (lack of natriuretic action) –Different clinical use than in other diuretics (and rather limited) To decrease intracranial or intraocular pressures –they enter neither eye nor brain, they just increase plasma osmolality and this result in the extraction of water from these compartments to prevent anuria in acute renal failure ( due to the pigment load - hemolysis, rhabdomyolysis, infections or hemorrhage…), some pts respond poorly (might be revealed by mannitol test)

27. Osmotic diuretics adverse reactions water extraction from the intracellular compartment expansion of the intravascular and interstitial fluid volume hyponatremia –dilution by water extracted from the tissues (in impaired kidney functions) complications –Acute pulmonary edema –HF –Common: headache, nausea, vomiting –Overdose: dehydration, hypernatremia