Diuretics

1. Diuretics Martin Sterba, PharmD. PhD. Department of Pharmacology LFHK UK

2. Diuretics • Drugs increasing excretion (volume) of urine (diuresis) • Most of them have very significant natriuretic properties – i.e, they increase urinary Na+ excretion • They mostly 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

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

4. Diuretics • Carbonic anhydrase inhibitors • Thiazides • Loop diuretics • Potassium-sparing diuretics • Osmotic diuretics • Aquaretics (ADH-antagonists)

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

6. Acetazolamide • Inhibitor of the carbonic acid anhydrase • Causes the inhibition of the bicarbonate reabsorption in the proximal tubule  bicarbonate loosing via urine - ↑ pH urine within 0,5-2h and persists 12h (after a single dose) • Result: hyperchloremic metabolic acidosis • Diuretic (natriuretic) effects is limited (compensated within the distal parts of the nephron) and decreased within few days of the treatment • Indication • Glaukoma treatment (shorter treatment, before surgery) carbonic acid anhydrase is also present in the cilliary body (it enables there a secretion of the bicarbonate and Na in the aqueous humour) acetolazamide  decreases the intraocular humour production  decreases intraocular pressure • Local glaucoma treatment - dorzalamid • Alkalization of the urine – e.g., in cysteinuria (excretion facilitation) • metabolic alkalosis in patients suffering from HF and oedema when standard treatment employing volume correction is not applicable

7. Acetazolamide – adverse reactions • Hyperchloremic metabolic acidosis • Predictable loses of the HCO3- stores is also a limitation for both long term safety and efficacy of the treatment • Phosphaturia a hypercalciuria - 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 NH4 excretion which may further contribute to the hyperammoneamia and hepatic encephalopathy in patients with cirrhosis

8. Loop diuretics • Furosemide • Torasemide • Etoziline,ethacrynic acid

9. Furosemid Lumen Vzestupné raménko Henleovy kličky Loop of Henle upraveno podle 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) • Inhibition of Na+/K+/2Cl- re-uptake • Decrease the lumen-positive potential that comes from K+ recycling  decreased reabsorption divalent cationts, resulting into the hypocalcaemia a hypomagnesaemia • Increased prostaglandine synthesis – improved renal perfusion • 2. Extrarenal effects • Vasodilation (venous system) – important in i.v. treatment of acute pulmonary oedema, where 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 diureticsPharmacokinetics • Oral administration (quite good absorption, torasemide is absorbed faster than furosemide) • 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 due to the competition with other drugs (e.g., NSAD)

12. Loop diureticsindications • Acute pulmonary oedema – i.v. treatment Active tubular secretion makes it useful even in shock-like • CHF (esp. with signs of blood congestion) • Decreased Na+ retention, intravascular volume and preload and reduction of oedema, improve symptoms! • Other diseases with fluid/sodium retention and oedema E.g. In the liver disease associated with ascites etc • Acute renal failure – useful even when Clcr is below 30 ml/min. • For prevention of Na/fluid retention with oligouria/anuria Esp. When oedema and/or hypokalemia occur • They can be useful for flush-out of intratubular casts arising from haemolysis or rhabdomyolysis • Acute hyperkalcemia (accompanying small cell lung cancer) • Hyperkalemia • Hypertension – only when associated with renal/heart failure (see further)!

13. Loop diureticsadverse reactions • Hypokalemia– hypokalemic metabolic alkalosis • ↓ Na reabsorption in LoH  ↑ Na concentrations in collecting tubule  ↑ Na reabsorption, but in exchange for K !!!! potassium wasting (H+) • Increased risk of potentially fatal ventricular arrhythmias • Prevention– low NaCl diet, K+ compensation (KCl) and most importanty combination with K+ sparring diuretics (see below) • Hypomagnesemia – predictable, most frequent in patients with dietary deficit • Hypocalcemia • Hypovolemia (diuresis up to 4 L/24 h), dehydratation and hypotension • Ototoxicity • Hyperuricemiaand gout precipitation– can also be attributable to hypovolemia • Allergic reactions– sulfonamide moiety - skin rashes, eosinophilia, exceptionally interstitial nephritis

14. Loop diuretics contraindications • Electrolyte imbalance (hyponatremia, hypokalemia, hypochloremic alkalosis, hypotension) • Liver failure with impaired consciousness (the risk of profound hypokalemia) • Hypersensitivity to furosemide + cross-hypersensitivity with sulphonamides

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

16. Thiazides • Hydrochlorothiazide • Chlorthalidone • Indapamide and metipamide • All the drugs are actively secreted into the tubule and act in the distal tubule

17. Thiazide diureticsstructure and pharmacokinetics • Thiazides – sulphonamide structure - indapamide a metipamide have different structure • All of them can be given orally (daily treatment, long treatment) • Different T1/2,hydrochlorothiazide (12h) others (>24h) • All of them are secreted actively by tubular secretion • Indapamide a metipamide are mainly excreted by the liver, but sufficient sufficient amount can get into the kidney

18. Thiazides pharmacodynamics 1. Renal effects • Inhibition of Na+ reabsorption in the distal tubule – decreased Na retention and intravascular volume • natriuretic and diuretic effects are less pronounced than those of loop diuretics!!! • increased Ca2+ reabsorption 2. Extrarenal effects • Decreased preload and consequently also afterload • After few weeks (2-3) the PVR gradually decreases • Indapamide a metipamide have also direct vasodilating effects

19. Thiazide diureticsIndications • Arterial hypertension • Chronic heart failure (rather milder forms) • Recurrent nephrolithiasis arising from idiopathic hypercalciuria • Might be useful in patient with osteoporosis • Nephrogenic diabetes insipidus

20. Thiazide diureticsadverse effects • Hypokalemia and metabolic alkalosis (the same mechanism and prevention, dose !) • Impaired glucose tolerance– mechanism – inhibition of insulin secretion due to the hypokalemia?! Dose! • Dyslipidemia– increased total cholesterol and LDL, potentially triglycerides – might be • Hyperuricemia– competition for secretion transporters with uric acid (prevention/correction with allopurinol) • Hyponatremia, hypovolemia • Allergic reaction– sulphonamide structure, skin rashes, very rarely haemolytic anaemia • Currently it is recommended to use quite low doses – still good therapeutic response along with much less complication (e.g., in hypertension the doses are: 6,25/12,5-25mg/den

21. Amiloride Triamterene Potassium-sparring diuretics Lumen Collecting tubule Spironolactone upraveno podle Katzung's Pharmacology: Examination and Board Review. McGraw-Hill/Appleton & Lange; 6th edition (August 6, 2001)

22. Potassium-sparing diuretics • Spironolactone • Eplerenone • Amiloride • Trimaterene

23. Potassium-sparing diuretics • 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 – quite small • PK • Amiloride – p.o., slower onset of action (peak at 6th , duration 24h) • Spironolacton – short plasma T1/2 but it is metabolised into its active metabolite canrenone (T1/2 = 16h) – 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) in patients on low NaCl diet • Superior alternative to long term KCl supplementation (it is not as practical, poor compliance) • It should be discourage to combine both approaches • Spironolactone and eplerenone • Primary and secondary hyperaldosteronism (e.g., induced by liver cirrhosis etc.)– 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 remodelling of the heart and vessels

25. Potassium-sparing diuretics adverse effects • Hyperkalemia • dose dependent • It is very likely to develop in combination with other drugs with antiladosterone effects – ACE-inhibitors, beta-blockers or K+ supplementation • Hyperchloremic metabolic acidosis • Spironolacton - gynaecomastia, menstrual disorders etc (much less in eplerenon)

26. Osmotic diuretics Mannitol10-20% solution • Osmotically active substances without specific pharmacological action • They act mostly in proximal tubule, thin descendent limb of the loop – where the nephron is penetrable for water • Non-reabsorbable osmotically active agents significantly increase diuresis via water excretion along with minor Na+ excretion • Indication – in the situations where the most important is to enhace water excretion without loss of Na+ • Indications – due to the lack of natriuretic action rather limited • E.g,. to prevent anuria in acute renal failure due to the pigment load (hemolysis, rhabdomyolysis), infections or haemorrhage… • To decrease pathologically elevated intracranial or intraocular pressures (they enter neither eye nor brain, they just increase plasma osmolarity and this result in the extraction of water from these compartments

27. Osmotic diureticsadverse reactions • Pronounced water extration from the intracellular compartment and expansion of the intravascular but also interstitial fluid volume • Hyponatremia • Complications • Acute pulmonary oedema • HF • Common: headache, nauzea, vomiting • Overdose:dehydratation, hypernatremia ADH antagonists - vaptans • conivaptan • - small molecule V1 and V2 receptor antagonists • decrease water (not Na) reabsorption which increase the diuresis • Poor bioavailability – i.v. formulationonly • Indications: hyponatremia associated with Syndrome of Inappropriate ADH (SIADH)…