Diureticsmedicenal chapter 7 about drug that.pptx

Medicinal chemistry abranch of integrated catagory

1. Diuretics

2. Diuretics Diuretic is an agent that increases urine volume, Natriuretic is an agent that causes an increase in renal sodium excretion Aquaretic is an agent that increases excretion of solute-free water Because natriuretics almost always also increase water excretion, they are usually called diuretics

3. Carbonic anhydrase inhibitors Carbonic anhydrase (CA) is predominantly located in the epithelial cells of the PCT, where it catalyzes the dehydration of H 2 CO 3 to CO 2 at the luminal membrane and rehydration of CO 2 to H 2 CO 3 in the cytoplasm By blocking CA, inhibitors blunt NaHCO 3 reabsorption and cause diuresis Include Acetazolamide , dichlorphenamide , methazolamide , dorzolamide , brinzolamide

4. Carbonic anhydrase inhibitors cont… Pharmacokinetics They are well absorbed after oral administration Excretion is by secretion in the proximal tubule S2 segment Therefore, dosing must be reduced in renal insufficiency R – Renal excretion, M – Metabolism is required for excretion

5. Carbonic anhydrase inhibitors cont… Pharmacodynamics Profoundly depresses HCO 3 − reabsorption in the PCT (85%) and significant HCO 3 − losses and hyperchloremic metabolic acidosis 45% inhibition of whole kidney HCO 3 − reabsorption (other absorption site is present) Because of reduced HCO 3 − in the glomerular filtrate and the fact that HCO 3 − depletion leads to enhanced NaCl reabsorption by the remainder of the nephron , the diuretic efficacy of acetazolamide decreases significantly with use over several days Mainly used to inhibit CA dependent HCO 3 − and fluid transport at site other than the kidney (eye and brain)

6. Carbonic anhydrase inhibitors cont… Clinical application A. Glaucoma The reduction of aqueous humor formation by CA inhibitors decreases the intraocular pressure B. Urinary Alkalinization Uric acid and cystine are relatively insoluble and may form stones in acidic urine

7. Carbonic anhydrase inhibitors cont… Clinical application - C. Metabolic Alkalosis Metabolic alkalosis is generally treated by correction of abnormalities in total body K+, intravascular volume, or mineralocorticoid levels However, when the alkalosis is due to excessive use of diuretics in patients with severe heart failure, acetazolamide can be useful in correcting the alkalosis as well as producing a small additional diuresis for correction of volume overload A lso used to rapidly correct the metabolic alkalosis that may appear following the correction of respiratory acidosis

8. Carbonic anhydrase inhibitors cont… Clinical application - D. Acute Mountain Sickness Weakness, dizziness, insomnia, headache, and nausea can occur in mountain travelers who rapidly ascend above 3000 m In more serious cases, rapidly progressing pulmonary or cerebral edema can be life threatening This mild metabolic central and CSF acidosis is also useful in the treatment of sleep apnea

9. Carbonic anhydrase inhibitors cont… Clinical application - E. Other Uses They have been used as adjuvants in the treatment of epilepsy and in some forms of hypokalemic periodic paralysis They are also useful in treating patients with CSF leakage By reducing the rate of CSF formation and intracranial pressure, CA inhibitors can significantly slow the rate of CSF leakage They also increase urinary phosphate excretion during severe hyperphosphatemia

10. Carbonic anhydrase inhibitors cont… Toxicity Hyperchloremic Metabolic Acidosis . Renal Stones Phosphaturia and hypercalciuria occur. Renal excretion of solubilizing factors ( eg , citrate) may also decline with chronic use Renal stone formation by calcium salts is enhanced Renal Potassium Wasting K+ wasting can occur because the increased Na+ presented to the collecting tubule (with HCO3−) This effect can be counteracted by simultaneous administration of potassium chloride or a K + -sparing diuretic

11. Carbonic anhydrase inhibitors cont… Other Toxicities Drowsiness and paresthesias (large doses) Accumulate in patients with renal failure, leading to nervous system toxicity Hypersensitivity reactions (fever, rashes, bone marrow suppression, and interstitial nephritis) may also occur Contraindication – In patient with cirrhosis

12. Loop diuretics Inhibit NaCl reabsorption in the TAL. Are the most efficacious diuretic agents currently available Include Furosemide , ethacrynic acid, bumetanide , torsemide

13. Loop diuretics cont… Pharmacodynamics They induce expression of cyclooxygenases (COX-2), which participates in the synthesis of prostaglandins (PGs) Prostaglandin E2 (PGE2) inhibits salt transport in the TAL and participates in the renal actions of loop diuretics Non- steriodal anti-inflammatory drugs ( eg , indomethacin ) interfere with the action of loop diuretics in patients with nephrotic syndrome or hepatic cirrhosis Loop diuretics affect the blood vessels – increase blood flow due to PG production

14. Loop diuretics cont… Clinical application - A. Hyperkalemia In mild hyperkalemia —or after acute management of severe hyperkalemia by other measures—loop diuretics can significantly enhance urinary excretion of K + B . Acute Renal Failure They increase the rate of urine flow and enhance K + excretion in acute renal failure

15. Loop diuretics cont… Clinical application – C. Anion Overdose Loop diuretics are useful in treating toxic ingestions of bromide, fluoride, and iodide, which are reabsorbed in the TAL Other use - The most important indications is for Acute pulmonary edema Other edematous conditions Acute hypercalcemia

16. Loop diuretics cont… Toxicity Hypokalemic Metabolic Alkalosis Ototoxicity – Dose –related and reversible Hyperuricemia Hypomagnesemia Allergic reaction - skin rash, eosinophilia , interstitial nephritis Sever dehydration and hyponatremia Mild hypocalcemia and secondary hyperparathyroidism or hypercalcemia in volume depleted patients

17. Loop diuretics cont… Contraindications Furosemide , bumetanide , and torsemide may exhibit allergic cross-reactivity in patients who are sensitive to other sulfonamides, but this appears to be very rare Overzealous use of any diuretic is dangerous in hepatic cirrhosis, borderline renal failure, or heart failure

18. Thiazide diuretics Thiazide and related drugs include Bendroflumethiazide , Chlorothiazide , Chlorthalidone, Hydrochlorothiazide (HCTZ), Hydroflumethiazide , Indapamide , Methyclothiazide , Metolazone, Polythiazide , Quinethazone, Trichlormethiazide All thiazides can be administered orally, but there are differences in their metabolism All thiazides are secreted by the organic acid secretory system in the proximal tubule and compete with the secretion of uric acid by that system

19. Thiazide diuretics Pharmacokinetics (R – renal, M- metabolism, B – Bilary excretion)

20. Thiazide diuretics cont… Pharmacodynamics Thiazides inhibit NaCl reabsorption from the luminal side of epithelial cells in the DCT by blocking the Na+/ Cl − transporter Their action depends in part on renal PG production.

21. Thiazide diuretics cont… Clinical application The major indications for thiazide diuretics are Hypertension Heart failure Nephrolithiasis due to idiopathic hypercalciuria Nephrogenic diabetes insipidus

22. Thiazide diuretics cont… Toxicity Hypokalemic Metabolic Alkalosis and Hyperuricemia Impaired Carbohydrate Tolerance – Hyperglycemia Hyperlipidemia Increase in total serum cholesterol and LDLs

23. Thiazide diuretics cont… Toxicity Hyponatremia – Due to hypovolemia -induced elevation of anti-diuretic hormone (ADH), reduction in the diluting capacity of the kidney, and increased thirst Allergic reaction Photosensitivity or generalized dermatitis occurs rarely Extremely rare reaction include hemolytic anemia, thrombocytopenia, and acute necrotizing pancreatitis. Weakness, fatigue, paresthesia , impotence Contraindication - Excessive use is dangerous in patients with hepatic cirrhosis, borderline renal failure, or heart failure

24. Potassium sparing diuretics Include spironlactone , eplerenone , amiloride , triameterene Prevent K + secretion by antagonizing the effects of aldosterone in collecting tubules It may occur by direct pharmacologic antagonism of mineralocorticoid receptors or by inhibition of Na+ influx through ion channels in the luminal membrane Nesiritide (available for intravenous use only) increases GFR and blunts Na+ reabsorption in both proximal and collecting tubules The actions of the aldosterone antagonists depend on renal prostaglandin production

25. Potassium sparing diuretics cont… Pharmacokinetics (M for metabolism, R – renal excretion)

26. Potassium sparing diuretics cont… Clinical application Most useful in states of mineralocorticoid excess or hyperaldosteronism (also called aldosteronism ), due either to primary hypersecretion (Conn’s syndrome, ectopic adrenocorticotropic hormone production) or secondary hyperaldosteronism (evoked by heart failure, hepatic cirrhosis, nephrotic syndrome, or other conditions associated with diminished effective intravascular volume Thiazides or loop agents can cause or exacerbate volume contraction and may cause secondary hyperaldosteronism .

27. Potassium sparing diuretics cont… Clinical application In the setting of enhanced mineralocorticoid secretion and excessive delivery of Na + to distal nephron sites, renal K + wasting occurs Potassium-sparing diuretics of either type may be used in this setting to blunt the K + secretory response Low doses of eplerenone may interfere with some of the fibrotic and inflammatory effects of aldosterone By doing so, it can slow the progression of albuminuria in diabetic patients More important is that eplerenone has been found to reduce myocardial perfusion defects after myocardia infarction

28. Potassium sparing diuretics cont… Toxicity Hyperkalemia Greatly ↑ by renal disease or by drugs that ↓ or inhibit renin ( β blockers, NSAIDs, aliskiren ) or angiotensin II activity ( angiotensin -converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs)) Hyperchloremic Metabolic Acidosis Gynecomastia , impotence, and benign prostatic hyperplasia with spironolactone Acute renal failure (ARF) and kidney stone – With triameterene Trameterene when combined with indomethacin may causes ARF

29. Potassium sparing diuretics cont… Contraindications P atients with chronic renal insufficiency – Hyperkalemia Concomitant use with agents that blunt the renin-angiotensin system (β-blockers, ACEIs, ARBs) increase the risk of hyperkalemia Patients with liver disease may have impaired metabolism of triamterene and spironolactone , so dosing must be carefully adjusted Strong CYP3A4 inhibitors ( eg , erythromycin, fluconazole , diltiazem , and grapefruit juice) can markedly increase blood levels of eplerenone , but not spironolactone Spironolactone in Peptic ulcer patients

30. Aquaretics Osmotic diuretics Are agent that is filtered by the glomerulus but not reabsorbed – Cause water to be retained in these segments and promotes a water diuresis . Such agents can be used to reduce intracranial pressure and to promote prompt removal of renal toxins Include mannitol , urea, Glycerin, Isosorbide Osmotic diuretics have their major effect in the proximal tubule and the descending limb of Henle’s loop

31. Aquaretics Osmotic diuretics cont… Pharmacokinetics (U – unknown, M – metabolism, R –renal, B – Bilary excretion)

32. Aquaretics Osmotic diuretics cont… Clinical application Increase of Urine Volume Can be useful when avid Na + retention limits the response to conventional agents It can be used to maintain urine volume and to prevent anuria that might otherwise result from presentation of large pigment loads to the kidney ( eg , from hemolysis or rhabdomyolysis ) Some oliguric patients do not respond to osmotic diuretics Therefore, a test dose of mannitol should be given Prolonged use is not advised

33. Aquaretics Osmotic diuretics cont… Clinical application Reduction of Intracranial and Intraocular Pressure Osmotic diuretics alter Starling forces so that water leaves cells and reduces intracellular volume This effect is used to reduce intracranial pressure in neurologic conditions and to reduce intraocular pressure before ophthalmologic procedures. Mannitol is administered intravenously

34. Aquaretics Osmotic diuretics cont… Toxicity Extracellular Volume Expansion This effect can complicate heart failure and may produce florid pulmonary edema Headache, nausea, and vomiting are commonly observed Dehydration, Hyperkalemia , and Hypernatremia Hyponatremia When used in patients with severe renal impairment, parenterally administered mannitol cannot be excreted and is retained intravenously. This causes osmotic extraction of water from cells, leading to hyponatremia

35. Anti-diuretic hormone antagonists Anti-diuretic hormone (ADH) also known as vasopressin Excessive ADH secretion in condition such as congestive heart failure (CHF) and the syndrome of inappropriate ADH secretion (SIADH), cause water retention Two drugs (lithium and demeclocycline ) non-selectively interfere with ADH There are three known vasopressin receptors,V1a , V1b and V2 V 1 receptors are expressed in the vasculature and CNS V2 receptors are expressed specifically in the kidney

36. ADH antagonists cont… Conivaptan ( only for intravenous use) exhibits activity against both V1a and V2 receptors The oral agents tolvaptan , lixivaptan , and satavaptan are selectively active against the V2 receptor Pharmacokinetics The half-life of conivaptan and demeclocycline is 5–10 hours, while that of tolvaptan is 12–24 hours. Pharmacodynamics ADH antagonists inhibit the effects of ADH in the collecting tubule

37. ADH antagonists cont… Clinical application Syndrome of Inappropriate ADH Secretion (SIADH) Demeclocycline or tolvaptan used when water restriction has failed Appropriate plasma levels of demeclocycline should be maintained by monitoring, but tolvaptan levels are not routinely monitored Conivaptan is administered intravenously and is not suitable for chronic use in outpatients

38. ADH antagonists cont… Clinical application Other Causes of Elevated Antidiuretic Hormone Antidiuretic hormone is also elevated in response to diminished effective circulating blood volume, as often occurs in heart failure In patients with heart failure, water restriction is often unsuccessful in view of increased thirst and the large number of oral medications being used Intravenous conivaptan may be particularly useful because it has been found that the blockade of V1a receptors by this drug leads to decreased peripheral vascular resistance and increased cardiac output

39. ADH antagonists cont… Toxicity Nephrogenic Diabetes Insipidus Can cause severe hypernatremia and nephrogenic diabetes insipidus If lithium is being used for a psychiatric disorder, nephrogenic diabetes insipidus can be treated with a thiazide diuretic or amiloride Renal Failure Both lithium and demeclocycline

40. ADH antagonists cont… Toxicity Other Dry mouth and thirst Tolvaptan may cause hypotension Multiple adverse effects associated with lithium therapy

41. Diuretic combination Loop diuretics show refractoriness in their action This can be reduced by combining loop diuretics with thiazide diuretics Reason – They act at different site and thiazide induced mild natriuresis in the proximal tubule is usually masked by increased reabsorption in the TAL and hence the combination of loop diuretics and thiazides can therefore block Na + reabsorption , to some extent, from all three segments K + wasting is extremely common and may require parenteral K + administration with careful monitoring of fluid and electrolyte status

42. Diuretic combination Potassium sparing diuretics with other diuretics Hypokalemia often develops in patients taking carbonic anhydrase inhibitors, loop diuretics, or thiazides This can usually be managed by dietary NaCl restriction or by taking dietary KCl supplements When hypokalemia cannot be managed in this way, the addition of a K + -sparing diuretic can significantly lower K + excretion. Such combination should be avoided in patients with renal insufficiency and in those receiving angiotensin antagonists, in whom life-threatening hyperkalemia can develop in response to K + -sparing diuretics