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Dr. Kaukab Azim

Introduction to Renal Pharmacology. Dr. Kaukab Azim. Drug List. Clinical Condition in which Diuretics are used. Edematous States. Non-edematous States. Hypertension Hypercalcemia Diabetes insipidus. Heart Failure Hepatic Ascites Increased portal pressure hypoalbuminemia

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Dr. Kaukab Azim

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  1. Introduction to Renal Pharmacology Dr. KaukabAzim

  2. Drug List

  3. Clinical Condition in which Diuretics are used Edematous States Non-edematous States Hypertension Hypercalcemia Diabetes insipidus • Heart Failure • Hepatic Ascites • Increased portal pressure • hypoalbuminemia • Secondary Aldosteronism:Chronic conditions like cirrhosis of the liver, nephrotic syndrome of the kidney or a tumour that produces the hormone renin (normally renin is produced by the adrenal glands) are responsible for secondary aldosteronism. • Nephrotic Syndrome • Premenstrual edema

  4. Site and Mechanism of Action of Diuretics

  5. Carbonic Anhydrase Inhibitors Chemistry • - Acetazolamide, dorzolamide (All compounds are sulfonamides). Mechanism of action • Inhibition of membrane-bound carbonic anhydrase (CA) in the cells of proximal tubule which leads to blockade of the reaction H2CO3 = H2O + CO2 that normally occurs in the proximal tubule lumen • Inhibition of cytoplasmic CA in the cells of proximal tubule which leads to blockade of the reaction: H2 O + CO2 = H2 CO3 that normally occurs in the cytoplasm • The final effect is a nearly complete abolition of NaHCO3 reabsorption in the proximal tubule (but NaHCO3 reabsorption by mechanisms independent from carbonic anhydrase still occur in other parts of the nephron).

  6. Acetazolamide Decreased Urinary secretion Increased Urinary secretion Na+ K+ HCO3- Volume of Urine Please see notes below

  7. Renal effects • - Increased renal excretion of: Na+, K+, HCO3- • - Decreased renal excretion of: NH4+, H+. • - Urine pH: alkaline. • - Acid-base balance: metabolic acidosis (acidosis is associated with hyperchloremiabecause Cl tend to exit from cells when H+ is high, in order to maintain electroneutrality) . • - Efficacy of diuretic: low (the maximum increase in Na+ excretion is about 5% of the filtered Na+ load. Moreover, as metabolic acidosis develops, the filtered load of HCO3- decreases, and therefore the diuretic effect undergoes a complete tolerance in 2-3 days)

  8. Pharmacokinetics • Oral bioavailability: .100%. • Urinary excretion: .90% by tubular secretion. • Administration: acetazolamide PO, dorzolamidetopical (eyedrops)

  9. Adverse effects • Paresthesias(frequent), drowsiness • Nephrolithiasis (due to precipitation of calcium phosphate salts in alkaline urine) • Hyperchloremicmetabolic acidosis • Hyperuricemia • Hypokalemia (the main mechanism is the same as that of thiazides, loop diuretics and osmotic diuretics. In addition, the increased delivery of bicarbonate to the collecting duct increases the lumen negative potential which favors K+ excretion). • Sulfa-type allergic reactions

  10. Therapeutic Uses • Edema • Glaucoma (50-60% reduction in aqueous humor production) • Epilepsy (direct inhibition of carbonic anhydrase in the CNS, which increases carbon dioxide tension and inhibits neuronal transmission) • High altitude sickness • Metabolic alkalosis Please see notes below

  11. Contraindications and Precautions • Hepatic cirrhosis (alkalinization of urine decreases urinary trapping of NH 4+) • Chronic obstructive pulmonary disease (the risk of metabolic acidosis is increased) • Hypersensitivity to sulfa drugs. • Hypokalemic states

  12. Loop Diuretics Chemistry • Furosemide, bumetanide,and torsemide are sulfonamides. Ethacrynicacid is not a sulfonamide Mechanism of action • Inhibition of electroneutral Na+/K+/2Cl- cotransport located on the luminal surface of the thick ascending limb of Henle's loop, which leads to: • a decreased lumen-positive potential which normally drives divalent cation reabsorption. • a decreased hypertonicity of the medulla and therefore a decreased ability of the kidney to concentrate the urine. • an inhibition of macula densa sensitivity (by inhibiting Na+ and Cl- transport into macula densa, the macula densa is no longer able to sense salt concentration in the tubular fluid. Therefore it initiates two responses that can increase GFR: • It inhibits the tubuloglomerular feed back • It stimulates renin release from the adjacent juxtaglomerular cells. • Loop diuretics that are sulfonamide compounds also cause a slight inhibition of carbonic anhydrase.

  13. Pharmacology of Loop Diuretics Renal effects • Increased renal excretion of: Na+,Cl-, K+, H+, Ca++, (sulfonamides also increase the excretion of HCO3). • Acid-base balance: metabolic alkalosis. • The diluting and concentrating capacity of the kidney are decreased. • Efficacy of diuretic effect: high (the maximum increase in Na+ excretion is 20-25% of the filtered Na+ load. Moreover the diuretic effect remains even when the GFR is less than 30 mL/min). • Duration of diuretic effect: 2-6 hours. Vascular effects • Vasodilation, mainly in the venous bed. • Redistribution of blood flow within the renal cortex. (these effects are due, at least in part, to drug induced induction of prostaglandin synthesis and stimulation of prostaglandin release) Pharmacokinetics • Absorption, and biotransformation are drug-related. • Kidney excretion occurs by active secretion by the proximal tubule. • Administration: PO, IM, IV.

  14. Therapeutic uses of Loop Diuretics • Acutepulmonaryedema (given IV). • Heartfailure. • Edema (associated with chronic renal failure or nephrotic syndrome). • Ascites (associated with hepatic cirrhosis or right-sided heart failure). • Hypertension (when associated with renal insufficiency or heart failure). • Hypercalcemia. • (Addition of a thiazide can cause a dramatic synergistic effect when a patient become refractory to a loop diuretic alone )

  15. Furosemide Decreased Urinary secretion Increased Urinary secretion Na+ K+ Ca2+ Volume of Urine

  16. Adverse Effects • Ototoxicity • Hyperuricemia • Hypotension • Hypokalemia • Hypomagnesemia

  17. Remember the one’s in the red box

  18. Thiazide Diuretics The most commonly used diuretics

  19. Pharmacology of Thiazide(and congeners) Chemistry • Thiazides are benzothiadiazine derivatives • Other compounds (congeners) are not thiazides but are pharmacologically similar to thiazides. • All compounds are sulfonamides. Mechanism of action • Inhibition of electroneutral Na+/Cl- cotransport located on the luminal surface of early distal convolute tubule • Slight inhibition of carbonic anhydrase.

  20. Renal effects • Increased renal excretion of: Na+, K+, H+, Cl-, HCO3-,. • Decreased renal excretion of: Ca++, NH4+, urates. • Urine pH: alkaline (due to inhibition of carbonic anhydrase). • Acid-base balance: metabolic alkalosis. • Kidney diluting capacity: decreased. • Efficacy of diuretic effect: moderate (the maximum increase in Na+ excretion is 5-10% of the filtered Na+ load. Moreover, with the exception of indapamide and metolazone, the diuretic effect disappears if the glomerular filtration rate is less than 30 mL/min). • Duration of diuretic effect: variable (6-48 hours).

  21. Hydrochlorothiazide Decreased Urinary secretion Increased Urinary secretion Na+ K+ Ca2+ Volume of Urine

  22. Other effects Vascular effects • Arteriolar vasodilation (after chronic administration) that occurs at lower dosages than are required for diuresis Pharmacokinetics • Absorption, distribution and biotransformation are drug-related. • Kidney excretion occurs by glomerular filtration and active secretion by the proximal tubule. • Administration: PO, IM, IV.

  23. Therapeutic Uses Hypertension (first choice diuretics). - Edema associated with diseases of: a) the heart (i.e. heart failure) b) the liver (i.e. hepatic cirrhosis) c) the kidney (i.e. nephrotic syndrome). - Ascites (due to venous occlusion, cirrhosis, endometriosis, etc.) - Calcium nephrolithiasis, idiopathic hypercalciuria. - Meniere’s disease (they can prevent the endolymphatic fluid buildup) - Nephrogenic diabetes insipidus(this seemingly paradoxical effect is likely mediated through the extracellular volume contraction which promotes proximal tubular reabsorption of Na+ and water. Therefore a reduced volume is delivered to the distal tubule)

  24. Contraindications and Precautions Absolute Anuria Sulfonamide hypersensitivity, thiazide diuretic hypersensitivity Precautions Hyperglycemia, Hyperuricemia, breast feeding, electrolyte imbalance, renal failure

  25. Adverse Effects • Hypokalemia • Hyperuricemia • Hypercalcemia • Hyperlipidemia • Hyperglycemia

  26. Potassium Sparing Diuretics Chemistry • Triamterene and amiloride are organic bases. • Spironolactone is a steroid drug. Mechanism of action • Spironolactone blocks aldosterone receptors in the late distal tubule and cortical collecting tubule (the synthesis of Na+/K+ ATPase in the basolateralmembrane, as well as the synthesis of protein Na+ channels in the luminal membrane are impaired). • Triamterene and amiloridedirectly block Na+ channels in the luminal membrane of late distal tubule and cortical collecting tubule.

  27. Triamterene Decreased Urinary secretion Increased Urinary secretion Na+ K+ Volume of Urine

  28. Absolute contraindications Hyperkalemia Renal failure Precautions Gout Pregnancy Acid base imbalance Therapeutic uses Most commonly used in combination with other diuretics

  29. PHARMACOLOGY OF ANTIDIURETIC HORMONE ANTAGONISTS Drugs • - Conivaptan, tolvaptan Mechanism of action • Competitive antagonists at vasopressin receptors (conivaptan at V1a and V2, tolvaptan at V2) Renal effects • Increased water diuresis (these drugs are also called aquaretics) • Water diuresis increases more than salt diuresis (in this way hyponatremiais relieved). • Increased renal excretion of: Na+, K+, Ca++ • Urine osmolality: decreased

  30. Other effects Other effects • Conivaptanis a strong inhibitor of CYP3A4 Pharmacokinetics • Half lives: Conivaptan 5-10 hrs, tolvaptan < 12 hrs • Administration: Conivaptan IV. Tolvaptan PO. Adverse effect • Infusion-site reactions (with conivaptan) • Nephrogenicdiabetes insipidus • Postural hypotension (if hypovolemia develops) • Hypokalemia(. 9%) Therapeutic uses • Syndrome of inappropriate ADH secretion (when water restriction failed to correct the disorder) • Chroniceuvolemichyponatremia

  31. Mannitol (An IV osmotic diuretic) Therapeutic Uses Cerebral edema (To reduce raised intracranial pressure) Oliguria in renal failure Acute attack of Glaucoma Contraindications and Precautions Absolute Heart Failure, dehydration, intracranial bleeding Precautions Electrolyte imbalance, hypovolemia, geriatiric, Pregnancy, lactation

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