Dr. Kaukab Azim

1. Introduction to Renal Pharmacology Dr. KaukabAzim

2. Drug List

3. In the next few slides we will revisit some useful physiological concepts For each nephron unit, the glomerular filtration rate (GFR) is a function of the: a) hydrostatic pressure in the glomerulus b) hydrostatic pressure in the proximal tubule c) mean oncotic pressure in the glomerulus d) mean oncotic pressure in the proximal tubule (this is negligible as no proteins are filtered into nephron under normal physiological conditions) e) ultrafiltration coefficient (Kf)

4. The proximal Tubule About 65% of the solutes are reabsorbed by the proximal tubule(since this tubule is highly permeable to water the reabsorption is isotonic) Na+ is transported across the proximal tubule by: • Symportsthat reabsorb Na+ with other organic nutrients like amino acids and glucose. • Antiportsthat reabsorb Na+ while secreting H+ into the tubular lumen. The energy for these secondary active transport systems is furnished by the Na+/K+ pump in the basolateral membrane.

6. The loop of Henle • The thin descending limb is permeable to water, yet its permeability to NaCl and other solutes is low. • The thick ascending limbs are impermeable to water and urea. • The thick ascending limb (TAL) actively reabsorbs NaCl through a Na+/K+/2Cl symport (about 25% of the Na+ filtered load is reabsorbed) so diluting the tubular fluid. • This symport is capable of establishing about 200 milliosmoleconcentration gradient between the tubular lumen and the interstitial fluid and so is the most important cause of the high renal medullary osmolarity.

8. The Macula Densa • TAL makes contact with the afferent and efferent arterioles via macula densawhich senses the concentration of Na+ in the tubule. • If the amount of sodium is increased macula densa stimulates the formation and release of ATP (and/or adenosine) which causes contraction of mesangialcells and afferent arterioles through purinergicreceptor activation, so decreasing GFR (tubuloglomerular feedback) • If the amount of sodium is decreased macula densa stimulates renin release which increases the synthesis of angiotensin II. Angiotensin II constricts the efferent arterioles more than the afferent, so increasing GFR. [these mechanisms are specifically directed toward stabilizing GFR]

10. The Distal Tubule The early distal tubule • This tubule also actively reabsorbs NaCl through a Na+/Cl- symport(about 5-10% of the Na+ filtered load is reabsorbed) but is impermeable to water. • The TAL and the early distal tubule are parts of the ‘diluting segment’ of the nephron which regulates the diluting ability of the kidney. The late distal tubule and the cortical collecting tubule • Water permeability here depends on ADH. With high levels of ADH these tubules are highly permeable to water thus causing large amount of water to be reabsorbed into the hypertonic interstitium.

12. The Medullary Collecting Duct • Water reabsorption here depends on: • ADH • The osmolarity of the medullary interstitiumestablished by the countercurrent mechanism. • This high osmolarity contributes to the high concentrating ability of the kidney.

13. Name the hormones secreted by the kidneys? 3 of them So what will you treat in chronic renal failure? Are there any waste products that are going to accumulate in the body? Name 2 that you will clinically measure?

14. 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 • Nephrotic Syndrome • Premenstrual edema

15. Site and Mechanism of Action of Diuretics

16. 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).

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

20. 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)

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

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

23. 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

24. 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.

26. 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.

27. 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 )

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

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

30. Remember the one’s in the red box

31. Thiazide Diuretics The most commonly used diuretics

32. 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.

34. 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).

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

36. 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.

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

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

40. 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.

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

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

44. 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

45. 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

46. 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