Drugs Acting on Kidney, Prepared by Mriganka Giri

Drugs Acting on the Kidney
Definition, classification, pharmacological actions, dose,
indications, and contraindications of
1. Diuretics
2. Anti-Diuretics

1. GURU NANAK INSTITUTE OF PHARMACEUTICAL SCIENCE AND TECHNOLOGY D.Pharm [Part-II] DRUGS ACTING ON KIDNEY 1 PHARMACOLOGY [ER20-21T]

2. CONTENTS TOPIC SLIDE NO. Relevant Physiology of Urine Formation Diuretics a. Definition b. Classification c. Pharmacological Actions d. Dose e. Indications f. Contraindications Anti-Diuretics a. Definition b. Classification c. Pharmacological Actions d. Dose e. Indications f. Contraindications 2 PHARMACOLOGY [ER20-21T] 3 5-10 11-16

3. i . Relevant Physiology of Urine Formation: Kidney, the excretory organ of our body, serves the important functions of excretion of waste products and, regulation of fluid volume and electrolyte content of the extracellular fluid . Physiology of Urine Formation: The nephron is the functional unit of the kidney. Glomerular filtration occurs in the Bowman’s Capsule. 3 PHARMACOLOGY [ER20-21T]

4. PHARMACOLOGY [ER20-21T] 4 Blood enters into the glomerulus via afferent arteriole Blood gets filtered into the glomerulus in high pressure (pressure difference is created via the difference in diameter between afferent and efferent arteriole) Filtrate (96% water, 2% urea, 1% NaCl, 1% creatinine, Ca2+, HCO3-, K+, etc.) liberates into PT Symport of Na+, K+, 2Cl-, occurs in PT, Ascending LOH, DT, and CD, and also the movement of water, glucose, urea, etc from the nephron tubules to the blood vessels are collectively known as tubular reabsorption Movement of H+, K+, Creatinine, etc from blood vessels to nephron tubules is known as tubular secretion The filtrate substances then come into the collecting duct Then they are directed to the ureter to the urinary bladder and finally urination is done

5. ii. Diuretics: a. Definition- Diuretics are the drugs which increase the rate of urine formation together with natriuresis (increase Na+ excretion). Only a few drugs produce diuresis by increasing the GFR; most of the diuretics used therapeutically act by interfering with sodium reabsorption by the tubules. b. Classification- Nephron PCT 65-70% reabsorption; No drug applied (If drug is applied in this portion then abnormally high urination would cause dehydration) LOH 15-20% reabsorption; High ceiling diuretics DCT 5-7% reabsorption; Medium efficacy CD <1% reabsorption; Weak diuretics 5 PHARMACOLOGY [ER20-21T]

6. c. Pharmacological action- High ceiling diuretics- (1) Inhibit Na +–K+–2Cl – symport. (2) Have a rapid onset and short duration of action. (3) Cause excretion of 15-20% of the filtered NaCl. (4) Are effective even in the presence of markedly reduced GFR (5) Tend to be effective when drugs from group II, given in maximum doses, fail to act. Medium efficacy diuretics- (1) Inhibit Na + – Cl – symport. (2) Have a moderately rapid onset of action, lead to excretion of 5-10% of the filtered NaCl (3) Have a wide spectrum of duration of action (8-72 hours) (4) Are ineffective with GFR 6 PHARMACOLOGY [ER20-21T]

7. Weak diuretics- d. Dose- Furosemide (Frusemide) : Oral : The usual dose for adults with high blood pressure is  40 mg to 80 mg  per day. IV : The initial dose is  20 mg to 40 mg  administered slowly over 1 to 2 minutes.  Maintenance doses can be given once or twice a day . 7 PHARMACOLOGY [ER20-21T] SITE OF ACTION DRUG GROUP MECHANISM OF ACTION EFFECT ON IONS Proximal Tubule Carbonic Anhydrase inhibitors Inhibition of Carbonic Anhydrase Inhibition of N a + -H + exchange indirectly Loop of Henle and Proximal Tubule Osmotic Diuretics Osmotic effect to reduce medullary tonocity Limits passive reabsorption of N a + Late segment of Distal tubule (site of Na + / H + exchange) and collecting duct Aldosterone antagonist Triamterene Amiloride Blockade of mineralocorticoid receptors Inhibition of renal epithelial sodium chloride Inhibition of Na + reabsorption and reduced excretion of K + Renal Epithelial Na + ion channel inhibitors Amiloride, Triamterene By inhibiting ENaC, these drugs can reduce sodium reabsorption, leading to increased sodium excretion and subsequent water loss. ENaC inhibitors directly target the sodium channels in the renal tubules, leading to decreased sodium reabsorption

8. Bumetanide : Oral : 1 mg of bumetanide is equivalent to 40 mg of oral furosemide. Intravenous (IV) : 1 mg of bumetanide is equivalent to 20 mg of IV furosemide. Torasemide : Oral/IV : The equivalent dosage varies depending on reference sources. Generally,  10 mg to 20 mg  of oral or IV torasemide is considered equivalent to  40 mg  of oral furosemide or  20 mg  of IV furosemide. Benzothiadiazines- Hydrochlorothiazide : Usual dose:  12.5 mg to 50 mg  once daily. Hydroflumethiazide : Usual dose:  50 mg to 100 mg  once daily. Benzthiazide : Usual dose:  25 mg to 50 mg  once daily. 8 PHARMACOLOGY [ER20-21T]

9. Thiazide-like- Chlorthalidone : Usual dose:  12.5 mg to 50 mg  once daily. Metolazone : Usual dose:  2.5 mg to 10 mg  once daily. Xipamide : Usual dose:  10 mg to 20 mg  once daily. Indapamide : Usual dose:  1.25 mg to 5 mg  once daily. Clopamide : Usual dose:  5 mg to 15 mg  once daily. Carbonic anhydrase inhibitor- Acetazolamide: 125 mg to 250 mg  orally once to three times daily Osmotic diuretic- Mannitol: 10%, 20%, in 100, 350 and 500 ml ,vac. Isosorbide/ Glycerol: 0.5 1.5 g/kg as oral solution. Potassium-sparing diuretics- Aldosterone antagonist: Spironolactone- 25, 50. 100 mg Eplerenone- : 25 50 mg BD. Renal epithelial Na+ channel inhibitors- Amiloride- 5 mg 9 PHARMACOLOGY [ER20-21T]

10. Class of Diuretic e. Indications f. Contraindications High Ceiling (Loop) Diuretics  (e.g., Furosemide) - Acute pulmonary edema - Cerebral edema - Hypertension - Hyperglycemia - Hypokalemia - Hyponatremia - Hypercalcemia - Addison’s disease - Symptomatic hyperuricemia - Severe liver disease Benzothiadiazines  (e.g., Hydrochlorothiazide) - Hypertension - Edema - Hypoglycemia Thiazide-like Diuretics  (e.g., Chlorthalidone, Metolazone) - Heart failure - Refractory hypokalemia - Hyponatremia - Hypercalcaemia - Addison’s disease - Symptomatic hyperuricemia - Severe liver disease Carbonic Anhydrase Inhibitors  (e.g., Acetazolamide) -Glaucoma - Epilepsy - Acute mountain sickness - Chronic heart failure - None specified Osmotic Diuretics  (e.g., Mannitol, Isosorbide) -Acute pulmonary edema - Cerebral edema - Prevention of acute renal failure - None specified Potassium-Sparing Diuretics - Aldosterone antagonists  (e.g., Spironolactone, Eplerenone): - Heart failure - Hypertension - Primary hyperaldosteronism -  Renal epithelial Na+ channel inhibitors  (e.g., Amiloride, Triamterene): - Adjunctive diuretics - None specified 10 PHARMACOLOGY [ER20-21T]

11. iii. Anti-Diuretics: a. Definition- These are drugs that reduce urine volume, particularly in diabetes insipidus, which is their primary indication. B. Classification- 11 PHARMACOLOGY [ER20-21T] ANTIDIURETICS Antidiuretic hormone and its analogues Vasopressin (ADH) Desmopressin Lypressin Terlipressin Natriuretics Thiazides Amiloride Miscellaneous Carbamazepine Chlorpropamide Indomethacin

12. c. Pharmacological action- Vasopressin- ADH acts on vasopressin receptors - V₁ and V2. V₁ receptors mediate vasoconstriction. V2 receptors mediate water retention in the collecting duct. ADH Analogues- Drug Mechanism of Action Desmopressin - Binds to  V2 receptors  in distal tubules and collecting ducts. - Increases water reabsorption. Lypressin - Mechanism not fully understood. Shows vasoconstrictor and antidiuretic effect. Terlipressin - Binds to the V1 receptor causes  vasoconstriction  and has antidiuretic effects. 12 PHARMACOLOGY [ER20-21T]

13. Natriuretics- Drug Mechanism of Action Key Sites of Action Thiazides Electrolyte depletion : Thiazides cause electrolyte depletion, leading to more complete glomerular filtrate reabsorption in the  proximal tubule (PT) . -  Reduced salt reabsorption : They decrease salt reabsorption in the  ascending limb of the loop of Henle (LOH) , resulting in less dilute urine. -  Reduced glomerular filtration rate (GFR) : Thiazides also reduce GFR, thereby decreasing the fluid load on tubules. Proximal tubule (PT)  - Ascending limb of the loop of Henle (LOH) Amiloride Blocking Na+ entry : Amiloride acts by blocking the entry of  sodium ions (Na+)  into the  principal cells of the collecting duct (CD) . -  Collecting duct (CD) 13 PHARMACOLOGY [ER20-21T]

14. Miscellaneous- Drug Mechanism of Action Carbamazepine - Inhibits  sodium channels , reducing neuronal excitability. - Promotes water reabsorption in renal tubules. - Used for seizures, trigeminal neuralgia, and bipolar disorder. Chlorpropamide - Binds to  ATP-sensitive potassium channels  on pancreatic cells. - Reduces potassium conductance, leading to cell depolarization. - Enhances water reabsorption. - Used for type 2 diabetes. Indomethacin - Mechanism not fully understood. - Thought to involve  inhibition of prostaglandin synthesis . - Used to close patent ductus arteriosus (PDA) in neonates. 14 PHARMACOLOGY [ER20-21T]

15. d. Dose- Drug Usual Adult Dose Vasopressin (ADH) -  Vasodilatory Shock : Initial dose: 0.03 units/minute IV. Septic shock: Initial dose: 0.01 unit/minute IV. Amiloride -  Congestive Heart Failure : Initial dose: 5 mg orally once a day. Maintenance dose: 5-10 mg once a day. Chlorpropamide -  Diabetes Type 2 : Initial dose: 100 mg to 250 mg orally once a day. Maintenance dose: 100 mg to 500 mg per day. Desmopressin -  Diabetes Insipidus : Initial dose: 0.05 mg orally twice a day or 1 to 2 mcg IV or subcutaneously twice a day. 15 PHARMACOLOGY [ER20-21T]

16. Drug e.Indications f.Contraindications Vasopressin (ADH) -  Vasodilatory Shock : To increase blood pressure in adults with vasodilatory shock who remain hypotensive despite fluids and catecholamines. -  Post cardiotomy shock  (initial dose): 0.03 units/minute IV. -  Septic shock  (initial dose): 0.01 unit/minute IV. - Hypersensitivity - Multiple dose vial (10 mL) in patients with known allergy or hypersensitivity to 8-L-arginine vasopressin or chlorobutanol. Thiazide -  Hypertension  -  Thiazide-Induced Hypokalemia - Not specified Amiloride -  Congestive Heart Failure  -  Thiazide-Induced Hypokalemia  -  Renal Impairment  (CrCl <50 mL/min) - Hypersensitivity to sulphonamides Chlorpropamide -  Type 2 Diabetes - Type 1 diabetes - Hypersensitivity Desmopressin -  Diabetes Insipidus  -  Abdominal Distention  -  Abdominal Roentgenography -  Gastrointestinal Haemorrhage   - Hypersensitivity - Multiple dose vial (10 mL) in patients with known allergy or hypersensitivity to 8-L-arginine vasopressin or chlorobutanol. 16 PHARMACOLOGY [ER20-21T]

17. References- (a) Essentials of Medical Pharmacology ( by K. D. Tripathi ) (b) Pharmacology and Pharmacotherapeutics ( by Satoskar, R.S.; Bhandarkar, S.D. & Nirmala N. Rege ) 17 PHARMACOLOGY [ER20-21T]