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Renal pharmacology


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This PPT is very helpful to all the Nursing student, and understand the role of medicine in different renal disorder.

Published in: Health & Medicine
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Renal pharmacology

  2. 2. Introduction • Kidney is mainly a regulatory organ; it also has excretory function. The functional unit of the kidney is nephron. Each kidney contains about 1 million nephrons, the function of kidney are: 1. Regulatory: Acid-base, fluid and electrolyte balance. 2. Excretory: Excretion of nitrogenous waste products. 3. Hormonal: Activation of vitamin D, production of renin and erythropoietin.
  3. 3. MECH ANISM OF URINE FORMATION it consist of the following steps:  Glomerular filtration  Tubular reabsorption  Active tubular secretion Urine formation begins with glomerular filtration. The volume of fluid filtered is about 180/L day of which more than 99 % gets reabsorbed in the renal tubules; urine output is about 1-1.5 L/day. After filtration, fluid traverses in the renal tubules. The tubular fluid contains Na+, K+, HCO3-, amino acids, glucose etc.
  4. 4. Proximal convoluted tubule: site-1 • Most of the filtered Na+ is actively reabsorbed; chloride is reabsorbed passively along with sodium. Carbonic anhydrase plays an important role in Na+-H+ exchange and helps in the reabsorption of HCO3-. Potassium, glucose, amino acids etc. are also reabsorbed in the PCT. Proportionately water also gets reabsorbed, so tubular fluid in the PCT remains isotonic.
  5. 5. Loop of Henle • The descending limb is miserable to Na+ and urea and highly permeable to water. • Hence fluid in the loop become hypertonic.
  6. 6. Thick ascending limb of loop of Henle site-2 • The thick ascending limb is permeable to water but highly permeable to Na+ and Cl-. • Active reabsorption of sodium and chloride occurs by Na+-K+, 2Cl- Co- transporter. This is selectively blocked by loop diuretics. • Ca2+ and Mg2+ are also reabsorbed at this site.
  7. 7. Early distal table site-3 • It is impermeable to water but sodium and chloride are reabsorbed with the helps of Na+, Cl- symporter. • This is blocked by thiazide.
  8. 8. Early distal tubule and collecting duct site-4 • Sodium is actively reabsorbed; chloride and water diffuse passively. Exchange of Na+- K+, H+ ions occur. The Na+- K+ exchange under the influence of aldosterone (aldosterone promote Na+ absorption and K+ depletion). • Absorption of fluid in the collecting duct (CD) is under the influence of ADH. In the absence of ADH, the CD becomes impermeable to water and large amount of dilute urine is excreted. Normally H+ ions present in urine convert NH3 to NH4 which is excreted.
  9. 9. Diuretics • Diuretics are drug that promote excretion of Na+ and water in urine.
  10. 10. Classification of diuretics 1. Drugs acting at proximal convoluted tubule (PCT) site-1 • Carbonic anhydrase inhibitor: Acetazolamide 2. Drugs acting at thick ascending limb of loop of Henle site-2 • Loop diuretics: furosemide, bumetadine, torsemide, ethacrynic acid. 3. Drugs acting at early distal tubule site-3 • Thiazides: chlorothiazide, hydrochlorothiazide, polythiazide. Benzthiazide. • Thiazide related diuretics: chlorthalidone, indapamide, metolazone. 4. Drug acting at late distal tubule and collecting duct site-4 • Aldosterone antagonist: spironolactone and eplerenone. • Direct inhibitor of Na+ channels: Amiloride and triamterene. 5. Drugs acting on entire nephron (main site of action in loop of Henle) • Osmotic diuretics: Manito, glycerol, isosorbide.
  11. 11. 1) Carbonic Anhydrase Inhibitors • Mechanism of action:  Both CO2 and H2O diffuse into the tubular cell where H2CO3 is formed under the influence of carbonic anhydrase. Carbonic acid dissociates into H+ and HCO3-. The H+ ions exchange with luminal Na+ . In the lumen the H+ ions combine with HCO3- and form H2CO3.  The H2CO3 dissociates into CO2 and H2O with the help of carbonic anhydrase, which is present near the brush border. The main site of action of acetazolamide is proximal tubule.; it also acts in the collecting duct. Acetazolamide by inhibiting carbonic anhydrase enzyme, prevents the formation of H+ ions. Na+- H+ exchange is prevented. Na+ is excreted along with HCO3- in urine.  In the DCT, increase Na+, K+ exchange leads to loss of K+. The net effect is loss of Na+, K+ and HCO3- in urine resulting in alkaline urien
  12. 12. Uses of CAI • Acetazolamide is not used as diuretic because of its low efficacy. It is used in the following condition: 1. Glaucoma: CAI decrease the intraocular pressure by reducing the formation of aqueous humor. 2. To alkalinize urine in acidic drug poisoning. 3. Acute mountain sickness: The beneficial effect to decrease the PH and formation of cerebrospinal fluid. 4. Miscellaneous: as an adjuvant in epilepsy, periodic paralysis, treatment of metabolic alkalosis resulting from use of diuretics in congestive heart failure.
  13. 13. Adverse effect of CAI • Hypersensitivity reaction • Skin rashes • Fever • Drowsiness • Paresthesia • Hypokalemia • Metabolic acidosis • Headache • Renal stone
  14. 14. Contraindication of CAI • LIVER DISEASE: Hepatic coma may be precipitated in patient with cirrhosis due to decreased excretion of NH3 in alkaline urine. • COPD: Worsening of metabolic acidosis is seen in patient with chronic obstructive pulmonary disease.
  15. 15. 2) Loop Diuretics (high ceiling diuretics) • MOA: sites of action is the ascending limb of loop of Henle. Loop diuretics binds to luminal side of Na+, K+- 2Cl- cotransporter and block its function. There is an increased excretion of Na+ and Cl- in urine. The tubular fluid reaching the DCT contains large amount of Na+. Hence more Na+ exchanges with K+ loss. Furosemide has weak carbonic anhydrase inhibiting activity hence increase the excretion of HCO3- and PO34-. They also increase the excretion of Ca2+ and Mg2+. Loop diuretics are called high-celling diuretics because they are highly efficacious – have maximal Na+ excreting capacity when compared to thiazides and potassium sparing diuretics. • The loop diuretics are rapidly absorbed through the gastrointestinal tract. Furosemide and bumetadine are administered by oral I.V and I.M. Routes. Torsemide is given orally. Furosemide has a rapid onset of action within 2-5 min of I.V; 10-20 min after I.M and 30-40 min after oral administration. The duration of action of furosemide is short (2-4) hours.
  16. 16. Therapeutic uses of furosemide • During the initial stage of renal, hepatic and cardio oedema, loop diuretics are preferred. • Intravenous furosemide is used in hypercalcemia as it promotes the excretion of ca2+ in urine. • Acute pulmonary oedema- loop diuretics act in the following way IV furosemide increase PG synthesis increase renal blood flow increase systemic venous capacitance results in shift of blood from central pulmonary to systemic vessels, decrease left ventricular pressure Produce quick relief from pulmonary oedema
  17. 17. Cont.. • Loop diuretics may be used in cerebral oedema but IV Manitol is the preferred drug. • Hypertension: loop diuretics can be used in hypertensions associated with CCF/ renal failure and in hypertensive emergencies. Furosemide is not preferred in uncomplicated primary hypertension because of short duration of action. • Loop diuretics can be used in the mild hyperkalemia.
  18. 18. Adverse effect 1. Electrolyte disturbances: are the common adverse effects seen with loop diuretics. They are: A. Hypokalemia: it is the most important adverse effect. It can caused fatigue, muscular weakness and cardiac arrhythmia, especially in patients taking digitalis. It can be treated by K+ supplementation. B. Hyponatremia: overuse of loop diuretics can cause depletion of sodium from the body. C. Hypokalemic metabolic alkalosis: as less K+ is available for exchange with Na+ in the DCT, more Na+/ H+ exchange takes place leading to H+ loss, thus causing hypokalemic alkalosis. D. Hypocalcaemia and hypomagnesaemia: These are due to the increased urinary excretion of Ca2+ and Mg2+ respectively.
  19. 19. Cont.. 2. The metabolism disturbances include: Hyperglycemia: This can occur due to decreased insulin secretion. Hyperuricaemia: these drug decrease the renal excretion of uric acid and may precipitate attacks of gout. Hyperlipidemia: they increase plasma triglycerides and LDL cholesterol levels. 3. Ototoxicity: manifest as deafness, vertigo and tinnitus. The symptoms are usually reversible on stoppage of therapy. The risk of ototoxicity is increased in patients with renal impairment and in those receiving other ototoxic drugs like cyclosporine, aminoglycosides etc. 4. Hypersensitivity: skin rashes, eosinophilia, photosensitivity etc. may occur.
  20. 20. Drug interaction • Furosemide × digoxin • Furosemide × aminoglycoside • Furosemide × NSAIDs • Furosemide × lithium • Furosemide × amiloride
  21. 21. 3) Thiazide- like diuretics • Chlorthalidone is a frequently used thiazide like diuretic in hypertension as it has a long duration of action. Indapamide and metolazone are more potent, longer acting and produce fewer adverse effects than thiazides. They are used in hypertension.
  22. 22. Mechanism of action • Thiazides inhibits Na+- Cl- symport in early distal tubule and increase Na+ and Cl- excretion. There is increased delivery of Na+ to the late distal tubule, hence there is increased exchange of Na+- K+ which results in K+ loss. Some of thiazide also have weak carbonic anhydrase inhibitory action and increase HCO3- loss. Therefore there is a net loss of Na+, K+, Cl-, Hco3- in urine. Unlike loop diuretics, thiazides decrease Ca2+ excretion. • Pharmacokinetics: Thiazide are administered orally. They have long duration and are excreted in urine.
  23. 23. Uses 1. Hypertension: thiazides are used in the treatment of essential hypertension. 2. Heart failure: thiazides are used for mild to moderate cases of heart failure. 3. Hypercalcemia: thiazides are used in calcium nephrolithiasis as they reduce the urinary excretion of calcium. 4. Diabetes insipidus
  24. 24. Adverse effects 1. Thiazides cause electrolyte disturbance which include hypokalemia, Hyponatremia, metabolic alkalosis, hypomagnesaemia and hypercalcemia. 2. The metabolic disturbances are similar to that of loop diuretics – hyperglycemia, hyperlipidemia and hyperuricaemia. 3. They may cause impotence, hence thiazides are not the preferred antihypertensive in young males. 4. Others: skin rashes, photosensitivity, gastrointestinal disturbances like nausea, vomiting, diarrhea etc. can occur.
  25. 25. 4) Potassium Sparing Diuretics Aldosterone Antagonist • Spironolactone: it is an aldosterone antagonist. It is a synthetic steroid and structurally related to aldosterone. • Aldosterone enters the cell and binds to specific mineral corticoid receptor (MR) in the cytoplasm of late distal tubule and collecting duct cells. The hormone receptor complex enters the cell nucleus, where it induces synthesis of aldosterone induced proteins (AIP). The net effect of AIP is to retain sodium and excrete potassium. • Spironolactone competitively blocks the mineral corticoid receptors and prevents the formation of AIPs. Therefore, spironolactone promotes Na+ excretion and K+ excretion. Spironolactone is most effective when circulating aldosterone levels are high. It also increase Ca2+ excretion.
  26. 26. Pharmacokinetics • Spironolactone is administered orally, gets partly absorbed and is highly bound to plasma proteins; extensively metabolized in liver and forms active metabolite, canrenone, which has long plasma half- life.
  27. 27. Uses • In edematous condition associated with secondary hyperaldosteronism. (congestive cardiac failure, hepatic cirrhosis and nephrotic syndrome). • Spironolactone is often used with thiazides / loop diuretics to compensate K+ loss. • Resistant hypertension due to primary hyperaldosteronism. (conn’s syndrome)
  28. 28. Drug interaction • ACE inhibitors × spironolactone • Eplerenone an aldosterone antagonist is more selective for mineralocorticoid receptor. Hence it is less likely to cause Gynacomastia.
  29. 29. 5) Osmotic diuretics • These include Mannitol, glycerol and isosorbide. Manitol: it is administered intravenously. It is neither metabolized in the body nor reabsorbed from the renal tubules. It is pharmacologically inert and is freely filtered at the glomerulus. Mechanism of action: osmotic diuretics draw water from tissues by osmotic action. This results in increased excretion of water and electrolytes. Their site of action is in the loop of Henle and proximal tubule.
  30. 30. Mechanism of action 20% Mannitol on IV administration Increase osmolality of plasma Shift of Fluid from the ICF to ECF Expansion of ECF Volume Increase glomerular filtration rate; Mannitol is freely filtered at the glomerulus Increase osmolality of tubular fluid Inhibit reabsorption of water The net effect is: Increase in urine volume - Increased urinary excretion of Na+, K+, Ca2+, Mg2+, HCO3- and PO43-
  31. 31. Uses of osmotic diuretics 1. Mannitol is used to prevent acute renal shutdown in shock, cardiovascular surgery, hemolytic transfusion etc. 2. Mannitol is used to reduce the elevated intracranial tension (ICT) following head injury or tumor. It draws fluid from the brain into the circulation by osmotic effect, thus lowering ICT. 3. Mannitol 20% (IV), glycerol 50% (oral) and isosorbide (oral) are used to reduce the elevated IOP in acute congestive glaucoma. They draw fluid from the eye by osmotic effect, in to blood – IOP is decreased.
  32. 32. Adverse effects • Too rapid and too much quantity of iv Manitol can cause marked expansion of ECF volume which can lead to pulmonary oedema. • Headache, nausea and vomiting may occur. • Glycerol can cause hyperglycemia.
  33. 33. Contraindication • Manitol is contraindicated in CCF and pulmonary oedema because it expands ECF volume by increasing the osmolality of extracellular compartment and increase the load on heart, thus aggravating the above condition. Other contraindication are chronic oedema, anuric renal disease and active intracranial bleeding.
  34. 34. Antidiuretics • Vasopressin: it is peptide hormone synthesized in the supraoptic and paraventricular nuclei of the hypothalamus and stored in the posterior pituitary.
  35. 35. Vasopressin analogues • Desmopresin: it is a selective V2 receptors agonists and it more potent than vasopressin as an antidiuretic. It has negligible vasoconstrictor action. • Lypressin: it act both V1 and V2 receptors. It is less potent but longer acting than vasopressin. It is administered parentrally. • Telipressin: it is prodrug of vasopressin with selective V1 action. It is administered intravenously. • Felypressin: it is mainly used for its vasoconstrictor (V1) action along with local anesthetics to prolong their duration of action.
  36. 36. Uses of vasopressin analogues 1. Due to V1 receptor-mediated actions: - For emergency control of bleeding esophageal varices: Telipressin is preferred over vasopressin because it is safer. It control bleeding by constricting of the mesenteric blood vessels –decrease blood to the portal vessels – reduce pressure in the varices – stops bleeding. - vasopressin may be used before abdominal radiography to expel intestinal gas.
  37. 37. Cont.. 2. Due to V2 receptor- mediated actions: - Central diabetes insipidus- desmopresin is the drug of choice. - Heamohopila and von Willebrand's disease- decompression, administered intravenously, controls bleeding by increasing factors VIII and von Willebrand's factors. - Primary nocturnal enuresis: administration of desmopresin at bedtime reduces nocturnal urine volume.
  38. 38. Adverse effect • Nausea, vomiting, diarrhea, bleaching and abdominal cramps. • Backache is due to uterine contraction. • Vasopressin can precipitate an attack of angina by constricting coronary blood vessels. (V1 mediated). Hence, it is contraindicated in patients with hypertension and coronary artery disease. • Intranasal administration of desmopresin may cause local irritation and ulceration. • Fluid retention and Hyponatremia can occur (V1 mediated). It should not be given to patients with acute renal failure.
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