Diuretics PDF

DIURETICS Prof. Olayinka. O. Ogunleye FMCP (Nig), FAMedS, FBPhS Introduction Aldosterone – stimulates Na+ reabsorption in the distal tubule and increase K+ and H+ secretion. – Induces synthesis of the Na+/K+-ATPase in the basolateral membrane and Na+ channels in the luminal me...

DIURETICS Prof. Olayinka. O. Ogunleye FMCP (Nig), FAMedS, FBPhS Introduction Aldosterone – stimulates Na+ reabsorption in the distal tubule and increase K+ and H+ secretion. – Induces synthesis of the Na+/K+-ATPase in the basolateral membrane and Na+ channels in the luminal membrane. Cell surface aldosterone receptors may mediate a more rapid increase in Na+ channel permeability. Introduction Diuretics increase the Na+ load in the distal tubules and → increase K+ secretion and excretion (except for the K+-sparing agents). Vasopressin (ADH) released from the Post Pit. – Increase the number of H2O channels in the collecting ducts → passive reabsorption of H2O. In cranial diabetes insipidus, absence of ADH → large vols of hypotonic urine: treated with vasopressin (or desmopressin, a longer acting analogue)  Introduction These are drugs which cause net loss of Na+ and water in urine – increase the excretion of NaCl and H2O, normally controlled by aldosterone and vasopressin, respectively. Most work by decreasing the reabsorption of electrolytes by the tubules. Accompanied by an increase in H2O excretion so that osmotic balance is maintained. Are among the most widely prescribed drugs worldwide  Classification High Efficacy diuretics – Inhibitors of Na+-K+-2Cl- cotransport 1. Sulphamoyl derivatives : Furosemide, Bumetanide 2. Phenoxyacetic acid derivative: Ethacrynic acid 3. Organomercurials: Mersalyl  Medium Efficacy diuretics – Inhibitors of Na+-Cl- symport 1. Benzothiadiazine (Thiazides) : Chlorothiazide, Hydrochlorothiazide, Bendroflumethiazide, Hydroflumethiazide, Clopamide 2. Thiazide like compd: Indapamide, Xipamide, Metolazone  Weak or Adjunctive diuretics 1. Carbonic anhydrase inhibitors: Acetazolamide, Ethoxzolamide 2. Potassium sparing diuretics I. Aldosterone antagonist:Spironolactone II. Directly acting ( Inhibitors of renal epithelia Na channel) : Triamterene, Amiloride, 3. Xanthines:Theophylline 4. Osmotic diuretics: Mannitol, Isosorbide, Glycereol 5. Acidifying or Alkalinizing salts: Ammonium chloride, Potassium citrate, Potassium acetate  High Ceiling(Loop) Diuretics Natriuretic effects much greater than that of other classes Diuretic response increases with increasing doses : may produce up to 10L of urine/day Active in patients with severe renal failure Major site of action is the thick ascending loop of Henle Inhibits Na+-K+-2Cl- cotransport  Inhibit NaCl reabsorption in the thick ascending loop of Henle. This segment has a high binding capacity for absorbing NaCl → diuresis produced at this site is much greater than at other sites. – Act on the luminal membrane where they inhibit the cotransport of Na+/K+/2Cl-. – [Recall that Na+ is actively transported out of the cells into the interstitium by a Na+/K+-ATPase- dependent pump at the basolateral membrane].  Abolishes the cortico-medullary osmotic gradient and blocks the positive and negative free water clearance Increase potassium excretion Transient increase in renal blood flow and redistribution from outer to mid cortical zone Rapidly absorbed orally with about 60% bioavailability  Low lipid solubility and highly bound to plasma proteins Mainly excreted unchanged by the glomerular filtration as well as tubular secretion Plasma half life is about 1-2 hours but prolonged in hepatic, renal disease  Uses of Loop Diuretics – Edema – Acute pulmonary edema ( acute LV failure) – Cerbral edema – Forced diuresis – Hypertension – In blood transfusion Adverse Effects of Loop Diuretics Hyponatraemia Hypotension Hypovolemia Hypokalemia – may be unimportant unless there are additional risk factors for arrhythmia (e.g., digoxin). Can cause severe electrolyte imbalance and dehydration. Ca2+ and Mg2+ excretion often increased -> hypomagnesmia may occur. Over-enthusiastic use (high doses, i.v.) can cause deafness, which may not be reversible.  Thiazide and Related Diuretics Primary site of action of these agents is the cortical diluting segment or the early Distal Tubules Inhibits Na+-Cl- symport at the luminal membrane Do not affect the cortico-medullary osmotic gradient indicating that they lack action at the medullary thick ascending loop of henle Decrease positive free water clearance( in the absence of ADH) but do not affect the negative free water balance ( in the presence of ADH) Thiazide -MOA Act mainly on the distal segments of tubules, where they inhibit NaCl reabsorption by binding to the symporter responsible for the electroneutral cotransport of Na+/Cl-. – → incr excretion of Na+, Cl-, and H2O. The increased Na+ in the distal tubule stimulates Na+ exchange with K+ and H+, increasing their excretion and → hypokalemia and metabolic acidosis.  By reducing blood volume, as also intra-renal haemodynamic changes, they tend to reduce GFR – This is one reason they are ineffective in low GFR All thiazides and related drugs are well absorbed orally Administered only by oral route Onset of action within 1 hour  Little hepatic metabolism and are excreted as such More lipid soluble forms have larger volume of distribution, lower rate of hepatic clearance, tubular re-absorption and hence prolonged effect.  Uses of the Thiazide/Related Compounds – Edema – Hypertension – Diabetes Insipidus – Hypercalciuria Adverse Effects of Thiazide Diuretics Hypokalemia may precipitate cardiac arrhythmias, especially in patients on digitalis. – Can be prevented by giving K supplements, or by combining therapy with K-sparing drugs. Hyperuricemia: Serum Uric acid is often increased because thiazides are secreted by the organic acid secretory system in the tubules and compete for uric acid secretion. This may ppt gout. Glucose tolerance may be impaired Lipids: Thiazides increase Serum Cholesterol at least during the 1st 6 months of administration, but the significance of this is uncertain.  Drug Interactions – Thiazides potentiates all other antihypertensives – Hypokalemia induced by diuretics enhances digitalis toxicity – High ceiling diuretics enhances nephrotoxicity of aminoglycosides and the first generation cephalosporins – Indomethacin and most other NSAIDs diminish the action of high ceiling diuretics – Probenecid competitively inhibit tubular secretion of furosemide and thiazide. – Diuretics diminish the uricosuric action of probenecid Potassium Sparing Diuretics (KSDs) Weak when used alone. Given to retain K+. Often given with thiazides and Loop Diuretics to prevent hypokalemia. Act on aldosterone-responsive segments of the distal nephron, where K+ homeostasis is controlled. Aldosterone stimulates Na+ reabsorption → negative electric charge in the lumen, which drives K+ and H+ into the lumen (and hence their excretion).  The KSDs decrease Na+ reabsorption by either antagonizing aldosterone (spironolactone) or blocking Na+ channels (amiloride, triamterene). This causes the electrical charge across the tubular epithelium to fall, decreasing the driving force for K+ secretion. These drugs may cause severe hypokalemia, especially if renal impairment exists. Hypokalemia may also occur in the presence of ACEIs (e.g., catopril), because these drugs decrease aldosterone secretion (and therefore K+ excretion).  Competitively blocks the binding of aldosterone to its cytoplasmic receptor → increase Na+ (Cl- and H2O) excretion and decrease the ‘electrically coupled’ K+ secretion. Weak diuretic (only ~2 % of the total Na+ reabsorption is under aldosterone control). Used mainly in liver disease with ascites, Conn’s syndrome (1° hyperaldosteronism) and severe heart failure. KSDs (cont’d) – Amiloride and Triamterene Decrease the luminal membrane Na+ permeability in the distal nephron by blocking Na+ channels on a 1:1 basis. This increases Na+ (Cl- and H2O) excretion and decreases K+ excretion.  Carbonic Anhydrase Inhibitors Carbonic anhydrase is an enzyme the catalysis the reversible reaction between water, carbon dioxide and bicarbonate. Therefore functions in in CO2 and HCO3- transport and H+ secretion The enzyme is present in renal tubular cells, gastric mucosa, exocrine pancreas, ciliary body in the eyes, brain and RBC in gross excess  Acetazolamide This is like the prototype of this group of compounds A sulfonamide derivative Non-Competatively but reversibly inhibits CAse in proximal tubule cells resulting in slowing of hydration of CO2, decreasing availability of H+ to exchange with luminal Na+ through the Na+-H+ antiporter Net effect is inhibition of HCO3- reabsorbtion in proximal tubules with prompt but mild diuresis occurring  Urine produced is alkaline and rich in HCO3- which is matched by both Na+ and K+ Continued use depletes the body of HCO3- and causes acidosis Extra renal actions of acetazolamide includes 1. Lowering of intraocular tension due to decreased formation of aqueous humour 2. Decreased gastric secretion of HCl and pancreatic NaHCO3 3. Raised CO2 level in the brain and lowering of pH- raising seizure threshold  Acetazolamide is well absorbed orally and excreted unchanged in urine Duration of action of a single dose is 8-12 hours  Uses No longer used as a diuretic – Self limiting action – Production of acidosis and hypokalemia Glaucoma Urinary alkalization Epilepsy Periodic paralysis Acute mountain sickness  Adverse effects – Acidosis – Hypokalemia – Drowsiness – Paraesthesia – Fatigue – Abdominal discomfort – Hypersensitivity reactions – Acidosis  Contraindications – Liver disease  Osmotic diuresis Mannitol – A non electrolyte of low molecular weight – Pharmacologically inert – Can be given in large quantities – Not metabolised in the body  Limits tubular water and electrolyte reabsorbtion in a number of ways – Expands extracellular fluid volume- increase GFR and inhibits renin release – Increase renal blood flow, reducing medullary hypertonicity and passive salt re-absorption is reduces – Retains water iso-osmotically in proximal tubules – Inhibits transport process in the thick ascending loop of henle  Uses – To maintain GFR and urine flow in imminent renal failure – Forced diuresis – Intracranial pressure reduction – Intraoccular tension reduction – To counteract low osmolality of plasma or ECF due to rapid heamodialysis or peritoneal dialysis  Contraindications – Acute tubular necrosis – Anuria – Pulmonary edema – Acute LVF  S/E – Headache – Nausea – Vomiting Nephron anatomy and the site of action of Diuretics PCT: proximal convoluted tubule, SDL short descending limb, MTAL/CTAL: medullary/cortical thick ascending limb, DCT: distal convoluted tubule, CNT: connecting tubule, CCD: cortical collecting duct, OMCD/IMCD: outer/inner- medullary collecting duct ATL: Ascending Thin Limb TDL: Thick Descending Limb