Vilasinee Hirunpanich B.Pharm(Hon), M.Sc In Pharm (Pharmacology)

Outline of diuretic drugs  Basic knowledge in anatomy and physiology  Classification of diuretics

Classification of Diuretics  Loop Diuretics  Thiazides Diuretics  K + -sparing diuretics  Osmotic Diuretics  Carbonic anhydrase inhibitors

1. Loop diuretics (high ceiling diuretics)  block Na + -K + -2Cl - cotransport in the thick ascending limb of the loop of Henle  high efficacy: 25% of filtrated solute is reabsorbed

Structure of loop diuretics

Mechanism of action of Loop of Henle

pharmacokinetic  Rapidly absorbed  Eliminate by renal secretion  Torsemide (1h) is more rapidly than furosemide (Lasix  ) (2-3 h)  Duration 2-3 h (furosemide), 3-4 h(torsemide)

Adverse effects 1. Fluid and electrolytes imbalance  Hyponatremia, Hypokalemia and hypomagnesia 2. H + lossmetabolic alkalosis 3. Ototoxicity  ethacrynic most often

Adverse effects (cont) 4. Hyperuricemia 5. Hyperglycemia 6. Hypersensitivity to sulfonamide  skin rash 7. Others: dehydration

 Ototoxic drugs; aminoglycoside  digitalis glycoside  NSAIDs  probenecid  Litium  anticoagulant Drug interaction

Clinical indications 1. Hypertension and CHF 2. Acute pulmonary edema 3. Other edematous conditions 3. Mild hyperkalemia (simultaneous NaCl and water) 4. I -, Br - intoxication

2.Thiazide Diuretics

Thiazide diuretics  Sulfonamide and benzothiadiazide (thiazide) derivatives –Hydrochlorothiazide (HCTZ), indapamide, chlorthalidone, metolazone

Mechanism of action of thiazide diuretics

Mechanism of actions  Increase Na +, Cl -, K +, Mg 2+ in urine ….water retention  Some drug has vasodilator effect such as indapamide (Natrilix  )

Pharmacokinetic  Chlorothiazide is less lipid soluble and must given in large dose  Indapamide is excreted primarily by the billiary system

Adverse effects 1.Fluid and electrolytes imbalance Hypokalemia Hyponatremia Hypercalcemia 2. hyperglycemia due to impaired pancreatic release of insulin 3.hyperlipidemia 4. allergic reaction 5. Other: weakness, fatigability

Drug interaction Decrease the effect of  anticoagulant  uricosuric agent  sulfonylurea  insulin Increase the effect of  digitalis glycoside  lithium Decrease the effect of thiazide  NSAIDs  bile acid sequestering  probencid

Clinical indications  Hypertension, CHF  hepatic cirrhosis  nephrolithiasis due to idiopathic hypercalcinuria  nephrogenic diabetes insipidus  Br - intoxicity

3. K + -sparing diuretics

K + sparing diuretics 1. Aldosterone antagonists 2. Inhibitor of renal epithelium Na + channel

Aldosterone antagonist  Structure similar to aldosterone hormone Ex.  spironolactone (synthesis steriod),  eplerenone (spironolactone analog)

spironolactone  specific antagonist prevent protein synthesis that required for Na + and K + transport  increase Na + excretion and preserve of K +  Potentcy is low and depend on aldosterone level

pharmacokinetic Spironolactone  Onset and duration of action are determined by the kinetic of aldosterone response in target tissue.  Slow onset (48 hr)  Canrenone is the active metabolized which has very long t 12. than parent drug.

Adverse effects  hyperkalemia …..life threatening  Endocrine effects -gynecomastia -hirsutism -deepening voice - decrease libido

 Pts using salicylate because inhibiting canrenone  K + administration  coadministration with thiazide or loop diuretic for edema (additive effect)  hyperaldosteronism contraindication Clinical use

2. Inhibitor of renal epithelium Na + channel  Triamterene  amiloride

 late distal tubules and collecting ducts  block Na+ channel in the luminal membrane  increase NaCl excretion and decrease K+ excretion Mechanism of action of K+- sparing diuretic

Adverse effect  anemia: triamterene, folic antagonist  kidney stone (triamterene is poorly soluble)  ARF (acute renal failure) (combination of triamterene and indomethacin has been reported )  life-threatening: hyperkalemia

contraindication  Renal failure  other K + sparing diuretic  ACEI  K + supplement  NSIADs

 Co administration with other diuretic (additive effect)  prevent depletion of intracellular K + store Clinical Use

Osmotic diuretics  Properties 1. Freely filtered at the glomerulus 2. No reabsorption at the renal tubule 3. No pharmacological effects  Glycerine, Isosorbide, Mannitol, Urea  site of action: Proximal tubule and descending limb of Henle ’ s loop

Structure of osmotic diuretics

Mechanism of action  Limit water reabsorption  act as increase urine volume.  increase renal blood flow

Pharmacokinetic  Poorly absorbed so they must be given parenterally  Mannitol is excreted by glomerular filtration within min

Adverse effects 1. Extracellular volume expansion  Rapidly distributed in the extracellular compartment and extract water from the intracellular compartment 2. Dehydration 3. Nausea, vomiting, headache

Clinical Indications 1. To increase urine volume 2. Reduction of intracranial and intraocular pressure extract water from the eye and brain Glycerine: control intraocular pressure, pre/post operative ocular surgery Mannitol, urea: reduce cerebral edema before/after neuro-surgery

5. Carbonic anhydrase inhibitors  Inhibit carbonic anhydrase enzyme at proximal tubule  SO 2 NH 2 (sulfonamide) group is essential for activity.  Acetazolamide (Diamox  ), dichlorophenamide, ethoxalamide, methazolamide

Structure of carbonic anhydrase inhibitors

Mechanism of action of carbonic anhydrase inhibitors

1. increase the excretion of HCO 3 - (Urine alkalinization, pH 8)  Increase Na +, K +, secretion 2. Metabolic acidosis 3. eye; decrease formation of aqueous humor 4. Paresthesia, Drowsiness, Somnolence

Pharmacokinetic  Well absorbed after oral administration  The effect of increased of HCO 3 - is apparent within 30 min.  Maximal effect within 2 h  Persist for 12 h after single dose  Excrete by tubular secretion

Adverse effects 1. Hypersensitivity  sulfonamide derivative (fever, rashes, bone marrow suppression) 2. Renal stone  Ca 2+ salt are relatively insoluble at alkaline pH. 3. Metabolic acidosis and urine alkalinization 4. Renal potassium wasting 5. Others: drowsiness, paresthesia

Clinical indications 1. Glaucoma (decrease intraocular pressure)  Dorzolamide, brinzolamide (topically use) 2. Urinary alkalinization  increase the secretion of uric acid, weak acid drugs(aspirin) 3. Metabolic acidosis 4. Acute mountain sickness (24 h before ascent)

 Loop diuretic& thiazide (different position)  K + sparing diuretic& loop diuretic or thiazide (decrease ADR)  Moduretic  (amiloride + HCTZ)  Dyazide  (triamterene+HCTZ) Diuretic combination