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Overview
Anatomy and physiology of the renal system How diuretics work Adverse impact on Extracellular fluid Classification of diuretics High-ceiling (Loop) diuretics Thiazides and related diuretics Potassium sparing diuretics Osmotic diuretics
The Kidneys
Concept of Remember
The composition of blood is determined not so much by what the mouth takes in but by what the kidneys keep (Porth)
Kidney-Reabsorption
Movement of substances from the renal blood tubules into the blood vessels (vasculature)
Renal Secretion
Movement of substances from the renal vasculature (blood vessels) into the renal tubules
Diuretics
Drugs that increase the output of urine but not the reason for giving diuretics Two major applications for use of diuretics include: (1) the treatment of hypertension; (2) mobilization of edematous fluids associated with heart failure, cirrhosis, and kidney disease Also used to prevent renal failure
Cells and large molecules such as lipids, proteins, remain behind in the blood The most prevalent constituents of the filtrate are sodium ions and chloride ions Bicarbonate ions and potassium ions are also present, but in smaller amounts
Filtration
Is a non-selective process, and cannot regulate the composition of urine Reabsorption and secretion are the primary determinants of what the urine ultimately contains
Reabsorption
Greater than 99% of the water, electrolytes, and nutrients that are filtered at the glomerulus undergo reabsorption This conserves valuable constituents of the filtrate allowing wastes to undergo excretion Reabsorption of solutes (amino acids, electrolytes, glucose) takes place by way of active transport
Reabsorption
Water then follows passively along the osmotic gradient created by solute reuptake It is primarily through interfering with reabsorption that diuretics produce their effects
Kidney at Work
Loop of Henle
The descending limb of the Loop of Henle is freely permeable to water As tubular urine moves down the loop water is drawn from the loop into the interstitial space In the ascending loop of Henle, 20% of filtered sodium and chloride is reabsorbed
Aldosterone
The principal mineralcorticoid of the adrenal cortex, stimulates reabsorption of sodium from the distal nephron. It also causes potassium secretion
Classification of Diuretics
High ceiling (loop) diuretics e.g furosemide Thiazide diuretics e.g., hydrochlorothiazide Osmotic diuretics e.g., mannitol Potassium-sparing diuretics (can be divided into aldosterone antagonists (spironolactone) and nonaldosterone antagonists (triamterene)
Pharmacokinetics of Furosemide
Administered orally, IV or IM Oral administration- diuresis begins in 60 minutes and persists for 8 hours Oral therapy is used when rapid onset of effects is not required IV administration, effects begin in 5 minutes and last for 2 hours. Used in critical situations
Therapeutic Uses
Reserved for situations that require rapid or massive mobilization of fluid
Furosemide
Conditions that justify use of furosemide include pulmonary edema associated with congestive heart failure; edema of hepatic, cardiac, or renal origin for which less efficacious diuretics are ineffective Hypertension that cannot be controlled with other diuretics
furosemide
Useful in patients with severe renal impairment as this drug can promote diuresis when renal blood flow and glomerular filtration are low
Gentamycin
Parenteral Furosemide
Available for injection and IM administration IV administration should be done slowly (over 1 to 2 minutes) For high-dose therapy, furosemide can be administered by continuous infusion at a rate of 4mg/min
Mechanism of Action
Blocks the reabsorption of sodium and chloride in the early segment of the distal convoluted tubule. Retention of sodium and chloride in the nephrons causes water to be retained as well and an increased urine flow Ability of thiazides to promote diureses is dependent on adequate kidney funciton
Thiazides
Not effective when glomerular filtration rate is low Cannot be used in patients with severe renal impairment
Pharmocokinetics of Thiazides
Diuresis begins about 2 hours after oral administration Effects peak within 4 to 6 hours and may persist for up to 12 hours Excreted unchanged in the urine
Contraindicated in pregnancy and lactation Enters breast milk and can be hazardous to the nursing infant
Drug Interactions
Digoxin Antihypertensive drugs NSAIDs Can be combined with ototoxic drugs without an increased risk of hearing loss
Spironolactone-Aldactone
Blocks the action of aldosterone( promoting sodium uptake in exchange for potassium secretion ) in the distal nephron. It brings about the retention of potassium and the excretion of sodium Diuresis is very scanty Effects of spironalactone are delayed, taking up to 48 hours to develop
TRIAMENTERENE
Acts more quickly than spironolactone as it is a direct inhibitor of the exchange mechanism Like spironolactone, it is unable to cause more than a scant diuresis Used to treat hypertension and edema
Amiloride
Actions similar to triamterene Major adverse effect is hyperkalemia
Osmotic Diuretics
Four properties of an osmotic diuretic: It is freely filtered at the glomerulus It undergoes minimal reabsorption It is not metabolized to a significant degree It is physiologically inert- has no direct effect on the biochemistry or physiology of cells
Osmotic Diuretics
Mannitol Urea Glycerine isosorbide