Diuretics

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

A & P of Renal System

More than 99% of the water , electrolytes, and nutrients that are filtered at the glomerulus undergo reabsorption. Most diuretics block active reabsorption of sodium and chloride, which prevents passive reabsorption of water. The amount of diuresis that a drug produces is directly related to the amount of sodium and chloride reabsorption that it blocks.

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)

Overview of effect of diuretics in the kidney

Drugs that act early in the nephron are in a position to block the greatest amount of solute reabsorption; hence, these agents produce the greatest diuresis

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

The Three Basic Renal Processes

1. Filtration. Occurs at the glomerulus and is the first step in urine formation. All small molecules such as electrolytes, amino acids, glucose, drugs, metabolic wastes that are present in the plasma undergo filtration

 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

Active Tubular Secretion

The kidney has two kinds of pumps for active secretion The pumps transport compounds from the plasma into the lumen of the nephron One pump is selective for organic acids and the other transports organic bases The pumps for active secretion are located in the proximal convoluted tubules

Sites for Reabsorption- Proximal Convoluted Tubules

Has a high reabsorptive capacity. A large fraction (65%) of filtered sodium and chloride is reabsorbed at the PCT. All filtered bicarbonate and potassium are reabsorbed in the PCT. Since solutes and water are reabsorbed to an equal extent, the tubular urine remains isotonic.

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

Distal Convoluted Tubule (early segment)

10% of filtered sodium and chloride is reabsorbed here

Distal convoluted tubule and collecting duct

Here there is the exchange of sodium for potassium which is under the influence of aldosterone The determination of the final concentration of the urine and is regulated by antidiuretic hormone (ADH)

Aldosterone
The principal mineralcorticoid of the adrenal cortex, stimulates reabsorption of sodium from the distal nephron. It also causes potassium secretion

How Diuretics Work

Most diuretics share the same basic mechanism of action: blockade of sodium and chloride reabsorption By blocking reabsorption of prominent solutes, diuretics create osmotic pressure within the nephron that prevents the passive reabsorption of water

How diuretics work

They cause water and solutes to be retained by the nephron, and promote the excretion of both. The increase in urine flow that a diuretic produces is directly related to the amount of sodium and chloride reabsorption that is blocked.

How diuretics work

Diuretics with site of actions early in the nephron have the opportunity to block the greatest amount of solute reabsorption

Adverse Impact on Extracellular Fluid

Diuretics can cause hypovolemia Acid base imbalance Disturbance of electrolyte levels

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)

High Ceiling Diuretics

Furosemide How it works: acts in the thick segment of the ascending loop of Henle to block reabsorption of sodium and chloride. By so doing, furosemide prevents passive reabsorption of water Individual can have profound diuresis

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

Adverse Effects of high ceiling diuretics

Hyponatremia, hypochloremia, dehydration Because of excessive loss Observe for signs of dehydration Dehydration can promote thrombosis and embolism Hypotension due to loss of fluid volume and relaxation of venous smooth muscle which reduces venous return to the heart

Other Adverse Effects of Loop Diuretics

Hyperglycemia: inhibition of insulin release. When furosemide is taken by a client with diabetes, the client should be diligent about monitoring blood glucose levels Hyperuricemia: elevation of plasma uric acid content is a frequent side effect of treatment

Use of furosemide in pregnancy

Maternal death, abortion, fetal resorption may occur

Dont use it!!!!!!!

Furosemide (other adverse effects)

Reduced HDLs and raises LDLs and triglycerides High ceiling diuretics reduce the risk of coronary mortality by 25% Increases urinary excretion of magnesiumcomplaints of muscle weakness, twitching, dysrhythmias Increases urinary excretion of calcium

Adverse effect of high ceiling diuretics

Hypokalemia- potassium is lost through increased secretion into the distal nephron If serum potassium falls below 3.5 mEq/L, fatal dysrhythmias may result Client needs food high in potassium

Foods high in potassium

Dried fruits Nuts Spinach Citrus fruits Potatoes bananas

Adverse effects of high ceiling diuretics

Ototoxicity Hearing loss is transient with furosemide Hearing loss is permanent with ethacrynic acid Potential for hearing los is increased in clients taking ototoxic drugs such as aminoglycoside antibiotics

Example of an aminoglycoside antibiotics

Gentamycin

Drug interactions for high ceiling diuretics

Digoxin: used to treat heart failure and cardiac dysrhythmias. In the presence of low potassium levels, the risk of serious digoxin induced toxicity (ventricular dysrhythmias) is greatly increased To reduce the risk of toxicity, potassium levels should be monitored routinely, and when indicated a potassium supplement or potassium sparing diuretic should be given

Drug interactions for high ceiling diuretics

Ototoxic Drugs: the risk of furosemideinduced hearing loss is increased by concurrent use of other ototoxic drugs Combined use of these drugs should be avoided

Drug interactions for high ceiling diuretics

Potassium sparing diuretics: such as spironolactone, triamterene) can help counter balance the potassium wasting effects of furosemide thus reducing the risk for hypokalemia

Drug interactions for high ceiling diuretics

Lithium: used in the treatment of bipolar disorders. In the presence of low sodium levels, excretion of lithium is reduced and client at risk for lithium toxicity. May need to reduce lithium dose

Drug interactions for high ceiling diuretics

Antihypertensive agents: the hypotensive effects of furosemide add with those of other anti-hypertensive drugs Clients may need to reduce or eliminate use of other anti-hypertensive medications

High ceiling diuretics and NSAIDs

NSAIDs can attenuate the diuretic effects of furosemide By inhibiting prostaglandin synthesis, NSAIDs prevent the increase in renal blood flow, and thereby partially blunts diuretic effects

Preparations, Dosage, and Administration

Oral Furosemide available in tablets and liquids Administration late in the day can produce nocturia and should be discussed with the client

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

Other high ceiling diuretics

Ethacrynic acid (Edecrin) *** Bumetatanide (Bumex) **** Torsemide (Demadex) All are similar to furosemide in that they inhibit sodium and chloride reabsorption ***approved for hypertension but for heart failure, chronic renal disease and cirrhosis

Thiazides and Related Diuretics

Also known as benzothiadiazides Effects similar to loop diuretics Elevate plasma levels of uric acid and glucose Maximal diuresis produced by the thiazides are considerably lower than that produced by the loop diuretics Thiazides are not effective when urine flow is scant

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

Therapeutic Uses of Thiazides

Essential hypertension Edema associated with mild to moderate heart failure, cirrhosis, or renal disease

Adverse effects of Thiazides

Hyponatremia, hypochloremia, dehydration Hypokalemia

Contraindicated in pregnancy and lactation Enters breast milk and can be hazardous to the nursing infant

Other adverse effects

Hyperglycemia Hyperuricemia Increase LDL, lower HDL Hypocalcemia hypomagnesium

Drug Interactions
Digoxin Antihypertensive drugs NSAIDs Can be combined with ototoxic drugs without an increased risk of hearing loss

Potassium Sparing Diuretics

Elicit two potentially responses They produce a modest increase in urine output They produce a substantial decrease in potassium excretion Rarely used alone to promote diuresis because of their limited diuretic effects

Potassium Sparing Diuretics

Frequently used to counteract potassium loss caused by thiazide and loop diuretics

Potassium Sparing Diuretics

Categories of potassium-sparing diuretics: Aldosterone antagonists- (spiranolactone)

Nonaldosterone antagonists ( triamterene and amiloride

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

Spironolactone-Aldactone Therapeutic uses

Hypertension Edema Most commonly in combination with a thiazide or loop diuretic Can be used to block the effects of aldosterone in patients with primary hyperaldosteronism

Spironolactone- adverse effects

Hyperkalemia Benign and malignant tumors Endocrine effects because of its steroid properties

Drug interactions with spironolactone

Drugs that raise potassium levels: Must never be combined with potassium supplements or with another potassium sparing diuretic Careful when used with angiotensinconverting enzyme (ACE) inhibitors (they are known to increase potassium levels

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

Triamterene- Adverse Effects

Hyperkalemia Nausea Vomiting Leg cramps dizziness

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

Mechanism of Diuretic Action

Creates an osmotic force within the lumen of the nephron that inhibits passive reabsorption of water Degree of diuresis is directly related to the concentration of mannitol in the filtrate, the more present, the greater the diuresis

Therapeutic Uses for Osmotic Diuretics

Prophylaxis for renal failure Reduction of intracranial pressure Reduction of intraocular pressure

Adverse Effects of Osmotic Diuretics

Edema use with extreme caution in clients with heart disease, CHF, renal failure Headache, nausea, vomiting, fluid and electrolyte imbalance.