Diuretic TherapyIn Cardiovascular Disease

Saepudin, S.Si., M.Si., Apt.

• Diuretics increase the rate of urine flow and sodium excretion

• They are used to adjust the volume and/or composition of body fluids in a variety of clinical situations hypertension, heart failure, renal failure, nephrotic syndrome, and cirrhosis

Introduction • Diuretics remain important tools in

therapy for cardiovascular diseases• They are capable of reducing blood

pressure, while simultaneously decreasing the morbidity and mortality that attends the hypertensive state

• Diuretics are currently recommended as first-line therapy for the treatment of hypertension by the JNC

Individual classes of diuretics• Carbonic anhydrase inhibitors• Loop diuretics• Thiazides• Potassium-sparing diuretics• Osmotic diuretics

General mechanism• By definition, diuretics are drugs that

increase the rate of urine flow• However, clinically useful diuretics also

increase the rate of excretion of Na+ (natriuresis) and of an accompanying anion, usually Cl-

• NaCl in the body is the major determinant of extracellular fluid volume, and most clinical applications of diuretics are directed toward reducing extracellular fluid volume by decreasing total-body NaCl content

General mechanism• Although continued administration of a

diuretic causes a sustained net deficit in total-body Na+, the time course of natriuresis is finite renal compensatory mechanisms (diuretic braking )

• These mechanisms include activation of the SNS, activation of the RAA axis, decreased arterial BP, hypertrophy of renal epithelial cells, increased expression of renal epithelial transporters, and perhaps alterations in natriuretic hormones such as ANP

Nephron Structure

Renal Epithelial Cell Polarity Drives Na+ and Water Transport

Tubular Fluid

Blood

Proximal Tubule

• Na+ flows down concentration gradient

• Na/K ATPase maintains gradient• Water follows passively• 67% of Na and water reabsorption

Loop of Henle• TDL permeable to water but not Na+

• TAL impermeable to water and transports Na+

• Differences in permeabilities creates the countercurrent multiplier

• Countercurrent multiplier creates interstitial osmolar gradient

• 20% of filtered load of Na absorbed by the TAL

Distal Convoluted Tubule

• 5% of filtered load of Na+ reabsorbed• Segment mostly impermeable to water

Cortical Collecting Duct• Water permeability controlled by

antidiuretic hormone (ADH)• Driving force for water reabsorption is

created by the countercurrent multiplier• 2-3% of filtered Na+ reabsorbed here via

Na+ channels that are regulated by aldosterone

• Major site of K+ secretion

Several important principles• When a diuretic interferes with the

reabsorption of Na at any site of tubule, it results in inhibition of other renal functions related to reabsorption of Na at that site

• In other words, interference with Na reabsorption in the PT leads to increase delivery of NaCl to TAL and DT creation of free water and increase K loss

Several important principles• Diuretics act only if Na reachs their site of

action• More distally acting diuretics lose their

effectiveness if proximal sodium reabsorption is increased

• Diuretics acting at different sites or at the same site by different mechanism may be additive or sinergistic can be used to great clinical advantage

Definitions• Diuretic : substance that promotes the

excretion of urine• Natriuretic : substance that promotes the

renal excretion of sodium

Class of Diuretics• Thiazide diuretics

Thiazide Action

• Thiazides freely filtered and secreted in proximal tubule• Bind to the electroneutral NaCl cotransporter• Thiazides impair Na+ and Cl- reabsorption in the early

distal tubule: “low ceiling”

Increased K+ Excretion Due To:• Increased urine flow per se• Increased Na+-K+ exchange• Increased aldosterone release

Na+/K+ exchange in the cortical collecting duct

Whole Body Effects of Thiazides

• Increased urinary excretion of:– Na+

– Cl-

– K+

– Water– HCO3

- (dependent on structure)

• Reduced ECF volume (contraction)• Reduce blood pressure (lower CO)• Reduced GFR

Pharmacokinetics

• Oral administration - absorption poor• Diuresis within one hour• T1/2 for chlorothiazide is 1.5 hours,

chlorthalidone 44 hours

Therapeutic Uses

• Edema due to CHF (mild to moderate)• Essential hypertension• Diabetes insipidus• Hypercalciuria

Therapeutic use• Not only are thiazides usually effective when

given once daily as monotherapy also have additional benefit when combined with most antihypertensive drugs

• Typically, about 50% of patients will have a good blood pressure response to monotherapy with a low dose

• Poor responders tend to have a more marked augmentation in aldosterone concentration

Diabetes Insipidus• Thiazides: paradoxical reduction in urine volume• Mechanism: volume depletion causes decreased

GFR• Treatment of Li+ toxicity:

– Thiazides useful– Li+ reabsorption increased by thiazides. Reduce

Li dosage by 50%

Thiazide Use in Hypercalciuria - Recurrent Ca2+ Calculi

• Thiazides promote distal tubular Ca2+ reabsorption

• Prevent “excess” excretion which could form stones in the ducts of the kidney

• 50-100 mg HCT kept most patients stone free for three years of follow-up in a recent study

Thiazide Toxicity• Hypokalemia due to:

– Increased availability of Na+ for exchange at collecting duct

– Volume contraction induced aldosterone release • Hyperuricemia

– Direct competition of thiazides for urate transport– Enhanced proximal tubular reabsorption efficiency

• Hyperglycemia– Diminished insulin secretion– Related to the fall in serum K+

• Elevated plasma lipids

Class of Diuretics

Loop diuretics• More efficacious than the thiazides

greater risk of hypovolemia• For treatment of hpertension thiazides are

preferable and actually more efficacious compared with loop diuretics

Available Loop Diuretics

• Furosemide (prototype)

• Bumetanide• Torsemide• Ethacrynic acid

Molecular Mechanism of Action

• Enter proximal tubule via organic acid transporter

• Inhibition of the apical Na-K-2Cl cotransporter of the TALH

• Competition with Cl- ion for binding

Pharmacological Effects of Loop Diuretics

• Loss of diluting ability: Increased Na, Cl and K excretion

• Loss of concentrating ability: – reduction in the medullary osmotic gradient – Loss in ADH-directed water reabsorption in

collecting ducts• Loss of TAL electrostatic driving force:

increased excretion of Ca2+, Mg2+ and NH4+

• Increased electrostatic driving force in CCD: increased K+ and H+ excretion

Pharmacokinetics• Rapid oral absorption, bioavailability ranges

from 65-100%• Rapid onset of action • extensively bound to plasma proteins• secreted by proximal tubule organic acid

transporters

Therapeutic Uses

• Edema of cardiac, hepatic or renal origin• Acute pulmonary edema – (parenteral route)• Chronic renal failure or nephrosis• Hypertension • Symptomatic hypercalcemia

Therapeutic use• Furosemide is used at doses of 20 mg and

upward• Renal insufficiency need higher doses• Furosemide should be used in divided

doses of two or more per day duration of diuretic action may be qiute short and is likely dose-related

Loop Diuretic Toxicity• Hypokalemia• Magnesium depletion• Chronic dilutional hyponatremia• Metabolic alkalosis• Hyperuricemia• Ototoxicity

Drug Interactions• Displacement of plasma protein binding of

clofibrate and warfarin• Li+ clearance is decreased• Loop diuretics increase renal toxicity of

cephalosporin antibiotics• Additive toxicity w/ other ototoxic drugs• Inhibitors of organic acid transport (probenecid,

NSAID's) shift the dose-response curve of loop diuretics to the right

Spironolactone• Mechanism of action:

aldosterone antagonist• Aldosterone receptor

function• Spironolactone prevents

conversion of the receptor to active form, thereby preventing the action of aldosterone

Pharmacokinetics• 70% absorption in GI tract• Extensive first pass effect in liver and

enterohepatic circulation• Extensively bound to plasma proteins• 100% metabolites in urine• Active metabolite: canrenone (active)• Canrenoate (converted to canrenone)

Therapeutic Uses• Prevent K loss caused by other diuretics

in:– Hypertension– Refractory edema– Heart failure

• Primary aldosteronism

Administration

• Dose orally administered (100 mg/day)• Spironolactone/thiazide prep (aldactazide, 25

or 50 mg of each drug in equal ratio)

Toxicity• Hyperkalemia - avoid excessive K

supplementation when patient is on spironolactone

• Androgen like effects due to it steroid structure• Gynecomastia• GI disturbances

Triamterene and Amiloride

• Non-steroid in structure, not aldosterone antagonists

Mechanism of Action• Blockade of apical Na+

channel in the principal cells of the CCD

• Amiloride: blocks the Na/H exchanger (higher concentrations)

• Blockade of the electrogenic entry of sodium causes a drop in apical membrane potential (less negative), which is the driving force for K+ secretion

Pharmacokinetics• Triamterine

– 50% absorption of oral dose– 60% bound to plasma proteins– Extensive hepatic metabolism with active

metabolites– Secreted by proximal tubule via organic cation

transporters• Amiloride

– 50% absorption of oral dose– not bound to plasma proteins– not metabolized, excreted in urine unchanged– Secreted by proximal tubular cation transporters

Therapeutic uses

• Eliminate K wasting effects of other diuretics in:– Edema– Hypertension

Toxicity• Hyperkalemia. Avoid K+ supplementation• Drug interaction - do not use in combination with

spironolactone since the potassium sparing effect is greater than additive

• Caution with ACE inhibitors• Reversible azotemia (triamterine) • Triamterene nephrolithiasis. 1 in 1500 patients

Class of Diuretics• Carbonic anhydrase inhibitors

Acetazolamide

Developed from sulfanilamide, after it was noticed that sulfanilamide caused metabolic acidosis and alkaline urine.

Mechanism of Action: Na+

Bicarbonate Diuresis

• Inhibit carbonic anhydrase in proximal tubule• Blocks reabsorption of bicarbonate ion,

preventing Na/H exchange• Pharmacological effect

– Sodium bicarbonate diuresis– metabolic acidosis

Therapeutic Uses• Urinary alkalinization• Metabolic alkalosis• Glaucoma: acetazolamide, dorzalamide• As a diuretic in patients who are poorly

responsive or refractory to large doses of potent loop diuretics

• Acute mountain sickness

CA Inhibitor Toxicity

• Hyperchloremic metabolic acidosis• Nephrolithiasis: renal stones• Potassium wasting

Class of Diuretics• Osmotic Diuretics

Characteristics of Osmotic Diuretics

• Freely filterable• Little or no tubular reabsorption• Inert or non-reactive• Resistant to degradation by tubules

Mechanism of Action:Inhibition of Water Diffusion

• Free filtration in osmotically active concentration

• Osmotic pressure of non-reabsorbable solute prevents water reabsorption and increase urine volume– Proximal tubule– Thin limb of the loop of Henle

Osmotic Diuretics in Current Use

• Mannitol (prototype)• Urea• Glycerin• Isosorbide

Therapeutic Uses

Prophylaxis of renal failureMechanism:

• Drastic reductions in GFR cause dramatically increased proximal tubular water reabsorption and a large drop in urinary excretion

• Osmotic diuretics are still filtered under these conditions and retain an equivalent amount of water, maintaining urine flow

• Reduction of CSF pressure and volume

• Reduction of intraocular pressure

Therapeutic Uses (Cont.)Reduction of pressure in extravascular fluid compartments

Toxicity of Osmotic Diuretics

• Increased extracellular fluid volume• Hypersensitivity reactions• Glycerin metabolism can lead to

hyperglycemia and glycosuria• Headache, nausea and vomiting

Summary: Sites of Diuretic Action