Pharmacy Diuretics

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    Pharmacy Pharmacology:

    Diuretics Instructor:

    William B. Jeffries, [email protected]

    flap.creighton.edu

    Required Reading:

    Katzung, Chapter 15

    http://flap.creighton.edu/http://www.usrf.org/mannekin.htmlhttp://flap.creighton.edu/http://flap.creighton.edu/http://flap.creighton.edu/http://flap.creighton.edu/
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    Objective 1

    Review the pathways of Na+ and

    water reabsorption along the

    human nephron

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    Nephro

    nStructure

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    Renal Epithelial Cell Polarity DrivesNa+ and Water Transport

    TubularFluid Blood

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    Proximal Tubule

    Na+ flows down concentration gradient

    Na/K ATPase maintains gradient

    Water follows passively 67% of Na and water reabsorption

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    Loop of Henle

    TDL permeable to water but notNa+

    TAL impermeable to water andtransports Na+

    Differences in permeabilitiescreates the countercurrentmultiplier

    Countercurrent multiplier createsinterstitial osmolar gradient

    20% of filtered load of Na absorbed

    by the TAL

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    Distal Convoluted Tubule

    5% of filtered load of Na+reabsorbed

    Segment mostly impermeable towater

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    Cortical Collecting Duct

    Water permeability controlled byantidiuretic hormone (ADH)

    Driving force for water

    reabsorption is created by thecountercurrent multiplier

    2-3% of filtered Na+ reabsorbed

    here via Na+

    channels that areregulated by aldosterone

    Major site of K+ secretion

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    Classes of Diuretics:

    Definitions Diuretic: substance that promotes the

    excretion of urine Natriuretic: substance that promotes

    the renal excretion of sodium

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    Objective 2

    Discuss the chemical

    characteristics,

    pharmacological

    properties, therapeuticsuses and adverse

    effects of the thiazide

    and thiazide-like

    diuretics

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    Mechanismof 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

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    Increased K+ Excretion Due To:

    Increased urine flow per se Increased Na+-K+ exchange

    Increased aldosterone release

    Na+/K+ exchange

    in the corticalcollecting duct

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    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

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    Pharmacokinetics

    Oral administration - absorption poor

    Diuresis within one hour

    T1/2 for chlorothiazide is 1.5 hours,chlorthalidone 44 hours

    Bo-

    Ring

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    Therapeutic Uses

    Edema due to CHF (mild to moderate)

    Essential hypertension

    Diabetes insipidus

    Hypercalciuria

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    Diabetes Insipidus

    Thiazides: paradoxical reduction inurine volume

    Mechanism: volume depletion causes

    decreased GFR Treatment of Li+ toxicity:

    Thiazides useful

    Li+ reabsorption increased by thiazides.Reduce Li dosage by 50%

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    Thiazide Use in Hypercalciuria -

    Recurrent Ca2+ Calculi Thiazides promote

    distal tubular Ca2+reabsorption

    Prevent excessexcretion which couldform stones in theducts of the kidney

    50-100 mg HCT keptmost patients stonefree for three years offollow-up in a recentstudy

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    Thiazide Toxicity Hypokalemia due to:

    Increased availability of Na+ for exchange atcollecting 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

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    Objective 3

    Discuss the chemical

    characteristics, pharmacological

    properties, therapeutics usesand adverse effects of the

    loop diuretics

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    Available Loop

    Diuretics

    Furosemide

    (prototype)

    Bumetanide

    Torsemide

    Ethacrynic acid

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    Molecular Mechanism of Action

    Enter proximal

    tubule via organic

    acid transporter

    Inhibition of theapical Na-K-2Cl

    cotransporter of

    the TALH

    Competition withCl- ion for binding

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    Pharmacological Effects of

    Loop Diuretics Loss of diluting ability: Increased Na, Cl andK excretion

    Loss of concentrating ability:

    reduction in the medullary osmotic gradient

    Loss in ADH-directed water reabsorption incollecting 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

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    Pharmacokinetics

    Rapid oral absorption, bioavailabilityranges from 65-100%

    Rapid onset of action

    extensively bound to plasma proteins secreted by proximal tubule organicacid transporters

    Blah

    Blah

    Blah

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    Therapeutic Uses

    Edema of cardiac, hepatic or renalorigin

    Acute pulmonary edema (parenteral

    route) Chronic renal failure or nephrosis

    Hypertension

    Symptomatic hypercalcemia

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    Loop Diuretic Toxicity

    Hypokalemia

    Magnesium depletion

    Chronic dilutional hyponatremia

    Metabolic alkalosis

    Hyperuricemia

    Ototoxicity

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    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

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    Objective 4

    Discuss the chemicalcharacteristics,pharmacological

    properties, therapeuticsuses and adverse effectsof the potassium-sparing diuretics

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    Spironolactone Mechanism of

    action: aldosterone

    antagonist

    Aldosterone receptor

    function Spironolactone

    prevents conversion

    of the receptor to

    active form, thereby

    preventing the actionof aldosterone

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    Therapeutic Uses

    Prevent K loss caused by otherdiuretics in:

    Hypertension

    Refractory edema Heart failure

    Primary aldosteronism

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    Administration

    Dose orally administered (100 mg/day)

    Spironolactone/thiazide prep

    (aldactazide, 25 or 50 mg of each drugin equal ratio)

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    Toxicity

    Hyperkalemia - avoid excessive Ksupplementation when patient is on

    spironolactone

    Androgen like effects due to it steroidstructure

    Gynecomastia

    GI disturbances

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    Triamterene and Amiloride

    Non-steroid in

    structure, not

    aldosterone

    antagonists

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    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

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    Pharmacokinetics Triamterine

    50% absorption of oral dose

    60% bound to plasma proteins

    Extensive hepatic metabolism with activemetabolites

    Secreted by proximal tubule via organic cationtransporters

    Amiloride 50% absorption of oral dose

    not bound to plasma proteins not metabolized, excreted in urine unchanged

    Secreted by proximal tubular cation transporters

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    Therapeutic uses

    Eliminate K wasting effects of

    other diuretics in:

    Edema

    Hypertension

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    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

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    Objective 5

    Discuss the chemicalcharacteristics, pharmacologicalproperties, therapeutics usesand adverse effects of thecarbonic anhydrase inhibitors

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    Prototype: Acetazolamide

    Developed from

    sulfanilamide, after

    it was noticed thatsulfanilamide

    caused metabolic

    acidosis and

    alkaline urine.

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    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

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    Therapeutic Uses

    Urinary alkalinization

    Metabolic alkalosis

    Glaucoma: acetazolamide,dorzalamide

    Acute mountain sickness

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    Objective 6

    Discuss the chemical

    characteristics, pharmacological

    properties, therapeutics usesand adverse effects of the

    osmotic diuretics

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    Mechanism of Action:Inhibition of Water Diffusion

    Free filtration in osmotically active

    concentration

    Osmotic pressure of non-reabsorbablesolute prevents water reabsorption and

    increase urine volume

    Proximal tubule Thin limb of the loop of Henle

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    Osmotic Diuretics in Current Use

    Mannitol (prototype)

    Urea

    Glycerin

    Isosorbide

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    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

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    Reduction of CSF pressure andvolume

    Reduction of intraocular pressure

    Therapeutic Uses (Cont.)

    Reduction of pressure in extravascular fluidcompartments

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    Toxicity of Osmotic Diuretics

    Increased extracellular fluid volume

    Hypersensitivity reactions

    Glycerin metabolism can lead to

    hyperglycemia and glycosuria Headache, nausea and vomiting

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    Summary: Sites of Diuretic Action