Pharmacy Pharmacology: Diuretics

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Pharmacy Pharmacology Diuretics

• InstructorWilliam B. Jeffries,
  Ph.D.wbjeff_at_creighton.eduflap.creighton.edu
• Required Reading Katzung, Chapter 15

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Lecture Topics

• You need to know these things
• Mechanism of action
• Clinical indications
• Toxicity/adverse reactions

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Objective 1

• Review the pathways of Na and water reabsorption
  along the human nephron

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Nephron Structure
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Renal Epithelial Cell Polarity Drives Na and
Water Transport
Tubular Fluid
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 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

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Distal Convoluted Tubule

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

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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

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Classes of DiureticsDefinitions

• 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, therapeutics uses and
adverse effects of the thiazide and thiazide-like
diuretics
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Mechanism of 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 cortical collecting 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 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

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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

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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

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Objective 3

• Discuss the chemical characteristics,
  pharmacological properties, therapeutics uses and
  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 the apical Na-K-2Cl cotransporter
  of the TALH
• Competition with Cl- ion for binding

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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

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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
• Blah
• Blah
• Blah

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Therapeutic Uses

• Edema of cardiac, hepatic or renal origin
• 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 chemical characteristics,
  pharmacological properties, therapeutics uses and
  adverse effects of 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
  action of aldosterone

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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)

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Therapeutic Uses

• Prevent K loss caused by other diuretics 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 drug in equal ratio)

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Toxicity

• Hyperkalemia - avoid excessive K supplementation
  when patient is on spironolactone
• Androgen like effects due to it steroid structure
• 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 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

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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 chemical characteristics,
pharmacological properties, therapeutics uses and
adverse effects of the carbonic anhydrase
inhibitors
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Prototype Acetazolamide
Developed from sulfanilamide, after it was
noticed that sulfanilamide 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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CA Inhibitor Toxicity

• Hyperchloremic metabolic acidosis
• Nephrolithiasis renal stones
• Potassium wasting

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Objective 6

• Discuss the chemical characteristics,
  pharmacological properties, therapeutics uses and
  adverse effects of the osmotic diuretics

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Osmotic Diuretic Characteristics

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

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Mechanism of ActionInhibition 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

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Osmotic Diuretics in Current Use

• Mannitol (prototype)
• Urea
• Glycerin
• Isosorbide

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Therapeutic Uses

• Prophylaxis of renal failure
• Mechanism
• 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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Therapeutic Uses (Cont.)
Reduction of pressure in extravascular fluid
compartments

• Reduction of CSF pressure and volume
• Reduction of intraocular pressure

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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