Pharmacy Pharmacology: Diuretics

• Instructor: William B. Jeffries, Ph.D. wbjeff@creighton.edu flap.creighton.edu • Required Reading: Katzung, Chapter 15

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

Objective 1
Review the pathways of Na+ and water reabsorption along the human nephron

Nephro n Structur e

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

Classes of Diuretics:
Definitions
• Diuretic: substance that promotes the excretion of urine • Natriuretic: substance that promotes the renal excretion of sodium

Objective 2
Discuss the chemical characteristics, pharmacological properties, therapeutics uses and adverse effects of the thiazide and thiazide-like diuretics

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”

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+ ClK+ 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 • Bo• Ring

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

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

Objective 3
Discuss the chemical characteristics, pharmacological properties, therapeutics uses and adverse effects of the “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 • Blah • Blah • Blah

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

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 doseresponse curve of loop diuretics to the right

Objective 4
Discuss the chemical characteristics, pharmacological properties, therapeutics uses and adverse effects of the “potassiumsparing” diuretics

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

• Triamterine

Pharmacokinetics

– 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

Objective 5
Discuss the chemical characteristics, pharmacological properties, therapeutics uses and adverse effects of the carbonic anhydrase inhibitors

Prototype: 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 • Acute mountain sickness

CA Inhibitor Toxicity
• Hyperchloremic metabolic acidosis • Nephrolithiasis: renal stones • Potassium wasting

Objective 6
Discuss the chemical characteristics, pharmacological properties, therapeutics uses and adverse effects of the osmotic diuretics

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

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

Mechanism of Action:

Osmotic Diuretics in Current Use
• • • • Mannitol (prototype) Urea Glycerin Isosorbide

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

Therapeutic Uses (Cont.)
Reduction of pressure in extravascular fluid compartments • Reduction of CSF pressure and volume • Reduction of intraocular pressure

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