Diuretic and RAAS

Question 1

Carbonic Anhydrase Inhibitors - Acetazolamide (Diamox), Dorzolamide, Brinzolamide (K+ wasting)

Answer 1

• Pharmacodynamics
  
  •  Inhibition of carbonic anhydrase enzyme depresses NaHCO3 reabsorption in proximal tubule
  • carbonic anhydrase (CA) on luminal surface allows for reabsorption of HCO3- (and exchange of H+ for Na+)-> has diuretic effect, but NOT used clinically as a diuretic agent and NOT used in HF
  •  Also inhibits formation of aqueous humor and CSF that is dependent on HCO3- transport
• Pharmacokinetics
  
  •  Well absorbed orally; effects within 30 min that persist for 12 hrs; secreted into proximal tubule
• Clinical Uses. Major use is NOT as diuretic agent and NOT used in heart failure
  
  •  Glaucoma: Topical administration for chronic open angle glaucoma
  •  Acute mountain sickness. Systemic administration slows progression of pulmonary or cerebral edema via decrease in formation and pH of cerebrospinal fluid
• Adverse Reactions / Toxicities
  
  •  Minor: Loss of appetite, drowsiness, confusion, tingling in extremities, hypersensitivity rxns
  •  Hyperchloremic metabolic acidosis, renal stones (via increase in urinary pH), K+ wasting

Question 2

Loop of Henle Agents (High Ceiling Diuretics) e.g. Furosemide (K+ wasting)

Answer 2

Ascending limb is impermeable to H2O, but active NaCl reabsorption occurs in ascending limb via Na+-K+-2Cl- cotransporter (NKCC2 on the luminal side)

• • Although cotransporter itself is electrically neutral, action leads to excess intracellular K+ which then back diffuses into lumen creating a lumen positive potential. This potential then drives the reabsorption of cations Mg++ and Ca++.
• The loop agent’s Pharmacodynamics
  
  • Inhibit NaCl transport (Na+-K+-2Cl–transporter) in thick ascending limb of loop of Henle.
  • Loop diuretics have greatest diuretic effect because of large capacity of this segment.
  •  Associated with increase in Mg++, Ca++ excretion (diminish lumen-positive potential)
  •  Increase renal blood flow (via effect on renin-angiotensin and prostaglandin systems)
  •  Retain substantial diuretic effect even if renal function is compromised

• Pharmacokinetics

•  Rapidly absorbed orally; extremely rapid IV diuretic response
•  Handled by renal secretion and filtration
•  Duration of effect 2-3 hrs for furosemide, 4-6 hrs for torsemide, 6 hours for bumetanide

Clinical Uses

•  Congestive heart failure - Preferred diuretic class because of greater efficacy
  
  • Used in HF patients with volume overload
  • Efficacy of diuretics is enhanced with salt restriction (< 2 g/day)
  • Patients with HF have reduced diuretic response related to decreased drug delivery to kidney due to decreased RBF and hypoperfusion activation of RAAS and SNS
  • Refractory edema
    
    • A thiazide (metolazone) can be added to therapy if a loop diuretic produces insufficient diuresis. Thiazide action to block distal tubule Na+ reabsorption can counter loop-induced increases in Na+ delivery and reabsorption at that segment. Note that thiazides can add to loop-induced hypokalemia so careful monitoring of serum potassium is warranted with initiation of therapy.
    • An aldosterone antagonist (spironolactone) is recommended in some patients with systolic HF to improve survival. Its actions at the collecting tubule will also enhance diuresis and ameliorate the potassium wasting.
• Acute pulmonary edema. Rapid reduction of extracellular fluid and venous return (extra-renal hemodynamic response via decrease in RV output and pulmonary vascular pressure)
•  Refractory edema. Loop diuretics used if no response to Na+ restriction or thiazide diuretic; especially useful if renal disease and fluid overload present
•  Hypercalcemia. Given with saline infusion to prevent extracellular fluid (ECF) volume depletion

• Adverse Reactions / Toxicities

•  Hypokalemic metabolic alkalosis via enhanced secretion of K+ and H+. More pronounced than with thiazides. Hypokalemia predisposes patients to ectopic pacemakers and arrhythmias.
•  Ototoxicity. Especially for ethacrynic acid (also higher incidence with concomitant use of
• aminoglycoside antibiotics) and if diminished renal function present; usually reversible
•  Hyperuricemia / hyperglycemia
•  Hypomagnesemia
•  Overdose. Rapid blood volume depletion  dizziness, headache, orthostatic hypotension

Question 3

Thiazide Diuretics (K+ wasting)

Answer 3

• • Pharmacodynamics
  
  •  Thiazide diuretics act by inhibiting the Na+/Cl- cotransporter and increasing urinary excretion of NaCl (modest diuretic effect, only 5-10% of filtered Na+ is reabsorbed here)
  •  In contrast to loop diuretics, thiazides increase reabsorption of Ca++ (lowering of intracellular Na+ drives Ca++ exchanger or decreased blood volume increases absorption at PCT)
• • Pharmacokinetics
  
  •  All absorbed well orally (if GI upset, can take with food or milk); best to take early in day
•  Differences in metabolism / excretion:
  
  • Hydrochlorothiazide (Hydrodiuril): Prototype thiazide, twice daily dose
  • Chlorthalidone - Metolazone: longer durationsonce daily dosing
  •  All secreted by organic acid secretory system; competition with uric acid secretion may precipitate a gout attack
• Clinical Uses
  
  •  Congestive heart failure
    
    • Higher doses needed than in hypertension and more efficacious diuretics are usually required (i.e., loop diuretics)
    • True synergistic diuretic effect with loop diuretics (esp. metolazone) may be useful in refractory edema
  •  Hypertension: First line for mild hypertension (esp., blacks, elderly, obese)
  •  Hypercalcuria: Reduced urinary excretion of Ca++ decreases incidence of kidney stones
• Adverse Reactions / Toxicities
  
  •  Hypokalemia, can result in weakness, paresthesias, cardiac sensitization (predisposition to ectopic pacemakers), thus use not advisable in patients with arrhythmias, history of myocardial infarction, pre-infarction angina
  •  Volume contraction may lead to secondary hyperaldosteronism
  • and otherssss

Question 4

Potassium-Sparing Diuretics - Aldosterone Antagonists and Na+-channel Blockers

Answer 4

• Aldosterone, through effects on gene transcription, increases the number and activity of both Na+ (ENaC) and K+ membrane channels and the Na+-K+-ATPase
• Diuretics that block the Na+ channel (triamterene and amiloride) or antagonize the aldosterone receptor (spironolactone - eplerenone) will decrease Na+ reabsorption and decrease K+ excretion (known as “potassium-sparing” diuretics)
• Pharmacodynamics
•  Spironolactone / Eplerenone
  
  • Only mild diuresis possible if used alone
  • Competitive antagonist at aldosterone receptor, binds to cytosolic receptor preventing enhancement of protein synthesis. Eplerenone reported to have lower affinity for androgen and progesterone receptors.
  • Blocks aldosterone effect at collecting tubule, thus Na+ is not reabsorbed, lumen potential becomes more positive, thus less K+ and H+ ions move into urine
  • Promotes only moderate increase in Na+ excretion
•  Triamterene / Amiloride: Direct effect to block the Na+-channels on collecting duct lumen to decrease Na+ reabsorption (and thus decreases coupled K+ secretion)
• Pharmacokinetics
  
  •  Spironolactone (Aldactone): 1-2 doses/day; poor oral absorption. Slow onset of action.
  •  Eplerenone (Inspra): Dosed 1-2 times/day orally, metabolized by CYP3A4.
  •  Triamterene (Dyrenium) / Amiloride (Midamor): Triamterene metabolized in liver, amiloride excreted unchanged thus given less frequently. Effect within 2-4 hrs, but 1-3 days to maximal effect.

Clinical Uses

•  Congestive Heart Failure: Most important action is block of aldosterone receptors on heart rather than kidney.
  
  • Anti-remodeling action - block of deleterious effect of aldosterone on heart -> prevent cardiac hypertrophy and fibrosis
  • Additional benefits from raising serum potassium to counter risk of hypokalemia- induced arrhythmias resulting from use K+-wasting diuretics (loop and thiazides)
• Primary hyperaldosteronism (spironolactone and eplerenone)
•  Hirsutism of polycystic ovary syndrome via block of androgen receptor (spironolactone)
•  Hypertension (in combination with thiazides)
  
  • • Spironolactone-HCTZ (Aldactazide®), Triamterene-HCTZ (Dyazide®)

• Adverse Reactions

•  Hyperkalemia-> EKG changes, conduction abnormalities, arrhythmias
  
  • • Risk increased by: increasing age, underlying renal dysfunction, higher doses, combined use of ACEI or ARB, use of NSAID analgesics
•  Endocrine abnormalities (gynecomastia) with spironolactone via block of androgen receptor (∼ 10%). NOT seen with eplerenone which is more selective for aldosterone receptors.
•  Mild effects: GI upset, drowsiness

Question 5

Summary of Renal Tubule Transport

Answer 5