Autocoids

Diuretics

Na⁺/K⁺-ATPase: It is always located on the basolateral aspect of the cell, where it maintains the concentration gradient throughout the kidney.

• 3 Na⁺ are put back into blood, providing a net gradient for more tubular reabsorption of sodium.
• 2 K⁺ are put into cell, providing a net gradient for more tubular excretion of potassium.

CARBONIC ANHYDRASE INHIBITORS:

• PHYSIOLOGY: They act on the Proximal Tubule.
  • Net reabsorption of NaHCO₃ occurs in the proximal tubule. Net H⁺ is recycled between tubule and lumen as the reabsorption progresses.
  • Na⁺/H⁺-Antiport: Reabsorb Na⁺ and kick out H⁺ into tubular fluid.
    • INSIDE CELL: Carbonic Anhydrase catalyzes the formation of HCO₃^- + H⁺ from CO₂ and H₂O.
      • The HCO₃^- is put back into the blood.
      • The H⁺ is excreted into the urine, in exchange for Na⁺.
    • TUBULAR LUMEN: Carbonic Anhydrase catalyzes formation of H₂O + CO₂ from HCO₃^- and H⁺. The H₂O and CO₂ are reabsorbed. H⁺ is reabsorbed here, in the form of H₂O.
  • Cl^-/Base Exchanger: Poorly defined transporter. Cl^- is reabsorbed in exchange for a base.
    • The net reabsorption of HCO₃^- above, makes the urine more acidic. This creates a gradient for Cl^- reabsorption in the proximal tubule.
  • Regulation: Angiotensin II, Norepinephrine, Dopamine all increase the Na⁺/H⁺ exchanger and the production of carbonic anhydrase, thus increasing fluid reabsorption.
• MECHANISM: Carbonic Anhydrase Inhibitors cause an alkaline diuresis and a metabolic acidosis.
  • Block Carbonic Anhydrase ------> block reabsorption of NaHCO₃ ------> more HCO₃^- goes into urine (alkaline diuresis) and less HCO₃^- is reabsorbed into blood (metabolic acidosis).
  • STRUCTURE: The drugs have an unsubstituted sulfonamide group, which is required for inhibition of the enzyme.
• TOXICITY: Carbonic Anhydrase toxicity leads to:
  • Abnormal taste
  • Paresthesias
  • GI distress
  • Malaise
  • Decreased libido
  • Liver disease: It may increase blood-levels of NH₃ and precipitate hepatic encephalopathy.
• INDICATIONS:
  • They induce a weak alkaline diuresis, which improves the urinary excretion of weak acids (via ion trapping). They are therefore used for:
    • Salicylate Poisoning
    • Phenobarbitol Poisoning
    • Increase urate and cysteine excretion
  • Mountain Sickness: They are useful in acute mountain sickness, where they stimulate respiration.
  • Anti-Convulsive: Indicated for petit-mal siezures, but only short-term because tolerance develops. They are thought to increase CO₂ in brain ------> increase seizure threshold.

OSMOTIC DIURETICS:

• PHYSIOLOGY: Osmotic diuretics act throughout the tubules, but primarily on the proximal tubule and Descending Loop of Henle.
  • Osmotic diuretics, by definition, are impermeable to tubular reabsorption.
  • They prevent excessive water reabsorption by eliminating or attenuating the water-reabsorption gradient.
• MANNITOL:
  • INDICATIONS: Prophylaxis of acute renal failure, because:
    • It expands extracellular volume, thus it (1) maintains RBF and GFR, and (2) increases tubular fluid flow.
    • It reduces renal edema.
    • It redistributes blood to the hypoxic corticomedullary junction (inner cortical and outer medullar region)
    • It scavenges free radicals.
  • ADVERSE EFFECTS:
    • Metabolic Effects:
      • Expansion of extracellular fluid volume and hemodilution.
      • Metabolic acidosis from dilution of HCO₃^-
      • Pulmonary Edema
      • Severe hyponatremia
    • Headaches, CNS Depression (hypoxia from reduced blood volume)
    • GI: Nausea, vomiting
    • CV: Contraindicated in CHF because it expands extracellular fluid.

LOOP DIURETICS:

• PHYSIOLOGY: Loop diuretics act on the Thick Ascending Loop of Henle (TALH)
  • Na⁺/K⁺/2Cl^- Carrier: It creates the concentration gradient that drives the counter-current, and that allows for passive ADH-facilitated reabsorption of water in the distal tubule.
• SUBCLASSES:
  • SULFONAMIDES: Furosemide, Bumetanide, Torsemide.
    • They act fast and are reversible.
  • ERYTHRACRINIC ACID: Acts more slowly and is not fully reversible.
• MECHANISM: They inhibit the Na⁺/K⁺/2Cl^- transporter, essentially shutting down the counter-current multiplier ------> profuse natriuresis.
• INDICATIONS:
  • Edema, caused by CHF, cirrhosis, or nephrosis.
  • Management of hyponatremia or hypercalcemia. Given in combination with saline infusion.
  • Increase K^- and H⁺ excretion in patients with distal renal tubular acidosis.
• PHARMACOKINETICS:
  • Furosemide is secreted by a probenecid-sensitive transport mechanism into proximal tubule. Thus indomethacin or NSAID's decrease its effectiveness.
  • Bioavailability 50-70%. Extensively binds to plasma albumin.
• ADVERSE EFFECTS:
  • Metabolic effects:
    • Hyponatremia, hypomagnesemia, metabolic acidosis.
    • Hypokalemia: can be counteracted with K⁺-sparing diuretic, or with supplemental K⁺.
    • Hypochloremic Alkalosis: Increased delivery of Na⁺ to distal tubules ------> increased RAS and aldosterone ------> increased secretion of K⁺ and H⁺ ------> hypokalemic alkalosis.
  • Hyperuricemia, hypercholesterolemia
  • Ototoxicity, especially in patients with impaired renal function.
• DRUG INTERACTIONS:
  • Digoxin: Increases risk of arrhythmias
  • Thiazides: may lead to profound diuresis
  • Aminoglycosides: Synergism of ototoxicity
  • Heparin, Warfarin: Increase activity
  • Lithium and Propanolol: Increased plasma levels

THIAZIDE DIURETICS:

• PHYSIOLOGY: Thiazide diuretics act on the Distal Tubule.
  • Na⁺/Cl^- Coport: Flow-dependent passive transport of Na⁺, Cl^-.
  • Ca⁺²-ATPase Pump: Active reabsorption of Ca⁺² in the distal tubule, which is promoted by Vitamin-D and Parathyroid Hormone (PTH).
• MECHANISM: They inhibit Na⁺/Cl^- antiport ------> natriuresis.
• ADVERSE EFFECTS: Also see thiazides under Anti-HTN
  • Metabolic Effects:
    • Marked hyponatremia.
    • Hypokalemia and Hypomagnesemia: can be particularly bad in folks with CHF (taking glycosides), cirrhosis, MI, arrhythmias.
    • Slight hypercalcemia
    • Hyperuricemia
• INDICATIONS:
  • Hypertension
  • Kidney stones
  • Hypercalcuria
  • Diabetes Insipidus

POTASSIUM-SPARING DIURETICS:

• PHYSIOLOGY: K⁺-Sparing Diuretics act on the Collecting Duct.
  • Na⁺-Channels: Aldosterone-sensitive reabsorption of Na⁺.
  • K⁺ and H⁺ are excreted as Na⁺ is absorbed. Why this occurs is poorly understood. Explanations:
    • Na⁺ makes the luminal surface more electronegative, which promotes secretion of K⁺ and H⁺.
    • Na⁺ reabsorption retards the Na⁺/K⁺-ATPase on basolateral membrane ------> less K⁺ is excreted into blood ------> more K⁺ passively goes into urine.
    • The apical membrane is permeable to K⁺ and H⁺.
• SUBCLASSES:
  • Inhibit N⁺/K⁺-ATPase: Amiloride and Triamterene
    • This results in a modest natriuresis, and reduction in the secretion of K⁺ and H⁺ ------> more K⁺ remains in blood.
    • Results in slightly more alkaline urine.
  • Aldosterone Antagonist: Spironolactone
• INDICATIONS: Modest diuresis
  • Adjunct therapy with other diuretics
  • Primary (Conn's Disease) or secondary (glucocorticoid therapy) hyperaldosteronism.
• ADVERSE EFFECTS:
  • Hyperkalemia ------> fatal arrhythmias. Especially at risk for folks with renal failure, or in those receiving K⁺ supplements.
  • Hyperchloremic metabolic acidosis