VPT 311: General and Systemic Veterinary Pharmacology (2+1)

POTASSIUM SPARING DIURETIC

• There are 2 groups of drugs in this category.
• The only thing, they have in common is their site of action (late distal tubule and collecting duct).
• However their mechanism of action is quite different.
  • Inhibition of aldosterone - Spiranolactone
  • Inhibition of the Na⁺ K⁺ exchange in the collecting duct - Triamterene, Amiloride

Aldosterone antagonists

• Aldosterone (a steroid hormone) enters tubular cells and binds to a mineralocorticoid receptor in the cytoplasm.
• This hormone receptor complex binds to a response element on the DNA.
• Binding results in the expression of aldosterone induced proteins leading to activation of silent Na⁺ channels/pumps, alteration of the cycling of the channels and pumps, increased expression of channels and pumps and altered permeability of the tight junction (zonula occludens).
• All the above effects result in an increase in Na⁺ conductance (reabsorption) and secretion of K⁺ (One of the complications of excess aldosterone secretion is hypokalemia).
• Spiranolactone binds to the mineralocorticoid receptor and prevents aldosterone from binding.
• Spiranolactone a true competitive antagonist of aldosterone enhances direct reabsorption of sodium in more proximal areas of the distal tubules.
• This drug has a very slow onset of action, which is not dose dependent.
• It may exert oestrogen like activity
• It is used in combination with thiazide diuretics.
• Spiranolactone is not effective in the presence of low levels of aldosterone.
• It is available only for oral administration.
• If hyperkalemia occurs as a result of spiranolactone toxicity, thiazide diuretics can be administered.

Triamterene and amiloride

• These drugs have a limited diuretic efficacy.
• They act on the collecting tubules and collecting ducts, inhibiting sodium reabsorption and decreasing potassium excretion.
• Triamterene inhibits aldosterone specific ATPase.
• But, is not dependent on aldosterone levels.
• Amiloride blocks Na⁺ channels in the luminal membrane affecting Na⁺ permeability.
• Both the drugs promote excretion of uric acid.
• The main importance of these drugs lies in their potassium-sparing ability.
• They can be given with potassium-losing diuretics like thiazides to maintain potassium balance.
• They are useful in conditions where K⁺ loss cannot be tolerated (often used in conjunction with thiazides)
• In hypertension and congestive heart failure - If a person is being treated with digoxin for their heart failure, loss of K⁺ can enhance the toxicity of digoxin (cardiac glycoside).
• If K⁺ is reduced, the actions of digoxin are enhanced because normally, digoxin must compete with K⁺ for the Na⁺ K⁺ ATPase.
• By using the drugs in combination, there is an enhanced diuretic effect and the added benefit of not losing K⁺.
• Spironolactone is used in primary hyperaldosteronism (tumor of the adrenals) or secondary hyperaldosteronism (cardiac failure, hepatic cirrhosis).

Side effects

• Hyperkalemia,
• Metabolic acidosis,
• Gynaecomastia,
• Impotence,
• Decreased libido,
• Hirsuitism and
• Gastric upsets.