| Class | Mineralocorticoid receptor antagonist |
|---|---|
| Chemistry |
Steroid lactones (spironolactone and eplerenone) and pyrazinoylguanidines (amiloride)
|
| Routes of administration |
Oral only |
| Absorption |
The lactones have 95% bioavailability when taken with food, whereas amiloride and triamterine have only about 50% bioavailability
|
| Solubility |
The steroid lactones have excessively high pKa (~18.0) and are practically insoluble in water; amiloride is sparingly soluble
|
| Distribution |
VOD= about 2-5L/kg; the steroid lactones are 90% protein bound, and amiloride is less so (23%)
|
| Metabolism |
None of amiloride, but 100% of spironolactone, is metabolised in the liver - some of the metabolites are active and have long half-lives
|
| Elimination |
Elimination of amiloride and inactive spironolactone metabolites is renal. Half-life of spironolactone itself is only 2-3hours, whereas the metabolites have half-lives of 10-12 hrs.
|
| Time course of action |
For spironolactone, some effect is seen within 3-4 hours, but the maximum effect for the takes up to 2 days to develop. Whereas with amiloride it is more rapid.
|
| Target receptor |
The steroid lactones bind aldosterone receptors everywhere (particularly in the collecting duct and distal convoluted tubule); amiloride and triamterene bind directly to the ENaC channel. |
| Mechanism of action |
By decreasing the reabsorption of sodium via the ENaC channel, aldosterone receptor antagonists increase the loss of sodium. The increased sodium concentration in the lumen of the collecting duct creates a positive charge which repels potassium ions and therefore leads to potassium retention. |
| Clinical effects |
Decreased blood pressure and circulating volume, hyponatremia, hyperkalemia, metabolic acidosis (Type 4 RTA), and unless they specifically target the ENaC channel, hirsuitism and gynaecomastia (by cross-reactivity with other steroid receptors, eg. sex hormones). |
| Literature reference | |
| CICM details of understanding | Not specifically listed in the CICM syllabus |
| Mentioned around Deranged Physiology | |
| Related SAQs |
Question 10-2013, Paper 1 (carvedilol vs spironolactone) Question 14-2000, Paper 1 (from the most ancient strata of the Second Part Exam) |