| Mineralocorticoid receptor antagonist | |
|---|---|
| Drug class | |
 Spironolactone, the most widely used antimineralocorticoid. | |
| Class identifiers | |
| Synonyms | Aldosterone antagonistic; Mineralocorticoid antagonist |
| Use | Diuretic;Chronic heart failure;Hypertension;Hyperaldosteronism;Conn's syndrome |
| Biological target | Mineralocorticoid receptor |
| Chemical class | Steroidal;Nonsteroidal |
| Legal status | |
| In Wikidata | |
Amineralocorticoid receptor antagonist (MRA orMCRA)[1] oraldosterone antagonist, is adiureticdrug whichantagonizes the action ofaldosterone atmineralocorticoid receptors. This group ofdrugs is often used as adjunctive therapy, in combination with other drugs, for the management ofchronic heart failure.Spironolactone, the first member of the class, is also used in the management ofhyperaldosteronism (includingConn's syndrome) and femalehirsutism (due to additionalantiandrogen actions). Most antimineralocorticoids, includingspironolactone, aresteroidalspirolactones.Finerenone is anonsteroidal antimineralocorticoid.
Mineralocorticoid receptor antagonists arediuretic drugs that work primarily on thekidneys. They decreasesodium reabsorption, which leads to increased waterexcretion by thekidneys.[2] By regulating water excretion, mineralocorticoid receptor antagonists lowerblood pressure and reducefluid around the heart which can be very beneficial in somecardiovascular conditions.[3] Mineralocorticoid receptor antagonists have been used for many clinical conditions in thecardiovascular system. It has proven beneficial for diseases likeprimary aldosteronism, primary and resistanthypertension,heart failure andchronic kidney disease.[2] They are often used with other medications, such asACE inhibitors orbeta blockers.[4]
Increased urination is a commonly reported side effect, particularly during the initial phase following treatment initiation; this is mostly transient and tends to reduce with sustained treatment. Common side effects for antimineralocorticoid medications include nausea and vomiting, stomach cramps and diarrhoea.[4] Clinically significanthyperkalemia is possible, and warrants serum potassium monitoring on a periodic basis. Thepathophysiology of hyperkalemia is that antimineralocorticoid medications reducepotassium (K)excretion.
Aldosterone is a mineralocorticoid which is synthesized in theadrenal glands.[5] Whenaldosterone is secreted from theadrenal glands, it binds to the mineralocorticoid receptor in therenal tubule cell and forms a complex.[6]This complex enhancestranscription of specificDNA segments in thenucleus, leading to the formation of twoprotein transporters,Na+/K+ ATPase pump at thebasolateral membrane andNa+ channel called ENaC, located at theapical membrane of therenal tubule cell.[6]Theseprotein transporters increasesodium reabsorption andpotassium excretion in thedistal tubule and thecollecting duct of thekidneys. This helps the body to maintain normal volume andelectrolyte balance, increasing theblood pressure.
Mineralocorticoid receptor antagonists decrease thealdosterone effect by binding to the mineralocorticoid receptor inhibitingaldosterone. This leads to higher levels ofpotassium in serum and increased sodium excretion, resulting in decreased body fluid and lowerblood pressure.[5]
| Antimineralocorticoid | Structure | Formula | Use | Brand name |
|---|---|---|---|---|
| Spironolactone | | C24H32O4S | Heart failure, Hypertension, nephrotic syndrome, Ascites, antiandrogenic | Aldactone, Spirix, Spiron |
| Eplerenone |  | C24H30O6 | Hypertension, Heart failure, Central Serous Retinopathy | Inspra |
| Canrenone |  | C22H28O3 | Diuretic | Contaren, Luvion, Phanurane, Spiroletan |
| Finerenone |  | C21H22N4O3 | Potassium-sparing diuretic. | Kerendia |
| Mexrenone |  | C24H32O5 |
When comparing the pharmacokinetic properties ofspironolactone andeplerenone, it is clear that the two drugs differ.Spironolactone has shorterhalf-life (t1/2 = 1.3-1.4 hours) thaneplerenone (t1/2 = 4–6 hours).Eplerenone goes through rapidmetabolism by theliver to inactivemetabolites (t1/2 = 4–6 hours). However,spironolactone is metabolized to three activemetabolites, which give it prolonged activity (13.8 – 16. 5 hours).Spironolactone has a longhalf-life and isexcreted 47-51% throughkidneys. Patients withchronic kidney disease therefore require close monitoring when taking the drug. Spironolactone is also eliminated throughfeces (35-41%). Theexcretion ofeplerenone is 67% throughkidneys and 32% through feces. The information aboutexcretion plays a critical role when determining the appropriate doses for patients with renal and/or hepatic dysfunction. It is very important to adjust the doses for patients withrenal dysfunction because if they fail to eliminate the drug through theirkidneys it could accumulate in the body, causing high concentration ofpotassium in the blood.[5]
Spironolactone andEplerenone competitively block the binding ofaldosterone to the mineralocorticoid receptor and hindering thereabsorption of sodium and chloride ions. The activity of mineralocorticoid antagonists is dependent on the presence of a y-lactone ring on the C-17 position. The C-7 position is also important for activity assubstituents theresterically hinder the interaction of C-7-unsubstitutedagonists such asaldosterone.[7]
Eplerenone is a newer drug that was developed as aspironolactoneanalog with reduced adverse effects. In addition to the y-lactone ring and thesubstituent on C-7,eplerenone has a 9α,11α-epoxy group. This group is believed to be the reason whyeplerenone has a 20-40-fold lower affinity for the mineralocorticoid receptor thanspironolactone.[7]
Despite thenonsteroidal nature offinerenone which yields a differentlipophilicity and polarity profile for this compound,finerenone's affinity toward mineralocorticoid receptors is equal to that ofspironolactone and 500 times that ofeplerenone, hinting that thesteroidal core component of most antimineralocorticoids is not essential for mineralocorticoid receptor affinity.[8]
The main goal of the identification of the first aldosterone antagonists, which happened during the 1950s, was to identify inhibitors ofaldosterone activity. In those times, the main use ofaldosterone was recognized as the control of renalsodium and the excretion ofpotassium.[8]
Hans Selye, a Hungarian-Canadian endocrinologist, studied the effects ofaldosterone antagonists on rats and found that the use of one of the first aldosterone antagonists,spironolactone, protected them from aldosterone-induced cardiacnecrosis. The same year, 1959,spironolactone was launched as apotassium-sparing diuretic.It became clear years later thataldosterone antagonists inhibit a specificreceptor protein. This protein has high affinity foraldosterone but also forcortisol in humans andcorticosterone inmice andrats. For this reason, aldosterone antagonists were called mineralocorticoid receptor antagonists.[8]
There have been three major waves in thepharmaceutical industry when it comes toresearch and development of mineralocorticoid receptor antagonists: The first wave took place withinSearle Laboratories. This company identified, shortly after the purification ofaldosterone,steroid-basedspironolactone as the first anti-mineralocorticoid.The second wave was all about discovering much more specificsteroidal anti-mineralocorticoids. The main active companies wereSearle,Ciba-Geigy,Roussel Uclaf andSchering AG.[8]
Around 50 years afterSelye's work, several pharmaceutical companies begandrug discovery programs. Their goal was to discover novelnon-steroidal mineralocorticoid receptor antagonists for use asefficacious and safe drugs with thepharmacodynamics andpharmacokinetics well defined. Their goal was to use these candidates for a broad spectrum of diseases. This was essentially the third wave.The first mineralocorticoid receptor antagonists were all discovered and identified byin vivo experiments whereas the identification of novelnon-steroidal mineralocorticoid receptor antagonists were done withhigh-throughput screening of millions ofchemical compounds in various pharmaceutical companies.[8]
Members of this class in clinical use include:
Some drugs also have antimineralocorticoid effects secondary to their main mechanism of actions. Examples includeprogesterone,drospirenone,gestodene, andbenidipine.[9]