Mineralocorticoid receptor antagonist
Mineralocorticoid receptor antagonist | ||
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Chemical class Steroidal; Nonsteroidal | | |
Legal status | ||
In Wikidata |
A mineralocorticoid receptor antagonist (MRA or MCRA)
Medical uses
Mineralocorticoid receptor antagonists are
Adverse effects
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 significant hyperkalemia is possible, and warrants serum potassium monitoring on a periodic basis. The pathophysiology of hyperkalemia is that antimineralocorticoid medications reduce potassium (K) excretion.
Mechanism of action
Aldosterone is a mineralocorticoid which is synthesized in the adrenal glands.[5] When aldosterone is secreted from the adrenal glands, it binds to the mineralocorticoid receptor in the renal tubule cell and forms a complex.[6] This complex enhances
Mineralocorticoid receptor antagonists decrease the aldosterone effect by binding to the mineralocorticoid receptor inhibiting aldosterone. This leads to higher levels of potassium in serum and increased sodium excretion, resulting in decreased body fluid and lower blood pressure.[5]
List of mineralocorticoid receptor antagonists
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 |
Pharmacokinetics
When comparing the pharmacokinetic properties of
Structure-activity relationship
Eplerenone is a newer drug that was developed as a spironolactone analog with reduced adverse effects. In addition to the y-lactone ring and the substituent on C-7, eplerenone has a 9α,11α-epoxy group. This group is believed to be the reason why eplerenone has a 20-40-fold lower affinity for the mineralocorticoid receptor than spironolactone.[7]
Despite the
History
The main goal of the identification of the first aldosterone antagonists, which happened during the 1950s, was to identify inhibitors of aldosterone activity. In those times, the main use of aldosterone was recognized as the control of renal sodium and the excretion of potassium.[8]
Hans Selye, a Hungarian-Canadian endocrinologist, studied the effects of aldosterone antagonists on rats and found that the use of one of the first aldosterone antagonists, spironolactone, protected them from aldosterone-induced cardiac necrosis. The same year, 1959, spironolactone was launched as a potassium-sparing diuretic. It became clear years later that aldosterone antagonists inhibit a specific receptor protein. This protein has high affinity for aldosterone but also for cortisol in humans and corticosterone in mice and rats. For this reason, aldosterone antagonists were called mineralocorticoid receptor antagonists.[8]
There have been three major waves in the pharmaceutical industry when it comes to research and development of mineralocorticoid receptor antagonists: The first wave took place within Searle Laboratories. This company identified, shortly after the purification of aldosterone, steroid-based spironolactone as the first anti-mineralocorticoid. The second wave was all about discovering much more specific
Around 50 years after Selye's work, several pharmaceutical companies began drug discovery programs. Their goal was to discover novel non-steroidal mineralocorticoid receptor antagonists for use as efficacious and safe drugs with the pharmacodynamics and pharmacokinetics 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 by in vivo experiments whereas the identification of novel non-steroidal mineralocorticoid receptor antagonists were done with high-throughput screening of millions of chemical compounds in various pharmaceutical companies.[8]
Examples
Members of this class in clinical use include:
- Widespread use
- Spironolactone — the first and most widely used member of this class
- Eplerenone — much more selective than spironolactone on target, but somewhat less potent and efficacious
- Uncommon use (to date)
- Canrenone and potassium canrenoate — very limited use
- Finerenone — nonsteroidal and more potent and selective than either eplerenone or spironolactone
Some drugs also have antimineralocorticoid effects secondary to their main mechanism of actions. Examples include progesterone, drospirenone, gestodene, and benidipine.[9]
See also
References
- ^ The Krause/King-Lewis acronym, developed at Naval Medical Center San Diego Archived 2018-07-13 at the Wayback Machine, of MCRA was developed during February 2017 to distinguish between MRA for a specific MRI which are both widely recognized medical acronyms as compared to the use of MRA for mineralocorticoid receptor antagonist type medications which is only used as a medical acronym in the cardiology and nephrology word.
- ^ PMID 23836977.
- ^ "List of Aldosterone receptor antagonists - Drugs.com". Drugs.com. Retrieved 27 September 2018.
- ^ PMID 20177008.
- ^ PMID 21731887.
- ^ ISBN 9780128012383. Retrieved 27 September 2018.
- ^ a b Lemke, Thomas L.; Williams, David A.; Roche, Victoria F.; Zito, S. William. Foye's Principals of Medicinal Chemistry. Wolters Kluwer - Lippincott Williams and Wilkins.
- ^ PMID 28634268.
- PMID 20307534.
External links
- Aldosterone+Antagonists at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- MeSH list of agents 82000451