An antimineralocorticoid, also known as a mineralocorticoid receptor antagonist (MRA or MCRA) or aldosterone antagonist, is a

diuretic A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics in ...

drug A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via insuffla ...

which antagonizes the action of

aldosterone Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays a c ...

mineralocorticoid receptor The mineralocorticoid receptor (or MR, MLR, MCR), also known as the aldosterone receptor or nuclear receptor subfamily 3, group C, member 2, (NR3C2) is a protein that in humans is encoded by the ''NR3C2'' gene that is located on chromosome 4q31 ...

s. This group of

drugs A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhalat ...

is often used as adjunctive therapy, in combination with other drugs, for the management of

chronic heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...

Spironolactone Spironolactone, sold under the brand name Aldactone among others, is a medication that is primarily used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It is also used in the treatment of high blood pressure ...

, the first member of the class, is also used in the management of

hyperaldosteronism Hyperaldosteronism is a medical condition wherein too much aldosterone is produced by the adrenal glands, which can lead to lowered levels of potassium in the blood (hypokalemia) and increased hydrogen ion excretion (alkalosis). This cause of min ...

(including

Conn's syndrome Primary aldosteronism (PA)'','' also known as primary hyperaldosteronism or Conn's syndrome, refers to the excess production of the hormone aldosterone from the adrenal glands, resulting in low renin levels and high blood pressure. This abnormalit ...

) and female

hirsutism Hirsutism is excessive body hair on parts of the body where hair is normally absent or minimal. The word is from early 17th century: from Latin ''hirsutus'' meaning "hairy". It usually refers to a "male" pattern of hair growth in a female that ...

(due to additional

antiandrogen Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking the ...

actions). Most antimineralocorticoids, including

spironolactone Spironolactone, sold under the brand name Aldactone among others, is a medication that is primarily used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It is also used in the treatment of high blood pressure ...

, are

steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...

spirolactone Spirolactones are a class of functional group in organic chemistry featuring a cyclic ester attached spiro to another ring system. The name is also used to refer to a class of synthetic steroids, called steroid-17α-spirolactones, 17α-spirol ...

Finerenone Finerenone, sold under the brand name Kerendia, is a medication used to reduce the risk of kidney function decline, kidney failure, cardiovascular death, non-fatal heart attacks, and hospitalization for heart failure in adults with chronic kidne ...

is a

nonsteroidal A nonsteroidal compound is a drug that is not a steroid nor a steroid derivative. Nonsteroidal anti-inflammatory drugs (NSAIDs) are distinguished from corticosteroids as a class of anti-inflammatory agents. List of nonsteroidal steroid receptor mod ...

antimineralocorticoid.

Medical uses

Mineralocorticoid receptor antagonists are

drugs that work primarily on the

kidneys The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...

. They decrease sodium reabsorption which leads to increased water

excretion Excretion is a process in which metabolic waste is eliminated from an organism. In vertebrates this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific tasks after lea ...

by the

. By regulating water excretion, mineralocorticoid receptor antagonists lower

blood pressure Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure" r ...

and reduce fluid around the heart which can be very beneficial in some

cardiovascular conditions Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, hea ...

. Mineralocorticoid receptor antagonists have been used for many clinical conditions in the

cardiovascular system The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...

. It has proven beneficial for diseases like

primary aldosteronism Primary aldosteronism (PA)'','' also known as primary hyperaldosteronism or Conn's syndrome, refers to the excess production of the hormone aldosterone from the adrenal glands, resulting in low renin levels and high blood pressure. This abnormalit ...

, primary and resistant

hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...

and

chronic kidney disease Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vo ...

. They are often used with other medications, such as

ACE inhibitors Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of high blood pressure and heart failure. They work by causing relaxation of blood vessels as well as a decrease in blood volum ...

beta blockers Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage cardiac arrhythmia, abnormal heart rhythms, and to protect the heart from a second myocardial infarction, heart attack after a first heart ...

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. Clinically significant

hyperkalemia Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0mmol/L (3.5 and 5.0mEq/L) with levels above 5.5mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Occasi ...

is possible, and warrants serum potassium monitoring on a periodic basis. The

pathophysiology Pathophysiology ( physiopathology) – a convergence of pathology with physiology – is the study of the disordered physiological processes that cause, result from, or are otherwise associated with a disease or injury. Pathology is the ...

of hyperkalemia is that antimineralocorticoid medications reduce

potassium Potassium is the chemical element with the symbol K (from Neo-Latin ''kalium'') and atomic number19. Potassium is a silvery-white metal that is soft enough to be cut with a knife with little force. Potassium metal reacts rapidly with atmosphe ...

(K)

Mechanism of action

Aldosterone Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays a c ...

is a mineralocorticoid which is synthesized in the

adrenal glands The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex which ...

. When

is secreted from the

, it binds to the mineralocorticoid receptor in the

renal tubule The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a renal tubule. The renal corpuscle consists of a tuft of capillaries called a glomerulus and a cup-shaped structure ca ...

cell and forms a complex. This complex enhances

transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...

of specific DNA segments in the

nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucle ...

, leading to the formation of two

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

transporters, Na+/K+ ATPase pump at the

basolateral membrane Epithelial polarity is one example of the cell polarity that is a fundamental feature of many types of cells. Epithelial cells feature distinct 'apical', 'lateral' and 'basal' plasma membrane domains. Epithelial cells connect to one another via the ...

and

Na+ channel Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the chann ...

called ENaC, located at the

apical membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...

of the

cell. These

transporters increase sodium reabsorption and

excretion in the

distal tubule The distal convoluted tubule (DCT) is a portion of kidney nephron between the loop of Henle and the collecting tubule. Physiology It is partly responsible for the regulation of potassium, sodium, calcium, and pH. On its apical surface (lumen ...

and the

collecting duct The collecting duct system of the kidney consists of a series of tubules and ducts that physically connect nephrons to a minor calyx or directly to the renal pelvis. The collecting duct system is the last part of nephron and participates in elect ...

of the

. This helps the body to maintain normal volume and

electrolyte balance An electrolyte is a medium containing ions that is electrically conducting through the movement of those ions, but not conducting electrons. This includes most soluble salts, acids, and bases dissolved in a polar solvent, such as water. Upon dis ...

, increasing the

. Mineralocorticoid receptor antagonists decrease the

effect by binding to the mineralocorticoid receptor inhibiting

. This leads to higher levels of

in serum and increased sodium excretion, resulting in decreased body fluid and lower

List of Mineralocorticoid receptor antagonists

Pharmacokinetics

When comparing the pharmacokinetic properties of

and

eplerenone Eplerenone, sold under the brand name Inspra, is an aldosterone antagonist type of potassium-sparing diuretic that is used to treat chronic heart failure and high blood pressure, particularly for patients with resistant hypertension due to elevat ...

, it is clear that the two drugs differ.

has shorter

half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ato ...

(t1/2 = 1.3-1.4 hours) than

(t1/2 = 4-6 hours).

Eplerenone Eplerenone, sold under the brand name Inspra, is an aldosterone antagonist type of potassium-sparing diuretic that is used to treat chronic heart failure and high blood pressure, particularly for patients with resistant hypertension due to elevat ...

goes through rapid

metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

by the

liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...

to inactive

metabolites In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

(t1/2 = 4-6 hours). However,

is metabolized to three active

, which give it prolonged activity (13.8 – 16. 5 hours).

has a long

and is

excreted Excretion is a process in which metabolic waste is eliminated from an organism. In vertebrates this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific tasks after lea ...

47-51% through

. Patients with

therefore require close monitoring when taking the drug. Spironolactone is also eliminated through

feces Feces ( or faeces), known colloquially and in slang as poo and poop, are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the large intestine. Feces contain a relati ...

(35-41%). The

is 67% through

and 32% through feces. The information about

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 with

renal dysfunction Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...

because if they fail to eliminate the drug through their

it could accumulate in the body, causing high concentration of

in the blood.

Structure-activity relationship

and

competitively block the binding of

to the mineralocorticoid receptor and hindering the

reabsorption In renal physiology, reabsorption or tubular reabsorption is the process by which the nephron removes water and solutes from the tubular fluid (pre-urine) and returns them to the circulating blood. It is called ''reabsorption'' (and not ''absorpt ...

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 as

substituents A substituent is one or a group of atoms that replaces (one or more) atoms, thereby becoming a moiety in the resultant (new) molecule. (In organic chemistry and biochemistry, the terms ''substituent'' and ''functional group'', as well as ''side ...

there sterically hinder the interaction of C-7-unsubstituted

agonists An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an ...

such as

is a newer drug that was developed as a

analog Analog or analogue may refer to: Computing and electronics * Analog signal, in which information is encoded in a continuous variable ** Analog device, an apparatus that operates on analog signals *** Analog electronics, circuits which use analog ...

with reduced adverse effects. In addition to the y-lactone ring and the

substituent A substituent is one or a group of atoms that replaces (one or more) atoms, thereby becoming a moiety in the resultant (new) molecule. (In organic chemistry and biochemistry, the terms ''substituent'' and ''functional group'', as well as ''side ...

on C-7,

has a 9α,11α- epoxy group. This group is believed to be the reason why

has a 20-40-fold lower affinity for the mineralocorticoid receptor than

. Despite the

nature of

finerenone Finerenone, sold under the brand name Kerendia, is a medication used to reduce the risk of kidney function decline, kidney failure, cardiovascular death, non-fatal heart attacks, and hospitalization for heart failure in adults with chronic kidne ...

which yields a different

lipophilicity Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipop ...

and polarity profile for this compound,

's affinity toward mineralocorticoid receptors is equal to that of

and 500 times that of

, hinting that the

steroidal A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...

core component of most antimineralocorticoids is not essential for mineralocorticoid receptor affinity.

History

The main goal of the identification of the first aldosterone antagonists, which happened during the 1950s, was to identify inhibitors of

activity. In those times, the main use of

was recognized as the control of renal

sodium Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable iso ...

and the excretion of

Hans Selye János Hugo Bruno "Hans" Selye (; hu, Selye János; January 26, 1907 – October 16, 1982) was a pioneering Hungarian-Canadian endocrinologist who conducted important scientific work on the hypothetical non-specific response of an organism to s ...

, a Hungarian-Canadian endocrinologist, studied the effects of

antagonists on rats and found that the use of one of the first aldosterone antagonists,

, protected them from aldosterone-induced cardiac

necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dige ...

. The same year, 1959,

was launched as a

potassium-sparing diuretic Potassium-sparing diuretics refers to drugs that cause diuresis without causing potassium loss in the urine. They are typically used as an adjunct in management of hypertension, cirrhosis, and congestive heart failure. The steroidal aldosterone ...

. It became clear years later that

antagonists inhibit a specific

receptor Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...

protein. This protein has high affinity for

but also for

cortisol Cortisol is a steroid hormone, in the glucocorticoid class of hormones. When used as a medication, it is known as hydrocortisone. It is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal cortex in the adrenal gland ...

in humans and

corticosterone Corticosterone, also known as 17-deoxycortisol and 11β,21-dihydroxyprogesterone, is a 21-carbon steroid hormone of the corticosteroid type produced in the cortex of the adrenal glands. It is of minor importance in humans, except in the very rare ...

mice A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...

and

rats Rats are various medium-sized, long-tailed rodents. Species of rats are found throughout the order Rodentia, but stereotypical rats are found in the genus ''Rattus''. Other rat genera include ''Neotoma'' (pack rats), ''Bandicota'' (bandicoot ...

. For this reason, aldosterone antagonists were called mineralocorticoid receptor antagonists. There have been three major waves in the

pharmaceutical industry The pharmaceutical industry discovers, develops, produces, and markets drugs or pharmaceutical drugs for use as medications to be administered to patients (or self-administered), with the aim to cure them, vaccinate them, or alleviate symptoms. ...

when it comes to

research and development Research and development (R&D or R+D), known in Europe as research and technological development (RTD), is the set of innovative activities undertaken by corporations or governments in developing new services or products, and improving existi ...

of mineralocorticoid receptor antagonists: The first wave took place within

Searle Laboratories G.D. Searle, LLC is a wholly owned subsidiary of Pfizer. It is currently a trademark company and subsidiary of Pfizer, operating in more than 43 countries. It also operates as a distribution trademark for various pharmaceuticals that were develop ...

. This company identified, shortly after the purification of

-based

as the first anti-mineralocorticoid. The second wave was all about discovering much more specific

anti-mineralocorticoids. The main active companies were

Searle Searle may refer to: __NOTOC__ Persons * Searle (surname) * J. Searle Dawley (1877–1949), American film director, producer, screenwriter, stage actor and playwright * Searle Turton (born 1979), Canadian politician Places * Serle, a comune in Lomb ...

Ciba-Geigy Novartis AG is a Swiss-American multinational pharmaceutical corporation based in Basel, Switzerland and Cambridge, Massachusetts, United States (global research).name="novartis.com">https://www.novartis.com/research-development/research-loc ...

Roussel Uclaf Roussel Uclaf S.A. was a French pharmaceutical company and one of several predecessor companies of today's Sanofi. It was the second largest French pharmaceutical company before it was acquired by Hoechst AG of Frankfurt, Germany in 1997, with p ...

and

Schering AG Schering AG was a research-centered German multinational pharmaceutical company headquartered in Wedding, Berlin, which operated as an independent company from 1851 to 2006. In 2006, it was bought by Bayer AG and merged to form the Bayer subsi ...

. Around 50 years after Selye’s work, several pharmaceutical companies began

drug discovery In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered. Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by ...

programs. Their goal was to discover novel

non-steroidal A nonsteroidal compound is a drug that is not a steroid nor a steroid derivative. Nonsteroidal anti-inflammatory drugs (NSAIDs) are distinguished from corticosteroids as a class of anti-inflammatory agents. List of nonsteroidal steroid receptor ...

mineralocorticoid receptor antagonists for use as

efficacious Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as ''effectiveness'', and it has often been used synonymously, although in pharmacology a distinction is now often made between ...

and safe drugs with the

pharmacodynamics Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms (fo ...

and

pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...

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 Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

experiments whereas the identification of novel

mineralocorticoid receptor antagonists were done with

high-throughput screening High-throughput screening (HTS) is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology, materials science and chemistry. Using robotics, data processing/control software, liquid handlin ...

of millions of

chemical compounds A chemical compound is a chemical substance composed of many identical molecules (or molecular entities) containing atoms from more than one chemical element held together by chemical bonds. A molecule consisting of atoms of only one element ...

in various pharmaceutical companies.

Examples

Members of this class in clinical use include: * Widespread use **

— the first and most widely used member of this class **

— much more selective than spironolactone on target, but somewhat less potent and efficacious * Uncommon use (to date) **

Canrenone Canrenone, sold under the brand names Contaren, Luvion, Phanurane, and Spiroletan, is a steroidal antimineralocorticoid of the spirolactone group related to spironolactone which is used as a diuretic in Europe, including in Italy and Belgium. It ...

and

potassium canrenoate Potassium canrenoate ( INN, JAN) or canrenoate potassium (USAN) (brand names Venactone, Soldactone), also known as aldadiene kalium, the potassium salt of canrenoic acid, is an aldosterone antagonist of the spirolactone group. Like spironolact ...

— very limited use **

—

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 Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...

drospirenone Drospirenone is a progestin and antiandrogen medication which is used in birth control pills to prevent pregnancy and in menopausal hormone therapy, among other uses. It is available both alone under the brand name Slynd and in combination with ...

gestodene Gestodene, sold under the brand names Femodene and Minulet among others, is a progestin medication which is used in birth control pills for women. It is also used in menopausal hormone therapy. The medication is available almost exclusively in c ...

, and

benidipine Benidipine is a dihydropyridine calcium channel blocker for the treatment of high blood pressure (hypertension). It is a triple L-, T-, and N-type calcium channel blocker. It is reno- and cardioprotective. It was patented in 1981 and approve ...

References

External links

* * {{Mineralocorticoidics Potassium-sparing diuretics