 | |
 Above: molecular structure of amilorideBelow: 3D model of an amiloride molecule | |
| Clinical data | |
|---|---|
| Trade names | Midamor, others |
| Other names | MK-870 |
| AHFS/Drugs.com | Monograph |
| Pregnancy category |
|
| Routes of administration | By mouth |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Bioavailability | Readily absorbed, 15–25% |
| Protein binding | ~23% |
| Metabolism | Nil |
| Onset of action | 2 hours (peak at 6–10 hours, duration ~24 hours) |
| Eliminationhalf-life | 6 to 9 hours |
| Excretion | urine (20–50%), feces (40%) |
| Identifiers | |
| |
| CAS Number | |
| PubChemCID | |
| IUPHAR/BPS | |
| DrugBank |
|
| ChemSpider |
|
| UNII | |
| KEGG |
|
| ChEBI | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.018.205 |
| Chemical and physical data | |
| Formula | C6H8ClN7O |
| Molar mass | 229.63 g·mol−1 |
| 3D model (JSmol) | |
| Melting point | 240.5 to 241.5 °C (464.9 to 466.7 °F) |
| |
| |
| (verify) | |
Amiloride, sold under the trade nameMidamor among others, is a medication typically used with other medications to treathigh blood pressure orswelling due toheart failure orcirrhosis of the liver.[1][2] Amiloride is classified as apotassium-sparing diuretic. Amiloride is often used together with another diuretic, such as athiazide orloop diuretic.[2] It is takenby mouth.[1] Onset of action is about two hours and it lasts for about a day.[2]
Common side effects includehigh blood potassium,vomiting, loss of appetite, rash, and headache.[1] The risk of high blood potassium is greater in those withkidney problems,diabetes, and those who are older.[1] Amiloride blocks theepithelial sodium channel (ENaC) in the late distal tubule, connecting tubule, and collecting duct of thenephron,[3] which both reduces absorption of sodium ion from thelumen of the nephron and reduces excretion of potassium ion into the lumen.[2]
Amiloride was developed in 1967.[4] It is on theWorld Health Organization's List of Essential Medicines.[5]
Amiloride may be used in combination with a thiazide diuretic for treatment of high blood pressure or (less commonly) in combination with a loop diuretic for treatment ofheart failure. The potassium-sparing effects of amiloride offset the low blood potassium (hypokalemia) that is often induced by thiazides or loop diuretics, which is of particular importance in people for whom maintaining a normal level of potassium is critically important.[6] For example, people that are takingDigitalis (i.e.digoxin) are at higher risk forchanges in heart rhythm if their potassium levels get too high.[6] The 2017 clinical practice guidelines of theAmerican College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines list amiloride as a "secondary" oral antihypertensive, with minimal efficacy.[7] For people with resistant hypertension, already taking a thiazide diuretic, anangiotensin converting enzyme inhibitor (ACE-i) or anangiotensin II receptor blocker (ARB), and acalcium channel blocker, the addition of amiloride (orspironolactone) was better at reducing blood pressure than adding a beta-blocker (bisoprolol) or analpha-1 blocker (doxazosin).[8] When combined with hydrochlorothiazide, the addition of amiloride had positive effects on blood pressure and blood sugar tolerance.[9] Amiloride may therefore be useful for preventing the metabolic side effects of thiazide diuretics, allowing for the use of higher thiazide doses (in line with how they were originally studied).[10]
Amiloride is the treatment of choice forLiddle phenotype,[11] which is characterized by high blood pressure, low blood potassium, and metabolic alkalosis in conjunction with a low plasma renin activity and a low aldosterone. Some people with the Liddle phenotype haveLiddle syndrome, which involves a genetic mutation resulting in upregulation of the epithelial sodium channel (ENaC), located in the apical membrane of polarized epithelial cells in the late distal tubule andcollecting duct of the kidney.[12] Because Liddle phenotype usually involves an upregulation of ENaC channels, leading to retention of sodium and water and to hypokalemia, amiloride is useful as an ENaC channel inhibitor due to itspromotion of sodium excretion and its potassium-sparing effects, restoring potassium to normal levels.[13]
Amiloride can be used as a monotherapy (single-drug therapy) or an adjunctive therapy alongside other diuretics (e.g.hydrochlorothiazide,furosemide) for the treatment ofascites andedema (swelling) due tocirrhosis of the liver.[6] The 2012 clinical practice guidelines by theAmerican Association for the Study of Liver Diseases (AASLD) states that amiloride can be used to treat ascites in place ofspironolactone if it isn't tolerated (e.g. due to the side effect ofgynecomastia), though amiloride isn't a preferred drug due to cost and lack of efficacy.[14]
People with diabetes are at higher risk forkidney problems, which increases their risk for hyperkalemia (high blood potassium). The use of amiloride in people with diabetes requires careful potassium and kidney function monitoring to prevent toxicity. Amiloride must be discontinued for at least 3 days prior to glucose tolerance testing, due to the risk for fatal hyperkalemia.[6]
People with poor kidney function (e.g.blood urea nitrogen >30 mg/dL, orserum creatinine >1.5 mg/dL) are at high risk for hyperkalemia.[6]
There is no data on the use of amiloride in women that are breastfeeding. While diuretics can make lactation difficult, it is unlikely that amiloride would induce this effect in the absence of other diuretics.[15]
Data from the use of amiloride in animals suggests that it does not pose a risk to the developing fetus. However, when used in combination with the drugacetazolamide during the process oforgan formation, amiloride increases the risk for kidney and ureter abnormalities. Limited human data from use during pregnancy suggests an association with a specificcongenital penis abnormality if taken during the first trimester, as well as a risk for mildintrauterine growth restriction if taken throughout pregnancy.[16]
Amiloride is contraindicated in people with kidney problems (e.g. anuria, acute orchronic kidney disease, ordiabetic nephropathy), elevated blood potassium (≥5.5 mEq/L), or people that are hypersensitive to amiloride or any ingredients within the specific formulation. Use is also contraindicated in people that are already taking potassium-sparing drugs (e.g.spironolactone andtriamterene) or who are taking potassium supplements (e.g. potassium chloride) in most circumstances.[1]
Amiloride is generally well tolerated.[17] Common adverse effects of the use of amiloride include elevated blood potassium, mild skin rashes, headaches, and gastrointestinal side effects (nausea, vomiting, diarrhea,decreased appetite,flatulence, and abdominal pain).[1] Mild symptoms of high blood potassium concentrations includeunusual skin sensations, muscle weakness, or fatigue, but more severe symptoms such asflaccid paralysis of the limbs,slow heart rate, and evenshock can occur.[1]
There exists no overdose data on amiloride in humans, though it is expected than an overdose would produce effects consistent with its therapeutic effects; e.g. dehydration due to over-diuresis, and electrolyte disturbances related to hyperkalemia. It is unknown if amiloride can be dialyzed off, and no specific antidote against it exists. Treatment is generally supportive, though hyperkalemia can be treated.[17]
Amiloride may have importantdrug-drug interactions when combined with other medications that also increase potassium levels in the blood, leading to hyperkalemia.[18] For example, the combination of amiloride withangiotensin-converting enzyme (ACE) inhibitors likelisinopril, orangiotensin II receptor type 1 (AT1) antagonists likelosartan, may lead to high levels of potassium in the blood, requiring frequent monitoring.[18]
Amiloride works by directly blocking theepithelial sodium channel (ENaC) with anIC50 around 0.1μM, indicating potent blockade.[19] Antagonism of ENaC thereby inhibitssodium reabsorption in the latedistal convoluted tubules, connecting tubules, and collecting ducts in thenephron.[20] This promotes the loss of sodium and water from the body, and reducespotassium excretion. The drug is often used in conjunction with athiazide diuretic to counteract with a potassium-losing effect. Due to its potassium-sparing capacities,hyperkalemia (elevated potassium concentration in the blood) can occur. The risk of developing hyperkalemia is increased in patients who are also takingACE inhibitors,angiotensin II receptor antagonists, otherpotassium-sparing diuretics, or any potassium-containing supplements.
A fraction of the effects of amiloride is inhibition ofcyclic GMP-gated cation channels in theinner medullary collecting duct.[21]
Amiloride has a second action on the heart, blocking Na+/H+ exchangers such assodium–hydrogen antiporter 1 (NHE-1).
Amiloride also blocks the Na+/H+ antiporter on the apical surface of theproximal tubule cells in the nephron, abolishing more than 80% of the action ofangiotensin II on the secretion of hydrogen ions in proximal tubule cells.[22] Amiloride is not anangiotensin II receptor blocker (likelosartan, for example). The Na-H transporter is also found in the Jejunum of the small intestine, as a result, amiloride also blocks the reabsorption of Na, and thereby water in the intestines.[23]
Amiloride is considered to be a reversible, pan-acid-sensing ion channel (ASIC) inhibitor that prevents the transient flow of ions but not the sustained flow of ions. ASICs are members of the ENaCfamily of protein channels, and are found in thenervous system, thecardiovascular system, thegastrointestinal system, and theskin. Broadly, ASICs are involved inharm detection,chemosensation (pH changes specifically), andtouch.[24]
Amiloride has an oralbioavailability of 50%, meaning that about 50% of an oral dose is absorbed into the blood stream. Coadministration with food reduces the amount of amiloride that is absorbed by the body by about 30%, though it does not affect the rate of absorption. However, taking amiloride with food helps to reduce the incidence of its gastrointestinal side effects. After being taken, amiloride's diuretic effect occurs within 2 hours, with peak diuresis within 6–10 hours. The diuretic effects of amiloride persist for about 24 hours after administration.[1]
Amiloride cross the placenta and distributes into breast milkin vivo.[1]
Amiloride is notmetabolized by the liver.[1] In comparison, the ENaC inhibitortriamterene is metabolized by the liver.[25]
About 50% of amiloride is excreted unchanged by the kidneys, while around 40% is excreted in the feces (likely drug that wasn't absorbed). Thehalf-life of amiloride in humans is between 6 and 9 hours, which may be prolonged in people with poor kidney function.[1]
Asingle nucleotide polymorphism (SNP) in the proteinNEDD4L may impact how amiloride affects a person's blood pressure in cases ofhypertension (high blood pressure).[26]
Amiloride is a pyrazinoylguanidine, composed of a substitutedpyrazine ring structure with a carbonylguanidinium substituent.[27] Amiloride's pKa is 8.67, which is due to theguanidinium group.[27] In high pH (alkaline, lowhydrogen concentration) environments, the guanidinium group is deprotonated and the compound is rendered neutral, depleting its activity on sodium channels.[27] Amiloride, as a pure substance, is highlyfluorescent, withexcitation wavelengths at 215, 288, and 360 nm,emitting light at 420 nm.[28]
Amiloride was first synthesized and discovered by the Merck Sharp and Dohme Research Laboratories in the late 1960s.[27] The drug was discovered as part of a screening process of chemicals that reversed the effects of mineralocorticoidsin vivo.[27] Amiloride was the only drug in the screen that was capable of causing the excretion of sodium (natriuresis) without a concomitant urinary excretion of potassium (kaliuresis).[27] Thousands of amiloride analogues have been studied since its initial discovery, which have been used to study the effects of sodium transporters.[27]
Amiloride was approved by the U.S.Food and Drug Administration (FDA) on October 5, 1981.[29]
It is on theWorld Health Organization's List of Essential Medicines.[5]
Amiloride is on theWorld Anti-Doping Agency's list of banned substances, as it is considered amasking agent.[30] Diuretics like amiloride act as masking agents by reducing the concentration of other doping agents due to promoting diuresis, increasing the total volume of the urine.[25] The list includes other potassium-sparing diuretics, such astriamterene andspironolactone.[30] In 2008, amiloride and the potassium-sparing diuretictriamterene were found in 3% of positive diuretic doping samples.[25]
Amiloride is an inhibitor of NHE-1, which helps to maintain normal pH within cells. Cancer cells inleukemia, a type of blood cancer, have higher pH compared to normal cells. Amiloride affects thesplicing andregulation of multiple genes involved in cancer, though they do not appear to be directly related to its effects on pH. Amiloride has been testedin vitro as an adjunct to the anticancer drugimatinib, which appeared to show a synergistic effect. Modified versions of amiloride, known as 5'-(N,N-dimethyl)-amiloride (DMA), 5-N-ethyl-N-isopropyl amiloride (EIPA), and 5-(N,N-hexamethylene)-amiloride (HMA), are being studied for the treatment ofleukemia.[31]
Cystic fibrosis is a genetic disorder due to a mutation in theCFTR gene, which encodes for the CFTR chloride channel.[19] There is evidence that suggests that the molecular target of amiloride, ENaC, is also implicated in cystic fibrosis due to its effects on mucus in the lungs.[19] Aerosolized formulations of amiloride have been tested in clinical trials, though long-term clinical trials have failed to show much utility.[19] Due to its short duration of action, it was thought that longer-acting ENaC inhibitors may prove more effective.[32] However, longer-acting ENaC inhibitors (i.e.benzamil) have also failed clinical trials, despite an improvement in both the solubility and potency of the drugs.[19] A third generation amiloride analogue (N-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N'-4-[4-(2,3-dihydroxypropoxy)phenyl]butyl-guanidine methanesulfonate,[33] research name "552-02"), with betterpharmacokinetic properties, is being studied.[19]
![Side-by-side comparison of the chemical structures of amiloride and one of its analogues, research name 552-02 (N-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N'-4-[4-(2,3-dihydroxypropoxy)phenyl]butyl-guanidine methanesulfonate).](/mt/?noimg=&dark=on&url=http%3a%2f%2fen.wikipedia.org%2fwiki%2fFile%3aAmiloride55202.jpg)
Pain induced by exposure to acid is attenuated by amiloride in human trials, which may indicate a role for amiloride in the treatment of pain in the future.[19]
Media related toAmiloride at Wikimedia Commons
