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Amiloride, sold under the trade name Midamor among others, is a medication typically used with other medications to treat high blood pressure or swelling due to heart failure or cirrhosis of the liver.
Common side effects include high blood potassium, vomiting, loss of appetite, rash, and headache.
Amiloride was developed in 1967.
Contents
1 Medical uses
1.1 Specific populations
1.1.1 Diabetics
1.1.2 Poor kidney function
1.1.3 Lactation
1.1.4 Pregnancy
2 Contraindications
3 Adverse effects
4 Overdose
5 Pharmacology
5.1 Mechanism of action
5.1.1 Diuresis
5.1.2 Miscellaneous
5.2 Pharmacokinetics
5.2.1 Absorption
5.2.2 Distribution
5.2.3 Metabolism
5.2.4 Excretion
5.3 Pharmacogenomics
6 Chemistry
7 History
8 Society and culture
8.1 Formulations and trade names
9 Research
10 References
Medical uses
Amiloride can be used as a monotherapy (single-drug therapy) or an adjunctive therapy alongside other diuretics (e.g. hydrochlorothiazide, furosemide ) for the treatment of ascites and edema (swelling) due to cirrhosis of the liver.
As an adjunct to other diuretics, amiloride can be use to reduce edema due to heart failure or high blood pressure in people that have low blood potassium (hypokalemia) or in people for which maintaining a normal level of potassium is critically important for their health.
Amiloride is also used in the treatment of Liddle syndrome, a rare genetic disorder that causes mutations in the genes that encode for the ENaC channel (where amiloride acts). Because Liddle syndrome usually involves an upregulation of ENaC channels, leading to hypokalemia, amiloride is a useful as an ENaC channel inhibitor due to its potassium-sparing effects, restoring potassium to normal levels.
Specific populations
Diabetics
People with diabetes are at higher risk for kidney 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.
Poor kidney function
People with poor kidney function (e.g. blood urea nitrogen >30 mg/dL, or serum creatinine >1.5 mg/dL) are at high risk for hyperkalemia.
Lactation
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.
Pregnancy
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 drug acetazolamide during the process of organ formation, amiloride increases the risk for kidney and ureter abnormalities. Limited human data from use during pregnancy suggests an association with a specific congenital penis abnormality if taken during the first trimester, as well as a risk for mild intrauterine growth restriction if taken throughout pregnancy.
Contraindications
Amiloride is contraindicated in people with kidney problems (e.g. anuria, acute or chronic renal insufficiency, or diabetic 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 and triamterene ) or whom are taking potassium supplements (e.g. potassium chloride) in most circumstances.
Adverse effects
Amiloride is generally well-tolerated.
Overdose
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.
Pharmacology
Mechanism of action
Diuresis
Amiloride works by directly blocking the epithelial sodium channel (ENaC) with an IC 50 around 0.1 μM, indicating potent blockade. This promotes the loss of sodium and water from the body, and reduces potassium excretion. The drug is often used in conjunction with a thiazide diuretic to counteract the 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 taking ACE inhibitors, angiotensin II receptor antagonists, other potassium-sparing diuretics, or any potassium-containing supplements.
Miscellaneous
A fraction of the effects of amiloride is inhibition of cyclic GMP-gated cation channels in the inner medullary collecting duct.
Amiloride has a second action on the heart, blocking Na + /H + exchangers sodium–hydrogen antiporter 1 or NHE-1. This minimizes re-perfusion injury in ischemic attacks.
Amiloride also blocks the Na + /H + antiporter on the apical surface of the proximal tubule cells in the nephron, abolishing more than 80% of the action of angiotensin II on the secretion of hydrogen ions in proximal tubule cells. Note that amiloride is not an angiotensin II receptor blocker (like losartan, for example).
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 ENaC family of protein channels, and are found in the nervous system, the cardiovascular system, the gastrointestinal system, and the skin. Broadly, ASICs are involved in harm detection, chemosensation (pH changes specifically), and touch.
Pharmacokinetics
Absorption
Amiloride has an oral bioavailability 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.
Distribution
Amiloride cross the placenta and distributes into breast milk in vivo.
Metabolism
Amiloride is not metabolized by the liver.
Excretion
About 50% of amiloride is excreted unchanged by the kidneys, while around 40% is excreted in the feces (likely drug that wasn’t absorbed). The half-life of amiloride in humans is between 6 and 9 hours, which may be prolonged in people with poor kidney function.
Pharmacogenomics
A single nucleotide polymorphism (SNP) in the protein NEDD4L may impact how amiloride affects a person’s blood pressure in people with high blood pressure.
Chemistry
A photograph of pure amiloride HCl powder.
Amiloride’s chemical structure is composed of a substituted pyrazine ring structure with a carbonylguanidinium substituent.
Light at wavelength 420nm. This is the emission wavelength for light due to amiloride fluorescence.
History
Amiloride was first synthesized and discovered by the Merck Sharp and Dohme Research Laboratories in the late 1960s.
Amiloride was approved by the U.S. Food and Drug Administration (FDA) on October 5, 1981.
Society and culture
It is on the World Health Organization’s List of Essential Medicines, the most important medications needed in a basic health system.
Amiloride is listed on the World Anti-Doping Agency’s list of banned substances, as it is considered a masking agent.
Formulations and trade names
Amiloride hydrochloride
Midamor (U.S.)
Co-amilozide (amiloride hydrochloride with hydrochlorothiazide )
Co-amilofruse (amiloride hydrochloride with furosemide )
Amiloride hydrochloride with cyclopenthiazide
Amiloride hydrochloride with bumetanide
Research
Amiloride is an inhibitor of NHE-1, which helps to maintain normal pH within cells. Cancer cells in leukemia, a type of blood cancer, have higher pH compared to normal cells. Amiloride affects the splicing and regulation of multiple genes involved in cancer, though they do not appear to be directly related to its effects on pH. Amiloride has been tested in vitro as an adjunct to the anticancer drug imatinib, 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 of leukemia.
Cystic fibrosis is a genetic disorder due to a mutation in the CFTR gene, which encodes for the CFTR chloride channel.
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.

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