Amiloride

Amiloride

Systematic (IUPAC) name
3,5-diamino-6-chloro-N-(diaminomethylene)pyrazine-2-carboxamide
Clinical data
Trade names	Midamor
AHFS/Drugs.com	monograph
Pregnancy category	US: B (No risk in non-human studies)
Legal status	UK: POM (Prescription only) US: ℞-only
Routes of administration	Oral
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)
Biological half-life	6 to 9 hours
Excretion	Urine (20–50%), feces (40%)
Identifiers
CAS Number	2016-88-8 Y
ATC code	C03DB01 (WHO)
PubChem	CID: 16231
IUPHAR/BPS	2421
DrugBank	DB00594 Y
ChemSpider	15403 Y
UNII	7M458Q65S3 Y
KEGG	D07447 Y
ChEBI	CHEBI:2639 Y
ChEMBL	CHEMBL945 Y
Chemical data
Formula	C6H8ClN7O
Molecular mass	229.627 g/mol
SMILES Clc1nc(C(=O)\N=C(/N)N)c(nc1N)N
InChI InChI=1S/C6H8ClN7O/c7-2-4(9)13-3(8)1(12-2)5(15)14-6(10)11/h(H4,8,9,13)(H4,10,11,14,15) Y Key:XSDQTOBWRPYKKA-UHFFFAOYSA-N Y
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Amiloride is a potassium-sparing diuretic, first approved for use in 1967 (then known as MK 870), used in the management of hypertension and congestive heart failure. Amiloride was also tested as treatment of cystic fibrosis, but it was revealed inefficient in vivo due to its short time of action, therefore longer-acting epithelial sodium channel (ENaC) inhibitors may prove more effective, e.g. benzamil.

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.

Structure

Amiloride is a guanidinium group containing pyrazine derivative.

Contraindications

Amiloride is contraindicated in patients with Addison's disease, hyperkalaemia and anuria.

Mechanism of action

Amiloride works by directly blocking the epithelial sodium channel (ENaC) thereby inhibiting sodium reabsorption in the late distal convoluted tubules, connecting tubules, and collecting ducts in the kidneys (this mechanism is the same for triamterene). This promotes the loss of sodium and water from the body, but without depleting potassium. The drug is often used in conjunction with thiazide (e.g. co-amilozide) or loop diuretics (e.g. co-amilofruse). Due to its potassium-sparing capacities, hyperkalemia (high blood potassium levels) is occasionally observed in patients taking amiloride. The risk is high in concurrent use of ACE inhibitors or spironolactone. Patients are also advised not to use potassium-containing salt replacements. Amiloride also carries the risk of developing an acidosis.

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 reperfusion injury in ischemic attacks.

Amiloride also blocks the Na⁺/H⁺ antiporter on the apical surface of the proximal tubule cells, in the kidney, abolishing more than 80% of the action of angiotensin II on the secretion of hydrogen ions in proximal tubule cells.

Acid-sensing ion channels (ASICs) are also sensitive to inhibition by amiloride. ASICs are involved in nociceptor responses to pH.

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

See also

• Benzamil
• Triamterene
• Liddle's syndrome