Amiloride

Amiloride
Clinical data
Trade names	Midamor
AHFS/Drugs.com	Monograph
Routes of; administration	Oral
ATC code	C03DB01 (WHO) ;
Legal status
Legal status	UK: POM (Prescription only); US: ℞-only;
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)
Elimination half-life	6 to 9 hours
Excretion	Urine (20–50%), feces (40%)
Identifiers
	IUPAC name 3,5-diamino-6-chloro-N-(diaminomethylene)pyrazine-2-carboxamide;
CAS Number	2016-88-8 ;
PubChem CID	16231;
IUPHAR/BPS	2421;
DrugBank	DB00594 ;
ChemSpider	15403 ;
UNII	7M458Q65S3;
KEGG	D07447 ;
ChEBI	CHEBI:2639 ;
ChEMBL	ChEMBL945 ;
CompTox Dashboard (EPA)	DTXSID9043853 ;
ECHA InfoCard	100.018.205
Chemical and physical data
Formula	C6H8ClN7O
Molar mass	229.627 g/mol g·mol−1
3D model (JSmol)	Interactive image;
	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) ; Key:XSDQTOBWRPYKKA-UHFFFAOYSA-N ;
	(verify)

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.^[1]

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.^[2]

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).^[3] 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.^[4] 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.^[5]

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.^[6]

Acid-sensing ion channels (ASICs) are also sensitive to inhibition by amiloride. ASICs are involved in nociceptor responses to pH.^[7]

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

References

^ (Review)Pharmacological treatment of the biochemical defect in cystic fibrosis airways, H.C. Rodgers, A.J. Knoxhttp://erj.ersjournals.com/content/17/6/1314.full.pdf+html
^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
^ Loffing, Johannes; Kaissling, Brigitte (2003). "Sodium and calcium transport pathways along the mammalian distal nephron: from rabbit to human". Am J Physiol Renal Physiol. 284 (4): F628–F643. doi:10.1152/ajprenal.00217.2002. PMID 12620920.
^ LoSalt Advisory Statement (PDF)
^ Walter F. Boron. Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. ISBN 1-4160-2328-3. page 875
^ M G Cogan, Angiotensin II: a powerful controller of sodium transport in the early proximal tubule, Hypertension. 1990;15:451-458, doi: 10.1161/01.HYP.15.5.451, http://hyper.ahajournals.org/content/15/5/451
^ Hunt and Koltzenburg 2005 'The neurobiology of pain'

[1] (Review)Pharmacological treatment of the biochemical defect in cystic fibrosis airways, H.C. Rodgers, A.J. Knoxhttp://erj.ersjournals.com/content/17/6/1314.full.pdf+html

[2] "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.

[3] Loffing, Johannes; Kaissling, Brigitte (2003). "Sodium and calcium transport pathways along the mammalian distal nephron: from rabbit to human". Am J Physiol Renal Physiol. 284 (4): F628–F643. doi:10.1152/ajprenal.00217.2002. PMID 12620920.

[4] LoSalt Advisory Statement (PDF)

[boron875-5] Walter F. Boron. Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. ISBN 1-4160-2328-3. page 875

[6] M G Cogan, Angiotensin II: a powerful controller of sodium transport in the early proximal tubule, Hypertension. 1990;15:451-458, doi: 10.1161/01.HYP.15.5.451, http://hyper.ahajournals.org/content/15/5/451

[7] Hunt and Koltzenburg 2005 'The neurobiology of pain'

[1]

[2]

[3]

[4]

[5]

[6]

[7]

Structure

Contraindications

Mechanism of action

Formulations and trade names

See also

References