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.
Amiloride is a guanidinium group containing pyrazine derivative.
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
- co-amilozide (amiloride hydrochloride with hydrochlorothiazide)
- ^ (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 and 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. PMID 12620920. doi:10.1152/ajprenal.00217.2002.
- ^ LoSalt Advisory Statement (PDF)
- ^ Walter F., PhD. 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'
- PAMs (abridged; see here for a full list): α-EMTBL
- Alcohols (e.g., ethanol)
- Avermectins (e.g., ivermectin)
- Barbiturates (e.g., phenobarbital)
- Benzodiazepines (e.g., diazepam)
- Bromide compounds (e.g., potassium bromide)
- Carbamates (e.g., meprobamate)
- Dihydroergolines (e.g., ergoloid (dihydroergotoxine))
- Fenamates (e.g., mefenamic acid)
- Flavonoids (e.g., apigenin, hispidulin)
- Imidazoles (e.g., etomidate)
- Kava constituents (e.g., kavain)
- Neuroactive steroids (e.g., allopregnanolone, cholesterol)
- Nicotinamide (niacinamide)
- Nonbenzodiazepines (e.g., β-carbolines (e.g., abecarnil), cyclopyrrolones (e.g., zopiclone), imidazopyridines (e.g., zolpidem), pyrazolopyrimidines (e.g., zaleplon))
- Phenols (e.g., propofol)
- Piperidinediones (e.g., glutethimide)
- Pyrazolopyridines (e.g., etazolate)
- Quinazolinones (e.g., methaqualone)
- Retigabine (ezogabine)
- Skullcap constituents (e.g., baicalin)
- Sulfonylalkanes (e.g., sulfonmethane (sulfonal))
- Valerian constituents (e.g., valerenic acid)
- Volatiles/gases (e.g., chloral hydrate, chloroform, diethyl ether, paraldehyde, sevoflurane)
- NAMs: 1,3M1B
- α5IA (LS-193,268)
- β-Lactams (e.g., penicillins, cephalosporins, carbapenems)
- FG-7142 (ZK-31906)
- Fiproles (e.g., fipronil)
- Flavonoids (e.g., amentoflavone, oroxylin A)
- Fluoroquinolones (e.g., ciprofloxacin)
- Iomazenil (123I)
- Isopregnanolone (sepranolone)
- Pentetrazol (metrazol)
- Picrotoxin (i.e., picrotin and picrotoxinin)
- Pregnenolone sulfate
- Ro 15-4513
- Ro 19-4603
- PAMs: Alcohols (e.g., brometone, chlorobutanol (chloretone), ethanol, tert-butanol (2M2P), tribromoethanol, trichloroethanol, trifluoroethanol)
- Alkylbenzene sulfonate
- Barbiturates (e.g., pentobarbital, sodium thiopental)
- Dihydropyridines (e.g., nicardipine)
- Ginseng constituents (e.g., ginsenosides (e.g., ginsenoside-Rf))
- Glutamic acid (glutamate)
- Neuroactive steroids (e.g., alfaxolone, pregnenolone (eltanolone), pregnenolone acetate, minaxolone, Org 20599)
- Nitrous oxide
- Penicillin G
- Tropeines (e.g., atropine, bemesetron, cocaine, LY-278584, tropisetron, zatosetron)
- Volatiles/gases (e.g., chloral hydrate, chloroform, desflurane, diethyl ether (ether), enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, toluene, trichloroethane (methyl chloroform), trichloroethylene)
- Antagonists: 2-Aminostrychnine
- Endocannabinoids (e.g., 2-AG, anandamide (AEA))
- Gaboxadol (THIP)
- Isobutyric acid
- Isonipecotic acid
- Nipecotic acid
- Quinolines (e.g., 4-hydroxyquinoline, 4-hydroxyquinoline-3-carboxylic acid, 5,7-CIQA, 7-CIQ, 7-TFQ, 7-TFQA)
- NAMs: Amiloride
- Benzodiazepines (e.g., bromazepam, clonazepam, diazepam, flunitrazepam, flurazepam)
- Dihydropyridines (e.g., nicardipine, nifedipine, nitrendipine)
- Ginkgo constituents (e.g., bilobalide, ginkgolides (e.g., ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, ginkgolide M))
- Neuroactive steroids (e.g., 3α-androsterone sulfate, 3β-androsterone sulfate, deoxycorticosterone, DHEA sulfate, pregnenolone sulfate, progesterone)
- Opioids (e.g., codeine, dextromethorphan, dextrorphan, levomethadone, levorphanol, morphine, oripavine, pethidine, thebaine)
- Picrotoxin (i.e., picrotin and picrotoxinin)
- Tropeines (e.g., bemesetron, LY-278584, tropisetron, zatosetron)