Amiloride Hydrochloride
(British Approved Name Modified, US Adopted Name, rINNM)
Drug Nomenclature
INNs in main languages (French, Latin, Russian, and Spanish):
Note. Compounded preparations of amiloride hydrochloride may be represented by the following names:
• Co-amilofruse (BAN)—amiloride hydrochloride 1 part and furosemide 8 parts (w/w)
• Co-amilozide (BAN)—amiloride hydrochloride 1 part and hydrochlorothiazide 10 parts (w/w)
• Co-amilozide (PEN)—amiloride hydrochloride and hydrochlorothiazide.
Pharmacopoeias. In China, Europe, International, and US.
European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Amiloride Hydrochloride). A pale yellow to greenish-yellow powder. Slightly soluble in water and in dehydrated alcohol. Protect from light.
The United States Pharmacopeia 31, 2008, and Supplements 1 and 2 (Amiloride Hydrochloride). A yellow to greenish-yellow, odourless or practically odourless, powder. Slightly soluble in water; insoluble in acetone, in chloroform, in ether, and in ethyl acetate; freely soluble in dimethyl surfoxide; sparingly soluble in methyl alcohol.
Adverse Effects
Amiloride can cause hyperkalaemia, particularly in elderly patients, diabetics, and patients with renal impairment. Hyponatraemia has been reported in patients taking amiloride with other diuretics. Amiloride may cause nausea, vomiting, abdominal pain, diarrhoea or constipation, paraesthesia, thirst, dizziness, skin rash, pruritus, weakness, muscle cramps, headache, and minor psychiatric or visual changes. Orthostatic hypotension and rises in blood-urea-nitrogen concentrations have been reported. Other adverse effects of amiloride may include alopecia, cough, dyspnoea, jaundice, encephalopathy, impotence, angina pectoris, arrhythmias, and palpitations.
Effects on electrolyte balance. There have been reports of metabolic acidosis associated with amiloride or triamterene and with co-amilozide.
POTASSIUM. Hyperkalaemia is the main adverse effect when amiloride is given alone but may also occur when amiloride is given with a potassium-wasting diuretic. Severe hyperkalaemia has been reported during co-amilozide therapy, particularly in patients with renal impairment and has been accompanied by metabolic acidosis in one such patient.
SODIUM. For reports of severe hyponatraemia in patients taking diuretics such as amiloride with potassium-wasting diuretics, see Hydrochlorothiazide.
Effects on the skin. For a report of photosensitivity reactions in patients taking co-amilozide, see Hydrochlorothiazide.
Precautions
Amiloride has the same precautions as spironolactone with regard to hyperkalaemia. It should be stopped at least 3 days before glucose-tolerance tests are performed in patients who may have diabetes mellitus because of the risks of provoking severe hyperkalaemia.
Interactions
There is an increased risk of hyperkalaemia if amiloride is given with potassium supplements or with other potassium-sparing diuretics. Hyperkalaemia may also occur in patients given amiloride with ACE inhibitors, angiotensin II receptor antagonists, NSAIDs, ciclosporin, or trilostane. In patients taking amiloride with NSAIDs or ciclosporin the risk of nephrotoxicity may also be increased. Diuretics may reduce the excretion of lithium and increase the risk of lithium toxicity, but this does not appear to occur with amiloride. Severe hyponatraemia may occur in patients taking a potassium-sparing diuretic with a thiazide; this risk may be increased in patients taking chlorpropamide. Amiloride may reduce the ulcer-healing properties of carbenoxolone. As with other diuretics, amiloride may enhance the effects of other antihypertensive drugs.
Digoxin. For the effects of amiloride on digoxin clearance.
Quinidine. For a report of amiloride producing arrhythmias in patients receiving quinidine.
Pharmacokinetics
Amiloride is incompletely absorbed from the gastrointestinal tract; bioavailability is about 50% and is reduced by food. It is not significantly bound to plasma proteins and has a plasma half-life of 6 to 9 hours; the terminal half-life may be 20 hours or more. It is excreted unchanged by the kidneys.
Hepatic impairment. In patients with acute hepatitis the terminal half-life of amiloride was 33 hours compared with 21 hours in healthy subjects. The proportion of the dose excreted in the urine was increased from 49 to 80%.
Renal impairment. Studies of the pharmacokinetics of amiloride have reported an increase in terminal elimination half-life from 20 hours in healthy subjects to 100 hours in patients with end-stage renal disease. The natriuretic effect of amiloride was reduced in patients with creatinine clearance below 50 mT/minute. In patients with renal impairment amiloride could aggravate potassium retention due to renal disease. Studies in elderly patients have found increased half-life and steady-state concentrations associated with reduced renal function.
Uses and Administration
Amiloride is a weak diuretic that appears to act mainly on the distal renal tubules. It is described as potassium-sparing since, like spironolactone, it increases the excretion of sodium and reduces the excretion of potassium. Unlike spironolactone, however, it does not act by specifically antagonising aldosterone. Amiloride does not inhibit carbonic anhydrase. It takes effect about 2 hours after oral dosage and its diuretic action reaches a peak in 6 to 10 hours and has been reported to persist for about 24 hours.
Amiloride diminishes the kaliuretic effects of other diuretics, and may produce an additional natriuretic effect. It is mainly used as an adjunct to thiazide diuretics such as hydrochlorothiazide and loop diuretics such as furosemide, to conserve potassium in those at risk from hypokalaemia during the long-term treatment of oedema associated with hepatic cirrhosis (including ascites) and heart failure. It is also used with other diuretics in the treatment of hypertension. Diuretic-induced hypokalaemia and its management, including the role of potassium-sparing diuretics such as amiloride, is discussed under Effects on Electrolyte Balance in the Adverse Effects of Hydrochlorothiazide. Amiloride is sometimes used to manage hypokalaemia in primary hyperaldosteronism.
Amiloride by inhalation has also been investigated in the management of cystic fibrosis patients with lung disease (see below).
In the treatment of oedema amiloride is given orally as the hydrochloride and doses are expressed in terms of the anhydrous substance. 1 mg of anhydrous hydro-chloride is equivalent to about 1.14 mg of the hydrated sub stance. Treatment may be started with a dose of 5 to 10 mg daily, increased, if necessary, to a maximum of 20 mg daily. An initial dose of 2.5 mg once daily may be used in patients already taking other diuretics or antihypertensives. Similar doses to those given for oedema are used to reduce potassium loss in patients receiving thiazide or loop diuretics. Potassium supplements should not be given.
Cystic fibrosis. Pulmonary disease is the major cause of mortality in cystic fibrosis. Experimental treatment aimed at modifying the pulmonary disease process has included giving amiloride by inhalation. No evidence of pulmonary or systemic toxicity was seen in 14 patients treated for 25 weeks. The mechanism of action is unclear but could be the sodium-channel blocking effect or anti-inflammatory effects of amiloride. Concern has been expressed over possible consequences of the inhibition of endogenous urokinase by amiloride although others considered this to be unlikely at the concentrations studied. However, a systematic review found no evidence that amiloride was of clinical benefit.
Diabetes insipidus. Thiazide diuretics are commonly used in nephrogenic diabetes insipidus and NSAfDs may also be employed; both result in an overall decrease in urine production. Hydrochlorothiazide with amiloride has been reported to be at least as effective as hydrochlorothiazide plus indometacin in 5 patients. In addition, amiloride obviated the need for potassium supplements. Hydrochlorothiazide with amiloride was also effective and well tolerated in a group of 4 children with nephrogenic diabetes insipidus who were treated for up to 5 years.
Renal calculi. Patients with idiopathic hypercalciuria and a history of renal calculi are usually given a thiazide diuretic such as hydrochlorothiazide to reduce calcium excretion. In patients with calcium oxalate calculi an inherited cellular defect in oxalate transport may also be involved and this might be corrected by amiloride.
Preparations
British Pharmacopoeia, 2008: Amiloride Tablets; Co-amilofruse Tablets; Co-amilozide Oral Solution; Co-amilozide Tablets;
The United States Pharmacopeia 31, 2008, and Supplements 1 and 2: Amiloride Hydrochloride and Hydrochlorothiazide Tablets; Amiloride Hydrochloride Tablets.
Single-ingredient Preparations
The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.
Australia: Amidal¤; Kaluril; Midamor; Midoride¤; Austria: Midamor; Canada: Midamor; Czech Republic: Amiclaran; Denmark: Amikal¤; Nirulid; Finland: Medamor; France: Modamide; Hong Kong: Midamor¤; Ireland: Berkamil¤; Netherlands: Midamor¤; Norway: Midamor¤; New Zealand: Midamor; Sweden: Amikal¤; Midamor; Switzerland: Midamor; United Kingdom: Amilamont; Amilospare¤; Berkamil¤; Midamor¤; United States: Midamor
Multi-ingredient Preparations
Argentina: Amiloclor; Diflux; Diur Pot; Diurex A; Errolon A; Furdiuren; Hidrenox A; Lasiride; Moducren¤; Moduretic; Nuriban A; Plenacor D; Prenomod¤; Ren-Ur; Vericordin Compuesto; Australia: Amizide; Hydrozide¤; Modizide¤; Moduretic; Austria: Aldoretic; Amiloral/HCT; Amiloretik; Amilorid comp; Amilorid/HCT¤; Amilostad HCT; Lanuretic; Loradur; Moducrin; Moduretic; Belgium: Belidral¤; Frusamil; Kalten¤; Moduretic; Brazil: Amiretic; Diupress; Diurisa; Moduretic; Canada: Apo-Amilzide; Moduret; Novamilor; Nu-Amilzide; Chile: Furdiuren; Hidrium; Hidropid; Czech Republic: Amicloton; Amilorid/HCT; Apo-Amilzide; Limorid; Loradur; Moduretic; Rhefluin; Denmark: Amilco; Amilohyd¤; Buram; Frusamil; Hydronet¤; Moduretic; Sparkal; Finland: Amitrid; Diuramin; Diurex; Miloride; Moduretic; Sparkal; France: Logirene; Moducren; Moduretic; Germany: Amiduret¤; Amilo-OPT¤; Amilocomp beta; Amiloretik; Amilorid comp; Amilorid/HCT; Amilothiazid¤; Amilozid; Aquaretic¤; Combiprotect¤; Diaphal; Dignoretik¤; Diursan; durarese; Esmalorid; Hydrocomp¤; Minoremed¤; Modu-Puren¤; Moducrin; Moduretik; Rhefluin¤; Tensoflux; Greece: Frumil; Ividol; Moduretic; Tiaden; Hong Kong: Amilco¤; Amithiazide; Apo-Amilzide; Frumil¤; Hydrozide¤; Moducren; Moduretic; Navispare; Sefaretic; Hungary: Amilozid-B; India: Biduret; Frumil; Hipres-D; Ireland: Amilco¤; Amizide¤; Buram; Clonuretic¤; Fru-Co; Frumil; Lasoride¤; Moducren; Moduret; Moduretic¤; Navispare¤; Israel: Kaluril; Italy: Moduretic; Malaysia: Ami-Hydrotride; Amizide; Apo-Amilzide; Moduretic¤; Mexico: Moducren¤; Moduretic; Netherlands: Elkin¤; Hykaten¤; Moducren¤; Moduretic; Norway: Moduretic; Normorix; New Zealand: Amizide; Frumil; Hydrozide¤; Moduretic¤; Portugal: Aldoretic; Amiloride Composto; Chibretico¤; Diurene; Moducren; Moduretic; South Africa: Acumod¤; Adco-Retic; Aldoretic¤; Amiloretic; Amizide¤; Aquadrex¤; Arcanaretic¤; Betaretic; Cliniretic¤; Diutec¤; Hexaretic; Moducren; Moduretic; Servatrin; Trimolex¤; Singapore: Apo-Amilzide; Spain: Ameride; Diuzine; Donicer¤; Frusamil¤; Kalten; Sweden: Amiloferm; Moduretic; Normorix; Sparkal; Switzerland: Agorex; Aldoretic¤; Amilo-basan; Amilorid comp¤; Amiloride/HCTZ; Betadiur¤; Co-Amilorid¤; Comilorid; Ecodurex; Escoretic; Esmaloride¤; Frumil; Grodurex; Hydrolid¤; Kalten; Modisal¤; Moducren; Moduretic; Rhefluin; Thailand: Amilhydrozide¤; Amilide¤; Bilduretic; Hydrozide Plus; Hyperretic; Miduret¤; Milorex¤; Miretic; Modulan; Moduretic; Poli-Uretic; Renase; Sefaretic; United Kingdom: Amil-Co; Amilmaxco¤; Aridil; Burinex A; Delvas¤; Froop Co; Fru-Co; Frumil; Frusemek¤; Hypertane¤; Kalten; Komil; Lasoride; Moducren; Moduret; Moduretic; Navispare; Normetic¤; Synuretic¤; Vasetic¤; Zida-Co¤; United States: Moduretic; Venezuela: Furdiuren; Moduretic
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