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AMILORIDE
Introduction
Amiloride is a mild potassium sparing diuretic and antihypertensive agent.
Its action is different to the more commonly used aldosterone antagonists. Rather than
acting indirectly by blocking the action of aldosterone, it acts directly by blocking sodium
channels in the distal tubule.
Its principal use is essentially to conserve potassium in patients receiving loop or thiazide
diuretics in whom excessive potassium losses occur or are expected.
Its principle adverse reaction is hyperkalemia.
History
Amiloride (then known as MK 870), was introduced into clinical use in 1967 for the
management of hypertension and congestive heart failure.
Amiloride was also tested as a treatment for cystic fibrosis, but it was shown in vivo to
have too short an action to be of clinical use in this disease.
Classification
The principle classes of diuretic agents include:
1.
The thiazides:
●
Bendroflumethiazide
●
Chlorothiazide
●
Hydrochlorothiazide
●
Chlorthalidone
●
Indapamide
●
Methyclothiazide
●
Metolazone
2.
3.
The loop diuretics:
●
Frusemide
●
Bumetanide
●
Ethacrynic acid
The potassium sparing diuretics:
●
●
4.
♥
Spironolactone
♥
Eplerenone
Direct sodium channel blockers in the distal tubule:
♥
Amiloride.
♥
Triamterene
The carbonic anhydrase inhibitors:
●
5.
The aldosterone antagonists:
Acetozolamide
The osmotic diuretics:
●
Mannitol
Preparation
Amiloride hydrochloride as:
Tablets:
●
5 mg.
Fixed-dose combination:
●
Fixed-dose combination preparations with 50 mg hydrochlorothiazide are
available.
Mechanism of Action
Amiloride is a weak potassium sparing diuretic agent.
It inhibits sodium reabsorption in the distal tubule by directly blocking sodium
channels.
As a result, it interferes with sodium/potassium exchange and reduces urinary potassium
excretion, thus elevating plasma potassium levels.
As amiloride hydrochloride is not an aldosterone antagonist its effects are seen even in
the absence of aldosterone.
Pharmacodynamics
Amiloride’s actions include:
1.
A mild diuretic agent
2.
Mild antihypertensive:
3.
●
When used in recommended low doses for hypertension, thiazides lower
blood pressure mostly by a vasodilator effect.
●
When combined with hydrochlorothiazide, amiloride produces an additive
antihypertensive effect.
It does not result in potassium loss.
Amiloride usually acts within 2 hours after an oral dose.
Its effect on electrolyte excretion reaches a peak between 6 - 10 hours.
It duration of action lasts approximately 24 hours.
Effects on electrolytes increase with single doses of amiloride hydrochloride up to
approximately 15 mg.
Pharmacokinetics
Absorption:
●
Amiloride is administered orally.
Distribution:
●
Protein binding is insignificant. 4
●
It is thought likely that some placental transfer can occur. 4
Metabolism and excretion:
●
Amiloride hydrochloride is not metabolised by the liver but is excreted unchanged
by the kidneys.
About 50 % of a 20 mg dose of amiloride hydrochloride is excreted in the urine
and 40 % in the stool within 72 hours.
Indications
Indications include: 2
1.
Prevention of diuretic-induced hypokalaemia:
●
Its principal use is essentially to conserve potassium in patients
receiving diuretic agents in whom excessive potassium losses occur or are
expected.
2.
Oedema due to heart failure, hepatic cirrhosis or nephrotic syndrome, as an
adjunct to thiazides or loop diuretics.
3.
Hypertension
4.
Primary hyperaldosteronism, (second line to the aldosterone antagonists).
In Fixed-dose combination with hydrochlorothiazide:
1.
Hypertension
2.
Oedema due to heart failure or hepatic cirrhosis
Contra-indications/precautions
These include:
1.
Known hypersensitivity to amiloride.
2.
Hyperkalaemia: 2
●
Contraindicated if serum potassium concentration > 5 mmol/L.
Avoid use or use cautiously if potassium is > 3.5 mmol/L.
3.
Renal failure (contraindicated):
●
Renal impairment increases risk of hyperkalaemia.
Anuria, acute renal failure, severe progressive renal disease, and diabetic
nephropathy are all contraindications to the use of amiloride
hydrochloride.
4.
Debilitated patients with cardiopulmonary disease or uncontrolled diabetes:
●
5.
Drug interactions:
●
6.
The is an increased risk of hyperkalaemia and respiratory or metabolic
acidosis. 2
Amiloride should not be used in combination with agents that raise
potassium levels, such as, ACE inhibitors, sartans, aldosterone
antagonists or potassium supplements, as severe hyperkalemia may
result.
Contraindicated in pregnancy (see below).
Pregnancy:
Amiloride is a category C drug with regard to pregnancy.
Category C drugs are those drugs which, owing to their pharmacological effects, have
caused or may be suspected of causing harmful effects on the human fetus or neonate
without causing malformations. These effects may be reversible. Specialised texts should
be consulted for further details.
There is still a lack of safety information on the use of amiloride during pregnancy. A
small number of case reports have shown that the use of amiloride during pregnancy has
not been associated with an increased risk of fetal adverse effects or congenital
malformations. Theoretically, diuretics have the potential to decrease plasma volume,
cardiac output and uteroplacental perfusion. 4
If amiloride is the medicine of choice during pregnancy, closely monitor maternal and
fetal progress and electrolyte levels, particularly potassium levels. 4
Breast feeding:
There are no published reports describing the use amiloride during breastfeeding.
Historically, diuretics may reduce breast milk production.
If amiloride is the medicine of choice during breastfeeding, monitor breast milk supply
and observe the breastfed infant for possible side effects, such as dry mouth, poor
feeding, vomiting and constipation. 4
Adverse Effects
1.
GIT upset.
2.
Postural hypotension
3.
Hyperkalemia:
This is the principle adverse reaction of amiloride.
It is especially prone to occur in:
●
Patients with renal failure
●
Patients concomitantly taking other agents which elevate the serum
potassium.
Dosing 2
Daily dose is usually taken in the morning (may be taken in 2 doses).
Adults:
Prevention of diuretic-induced hypokalaemia:
●
2.5 - 5 mg daily.
Oedema:
●
Initially 5 mg daily; may be increased up to a maximum of 20 mg daily; after
diuresis, gradually reduce to lowest effective dose.
Hypertension:
●
5-10 mg daily; may be increased up to a maximum of 20 mg daily.
Primary hyperaldosteronism:
●
5-20 mg daily; higher doses have been used, seek specialist advice.
Fixed-dose combination with hydrochlorothiazide:
●
Hypertension, initially half a tablet once daily; if necessary, increase to 1 tablet
daily.
●
Oedema, initially 1–2 tablets daily; may be increased up to a maximum of 4
tablets daily; after diuresis, gradually reduce to lowest effective dose.
Appendix 1
Sites of action of the 5 principle groups of diuretic agents:
(Cassandra Uy - www.pathophys.org/diuretics/)
References
1.
eTG - November 2015
2.
Amiloride in Australian Medicines Handbook Website, Accessed May 2016.
3.
Amiloride in MIMs Website, 1 November 2013.
4.
Amiloride in RWH Pregnancy & Breastfeeding Guidelines, 27 February 2015.