Beta-agonist bronchodilators + Potassium-depleting drugs - Drug Interactions

Beta agonists (e.g. fenoterol,salbutamol (albuterol), terbutaline)can cause hypokalaemia. This can be increased by other potassium-depleting drugs such as corticosteroids, diuretics (e.g.bendroflumethiazide,furosemide) and theophylline. The risk ofserious cardiac arrhythmias in asthmatic patients may beincreased.

Hypokalaemia. The hypokalaemic effects of beta2 agonists may be increased by corticosteroids. Twenty-four healthy subjects had a fall in their serum potassium levels when they were given either salbutamol (albuterol) 5mg or fenoterol 5mg by nebuliser over 30 minutes. The fall in potassium levels was increased after they took prednisone 30mg daily for a week. The greatest fall (from 3.75 to 2.78 mmol/L) was found 90 minutes after fenoterol and prednisone were taken. The ECG effects observed included ectopic beats and transient T wave inversion,but no significant ECG disturbances were noted in these healthy subjects (See reference number 1).

Anti-inflammatory/bronchodilator effects. A marked rise in asthma deaths was noted in New Zealand in 1980s. A case-control study found that risk of death was increased in oral corticosteroid-dependent asthmatics (severe asthma) who were also taking inhaled fenoterol (See reference number 2). This, and other data, suggested possibility that combined use of short-acting beta2 agonists and corticosteroids might be deleterious in some situations, prompting numerous studies, which were reviewed in 2000 (See reference number 3). The overall findings were, that although inhaled corticosteroids do not prevent pro-inflammatory effects of short-acting beta2 agonists, combination is beneficial in treatment of asthma at usual therapeutic doses of both drugs. The authors caution that this might not apply with excessive use of short-acting beta2 agonists (See reference number 3). The addition of a long-acting beta2 agonist (e.g. salmeterol) to treatment in patients with chronic asthma inadequately controlled by inhaled corticosteroids and as required short-acting beta2 agonists is beneficial (See reference number 3,4).

The serum potassium level of 15 healthy subjects was measured after they were given inhaled terbutaline 5mg with either a placebo,furosemide 40mg daily, or furosemide 40mg with triamterene 50mg daily for 4 days. With terbutaline alone potassium levels fell by 0.53 mmol/L; after taking furosemide as well they fell by 0.75 mmol/L; and after furosemide and triamterene they fell by 0.59 mmol/L. These falls were reflected in some ECG (T wave) changes (See reference number 5).

After 7 days of treatment with bendroflumethiazide 5mg daily serum potassium levels of 10 healthy subjects had fallen by 0.71 mmol/L. After taking 100 micrograms to 2mg of inhaled salbutamol (albuterol) as well, levels fell by 1.06 mmol/L,to 2.72 mmol/L. ECG changes consistent with hypokalaemia and hypomagnesaemia were seen (See reference number 6). In another study same authors found that addition of bendroflumethiazide 5mg daily to inhaled salbutamol 2mg further reduced serum potassium levels by 0.4 mmol/L,to 2.92 mmol/L. This reduction was abolished by addition of triamterene 200mg (serum potassium increased to 3.43 mmol/L) or spironolactone 100mg (serum potassium increased to 3.53 mmol/L) but triamterene 50mg only attenuated effect of bendroflumethiazide (serum potassium 3.1 mmol/L). ECG effects with this combination were also reduced by addition of triamterene or spironolactone (See reference number 7).

Other diuretics that can cause potassium loss include bumetanide, furosemide, etacrynic acid, thiazides, and many other related diuretics, see table 1 below,.

The concurrent use of salbutamol (albuterol) or terbutaline and theophylline can cause an additional fall in serum potassium levels,and other beta2 agonists will interact similarly. See Theophylline + Beta-agonist bronchodilators interaction.

Established interactions. The CSM in UK(See reference number 8) advises that, as potentially serious hypokalaemia may result from beta2 agonist therapy, particular caution is required in severe asthma, as this effect may be potentiated by theophylline and its derivatives, corticosteroids, diuretics, and by hypoxia. Hypokalaemia with concurrent use of thiazide and loop diuretics may be reduced or even abolished by addition of spironolactone or high-dose triamterene. Plasma potassium levels should therefore be monitored in patients with severe asthma. Hypokalaemia may result in cardiac arrhythmias in patients with ischaemic heart disease and may also affect response of patients to drugs such as digitalis glycosides and antiarrhythmics.

Note that combined use of beta2 agonists and corticosteroids in asthma is usually beneficial

Taylor DR,Wilkins GT, Herbison GP, Flannery EM. Interaction between corticosteroid and :5.5pt; font-weight:normal; color:#000000″>βagonist drugs. Biochemical and cardiovascular effects in normal subjects. Chest (1992) 102, 519–24.

Crane J,Pearce N, Flatt A, Burgess C, Jackson R, Kwong T, Ball M, Beasley R. Prescribedfenoterol and death from asthma in New Zealand, 1981–1983: case-control study. Lancet (1989) i, 917–22.

Taylor DR,Hancox RJ. Interactions between corticosteroids and :5.5pt; font-weight:normal; color:#000000″>β agonists. Thorax (2000) 55, 595–602.

Shrewsbury S,Pyke S, Britton M. Meta-analysis of increased dose of inhaled steroid or addition of salmeterol in symptomatic asthma (MIASMA). BMJ (2000) 320, 1368–73.

Newnham DM,McDevitt DG, Lipworth BJ. The effects of frusemide and triamterene on thehypokalaemic and electrocardiographic responses to inhaled terbutaline. Br J Clin Pharmacol (1991) 32, 630–2.

Lipworth BJ,McDevitt DG, Struthers AD. Prior treatment with diuretic augments the hypokalemic and electrocardiographic effects of inhaled albuterol. Am J Med (1989) 86, 653–7.

Lipworth BJ,McDevitt DG, Struthers AD. Hypokalemic and ECG sequelae of combined betaagonist/diuretic therapy. Protection by conventional doses of spironolactone but not triamterene. Chest (1990) 98, 811–15.

Committee on Safety of Medicines. :5.5pt; font-weight:normal; color:#000000″>β2 agonists,xanthines and hypokalaemia. Current Problems (1990) 28.

Table 1 Diuretics
Group Drugs
Potassium-depleting diuretics
Carbonic anhydrase inhibitors* Acetazolamide, Diclofenamide (Dichlorphenamide), Methazolamide
Loop diuretics Bumetanide, Etacrynic acid, Furosemide, Piretanide, Torasemide
Thiazides and related diuretics Altizide, Bemetizide, Bendroflumethiazide, Benzthiazide, Butizide, Chlorothiazide, Chlortalidone, Clopamide, Cyclopenthiazide, Cyclothiazide, Epitizide, Hydrochlorothiazide, Hydroflumethiazide, Indapamide, Mefruside, Methyclothiazide, Metolazone, Polythiazide, Teclothiazide, Trichlormethiazide, Xipamide
Potassium-sparing diuretics
Aldosterone inhibitors Eplerenone, Potassium canrenoate, Spironolactone
Other Amiloride, Triamterene