Theophylline + Nefazodone - Drug Interactions

Clinical evidence,mechanism, importance and management

Nefazodone 200mg twice daily for 7 days had no effect on pharmacokinetics or pharmacodynamics of theophylline 600mg to 1.2 g daily in patients with chronic obstructive airways disease,nor was there any effect on their FEV1 values (See reference number 1). No special precautions would seem necessary if both drugs are used.

1. Dockens RC,Rapoport D, Roberts D, Greene DS, Barbhaiya RH. Lack of an effect of nefazodone on the pharmacokinetics and pharmacodynamics of theophylline during concurrent administration in patients with chronic obstructive airways disease. Br J Clin Pharmacol (1995)40, 598–601.

Theophylline + Loperamide - Drug Interactions

Loperamide delays absorption of theophylline from a sustained-release preparation

Clinical evidence,mechanism, importance and management

A study of effects of altering transit time of drugs through small intestine found that when 12 healthy subjects were given high-dose loperamide (8 mg every 6 hrs for a total of 8 doses), rate, but not extent, of absorption of a single 600mg dose of sustained-release theophylline (Theo-24) was decreased. The maximum serum theophylline levels were reduced from 4.6 to 3.2 micrograms/mL,and this peak level occurred at 20 hrs instead of 11 hours. One suggested reason for these effects is that loperamide inhibits movement of gut, thereby decreasing dissolution rate of Theo-24 pellets (See reference number 1). More study is needed to establish clinical significance of interaction in patients receiving long-term theophylline.

1. Bryson JC,Dukes GE, Kirby MG, Heizer WD, Powell JR. Effect of altering small bowel transittime on sustained release theophylline absorption. J Clin Pharmacol (1989) 29, 733–8.

Theophylline + Carbamazepine - Drug Interactions

An 11-year-old girl with asthma was stable for 2 months taking theophylline, and phenobarbital until phenobarbital was replaced by carbamazepine. The asthma worsened, her theophylline serum levels became subtherapeutic and half-life of theophylline was reduced from 5.25 to 2.75 hours. Asthmatic control was restored, and half-life returned to pre-treatment levels 3 weeks after carbamazepine was replaced by ethotoin (See reference number 1). The clearance of theophylline in an adult patient was doubled by carbamazepine 600mg daily (See reference number 2).

The trough carbamazepine levels of a 10-year-old girl were roughly halved when she was given theophylline for 2 days,and she experienced a grand mal seizure. Her serum theophylline levels were also unusually high at 26 mg/L for 5 mg/kg dosage she was taking, so it may be that convulsions were as much due to this as to fall in carbamazepine levels (See reference number 3).

A single-dose pharmacokinetic study in healthy subjects found that AUC and maximum serum levels of carbamazepine were reduced by 31 % and 45%, respectively, by oral aminophylline (See reference number 4).

Not established, but it seems probable that each drug increases liver metabolism and clearance of other drug, resulting in a reduction in their effects (See reference number 1,3). It is also possible that aminophylline interferes with absorption of carbamazepine (See reference number 4).

Information seems to be limited to reports cited so that general importance is uncertain. Concurrent use need not be avoided, but it would be prudent to check that serum concentrations of each drug (and their effects) do not become subtherapeutic. Note that theophylline should be used with caution in patients with epilepsy as it can cause seizures,although this is usually a sign of toxicity.

Rosenberry KR,Defusco CJ, Mansmann HC, McGeady SJ. Reduced theophylline half-life induced by carbamazepine therapy. J Pediatr (1983) 102, 472–4.

Reed RC,Schwartz HJ. Phenytoin-theophylline-quinidine interaction. N Engl J Med (1983) 308, 724–5.

Mitchell EA,Dower JC, Green RJ. Interaction between carbamazepine and theophylline. N Z Med J (1986) 99, 69–70.

Kulkarni C,Vaz J, David J, Joseph T. Aminophylline alters pharmacokinetics of carbamazepine but not that of sodium valproate — a single dose pharmacokinetic study in humanvolunteers. Indian J Physiol Pharmacol (1995) 39, 122–6.

Doxofylline + Miscellaneous - Drug Interactions

There is some limited evidence to suggest that erythromycin mayincrease effects of doxofylline, but clinical importance ofthis is uncertain. Digoxin initially raises, then lowers serum doxofylline levels, but bronchodilator effects do not appear to besignificantly affected. Allopurinol and lithium carbonate appearto have no significant effects on doxofylline.

Clinical evidence,mechanism, importance and management

Healthy subjects were given doxofylline 400mg three times daily,either alone, or with allopurinol 100mg once daily, erythromycin 400mg three times daily or lithium carbonate 300mg three times daily. None of pharmacokinetic parameters measured, including maximum serum levels, were significantly altered by any of these drugs apart from AUC of doxofylline, which was raised by about 40 % by allopurinol, 70 % by erythromycin, and 35 % by lithium carbonate. Only erythromycin result was statistically significant (See reference number 1). The clinical significance of these changes is uncertain,and their mechanism is not understood. Until situation is much clearer it would be prudent to check outcome of addingerythromycin to established treatment with doxofylline, being alert for evidence of increased effects.

In a comparative study in 9 patients taking doxofylline 800mg daily,digoxin 500 micrograms daily was given to 5 patients. It was found that digoxin increased serum levels of doxofylline by 50 % on first day of treatment, 3 hrs after administration but then reduced doxofylline levels by about 30 % at steady-state (day 30). Nevertheless, bronchodilating effects of doxofylline were little different between two groups. It was concluded that concurrent use is normally safe and effective, but initial doxofylline dose should be chosen to avoid too high a serum level on first day, and pulmonary function should be well monitored (See reference number 2).

Harning R,Sekora D, O’Connell K, Wilson J. A crossover study of the effect of erythromycin,lithium carbonate, and allopurinol on doxofylline pharmacokinetics. Clin Pharmacol Ther (1994) 55, 158.

Provvedi D,Rubegni M, Biffignandi P. Pharmacokinetic interaction between doxofylline anddigitalis in elderly patients with chronic obstructive bronchitis. Acta Ther (1990) 16, 239–46.

Montelukast + Antihistamines - Drug Interactions

Clinical evidence,mechanism, importance and management

Healthy subjects were given terfenadine 60mg every 12 hrs for 14 days,with montelukast 10mg daily from day 8 to day 14. It was found that terfenadine pharmacokinetics and QTc interval were unaltered by concurrent use (See reference number 1). No adverse interactions were seen in large numbers of patients given montelukast 10 or 20mg and loratadine 10 mg, and combination was found to be beneficial in treatment of allergic rhinitis and conjunctivitis (See reference number 2). No special precautions are therefore needed if these drugs are given concurrently.

Holland S,Gertz B, DeSmet M, Michiels N, Larson P, Freeman A, Keymeulen B. Montelukast(MON) has no effect on terfenadine (T) pharmacokinetics (PK) or QTc. Clin Pharmacol Ther (1998) 63, 232.

Malstrom K,Meltzer E, Prenner B, Lu S, Weinstein S, Wolfe J, Wei LX, Reiss TF. Effects of montelukast (a leukotriene receptor antagonist), loratadine, montelukast + loratadine and placebo in seasonal allergic rhinitis and conjunctivitis. J Allergy Clin Immunol (1998) 101, S97.

Caffeine + Psoralens - Drug Interactions

Oral methoxsalen and 5-methoxypsoralen markedly reduce caffeine clearance but clinical significance of this is uncertain

A single 1.2-mg/kg oral dose of methoxsalen (8-methoxypsoralen), given to 5 subjects with psoriasis 1 hour before a single 200mg oral dose of caffeine, reduced clearance of caffeine by 69%. The elimination half-life of caffeine over period from 2 to 16 hrs after taking methoxsalen increased tenfold (from 5.6 to 57 hours) (See reference number 1). In a similar study,8 patients with psoriasis were given caffeine 200mg with or without 5-methoxypsoralen 1.2 mg/kg. The AUC of caffeine increased by about threefold and there was a threefold decrease in its clearance (See reference number 2).

A study in patients receiving PUVA therapy (methoxsalen either orally, in 4 patients, or topically as a bath in 7 patients, plus UVA) found that clearance of a single 150mg dose of caffeine was markedly reduced in patients given oral methoxsalen but not altered in those given top

Both methoxsalen and 5-methoxypsoralen inhibit hepatic metabolism of caffeine by cytochrome P450 isoenzyme CYP1A2, thereby markedly increasing caffeine levels (See reference number 2,3).

The practical consequences of this interaction are as yet uncertain, but it seems possible that toxic effects of caffeine will be increased. In excess,caffeine (including that from tea, coffee and cola drinks) can cause jitteriness, headache and insomnia. The interaction does not appear to occur with topical methoxsalen.

Mays DC,Camisa C, Cheney P, Pacula CM, Nawoot S, Gerber N. Methoxsalen is a potent inhibitor of the metabolism of caffeine in humans. Clin Pharmacol Ther (1987) 42, 621–6.

Bendriss EK,Bechtel Y, Bendriss A, Humbert P, Paintaud G, Megnette J, Agache P, BechtelPR. Inhibition of caffeine metabolism by 5-methoxypsoralen in patients with psoriasis. Br J Clin Pharmacol (1996) 41, 421–4.

Tantcheva-Poór I,Servera-Llaneras M, Scharffetter-Kochanek K, Fuhr U. Liver cytochromeP450 CYP1A2 is markedly inhibited by systemic but not by bath PUVA in dermatological patients. Br J Dermatol (2001) 144, 1127–32.

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

Caffeine + Disulfiram - Drug Interactions

Disulfiram reduces clearance of caffeine, which might complicate withdrawal from alcohol.

Clinical evidence,mechanism, importance and management

A study in healthy subjects and recovering alcoholics found that disulfiram 250 or 500mg daily reduced clearance of caffeine by about 30%, but a few of alcoholics had a more than 50 % reduction (See reference number 1). As a result levels of caffeine in body increased. Raised levels of caffeine can cause irritability, insomnia and anxiety, similar to symptoms of alcohol withdrawal. As coffee consumption is often particularly high among recovering alcoholics, there is risk that they may turn to alcohol to calm themselves down. To avoid this possible complication it might be wise for recovering alcoholics not to drink too much tea or coffee. Decaffeinated coffee and tea are widely available.

1. Beach CA,Mays DC, Guiler RC, Jacober CH, Gerber N. Inhibition of elimination of caffeineby disulfiram in normal subjects and recovering alcoholics. Clin Pharmacol Ther (1986) 39, 265–70.

MAOIs or RIMAs + Venlafaxine - Drug Interactions

Serious and potentially life-threatening reactions (the serotoninsyndrome) can develop if venlafaxine and non-selective MAOIs(isocarboxazid,phenelzine, tranylcypromine) are given concurrently, or even sequentially if insufficient time is left in between.The situation with moclobemide,in therapeutic doses, is uncertain.

Isocarboxazid. A man with recurrent depression taking isocarboxazid 30mg daily was additionally given venlafaxine 75 mg. After second dose he developed agitation, hypomania, diaphoresis, shivering and dilated pupils. These symptoms subsided when venlafaxine was stopped. He subsequently developed myoclonic jerks and diaphoresis when given both drugs (See reference number 1).

Phenelzine. A woman who had stopped taking phenelzine 45mg daily 7 days previously,developed sweating, lightheadedness and dizziness within 45 minutes of taking a single 37.5mg dose of venlafaxine. In emergency department she was found to be lethargic, agitated and extremely diaphoretic. The agitation was treated with lorazepam. A week later, after she had recovered, she was again started on same regimen of venlafaxine without problems (See reference number 2). A man similarly developed serotonin syndrome when he started venlafaxine day after he stopped taking phenelzine (See reference number 3). A woman developed serotonin syndrome within less than an hour of taking phenelzine and venlafaxine together,(See reference number 4) and 4 other patients similarly developed reaction when phenelzine was replaced by venlafaxine (See reference number 5). Twelve days after an overdose of phenelzine (53 tablets of 15 mg),benztropine, haloperidol and lorazepam, a 31-year-old man was given venla

faxine 75mg every 12 hrs in addition to existing treatment with olanzapine and diazepam. About an hour after first dose, he developed leg shakiness and stiffness, diaphoresis, blurred vision, difficulty breathing, chills, nausea and palpitations. Venlafaxine and olanzapine were discontinued and man recovered within 24 hours, after treatment with intravenous fluids, propranolol and paracetamol (See reference number 6).

3. Tranylcypromine. A woman who had been taking tranylcypromine for 3 weeks developed a serious case of serotonin syndrome within 4 hrs of inadvertently taking a single tablet of venlafaxine. She recovered within 24 hours,when treated with ice packs, a cooling blanket, diazepam and dantrolene (See reference number 7). The serotonin syndrome developed in a man taking tranylcypromine within 2 hrs of taking half a venlafaxine tablet (See reference number 8). Another case of serotonin syndrome has been described in a man taking tranylcypromine 60mg daily who accidentally took venlafaxine 300mg (See reference number 9).

A 32-year-old man taking moclobemide 20mg twice daily and diazepam developed serotonin syndrome 40 minutes after taking a single 150mg dose of venlafaxine (See reference number 10). Serotonin toxicity (the serotonin syndrome) occurred in 4 patients who took an overdose of moclobemide with venlafaxine (just 150mg in one case and 750mg in another). In this analysis of moclobemide overdoses, risk of developing serotonin toxicity was increased 35 times in patients who also took another serotonergic drug. Venlafaxine was taken in 4 of 11 cases mentioned (See reference number 11). Another man very rapidly developed serotonin syndrome after taking considerable overdoses of moclobemide (3 g) and venlafaxine (2.625 g) (See reference number 12).

The serotonin syndrome is thought to occur because venlafaxine can inhibit serotonin re-uptake (its antidepressant effect is related to this activity), and MAOIs and RIMAs inhibit metabolism of serotonin. The result is an increase in concentrations of serotonin apparently causing overstimulation of 5-HT1A receptors in brain and spinal cord. See also the serotonin syndrome,.

An established,serious and potentially life-threatening interaction. The manufacturers of venlafaxine say that adverse reactions,some serious, have been seen in patients who had recently stopped taking an MAOI and started venlafaxine, or who had stopped venlafaxine and then started an MAOI. Some have been fatal (See reference number 13,14). They recommend that venlafaxine should not be used in combination with an MAOI or within 14 days of stopping treatment with MAOI (See reference number 13,14). Based on half-life of venlafaxine they say that at least 7 days should elapse between stopping venlafaxine and starting an MAOI. The manufacturers do not distinguish in this recommendation between irreversible older non-selective MAOIs and RIMAs such as moclobemide. In one of studies it was suggested that a wash-out period of several weeks is required between stopping MAOIs such as phenelzine and initiating a second serotonergic drug such as venlafaxine (See reference number 6).

Klysner R,Larsen JK, Sørensen P, Hyllested M, Pedersen BD. Toxic interaction of venlafaxine and isocarboxazide. Lancet (1995) 346, 1298–9.

Phillips SD,Ringo P. Phenelzine and venlafaxine interaction. Am J Psychiatry (1995) 152, 1400–1401.

Heisler MA,Guidry JR, Arnecke B. Serotonin syndrome induced by administration of venlafaxine and phenelzine. Ann Pharmacother (1996) 30, 84.

Weiner LA,Smythe M, Cisek J. Serotonin syndrome secondary to phenelzine-venlafaxine interaction. Pharmacotherapy (1998) 18, 399–403.

Diamond S,Pepper BJ, Diamond ML, Freitag FG, Urban GJ, Erdemoglu AK. Serotonin syndrome induced by transitioning from phenelzine to venlafaxine: four patient reports. Neurology (1998) 51, 274–6.

Mason PJ,Morris VA, Balcezak TJ. Serotonin syndrome. Presentation of 2 cases and reviewof the literature. Medicine (2000) 79, 201–9.

Hodgman M,Martin T, Dean B, Krenzelok E. Severe serotonin syndrome secondary to venlafaxine and maintenance tranylcypromine therapy. J Toxicol Clin Toxicol (1995) 33, 554.

Brubacher JR,Hoffman RS, Lurin MJ. Serotonin syndrome from venlafaxine-tranylcypromine interaction. Vet Hum Toxicol (1996) 38, 358–61.

Claassen JAHR,Gelissen HPMM. The serotonin syndrome. N Engl J Med (2005) 352, 2455.

Chan BSH,Graudins A, Whyte IM, Dawson AH, Braitberg G, Duggin GG. Serotonin syndrome resulting from drug interactions. Med J Aust (1998) 169, 523–5.

Isbister GK,Hackett LP, Dawson AH, Whyte IM, Smith AJ. Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity. Br J Clin Pharmacol (2003) 56, 441–50.

Roxanas MG,Machado JFD. Serotonin syndrome in combined moclobemide and venlafaxine ingestion. Med J Aust (1998) 168, 523–4.

Efexor (Venlafaxine hydrochloride). Wyeth Pharmaceuticals. UK Summary of product characteristics,May 2006.

Effexor XR (Venlafaxine hydrochloride). Wyeth Pharmaceuticals Inc. US Prescribing information,June 2007.

Anti-asthma drugs + Beta blockers - Drug Interactions

Non-cardioselective beta blockers (e.g. propranolol,timolol)should not be used in asthmatic subjects because they may causeserious bronchoconstriction, even if given as eye drops. Non-cardioselective beta blockers oppose bronchodilator effects ofbeta-agonist bronchodilators, and higher doses may be requiredto reverse bronchospasm. Even cardioselective blockers (e.g. atenolol) can sometimes cause acute bronchospasm in asthmatics.However,cardioselective beta blockers do not generally inhibitthe bronchodilator effect of beta-agonist bronchodilators.

A review of 29 studies (including 19 single-dose studies) on use of cardioselective beta blockers in patients with reversible airway disease indicated that in patients with mild to moderate disease, short-term use of cardioselective beta blockers does not cause significant adverse respiratory effects. Information on effects in patients with more severe or less reversible disease, or on frequency or severity of acute exacerbations was not available (See reference number 1). Another review indicated that when low doses of cardioselective beta blockers are given to patients with mild, intermittent or persistent asthma, or moderate persistent asthma, and heart failure or myocardial infarction, benefits of treatment outweigh risks. However,it was considered that further study is required to establish long-term safety, and also that beta blockers should be avoided in severe persistent asthma (See reference number 2).

The cardioselective beta blockers would not be expected to affect beta receptors in bronchi, but bronchospasm can sometimes occur following their use by asthmatics and others with obstructive airways diseases, particularly if high doses are used. Deterioration of asthma was reported in a patient taking oral betaxolol with theophylline and pranlukast,although betaxolol is considered to be highly cardioselective and less likely to cause pulmonary adverse effects than other cardioselective beta blockers (See reference number 3).

Celiprolol in asthmatic patients with isoprenaline (isoproterenol),or salbutamol,(See reference number 4,6,7) or terbutaline infusion or inhalation(See reference number 8)

• Metoprolol in asthmatic patients at rest with isoprenaline infusion(See reference number 9,10)In contrast, another study found that increase in forced expiratory volume (FEV) with a terbutaline inhalation and infusion was reduced by about 300 mL by atenolol and metoprolol. The authors considered that this would be clinically relevant in severe asthma (See reference number 11). Another study in 12 patients with mild asthma found that single doses of celiprolol 200mg or nebivolol 5mg reduced FEV1 by 272 mL and 193 mL, respectively, when compared with placebo. Increasing inhalation of salbutamol to a total dose of 800 micrograms reversed these reductions but did not restore FEV1 back to its initial value. None of these changes was considered to be clinically significant by authors (See reference number 12). Fifteen patients with mild to moderate COPD and airways hyperrespon

siveness were given celiprolol 200mg daily,metoprolol 100mg daily or propranolol 80mg daily for 4 days. Propranolol significantly reduced FEV1 and increased airways hyper-responsiveness compared with placebo whereas metoprolol only increased airways hyper-responsiveness. Celiprolol had no significant effects on pulmonary function. The bronchodilating effects of a single 12-microgram dose of formoterol were significantly reduced by propranolol,but not by metoprolol or celiprolol (See reference number 7).

Non-selective beta blockers (e.g. propranolol) are contraindicated in asthmatic subjects because they can cause bronchospasm,reduce lung ventilation and may possibly precipitate a severe asthmatic attack in some subjects. An example of danger is illustrated by an asthmatic patient who developed fatal status asthmaticus after taking just one dose of propranolol (See reference number 13). Another case report describes a patient with bronchial asthma receiving salbutamol who collapsed and died after taking three 20mg propranolol tablets,which had been supplied in error instead of 20mg prednisone tablets (See reference number 14). The manufacturers of propranolol note that from 1965 to 1996, CSM in UK had received 51 reports of bronchospasm due to propranolol, 13 of them fatal, and 5 of them in patients who had a history of asthma, bronchospasm or wheeze (See reference number 15). The non-cardioselective beta blockers oxprenolol(See reference number 5) and propranolol(See reference number 4,5,8-10) oppose effects of bronchodilators such as isoprenaline (isoproterenol),(See reference number 4,9,10)salbutamol (albuterol),(See reference number 4,5) and terbutaline (See reference number 8). Even eye drops containing non-selective beta blockers timolol(See reference number 16,17) and metipranolol(See reference number 18) have been reported to precipitate acute bronchospasm. In patients with heart failure treated with carvedilol,3 of 12 with concurrent asthma had wheezing requiring carvedilol withdrawal. In contrast,only 1 of 31 patients with COPD had wheezing (See reference number 19).

Non-selective beta blockers such as propranolol also block beta2 receptors in bronchi so that normal bronchodilation, which is under control of sympathetic nervous system, is reduced or abolished. As a result bronchoconstriction of asthma can be made worse. Cardioselective beta blockers on other hand, preferentially block beta1 receptors in heart, with less effect on beta2 receptors, so that beta2 stimulating bronchodilators, such as isoprenaline, salbutamol and terbutaline, continue to have bronchodilator effects.

A well established drug-disease interaction. In 1996, CSM in UK(See reference number 20)re-issued following advice: “Beta blockers, including those considered to be cardioselective, should not be given to patients with a history of asthma/bronchospasm.” Non-cardioselective beta blockers (indicated in table 1 below,) should certainly be avoided in asthmatics and those with chronic obstructive pulmonary disease,whether given systemically or in eye drops, because serious and life-threatening bronchospasm may occur. The cardioselective beta blockers are generally safer but not entirely free from risk in some patients,particularly in high dosage. In contrast to 1996 recommendations of CSM on cardioselective beta blockers, one recent review from 2002/3(See reference number 1,21) recommends that “cardioselective beta blockers should not be withheld from patients with mild to moderate reversible airway disease”. However, some concern has been expressed that this conclusion was based on results from short-term studies and state that question of safety in asthmatics over long term has not been answered (See reference number 22). Further, there are no studies to suggest safety of cardioselective beta blockers in patients with exacerbations of asthma,(See reference number 23) and even a highly cardioselective drug such as betaxolol may cause bronchospasm (See reference number 3). In 2004, American College of Cardiology and American Heart Association guidelines for management of ST-elevation myocardial infarction stated that benefits of using beta blockers strongly outweigh risk of adverse events in patients with COPD or mild asthma (non-active), and noted that most patients with asthma are able to tolerate cardioselective beta blockers. Therefore if a beta blocker is required a cardioselective beta blocker should be used, and patient’s pulmonary function monitored (See reference number 24). A recent Cochrane review concluded that cardioselective beta blockers did not produce any significant adverse respiratory effects or reduction in response to beta2 agonists, and it recommended that cardioselective beta blockers should not be withheld from patients with COPD (See reference number 25).

Celiprolol (a cardioselective beta blocker) appears to be exceptional in causing mild bronchodilatation in asthmatics and not bronchoconstriction, although it may still produce a reduction in expiratory volume, as seen in study above,(See reference number 12) but some caution is still necessary as this requires confirmation (See reference number 6).

The bronchoconstrictive effects of beta blockers can be opposed by beta2 agonist bronchodilators such a salbutamol, but as manufacturers point out, large doses may be needed and they suggest that ipratropium and intravenous aminophylline may also be needed (See reference number 15).

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