chapter
Bronchodilators
Pages 11

Altered metabolism so parent drug accumulates

Avoid concomitant intake

LORATADINE H2 RECEPTOR BLOCKERS Possibly ≠ loratadine levels Inhibition of metabolism Be aware BRONCHODILATORS

ANTIMUSCARINICS (IPRATROPIUM, TIOTROPIUM) ➣ Drugs Acting on the Nervous System, Antiparkinson’s drugs

BETA-2 AGONISTS

TERBUTALINE ANAESTHETICS GENERAL – HALOTHANE

Cases of arrhythmias when terbutaline co-administered with halothane

Possibly due to sensitization of the myocardium to circulating catecholamines

Risk of cardiac events is higher with halothane. Desflurane is irritant to the upper respiratory tract, and ≠ secretions can occur; it is best avoided in patients with bronchial asthma. Sevoflurane is non-irritant and unlikely to cause serious adverse effects

BETA-2 AGONISTS ANALGESICS – NSAIDs Etoricoxib may ≠ oral salbutamol levels

Etoricoxib inhibits sulphotransferase activity

Monitor PR and BP closely

BETA-2 AGONISTS ANTIBIOTICS – LINEZOLID Theoretical risk of hypertensive reactions

Linezolid has weak MAOI properties

Monitor BP closely during co-administration

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Additive effect. The CSM notes that this effect occurs with beta-2 agonists, theophyllines and corticosteroids, all of which may be given during severe asthma; hypoxia exacerbates this effect

Monitor blood potassium levels prior to concomitant administration and during therapy (monitor 1-2-hourly during parenteral administration). Administer potassium supplements to prevent hypokalaemia, which may also be worsened by hypoxia during severe attacks of asthma

BETA-2 AGONISTS ANTIDEPRESSANTS – MAOIs

≠ occurrence of headache and hypertensive episodes. Unlikely to occur with moclobemide and selegiline

Due to impaired metabolism of these sympathomimetic amines due to inhibition of MAO. Moclobemide is involved in the breakdown of serotonin, while selegiline is mainly involved in the breakdown of dopamine

Be aware. Monitor BP closely

BETA AGONISTS ANTIDIABETIC DRUGS ≠ risk of hyperglycaemia. If administered during pregnancy, there is a risk of hypoglycaemia in the fetus, independent of maternal blood glucose levels. ≠ risk of ketoacidosis when administered intravenously

By inducing glycogenolysis, beta-adrenergic agonists cause elevation of blood sugar in adults. In the fetus, these agents cause a depletion of fetal glycogen stores

Monitor blood sugar closely during concomitant administration until blood sugar levels are stable. Be cautious during use in pregnancy. Formoterol and salmeterol are long-acting beta-agonists

BETA-2 AGONISTS ANTIHYPERTENSIVE AND HEART FAILURE DRUGS – CENTRALLY ACTING ANTIHYPERTENSIVES

Cases of ↓ BP when intravenous salbutamol is given with methyldopa

Uncertain at present Monitor BP closely

BETA-2 AGONISTS BETA-BLOCKERS Non-selective beta-blockers (e.g. propanolol) ↓ or prevent the bronchodilator effect of beta-2 agonists

Non-selective beta-blockers antagonize the effect of beta-2 agonists on bronchial smooth muscle

Avoid co-administration

RESPIRATORY DRUGS BRONCHODILATORS Beta-2 agonists

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Mechanism Precautions

Betahistine causes bronchoconstriction

Avoid co-administration

BETA-2 AGONISTS BRONCHODILATORS

BETA-2 AGONISTS THEOPHYLLINE Risk of hypokalaemia Additive effect. The CSM notes that this effect occurs with beta-2 agonists, theophyllines and corticosteroids, all of which may be given during severe asthma; hypoxia exacerbates this effect

Co-administration is useful for the management of severe asthma. Monitor blood potassium levels prior to concomitant administration and during therapy (monitor 1-2-hourly during parenteral administration). Administer potassium supplements to prevent hypokalaemia, which may also be worsened by hypoxia during severe asthma attacks

SALBUTAMOL IPRATROPIUM BROMIDE A few reports of acute closed-angle glaucoma when nebulized ipratropium and salbutamol were co-administered

Ipratropium dilates the pupil, which ↓ drainage of aqueous humour, while salbutamol ≠ production of aqueous humour

Warn patients to prevent the solution/ mist entering the eye. Use extreme caution in co-administering these bronchodilators by the nebulized route in patients with a history of acute closed-angle glaucoma

BETA-2 AGONISTS CARDIAC GLYCOSIDES – DIGOXIN

1. Hypokalaemia may exacerbate digoxin toxicity 2. Salbutamol may ↓ digoxin levels (by 16-22%) after 10 days of concurrent therapy

1. Beta-2 agonists may cause hypokalaemia 2. Uncertain

1. Monitor potassium levels closely 2. Clinical significance is uncertain. Useful to monitor digoxin levels if there is a clinical indication of ↓ response to digoxin

SALBUTAMOL CNS STIMULANTS – ATOMOXETINE

≠ risk of arrhythmias with parenteral salbutamol

Additive effect Avoid co-administration of atomoxetine with parenteral salbutamol

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RESPIRATORY DRUGS BRONCHODILATORS Theophyllines

Additive effects Monitor blood potassium levels prior to concomitant administration and during therapy. Administer potassium supplements to prevent hypokalaemia

SALBUTAMOL EPHEDRA Risk of marked ≠ heart rate and of BP

Additive effect; ephedra causes vasoconstriction

The US FDA has banned products containing ephedra. Warn patients on salbutamol to avoid traditional remedies containing ephedra

BAMBUTEROL MUSCLE RELAXANTS – SUXAMETHONIUM

≠ effect of suxamethonium Bambuterol is an inhibitor of pseudocholinesterase, which hydrolyses suxamethonium

Be cautious of prolonged periods of respiratory muscle paralysis, and monitor respiration closely until complete recovery

SALBUTAMOL YOHIMBINE ≠ risk of CNS stimulation Uncertain; yohimbine may cause ≠ dopamine levels

Warn patients taking salbutamol to avoid remedies containing yohimbine

NON-SELECTIVE BETA-AGONISTS ➣ Sympathomimetics section – CVS Chapter

THEOPHYLLINES

THEOPHYLLINE ANAESTHETICS – GENERAL

THEOPHYLLINE HALOTHANE Case reports of arrhythmias Possibly due to sensitization of the myocardium to circulating catecholamines

Risk of cardiac events is higher with halothane. Desflurane is irritant to the upper respiratory tract, and ≠ secretions can occur; it is best avoided in patients with bronchial asthma. Sevoflurane is non-irritant and unlikely to cause serious adverse effects

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Mechanism Precautions Uncertain A careful risk-benefit assessment

should be made before using ketamine. However, there are significant benefits for the use of ketamine to anaesthetize patients for the emergency management of life-threatening asthma

AMINOPHYLLINE PROCAINE SOLUTIONS Precipitation of drugs, which may not be immediately apparent

A pharmaceutical interaction Do not mix in the same infusion or syringe

THEOPHYLLINE ANTIARRHYTHMICS

THEOPHYLLINE ADENOSINE ↓ efficacy of adenosine Theophylline and other xanthines are adenosine receptor antagonists

Watch for poor response to adenosine; higher doses may be required

THEOPHYLLINE AMIODARONE Theophylline levels may be ≠ by amiodarone (single case report of theophylline levels doubling)

Uncertain; amiodarone probably inhibits the metabolism of theophylline

Watch for theophylline toxicity; monitor levels regularly until stable

THEOPHYLLINE MEXILETINE Theophylline levels may be ≠ by mexiletine; cases of theophylline toxicity have been reported

Mexiletine inhibits CYP1A2mediated metabolism of theophylline

↓ theophylline dose (by up to 50%). Monitor theophylline levels and watch for toxicity

THEOPHYLLINE MORACIZINE ↓ plasma concentrations of theophylline and risk of therapeutic failure

Due to induction of microsomal enzyme activity

May need to ≠ dose of theophylline by 25%

THEOPHYLLINE PROPAFENONE Case reports of ≠ theophylline levels with toxicity when propafenone was added

Uncertain at present Watch for signs of theophylline toxicity

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RESPIRATORY DRUGS BRONCHODILATORS Theophyllines

clarithromycin, erythromycin, telithromycin), QUINOLONES

orally

1. Inhibition of CYP2D6-mediated metabolism of theophylline (macrolides and quinolones – isoniazid not known) 2. ↓ bioavailability; uncertain mechanism

1. Monitor theophylline levels before, during and after co-administration 2. Consider alternative macrolide

THEOPHYLLINE RIFAMPICIN ↓ plasma concentrations of theophylline and risk of therapeutic failure

Due to induction of CYP1A2 and CYP3A3

May need to ≠ dose of theophylline by 25%

THEOPHYLLINE ANTICANCER AND IMMUNOMODULATING DRUGS

THEOPHYLLINE CORTICOSTEROIDS Risk of hypokalaemia Additive effect. The CSM notes that this effect occurs with beta-2 agonists, theophyllines and corticosteroids, all of which may be given during severe asthma; hypoxia exacerbates this effect

Monitor blood potassium levels prior to concomitant administration and during therapy (monitor 1-2-hourly during parenteral administration). Administer potassium supplements to prevent hypokalaemia, which may also be worsened by hypoxia during severe attacks of asthma

THEOPHYLLINE INTERFERON ALFA ≠ theophylline levels Inhibition of theophylline metabolism

Monitor theophylline levels before, during and after co-administration

THEOPHYLLINE METHOTREXATE Possible ≠ theophylline levels Possibly inhibition of CYP2D6mediated metabolism of theophylline

Monitor clinically for toxic effects, and advise patients to seek medical attention if they have symptoms suggestive of theophylline toxicity. Measure theophylline levels before, during and after co-administration

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Mechanism Precautions

of therapeutic failure

Theophylline ≠ renal clearance of lithium

May need to ≠ dose of lithium by 60%

THEOPHYLLINE ST JOHN’S WORT ↓ theophylline levels Inhibition of CYP1A2-mediated metabolism of theophylline

Avoid co-administration

THEOPHYLLINE SSRIs – FLUVOXAMINE ≠ theophylline levels Fluvoxamine is potent inhibitor of CYP1A2

Consider an alternative antidepressant

THEOPHYLLINE TCAs Possible ≠ theophylline levels Inhibition of CYP1A2-and CYP2D6-mediated metabolism of theophylline. The clinical significance of this depends upon whether theophylline’s alternative pathways of metabolism are also inhibited by co-administered drugs

Warn patients to report any ≠ sideeffects of theophylline, and monitor PR and ECG carefully

THEOPHYLLINE ANTIEPILEPTICS – BARBITURATES, CARBAMAZEPINE, PHENYTOIN

↓ theophylline levels. Possibly ↓ carbamazepine and phenytoin levels

Due to induction of microsomal enzyme activity. Theophylline ↓ absorption of phenytoin

May need to ≠ dose of theophylline by 25%. Monitor for inadequate therapeutic response to carbamazepine and phenytoin. Measure levels of these drugs

THEOPHYLLINE ANTIFUNGALS

THEOPHYLLINE AZOLES – ITRACONAZOLE, KETOCONAZOLE

≠ theophylline levels, with risk of toxicity with itraconazole. Unpredictable effect on theophylline levels with ketoconazole

Theophylline is primarily metabolized by CYP1A2. Although azoles are best known as inhibitors of CYP3A4, they also inhibit other CYP isoenzymes to varying degrees

If concurrent use is necessary, monitor theophylline levels on initiation and discontinuation of itraconazole therapy. Other azoles or terbinafine may be a safer alternative

THEOPHYLLINE GRISEOFULVIN ≠ theophylline levels Inhibition of metabolism of theophylline

Uncertain clinical significance. Watch for early features of theophylline toxicity

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RESPIRATORY DRUGS BRONCHODILATORS Theophyllines

Allopurinol inhibits xanthine oxidase

Watch for early features of toxicity of theophylline (headache and nausea)

THEOPHYLLINE SULFINPYRAZONE ↓ theophylline levels Due to ≠ demethylation and hydroxylation, and thus ≠ clearance of theophylline

May need to ≠ dose of theophylline by 25%

THEOPHYLLINE ANTIVIRALS

THEOPHYLLINE ACICLOVIR/VALACICLOVIR ≠ theophylline levels Uncertain Monitor for signs of toxicity and check levels

THEOPHYLLINE INDINAVIR Possibly ≠ efficacy Inhibition of metabolism via CYP3A4, but mainly metabolized via CYP1A2, which is not inhibited

Not thought to be clinically significant; however, monitor levels more closely in unstable patients

THEOPHYLLINE RITONAVIR ( LOPINAVIR) ↓ efficacy ≠ metabolism via induction of CYP1A2; also altered metabolism via CYP3A4

Monitor clinical response; measure levels weekly after starting. ≠ doses may be required

THEOPHYLLINE ANXIOLYTICS AND HYPNOTICS – BZDs

↓ therapeutic effect of BZDs BZDs ≠ CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors

Larger doses of diazepam are required to produce desired therapeutic effects such as sedation. Discontinuation of theophylline without ↓ dose of BZDs ≠ risk of sedation and of respiratory depression

THEOPHYLLINE BETA-BLOCKERS – PROPRANOLOL

≠ plasma levels of theophylline with propranolol

Propranolol exerts a dosedependent inhibitory effect on the metabolism of theophylline

Monitor theophylline levels during propranolol co-administration

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Mechanism Precautions

Additive effect. The CSM notes

that this effect occurs with beta-2 agonists, theophyllines and corticosteroids, all of which may be given during severe asthma; hypoxia exacerbates this effect

Co-administration is useful for the management of severe asthma. Monitor blood potassium levels prior to concomitant administration and during therapy (monitor 1-2-hourly during parenteral administration). Administer potassium supplements to prevent hypokalaemia, which may also be worsened by hypoxia during severe attacks of asthma

THEOPHYLLINE CALCIUM CHANNEL BLOCKERS

THEOPHYLLINE DILTIAZEM, VERAPAMIL ≠ theophylline levels with diltiazem and verapamil. Mostly not clinically significant but two case reports of theophylline toxicity with verapamil

Uncertain but thought to be due to inhibition of CYP1A2-mediated metabolism of theophylline

Be aware of the small possibility of theophylline toxicity when commencing calcium channel blockers; check levels if any problems occur, and consider either ↓ dose of theophylline or using an alternative calcium channel blocker

THEOPHYLLINE NIFEDIPINE Clinically non-significant ↓ theophylline levels with nifedipine, but case reports of theophylline toxicity after starting nifedipine

Uncertain; probably due to alterations in either the metabolism or volume of distribution of theophylline

Be aware of the small possibility of theophylline toxicity when commencing calcium channel blockers; check levels if any problems occur, and consider either ↓ dose of theophylline or using an alternative calcium channel blocker

THEOPHYLLINE CNS STIMULANTS – MODAFINIL

May cause ↓ theophylline levels Modafinil is a moderate inducer of CYP1A2 in a concentrationdependent manner

Be aware; watch for poor response to theophylline and measure levels

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Additive effects Monitor blood potassium levels prior to concomitant administration and during therapy. Administer potassium supplements to prevent hypokalaemia

THEOPHYLLINE DOXAPRAM Reports of ≠ muscle tone and CNS excitation

Uncertain Be aware

THEOPHYLLINE DRUG DEPENDENCE THERAPIES

THEOPHYLLINE BUPROPION 1. ≠ theophylline levels 2. ≠ risk of seizures. This risk is marked in elderly people, patients with a history of seizures, with addiction to opiates/cocaine/stimulants, and in diabetics treated with oral hypoglycaemics or insulin

1. Smoking induces mainly CYP1A2 and CYP2E1. Thus, de-induction takes place following the cessation of smoking 2. Bupropion is associated with a dose-related risk of seizures. These drugs, which lower seizure threshold, are individually epileptogenic. Additive effects occur when they are combined

1. Be aware , particularly with drugs with a narrow therapeutic index ( see section). Monitor clinically and biochemically (e.g. INR, plasma theophylline levels) 2. Extreme caution. The dose of bupropion should not exceed 450 mg/day (or 150 mg/day in patients with severe hepatic cirrhosis)

THEOPHYLLINE DISULFIRAM ≠ theophylline levels Disulfiram ↓ theophylline clearance by inhibiting hydroxylation and demethylation

Monitor theophylline levels before, during and after co-administration

THEOPHYLLINE GRAPEFRUIT JUICE Possibly ↓ efficacy Unclear. ↓ bioavailability (significant from 1-4 hours)

Avoid concomitant intake if slowrelease theophylline preparations are used. Monitor levels and clinical state weekly if the intake of grapefruit is altered

RESPIRATORY DRUGS BRONCHODILATORS Theophyllines

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NIZATIDINE, RANITIDINE

conflicting information associated with ranitidine, famotidine and nizatidine

Inhibition of metabolism via CYP1A2, cimetidine being the best known inhibitor

Use alternative acid suppression, e.g. an H2 antagonist or proton pump inhibitor (not omeprazole or lansoprazole), or monitor closely; there is considerable patient variation. Check levels on day 3 and then at 1 week. A 30-50% ↓ dose of theophylline may be required. For doses400 mg/day, the interaction may not be clinically significant

THEOPHYLLINE LEUKOTRIENE RECEPTOR ANTAGONISTS – ZAFIRLUKAST

Possibly ≠ theophylline levels. Also possibly ↓ zafirlukast levels

Mutual alteration of metabolism Be aware; watch for features of theophylline toxicity and measure levels

THEOPHYLLINE MUSCLE RELAXANTS – PANCURONIUM

Antagonism of neuromuscular block

Uncertain Larger doses of pancuronium may be needed to obtain the desired muscle relaxation during anaesthesia; other non-depolarizing muscle relaxants do not seem to be affected

THEOPHYLLINE OESTROGENS ≠ theophylline levels ↓ clearance of theophylline in a dose-dependent manner

Be aware; watch for features of theophylline toxicity and measure levels

THEOPHYLLINE PERIPHERAL VASODILATORS – PENTOXIFYLLINE

Possibly ≠ theophylline levels Uncertain; possibly competitive inhibition of theophylline metabolism (pentoxifylline is also a xanthine derivative)

Warn patients of the possibility of adverse effects of theophylline; monitor levels if necessary

THEOPHYLLINE PHOSPHODIESTERASE INHIBITORS – ENOXIMONE

Theophylline may ↓ efficacy of enoximone

Possibly competitive inhibition of phosphodiesterases

Be aware; watch for poor response to enoximone

THEOPHYLLINE SUCRALFATE Possibly ↓ theophylline levels (with modified-release preparations)

Possibly ↓ absorption Watch for poor response to theophylline and monitor levels