METHYLXANTHINES
Use
Aminophylline(theophylline, 80%; ethylene diamine, 20%) is
occasionally used intravenously in patients with severe refrac-
tory bronchospasm. Oral theophyllinemay be used for less
severe symptoms or to reduce nocturnal asthma symptoms.
Recently, the use of theophyllinehas markedly declined, but
it is still sometimes used in refractory cases.
For intravenous aminophylline, a loading dose given
slowly (20–30 minutes) is followed by a maintenance infusion.
Oraltheophyllinesustained-release preparations can provide
effective therapeutic concentrations for up to 12 hours follow-
ing a single dose. Because of their slow release rate they have
a reduced incidence of gastro-intestinal side effects.Mechanism of action and pharmacological effects
It is not clear exactly how theophyllineproduces broncho-
dilation. Its pharmacological actions include the following:- relaxation of airway smooth muscle and inhibition of
mediator release (e.g. from mast cells). Theophylline
raises intracellular cAMP by inhibiting phosphodiesterase.
However, phosphodiesterase inhibition is modest at
therapeutic concentrations of theophylline; - antagonism of adenosine (a potent bronchoconstrictor) at
A 2 -receptors; - anti-inflammatory activity on T-lymphocytes by reducing
release of platelet-activating factor (PAF).
Adverse effects
The adverse effects of theophyllineare:- Gastro-intestinal: nausea, vomiting, anorexia.
- Cardiovascular: (1) dilatation of vascular smooth muscle –
headache, flushing and hypotension; (2) tachycardia and
cardiac dysrhythmias (atrial and ventricular). - Central nervous system: insomnia, anxiety, agitation,
hyperventilation, headache and fits.
Pharmacokinetics
Theophyllineis well absorbed from the small intestine. It is
85–90% eliminated by hepatic metabolism (CYP1A2). The
therapeutic concentration range is 5–20 mg/L, but it is prefer-
able not to exceed 10 mg/L in children.238 THERAPY OF ASTHMA,COPD AND OTHER RESPIRATORY DISORDERS
times daily from a metered-dose inhaler or nebulizer. Inhaled
muscarinic receptor antagonists are most effective in older
patients with COPD. The degree and rate of onset of bron-
chodilatation are less than those of salbutamol, but the dur-
ation of response is longer. Ipratropium has a place in
maintenance therapy and the treatment of acute severe attacks
of asthma and chronic bronchitis. It is compatible with
β 2 -agonists, and such combinations are additive. Tiotropium
is a long-acting antimuscarinic bronchodilator administered
by inhalation in the management of COPD patients. It is not
used to treat acute bronchospasm.
Mechanism of action
There is increased parasympathetic activity in patients with
reversible airways obstruction, resulting in bronchoconstric-
tion through the effects of acetylcholine on the muscarinic
(M 2 , M 3 ) receptors in the bronchi. The final common pathway
is via a membrane-bound G-protein which when stimulated
leads to a fall in cAMP and increased intracellular calcium,
with consequent bronchoconstriction. Antimuscarinic drugs
block muscarinic receptors in the airways.
Adverse effects
These include:
- bitter taste (this may compromise compliance);
- acute urinary retention (in patients with prostatic
hypertrophy); - acute glaucoma has been precipitated when nebulized
doses are given via a face mask; - paradoxical bronchoconstriction due to sensitivity to
benzalkonium chloride, which is the preservative in the
nebulizer solution.
Pharmacokinetics
When administered by aerosol, it is poorly absorbed system-
ically. Plasma t1/2is three to four hours and inactive metab-
olites are excreted in the urine.
Several formulations of β 2 -agonist combined with mus-
carinic antagonist bronchodilators are available to simplify
treatment regimens.
Key points
Bronchodilator agents- β 2 -Agonists.
- Bronchodilate by increasing intracellular cAMP.
- Short-acting, rapid-onset agents (e.g. salbutamol) are
used as needed to relieve bronchospasm in asthma. - Long-acting, slower-onset agents (e.g. salmeterol) are
used regularly twice daily. - Common side effects include tremor, tachycardias,
vasodilatation, hypokalaemia and hyperglycaemia.
Anticholinergics - Antagonist at M 2 and M 3 muscarinic receptors in the
bronchi, causing bronchodilatation. - Slow onset of long-lasting bronchodilatation (given six-
to eight-hourly), especially in older patients. - Bitter taste.
- Little systemic absorption and side effects are rare (dry
mouth, acute retention, exacerbation of glaucoma).
Theophylline - Potent bronchodilator (also vasodilator).
- Aminophylline i.v. for acute severe episodes.
- Slow-release oral preparations for chronic therapy.
- Hepatic metabolism, multiple drug interactions (e.g.
clarithromycin, ciprofloxacin). - Therapeutic drug monitoring of plasma concentrations.
- Side effects include gastro-intestinal disturbances,
vasodilatation, dysrhythmias, seizures and sleep
disturbance.
- Little systemic absorption and side effects are rare (dry