A Textbook of Clinical Pharmacology and Therapeutics

Drug interactions

Although synergism between β 2 -adrenergic agonists and theo-
phyllinehas been demonstrated in vitro, clinically the effect of
this combination is at best additive. Many drugs inhibit CYP1A2-
mediated theophyllinemetabolism, e.g. erythromycin (and
other macrolides), fluoroquinolones (e.g. ciprofloxacin),inter-
feronandcimetidine, thus precipitating theophyllinetoxicity.
Theophyllinemetabolism is induced in the presence of hepatic
CYP450-inducing agents, such as rifampicin.

GLUCOCORTICOSTEROIDS

Glucocorticosteroids are used in the treatment of asthma and
in severe exacerbations of COPD because of their potent
anti-inflammatory effect. This involves interaction with an
intracellular glucocorticosteroid receptor that in turn interacts
with nuclear DNA, altering the transcription of many genes and
thus the synthesis of pro-inflammatory cytokines, β 2 -adrenocep-
tors, tachykinin-degrading enzymes and lipocortin (an inhibitor
of phospholipase A 2 , reducing free arachidonic acid and thus
leukotriene synthesis). They are used both in maintenance ther-
apy (prophylaxis) and in the treatment of the acute severe attack.

SYSTEMIC GLUCOCORTICOSTEROIDS

For more information on the use of systemic glucocortico-
steroids, see Chapter 40.
Hydrocortisoneis given intravenously in urgent situations.
Improvement (a rise in FEV 1 and forced vital capacity, FVC) does
not begin until after six hours, and is usually maximal 10–12
hours following the start of treatment. This delay is due to the
action of glucocorticosteroids via altered gene transcription and
subsequent modified protein synthesis. Oral glucocorticosteroids
(e.g.prednisolone) are usually started within 12–24 hours.

INHALED GLUCOCORTICOSTEROIDS (E.G.
BECLOMETASONE, BUDESONIDE, FLUTICASONE,
MOMETASONE)

Use

Modern inhalational devices deliver up to 20% of the admin-
istered dose to the lungs.
Glucocorticosteroids can be administered via nebulizers,
‘spacer’ devices, metered-dose inhalers or as dry powders.
The fluorinated derivatives are extremely potent and mainly
exert a local action because they are highly polar and hence
only a small fraction of the dose is systemically absorbed.
Approximately 15–20% enters the lungs, the rest being swal-
lowed and then rapidly converted to inactive metabolites by
intestinal and hepatic CYP3A enzymes.
The comparative pharmacology of the commonly used
inhaled glucocorticosteroids is summarized in Table 33.2.

Adverse effects of inhaled steroids

• At the lowest recommended daily dose for adults, there is
  no prolonged suppression of the hypothalamic–pituitary–
  adrenal (HPA) axis. Higher doses can produce clinically
  important depression of adrenal function.
  
  
  • Candidiasis of the pharynx or larynx occurs in 10–15% of
    patients. Using the minimum effective dose, or a ‘spacer
    device’, or gargling/using mouthwashes after dosing,
    minimizes this problem.
  
  
  • A hoarse voice may develop due to a laryngeal myopathy
    at high doses. This is reversible and its occurrence is
    minimized by the use of a ‘spacer’.
  
  
  • Bruising and skin atrophy occur at high doses.
  
  
  • Inhibition of long bone growth during prolonged high-
    dose treatment in children.
  
  
  • Posterior subcapsular cataracts may develop following
    prolonged use.
  
  
  
  

CROMOGLICATE AND NEDOCROMIL

Use

Sodium cromoglicatemay be used to prevent exercise-induced

asthma and as prophylaxis for allergic asthma in children. Its

use as a prophylactic in children has been largely superseded

by inhaled glucocorticosteroids which are more effective. It is

used as a nasal spray for perennial and allergic rhin-itis, and as

eyedrops in allergic conjunctivitis. Cromoglicateproduces no

benefit during an acute asthmatic attack. Nedocromil sodium

is an alternative to cromoglicate.

Mechanism of action

Cromoglicateandnedocromilinhibit mediator release from

sensitized mast cells in vitro, and also reduce firing of sensory

DRUGSUSED TOTREATASTHMA ANDCHRONICOBSTRUCTIVEPULMONARYDISEASE 239

Key points

Anti-inflammatory agents – cromoglicate and

glucocorticosteroids

Sodium cromoglicate

• Its mechanism of action is unclear. It has an anti-
  inflammatory effect.


• Largely superseded in chronic prophylactic therapy of
  ‘allergic asthma’ by glucocorticosteroids.


• Prevents exercise-induced asthma.


• Inhaled therapy is administered via metered-dose
  inhaler or dry powder.


• Side-effects are minimal (headache, cough).


• Its use is very safe in children.

Glucocorticosteroids

• Mechanism is anti-inflammatory.


• They are administered systemically (i.v./p.o.) in severe
  acute and chronic asthma.


• They are inhaled topically or nebulized in chronic
  asthma.


• Glucocorticosteroids are well absorbed from the gastro-
  intestinal tract–hepatic (CYP3A) metabolism.


• Dosing is once daily for oral glucocorticosteroids and
  twice daily for inhaled agents.


• Side effects are minimal with topical therapy (oral
  thrush, hoarse voice, HPA suppression only at high dose).


• Side effects with systemic therapy are the features of
  Cushing’s syndrome.