Study unit 3.1

What are the therapeutic effects of theophylline in the treatment of bronchial asthma?

Beta-adrenoceptor agonists stimulate adenylyl cyclase (via the β2-adrenoceptor–Gs-coupling protein-adenylyl cyclase pathway) and increase cyclic adenosine monophosphate (cAMP) in smooth muscle cells . The increase in cAMP results in a powerful bronchodilator response.

• What are the primary mechanisms according to which the therapeutic effects are evoked? What is the mechanistic connection with b₂-agonists and antimuscarinic drugs? How would you describe the interaction with the b₂-agonists molecular-pharmacologically?

Primary mechanisms: Bronchodilation and smooth muscle relaxation

Mechanism Of Action of B-2 agonists: stimulate adenyl cyclase which causes cAMP to increase in bronchial smooth muscle which thereafter causes bronchodilation

Molecular pharmacology: Bronchodilation and Vasodilation of smooth muscle (SM) vessels are effects of B2 agonist stimulation. At high doses also B1 stimulating effects which cause possible side effects such as tachycardia.

• On which other systems in the body do the methylxanthines have an effect?  Where do you see the potential for undesirable side-effects and possibly also for other therapeutic applications of these side-effects?  Place special emphasis on the central and skeletal muscle effects.

• Stimulant, increased alertness, insomnia, high doses:  CENTRAL NERVOUS SYSTEM

• Elevated ino- and chronotropy: CVS

• Increased gastric acid and digestive enzyme secretion: GASTRO INTESTINAL TRACT

• Increased glomerular filtration rate, diuresis (Renal): KIDNEYS

• Strengthens contraction of diaphragm: SKELETAL MUSCLE

• What can you say about serious toxicities and the therapeutic index of theophylline?  How can the plasma levels of theophylline be influenced by pharmacokinetic drug interactions?  With which drugs can it be clinically important and why?

Theophylline has a very narrow therapeutic window, patients are at an increased risk of serious theophylline toxicity. Since nearly all of theophylline dose is biotransformed, drugs influencing microsomal enzyme systems in the liver may affect the elimination of theophylline. Other integrated mechanisms (e.g. hepatic uptake) may also be altered by concurrent administration of other drugs. Whatever the mechanism, the interaction may be sufficient to necessitate adjustment of the theophylline dosage, preferably guided by plasma theophylline determinations. Many drugs have been found to increase or decrease the clearance of theophylline, by interaction with one or more of the variants of the cytochrome P450 drug-metabolising system. Theophylline is susceptible to alteration of its clearance because of the particular forms of the P450 system involved, because its metabolism is saturable, and/or because 90% of its elimination is via metabolism. Drug examples include:

• How is theophylline administered?  What are the advantages of the slow-release forms? 

By aerosol, these drugs competitively block muscarinic receptors in the airways and effectively prevent bronchoconstriction mediated by vagal discharge. If given systemically (not an approved use), these drugs are indistinguishable from other short-acting muscarinic blockers.  Because these agents are delivered directly to the airway and are minimally absorbed, systemic effects are small. When given in excessive dosage, minor atropine-like toxic effects may occur.

• You have a patient who uses theophylline for the treatment of chronic asthma.  Your patient, however, develops a cold leading to a worsening of asthma.  After a week your patient develops a secondary bacterial infection and the doctor prescribes a penicillin antibiotic.  You are an alert pharmacist and quickly detect that your patient is allergic to penicillin.  You phone the doctor who suggests that you must rather give erythromycin antibiotic.  Do you think it is a good idea?  Assume your patient has developed a genitor-urinary tract infection, do you think
• it is a good idea to use ciprofloxacin?  And if she has a problem with heartburn, are there drugs that you should be careful to recommend?  Make use of your SAMF in considering the case

• no, because Theophylline’s clearance has been found to be decreased by around 25%, but often by far more, by erythromycin and ciprofloxacin.