Page 366 - Basic _ Clinical Pharmacology ( PDFDrive )

352 SECTION IV Drugs with Important Actions on Smooth Muscle

of patients treated with an LABA (see below). Studies of LABA Mechanism of Action
treatment have since shown, however, that differences in multiple
measures of asthma control are negligible in patient groups with Several mechanisms have been proposed for the actions of
different genotypes at that locus. Nonetheless, it is certain that methylxanthines, but none has been firmly established. At high
pharmacogenetic studies of asthma treatment will continue to be concentrations, they can be shown to inhibit several members
an active focus of research, as an approach to the development of of the phosphodiesterase (PDE) enzyme family in vitro, thereby
“personalized therapy.” increasing concentrations of intracellular cAMP and, in some tis-
sues, cGMP (Figure 20–3). Cyclic AMP regulates many cellular
functions including, but not limited to, stimulation of cardiac
METHYLXANTHINE DRUGS function, relaxation of smooth muscle, and reduction in the
immune and inflammatory activity of specific cells.
The three important methylxanthines are theophylline, theo- Another proposed mechanism for the bronchodilating action
bromine, and caffeine. Their major source is beverages (tea, of this class of drugs is inhibition of cell surface receptors for
cocoa, and coffee, respectively). The use of theophylline, once a adenosine. Adenosine has been shown to provoke contraction
mainstay of asthma treatment, has almost ceased with demon- of isolated airway smooth muscle and release of histamine from
stration of the greater efficacy of inhaled adrenoceptor agonists airway mast cells. It has been shown, however, that xanthine
for acute asthma and of inhaled anti-inflammatory agents for derivatives devoid of adenosine antagonism (eg, enprofylline) can
chronic asthma. Accelerating this decline in theophylline’s use are inhibit bronchoconstriction in asthmatic subjects.
its toxicities (nausea, vomiting, tremulousness, arrhythmias) and A third proposed mechanism of action for theophylline’s
the requirement for monitoring serum levels because of its narrow efficacy is enhancement of histone deacetylation. Acetylation of
therapeutic index. This monitoring is made all the more necessary core histones is necessary for activation of inflammatory gene
by individual differences in theophylline metabolism and frequent transcription. Corticosteroids act, at least in part, by recruiting
drug-drug interactions. Despite these disadvantages of theophyl- histone deacetylactylases to the site of inflammatory gene tran-
line, it is still used in some countries because of its low cost. scription, an action enhanced by low-dose theophylline. This
interaction should predict that low-dose theophylline treatment
Chemistry would enhance the effectiveness of corticosteroid treatment, but
this approach to treating patients with asthma or COPD uncon-
As shown below (Figure 20–5), theophylline is 1,3-dimethylx- trolled by ICS plus LABA therapy has not been widely adopted.
anthine; theobromine is 3,7-dimethylxanthine; and caffeine is Of the various isoforms of PDE identified, inhibition of PDE3
1,3,7-trimethylxanthine. A theophylline preparation commonly appears to be the most involved in relaxing airway smooth muscle
used for therapeutic purposes is aminophylline, a theophylline- and inhibition of PDE4 in inhibiting release of cytokines and che-
ethylenediamine complex. The pharmacokinetics of theophylline mokines, thus decreasing immune cell migration and activation.
are discussed below (see Clinical Uses of Methylxanthines). Its This anti-inflammatory effect is achieved at doses lower than those
metabolic products, partially demethylated xanthines (not uric necessary for bronchodilation.
acid), are excreted in the urine. In an effort to reduce toxicity while maintaining therapeutic
efficacy, selective inhibitors of PDE4 have been developed. Many
were abandoned after clinical trials showed that they induced
O O CH 3 unacceptably frequent side effects of nausea, headache, and diar-
H rhea. However, one, roflumilast, has been shown to be effective
HN 6 N HN N for reducing the frequency of exacerbations of COPD and is
1 5 7
8
2 4 9 approved by the US Food and Drug Administration (FDA) as a
O 3 N O N treatment for COPD, although not for asthma.
N N
H
CH 3 Pharmacodynamics
Xanthine Theobromine
The methylxanthines have effects on the central nervous system,
kidney, and cardiac and skeletal muscle as well as smooth muscle.
O CH 3 O Of the three agents, theophylline is most selective in its smooth
H C H C H
3
3
N N N N muscle effects, whereas caffeine has the most marked central ner-
vous system effects.
O N O N
N N A. Central Nervous System Effects
CH 3 CH 3 All methylxanthines, particularly caffeine, cause mild cortical
Caffeine Theophylline arousal with increased alertness and deferral of fatigue. The caf-
feine contained in beverages, approximately 100 mg in a cup of
FIGURE 20–5 Structures of theophylline and other coffee, is sufficient to cause nervousness and insomnia in sensitive
methylxanthines. individuals and slight bronchodilation in patients with asthma.