Page 374 - Basic _ Clinical Pharmacology ( PDFDrive )

360 SECTION IV Drugs with Important Actions on Smooth Muscle

LEUKOTRIENE ANTAGONISTS; therapies against IgE or IL-5 are unlikely to be of benefit. The
CROMOLYN & NEDOCROMIL initial promise of oral methotrexate or gold salt injections has not
been fulfilled. While the benefit from treatment with cyclosporine
A leukotriene pathway antagonist taken as an oral tablet is an alterna- seems real, this drug’s toxicity makes this finding only a source
tive to ICS treatment in patients with symptoms occurring more than of hope that other immunomodulatory therapies will ultimately
twice a week or those who are awakened from sleep by asthma more emerge. Advances in understanding the immunopathogenesis of
than twice a month. This place in asthma therapy was once held by asthma may permit the identification of specific phenotypes of
cromolyn and nedocromil, but neither is now available for asthma in asthma and identification of biomarkers of their importance in
the USA. Although these treatments are not as effective as a low dose particular patients. In this respect, asthma may benefit from the
of an ICS, both avoid the issue of “steroid phobia” described above rapid advances in treatments developed for other chronic inflam-
and are commonly used in the treatment of children. matory conditions such as rheumatoid arthritis, ankylosing spon-
The leukotriene receptor antagonist montelukast is the most dylitis, and inflammatory bowel disease.
widely prescribed of these treatments, especially by primary care
providers. This drug, taken orally, is easy to administer and is MANAGEMENT OF ACUTE ASTHMA
rarely associated with troublesome adverse effects. This mainte-
nance therapy is widely used for treating children in the USA, par- The treatment of acute attacks of asthma in patients reporting to the
ticularly those who have concurrent symptomatic allergic rhinitis, hospital requires close, continuous clinical assessment and repeated
which is also effectively treated by montelukast. objective measurement of lung function. For patients with mild
attacks, inhalation of a β-receptor agonist is as effective as subcutane-
TARGETED THERAPY ous injection of epinephrine. Severe attacks require treatment with
oxygen, frequent or continuous administration of aerosolized alb-
uterol, and systemic treatment with prednisone or methylpredniso-
Treatment with omalizumab, the monoclonal humanized anti-IgE lone (0.5 mg/kg every 6–12 hours). Even this aggressive treatment
antibody, and with any of the monoclonal anti-IL-5 antibodies is not invariably effective, and patients must be watched closely for
is reserved for patients with chronic severe asthma inadequately signs of deterioration. General anesthesia, intubation, and mechani-
controlled by ICS/LABA treatment. Omalizumab reduces lym- cal ventilation of asthmatic patients cannot be undertaken lightly but
phocytic, eosinophilic bronchial inflammation, oral and inhaled may be lifesaving if respiratory failure supervenes.
corticosteroid dose requirements, and the frequency and severity
of exacerbations. It is reserved for patients with demonstrated IgE-
mediated sensitivity (by positive skin test or radioallergosorbent test PROSPECTS FOR PREVENTION
[RAST] to common allergens) and an IgE level within a range that
can be reduced sufficiently by twice-weekly subcutaneous injection. The high prevalence of asthma in the developed world and its rapid
Other options for treatment of severe asthma uncontrolled by ICS/ increases in the developing world call for a strategy for primary pre-
LABA therapy, especially if associated with peripheral eosinophilia, vention. Strict antigen avoidance during infancy, once thought to
are the monoclonal antibodies reviewed earlier—mepolizumab, be sensible, has now been shown to be ineffective. In fact, growing
reslizumab, and benralizumab. up from birth on a farm with domestic animals or in a household
In addition to their high cost, several factors have limited the use where cats or dogs are kept as pets appears to protect against devel-
of targeted therapies. First, they must be given parenterally at 2- to oping asthma. The best hope seems to lie in understanding the
4-week intervals. Second, some can cause anaphylactic reactions or mechanisms by which microbial exposures during infancy foster
other hypersensitivity reactions, albeit in a small percentage (<0.5%) development of a balanced immune response and then mimicking
of patients, so they cannot be self-administered but must be moni- the effects of natural environmental exposures through administra-
tored for a period of time after the injection in a setting equipped to tion of harmless microbial commensals (probiotics) or of nutrients
manage anaphylaxis. In addition, a small number of patients receiving that foster their growth (prebiotics) in the intestinal tract during the
mepolizumab developed herpes zoster infection, and administration critical period of immune development in early infancy. Identifying
of the varicella-zoster vaccine to adults age 50 or older 4 weeks prior the particular microbes whose growth should be fostered, or the
to initiation with mepolizumab is recommended. microbial products responsible for inducing appropriate maturation
of immune function, has become an active focus of epidemiologic,
basic, and translational research.
OTHER ANTI-INFLAMMATORY
THERAPIES
TREATMENT OF CHRONIC OBSTRUCTIVE
For the 5–10% of the asthmatic population with severe asthma PULMONARY DISEASE (COPD)
inadequately controlled by standard therapies, the development of
an alternative treatment is an important unmet medical need. This COPD is now the third most common cause of death in the
is particularly important for patients with “T2-low” asthma, who United States and accounts for more than $40 billion per year
are less likely to respond to corticosteroids and for whom targeted in direct and indirect health care costs. COPD resembles asthma