240 THERAPY OF ASTHMA,COPD AND OTHER RESPIRATORY DISORDERS
Table 33.2:Comparative pharmacology of some inhaled glucocorticosteroidsDrug Relative binding affinity Relative blanching Comments
to receptorsa potencya
Beclometasone 0.4 600 Equi-effective compared to
dipropionate budesonide. May be used in children
Budesonide 9.4 980 Nebulized formulation (0.5–1mg/2 mL)
available. May be used in children to
avoid systemic steroids
Fluticasone 18 1200 May cause fewer systemic side
effects than others
aRelative to dexamethasone binding to glucocorticosteroid receptors in vitro and blanching of human skin in vitro.receptor to cause bronchoconstriction, attraction of eosinophils
and production of oedema.LEUKOTRIENE C 4 AND D 4 ANTAGONISTS
Use
Leukotriene receptor antagonists are used to treat asthma and
are given orally, usually in the evening. Montelukastwas the
first of these drugs to become available clinically. It reduced the
requirement for glucocorticosteroid and improved symptoms in
chronic asthma. It is also useful in the prophylaxis of exercise- or
antigen-induced asthma. Montelukastis effective in aspirin-
sensitive asthma, which is associated with diversion of arachi-
donic acid from the cyclo-oxygenase pathway (blocked by
aspirin) to the formation of leukotrienes via 5-lipoxygenase.Mechanism of action
Montelukastis a competitive inhibitor of LTD 4 and LTC 4 at
the Cys-LT 1 receptor.Adverse effects
Montelukastis generally well tolerated, but side effects include:- gastro-intestinal upsets;
- asthenia and drowsiness;
- rash, fever, arthralgias;
- elevation of serum transaminases.
Pharmacokinetics
This drug is rapidly absorbed from the gastro-intestinal tract. The
mean plasma t1/2is 2.7–5.5 hours. It undergoes hepatic metab-
olism by CYP 3A and 2C9, and is mainly excreted in the bile.Drug interactions
No clinically important drug–drug interactions are currently
recognized.5 -LIPOXYGENASE INHIBITORSZileuton(available in the USA) is a competitive inhibitor of
the 5-lipoxygenase enzyme. It is used in asthma therapy and
administered orally and undergoes hepatic metabolism. ItsC-fibres in response to tachykinins (e.g. bradykinin). However,
the complete mechanism underlying their therapeutic efficacy
is uncertain.
Adverse effects
- Sodium cromoglicateis virtually non-toxic. The
powder can (very rarely) produce bronchospasm or
hoarseness. - Nausea and headache are rare adverse effects.
- Nedocromil has a bitter taste.
Pharmacokinetics
Sodium cromoglicate, an inhaled powder, undergoes little
systemic absorption. Most of the powder is swallowed, about
10% reaching the alveoli. Nedocromil sodiumhas similarly
low systemic bioavailability.
LEUKOTRIENE MODULATORSThese fall into two classes, namely leukotriene receptor antag-
onists and 5-lipoxygenase inhibitors.
Leukotrienes (LT) are fatty acid-derived mediators contain-
ing a conjugated triene structure. They are formed when
arachidonic acid (Chapter 26) is liberated from the cell mem-
brane of cells, as a result of cell activation by allergic or other
noxious stimuli. 5-Lipoxygenase is the enzyme required for
the synthesis of LTA 4 , which is an unstable epoxide precursor
of the two subgroups of biologically important leukotrienes.
LTB 4 is a dihydroxy 20-carbon-atom fatty acid which is a
potent pro-inflammatory chemo-attractant. The other group is
the cysteinyl leukotrienes (LTC 4 , LTD 4 and LTE 4 ). LTC 4 is a
conjugate of LTA 4 plus glutathione, a tripeptide which com-
bines with LTA 4 via its cysteine residue. LTC 4 is converted to
an active metabolite (LTD 4 ) by the removal of the terminal
amino acid in the peptide side-chain. Removal of a second
amino acid results in a less active metabolite (LTE 4 ). LTC 4 ,
LTD 4 and LTE 4 , the ‘sulphidopeptide leukotrienes’ or ‘cys-
teinyl leukotrienes’, collectively account for the activity that
used to be referred to as ‘slow-reacting substance of anaphylaxis’
(SRS-A). They all (but especially LTD 4 ) bind to the Cys-LT 1