IPRATROPIUM BROMIDA

Ipratropium bromide (ATROVENT, others) is a quaternary ammonium compound

formed by the introduction of an isopropyl roup to the N atom of atropine! A similar
aent, oxitropium bromide, an N"ethyl"substituted, quaternary deri#ati#e of
scopolamine, is a#ailable in Europe! The most recently de#eloped and
bronchoselecti#e member of this family is tiotropium bromide ($%IRIVA), &hich has a
loner duration of action! Ipratropium appears to bloc' all subtypes of muscarinic
receptors and thus bloc's presynaptic muscarinic inhibition of A(h release, &hereas
tiotropium sho&s some selecti#ity for )* and )+ receptors! Tiotropium has a lo&er
a,nity for )- receptors, minimi.in its presynaptic e/ect on A(h release!
Ipratropium produces bronchodilation, tachycardia, and inhibition of secretion
similar to that of atropine &hen it is administered parenterally! Althouh some&hat
more potent than atropine, ipratropium and tiotropium lac' appreciable action on
the (N$ but ha#e reater inhibitory e/ects on anlionic transmission! An
une0pected and therapeutically important property of ipratropium and tiotropium,
e#ident upon either local or parenteral administration, is their minimal inhibitory
e/ect on mucociliary clearance relati#e to atropine! 1ence, the use of these aents
in patients &ith air&ay disease minimi.es the increased accumulation of lo&er
air&ay secretions encountered &ith atropine!
2hen ipratropium or tiotropium is inhaled, its action is con3ned almost e0clusi#ely
to the mouth and air&ays! 4ry mouth is the only side e/ect reported frequently!
$electi#ity results from the #ery ine,cient absorption of the dru from the luns or
the astrointestinal tract! The deree of bronchodilation achie#ed by these aents is
thouht to re5ect the le#el of basal parasympathetic tone, supplemented by re5e0
acti#ation of cholineric path&ays brouht about by #arious stimuli! In normal
indi#iduals, inhalation of the drus can pro#ide #irtually complete protection aainst
the bronchoconstriction produced by the subsequent inhalation of such irritants as
sulfur dio0ide, o.one, or ciarette smo'e! 1o&e#er, atopic patients &ith asthma or
patients &ith demonstrable bronchial hyperresponsi#eness are less &ell protected!
Althouh these drus cause a mar'ed reduction in sensiti#ity to methacholine in
asthmatic sub6ects, more modest inhibition of responses to challene &ith
histamine, brady'inin, or %78-a is achie#ed, and little protection is a/orded aainst
the bronchoconstriction induced by serotonin or the leu'otrienes!
The principal clinical use of ipratropium and tiotropium is in the treatment of chronic
obstructi#e pulmonary disease9 they are less e/ecti#e in most asthmatic patients
(:arnes and 1ansel, -;;<9 7ross, -;;<)! Ipratropium is 84A appro#ed for the
treatment of perennial and common cold"associated rhinorrhea! The therapeutic use
of ipratropium and tiotropium is discussed further in (hapter -=!
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Ipratropium (8iure DE-), a synthetic analo of atropine, is used as an inhalational
dru in asthma! The aerosol route of administration pro#ides the ad#antaes of
ma0imal concentration at the bronchial taret tissue &ith reduced systemic e/ects!
This application is discussed in reater detail in (hapter -;> 4rus Bsed in Asthma!
Ipratropium has also pro#ed useful in (O%4, a condition that occurs &ith hiher
frequency in older patients, particularly chronic smo'ers! %atients &ith (O%4 bene3t
from bronchodilators, especially antimuscarinic aents such as ipratropium!
In#estiational aents in this cateory include tiotropium, a lon"actin
quaternary aerosol antimuscarinic dru!
(linical Bse of )uscarinic Antaonists
Antimuscarinic aents are e/ecti#e bronchodilators! 2hen i#en intra#enously,
atropine, the prototypical muscarinic antaonist, causes bronchodilation at a lo&er
dose than that needed to cause an increase in heart rate! The selecti#ity of
atropineAs e/ect can be increased further by administerin the dru by inhalation or
by use of a more selecti#e quaternary ammonium deri#ati#e of atropine,
ipratropium bromide. Ipratropium can be deli#ered in hih doses to muscarinic
receptors in the air&ays because this compound is poorly absorbed and does not
readily enter the central ner#ous system! $tudies &ith this aent ha#e sho&n that
the deree of in#ol#ement of parasympathetic path&ays in bronchomotor responses
#aries amon sub6ects! In some, bronchoconstriction is inhibited e/ecti#ely9 in
others, only modestly! The failure of hiher doses of the muscarinic antaonist to
further inhibit the response in these indi#iduals indicates that mechanisms other
than parasympathetic re5e0 path&ays must be in#ol#ed!
E#en in the sub6ects least protected by this antimuscarinic aent, ho&e#er, the
bronchodilation and partial inhibition of pro#o'ed bronchoconstriction are of
potential clinical #alue, and antimuscarinic aents are #aluable for patients
intolerant of inhaled "aonist aents! 2hile antimuscarinic drus appear to be
slihtly less e/ecti#e than "aonist aents in re#ersin asthmatic bronchospasm,
the addition of ipratropium enhances the bronchodilation produced by nebuli.ed
albuterol in acute se#ere asthma!
Ipratropium appears to be at least as e/ecti#e in patients &ith chronic obstructi#e
pulmonary disease that includes a partially re#ersible component! A loner"actin,
selecti#e antimuscarinic aent, tiotropium, is in clinical trials as treatment for
(O%4! This druAs -<"hour duration of action is a potentially important ad#antae!
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