(Chest. 2000;117:63S-66S.)
© 2000
American College of Chest Physicians
The Pharmacological Properties of Tiotropium*
Peter J. Barnes, MA, DM, DSc
*
From the Department of Thoracic Medicine, National Heart and Lung Institute, London, UK.
Correspondence to: Peter J. Barnes MA, DM, DSc, Department of Thoracic Medicine, National Heart and Lung Institute, Dovehouse St, London SW3 6LY, UK; email: p.j.barnes{at}ic.ac.uk
 |
Abstract
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Tiotropium is a long-acting anticholinergic drug. Studies
with cloned human muscarinic receptors show that tiotropium binds
equally well to M1, M2, and M3
receptors. However, it dissociates very slowly from M1 and
M3 receptors compared with ipratropium, and more rapidly
from M2 receptors. Binding studies with
[3H]tiotropium in human lung show that it is
approximately 10-fold more potent than ipratropium. In
vitro, tiotropium has a potent inhibitory effect against
cholinergic nerve-induced contraction of airways. It dissociates
extremely slowly, compared with the dissociation of atropine and
ipratropium. Clinical studies with single doses of inhaled tiotropium
confirm that it is a potent and long-lasting bronchodilator.
Furthermore, it protects against cholinergic bronchoconstriction for
> 24 h. Pharmacokinetic studies show that little of the inhaled drug
is absorbed, thus predicting a high margin of safety.
Key Words: acetylcholine • anticholinergic • cholinergic nerve • ipratropium bromide • M1 receptor • M2 receptor • M3 receptor • muscarinic receptor • tiotropium bromide
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Introduction
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Anticholinergic
agents have proved to be of particular value in the treatment of COPD,
as vagal cholinergic tone appears to be the only reversible component
of airway narrowing. Anticholinergics block muscarinic receptors on
airway smooth muscle and possibly on submucosal gland cells. It is now
recognized that there are subtypes of muscarinic receptor, and five
human muscarinic (Hm) receptor genes have been identified.
M1 (Hm1), M2 (Hm2) and
M3 (Hm3) receptors have been demonstrated in
human airways by autoradiographic mapping and functional studies, and
appear to have differing physiologic functions.1
M1 receptors in parasympathetic ganglia
facilitate cholinergic neurotransmission and therefore enhance
cholinergic bronchoconstriction, whereas M3
receptors on airway smooth muscle cells and glands mediate
bronchoconstriction and mucus secretion. M2
receptors at cholinergic nerve endings inhibit the release of
acetylcholine and therefore act as feedback inhibitory receptors
(autoreceptors). Blockade of M2 receptors
therefore results in increased acetylcholine release in human airways.
Atropine and ipratropium bromide are nonselective muscarinic
antagonists and therefore block M2 receptors, as
well as M1 and M3
receptors, so that the increased acetylcholine release may overcome the
blockade of muscarinic receptors in the muscle. This has prompted a
search for selective muscarinic receptor antagonists that either block
M3 or M1 and
M3 receptors.
Tiotropium is a novel, potent, and long-lasting muscarinic antagonist
that has been developed for the treatment of COPD.2
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Pharmacology
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Tiotropium (Ba 679 BR) has a quaternary ammonium structure and is
derived from that of ipratropium bromide (Fig 1)
.
In a series of pharmacologic studies, tiotropium was shown to be a
potent muscarinic receptor antagonist, with a prolonged duration of
blockade in guinea pig trachea in vitro and after inhalation
in dogs in vivo.3
In Chinese hamster ovary
cells transfected with Hm receptor subtype cDNA, tiotropium was
approximately 10-fold more potent than ipratropium in binding to cloned
muscarinic receptors. The apparent binding affinity (dissociation
constant) of tiotropium and ipratropium was similar for
M1, M2, and
M3 receptors, but kinetic studies (at 23°C)
showed than [3H]tiotropium dissociated > 100
times more slowly than [3H]ipratropium from
M1 (14.6 h vs 0.11 h) and
M3 (34.7 h vs 0.26 h), whereas dissociation
from Hm2 (3.6 h vs 0.035 h) was more similar (Table 1) .3
4
This suggests that tiotropium has a kinetic
selectivity for M1 and M3
receptors over M2 receptors. A similar trend is
seen with ipratropium, but it is obscured by the relatively short
dissociation time of this drug.
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Binding Studies in Human Lung
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[3H]tiotropium binds with high affinity to
a uniform population of muscarinic receptors in human peripheral lung
membranes.5
The binding affinity of
[3H]N-methyl scopolamine (NMS) is approximately
sixfold lower, and competition studies show that tiotropium is
approximately 10-fold more potent than ipratropium and atropine in
displacing specific [3H]NMS binding, thus
confirming the potency differences reported in cloned Hm receptors.
There is no evidence for selectivity in the binding of
[3H]tiotropium rat cerebrocortical
M1receptors labeled with
[3H]telenzepine, or heart
M2 and salivary gland
M3receptors, labeled with
[3H]NMS. Tiotropium has a long-lasting
protective effect against [3H]NMS binding, and
this lasts for > 90 min, whereas ipratropium has little protective
effect. Similarly, [3H]tiotropium dissociates
extremely slowly from human lung membranes, with a half-life (at
30°C) of almost 4 h.
Autoradiographic mapping of [3H]tiotropium in
human lung sections, using techniques developed for mapping muscarinic
receptor subtypes in human lung,6
shows labeling of
alveolar walls and submucosal glands, with little specific labeling of
airway smooth muscle or epithelium. Both pirenzepine
(M1-selective) and
4-diphenylacetoxy-N-methypiperidine
(M3-selective) displace specific binding, but
methoctramine (M2-selective) is without
any effect, suggesting that M1 and
M3 receptors are predominantly labeled.
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Functional Studies In Vitro
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The long duration of action of tiotropium in binding studies has
been confirmed in functional studies with cholinergic neural responses
in guinea pig and human airways in vitro.7
Tiotropium potently inhibits cholinergic nerve-induced contraction of
guinea pig trachea and is approximately fivefold more potent than
ipratropium or atropine. The onset of action of tiotropium is somewhat
slower than seen with atropine or ipratropium, but, after washout, its
duration of action in blocking cholinergic neural responses is greatly
prolonged, with a half-life of 540 min, compared with 81 min for
ipratropium. In human bronchi, tiotropium has a similar inhibitory
effect and is 10 times more potent than atropine, in accordance with
the binding studies reported above. Again, the onset of action is slow
compared with atropine, and its offset very prolonged (half-life
> 300 min) compared with atropine (half-life 64 min). These studies
indicate that tiotropium has a very prolonged inhibitory effect against
endogenous acetylcholine (ACh) released from postganglionic nerve
endings in the airways, presumably via an inhibitory effect on
postjunctional M3 receptors.
In order to study the effect of tiotropium on prejunctional
M2 receptors in cholinergic nerves, its effect on
the electric-field-stimulated release of ACh has been determined.
Prejunctional muscarinic receptors in guinea pig and human airways are
of the M2 receptor subtype.8
Electric-field stimulation increases ACh release, measured by a
[3H]choline superfusion technique, by
approximately sixfold.9
Tiotropium, ipratropium, and
atropine all increase ACh release to a similar extent (30 to 40%), but
this is lost 2 h after washout of the antagonists. Thus, although
tiotropium causes prolonged blockage of airway smooth muscle
M3 receptors after washout, this does not appear
to apply prejunctional M2 autoreceptors. This
demonstrates the kinetic selectivity of tiotropium, first demonstrated
in binding studies to transfected cells,3
also applies to
in vitro functional studies.
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Clinical Pharmacology Studies
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Tiotropium is well tolerated, with no cardiovascular or
respiratory adverse effects, but dryness of the mouth may occur at
higher doses. After inhalation of a single dose, peak plasma levels
reach a maximum 5 min after the dose, with a subsequent rapid decline
in < 1 h to very low levels (in the 2 pg/mL range), which could
occupy < 5% of muscarinic receptors even at high doses. At this low
level, the plasma tiotropium is eliminated with a terminal half-life of
5 to 6 days, and this is independent of the dose.4
Single doses of inhaled tiotropium have been investigated in clinical
studies in patients with COPD and asthma. In asthmatic patients, there
is a prolonged bronchodilator effect after a single dose, lasting for
up to 36 h. There is also a prolonged dose-dependent protection
against inhaled methacholine challenge.10
At an inhaled
dose of 40 µg, there is a protection of over seven doubling dilutions
against methacholine, and the protection lasts for > 48 h (Fig 2)
.
This should be compared with a protective effect of oxitropium
bromide of < 6 h.11
There are no adverse effects of
inhaled tiotropium and no effects on heart rate or BP. In patients with
COPD, tiotropium gives a dose-related bronchodilatation that persists
for > 24 h (Fig 3)
.12
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Figure 2. Dose-related and prolonged protective effect of a
single dose of tiotropium against bronchoconstrictor challenge with
inhaled methacholine. Adapted with permission from O’Connor et
al.10
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These studies suggest that tiotropium is suitable for once-daily
dosing, and that at the lower doses where most improvement is seen,
there are unlikely to be significant side effects.
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Conclusion
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These clinical studies support the animal and in vitro
studies and show that tiotropium is a potent and long-acting
anticholinergic agent. It is likely to be a useful addition to the
therapy of COPD, where once-daily administration may prove to be more
convenient and provide more consistent bronchodilation than the
currently recommended three- to four-times daily treatment needed for
ipratropium. The prolonged protection against cholinergic neural
bronchoconstriction may also be useful in the control of nocturnal
asthma, where cholinergic mechanisms appear to be
important.13
Whether the kinetic selectivity for
M1 and M3 receptors over
M2 receptors will be useful clinically remains to
be determined. Side effects do not appear to be a problem at
doses that are useful clinically.
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Footnotes
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Abbreviations: ACh = acetylcholine; Hm = human
muscarinic; NMS = N-methyl scopolamine
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References
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Barnes, PJ (1993) Muscarinic receptor subtypes in airways. Life Sci 52,521-528[CrossRef][ISI][Medline]
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Barnes, PJ, Belvisi, MG, Mak, JCW, et al (1995) Tiotropium bromide (Ba 679 BR), a novel long-acting muscarinic antagonist for the treatment of obstructive airways disease. Life Sci 56,853-859[CrossRef][ISI][Medline]
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Disse, B, Reichal, R, Speck, G, et al (1993) Ba679BR, a novel anticholinergic bronchodilator: preclinical and clinical aspects. Life Sci 52,537-544[CrossRef][ISI][Medline]
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Disse, B, Speck, GA, Rominger, KL, et al (1999) Tiotropium (Spiriva): mechanistical considerations and clinical profile in obstructive lung disease. Life Sci 64,457-464[CrossRef][ISI][Medline]
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Haddad, E, Mak, JCW, Barnes, PJ (1994) Characterization of [3H]Ba 679, a slow-dissociating muscarinic receptor antagonist in human lung: radioligand binding and autoradiographic mapping. Mol Pharmacol 45,899-907[Abstract]
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Mak, JCW, Barnes, PJ (1990) Autoradiographic visualization of muscarinic receptor subtypes in human and guinea pig lung. Am Rev Respir Dis 141,1559-1568[ISI][Medline]
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Takahashi, T, Belvisi, MG, Patel, H, et al (1994) Effect of Ba 679 BR, a novel long-acting anticholinergic agent, on cholinergic neurotransmission in guinea-pig and human airways. Am J Respir Crit Care Med 150,1640-1645[Abstract]
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Patel, HJ, Barnes, PJ, Takahashi, T, et al (1995) Characterization of prejunctional muscarinic autoreceptors in human and guinea-pig trachea in vitro. Am J Respir Crit Care Med 152,872-878[Abstract]
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Ward, JK, Belvisi, MG, Fox, AJ, et al (1993) Modulation of cholinergic neural bronchoconstriction by endogenous nitric oxide and vasoactive intestinal peptide in human airways in vitro. J Clin Invest 92,736-743
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O’Connor, BJ, Towse, LJ, Barnes, PJ (1996) Prolonged effect of tiotropium bromide on methacholine-induced bronchoconstriction in asthma. Am J Respir Crit Care Med 154,876-880[Abstract]
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Wilson, NM, Green, S, Coe, C, et al (1987) Duration of protection by oxitropium bromide against cholinergic challenge. Eur J Respir Dis 71,455-458[ISI][Medline]
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Maesen, FPV, Smeets, JJ, Sledsens, TJM, et al (1995) Tiotropium bromide, a new long-acting antimuscarinic bronchodilator: a pharmacodynamic study in patients with chronic obstructive pulmonary disease (COPD). Eur Respir J 8,1506-1513[Abstract]
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Morrison, JFJ, Pearson, SB, Dean, HG (1988) Parasympathetic nervous system in nocturnal asthma. Br Med J 296,1427-1429
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TOP
Abstract
Introduction
