Pharmacology

Atropine-like alkaloids are classified as tertiary or quaternary ammonium compounds, depending on whether the nitrogen atom on the tropane ring is 3-valent or 5-valent, respectively (Fig. 3). All naturally occurring anticholinergic agents such as atropine and scopolamine are tertiary ammonium compounds. They are freely soluble in water and lipids and are well absorbed from mucosal surfaces and the skin. Following administration by the oral or inhalation route, they are rapidly absorbed and widely distributed in the body, cross the blood-brain barrier, enter the breast milk, and counteract parasympathetic activity in almost every system, producing widespread dose-related systemic effects. Atropine, for example, in the dose that results in bronchodilation (1.0-2.5 mg in adults) frequently produces skin flushing, dryness of the mouth, and some tachycardia. In slightly higher doses, it produces blurred vision, urinary retention, and mental effects such as irritability, confusion, and hallucinations. The therapeutic margin of atropine and its natural congeners is thus small, making these agents difficult to use. Tertiary ammonium compounds are no longer ch3-n

Br~-H20

O CH2OH It I

ATROPINE

O CH2OH It I

IPRATROPIUM BROMIDE

ATROPINE

IPRATROPIUM BROMIDE

Figure 3 Structures of some anticholinergic agents.

used (or approved in the United States) for the treatment of obstructive lung diseases.

All quaternary ammonium compounds, e.g., ipratropium bromide (Atrovent®), are synthetic. Importantly, the charge associated with the 5-valent nitrogen atom renders these molecules poorly absorbable from mucosal surfaces. Such agents retain their anticholinergic activity at the sites of deposition and will, for example, dilate the pupil if delivered to the eye or dilate the bronchi if inhaled. However, they are not sufficiently absorbed from these sites to produce either significant blood levels or systemic effects, even when delivered in supramaximal doses (14). Quaternary agents can thus be regarded for practical purposes as topical forms of atropine. The group includes, in addition to ipratropium, oxitropium bromide (Oxivent®), atropine methonitrate, glycopyrrolate bromide (Robinul®), and most recently tiotropium bromide (Spiriva®). Tiotropium is of particular interest in that it is functionally selective for the Ml and M3 receptors, sparing the M2 receptor (15-17).

A. Pharmacokinetics

Radiolabeling studies of ipratropium in humans show that, following oral or inhaled doses, the serum levels are very low, with a peak at about one to two hours and a half-life of about four hours. Most of the drug is excreted unchanged in the urine. Following inhalation, the bronchodilator effect is somewhat longer than that of atropine, probably because it is not removed from the airways by absorption. Most of an oral dose is recovered in the feces, a small amount as inactive metabolites in the urine. Very little crosses the blood-brain barrier to reach the central nervous system.

Tiotropium, whose chemical structure is similar to ipratropium and is also lipophilic and very poorly absorbed, has a distribution that is similar to

Table 1 Dissociation Half-Lifes of Ipratropium and Tiotropium on Muscarinic Receptor Subtypes (Hours)

Ml

M2

M3

Ipratropium

0.11

0.035

0.26

Tiotropium

14.6

3.6

34.7

Chinese hamster ovary cells. Source: From Ref. 18.

Chinese hamster ovary cells. Source: From Ref. 18.

ipratropium. However, its unique property is that its duration of action is very long, considerably exceeding that of ipratropium. The in vitro dissociation half-lifes of tiotropium and ipratropium on each muscarinic receptor subtype are shown in Table 1 (18), from which two features are evident. Tiotropium becomes dissociated from the (protective) M2 receptor relatively rapidly as compared to its residence on the Ml and M3 receptors and, more importantly, the half-life of tiotropium on both the Ml and M3 receptors exceeds that of ipratropium by a factor of more than a hundred. The latter indicates the uniquely long duration of action of this agent, consistent with clinical studies that show a duration of bronchodilator effect of more than one day, making it ideally suited for once-daily use.

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