DRUG	BRAND NAME	ADULT DOSAGE	TIME COURSE (ONSET, PEAK, DURATION)
Ipratropium bromide	Atrovent HFA	HFA MDI: 17 μg/puff. 2 puffs qid SVN: 0.02% solution (0.2 mg/mL), 500 μg tid, qid Nasal spray: 21 μg; 42 μg; 2 sprays per nostril 2 to 4 times daily (dosage varies)

Onset: 15 min

Peak: 1-2 hr

Duration: 4-6 hr

Ipratropium bromide and albuterol Combivent MDI: ipratropium 18 μg/puff and albuterol 90 μg/puff, 2 puffs qid

Onset: 15 min

Peak: 1-2 hr

Duration: 4-6 hr

DuoNeb SVN: ipratropium 0.5 mg and albuterol 2.5 mg Tiotropium bromide Spiriva DPI: 18 μg/inhalation, 1 inhalation daily (one capsule)

Onset: 30 min

Peak: 1-3 hr

Duration: 24 hr

DPI, Dry powder inhaler; HFA, hydrofluoroalkane; MDI, metered dose inhaler; SVN, small volume nebulizer.

^*A holding chamber is recommended with MDI administration to prevent accidental eye exposure.

Atropine sulfate had been administered as a nebulized solution, using either the injectable solution or, preferably, solutions marketed for aerosolization; however, this agent is no longer aerosolized. Duration of bronchodilation and the incidence of side effects are dose dependent. Dosages for children based on dose-response curves had been given as 0.05 mg/kg three or four times daily.¹ Dosages for adults are based on a schedule of 0.025 mg/kg three or four times daily.² Although greater bronchodilation and duration were seen with dosage schedules of 0.05 or 0.1 mg/kg for adults, the side effects of dry mouth, blurred vision, and tachycardia became unacceptable. Because it is a tertiary ammonium compound and not fully ionized, atropine is readily absorbed from the gastrointestinal tract and respiratory mucosa. Systemic side effects (which are discussed subsequently) were seen in doses required for effective bronchodilation when given as an inhaled aerosol. The drug is not recommended for inhalation as a bronchodilator because of its widespread distribution in the body and the availability of the approved agents ipratropium and tiotropium.

Ipratropium bromide (Atrovent) is a nonselective antagonist of M₁, M₂, and M₃ receptors (for a discussion of muscarinic receptors, see Chapter 5). Ipratropium is currently available in two formulations for bronchodilator use: as a hydrofluoroalkane-propelled metered dose inhaler (HFA MDI) with 17 μg/puff and as a nebulizer solution of 0.02% concentration in a 2.5-mL vial, giving a 500-μg dose per treatment. One other option for the delivery of ipratropium is the soft-mist, propellant-free Respimat inhaler. This formulation at the time of this edition is unavailable in the United States; however, it may soon become available. This agent is an N-isopropyl derivative of atropine. As a quaternary ammonium derivative of atropine, ipratropium is fully ionized and does not distribute well across lipid membranes, limiting its distribution more to the lung when inhaled. Ipratropium is approved specifically for the maintenance treatment of airflow obstruction in COPD.

Ipratropium is poorly absorbed into the circulation from either the nasal mucosa, when given by nasal spray, or the airway, when inhaled orally by aerosol. Approximately 20% of the nasal dose and the MDI dose is absorbed, with only 2% of the larger nebulizer solution absorbed into the bloodstream. Ipratropium is partially metabolized by ester hydrolysis to inactive products. It is minimally bound to plasma proteins such as albumin (less than 9%), and the elimination half-life is about 1.6 hours.

The profile of clinical effect for ipratropium differs from that of inhaled β-adrenergic agonists. The onset of bronchodilation begins within minutes but proceeds more slowly to a peak effect 1 to 2 hours after inhalation. β agonists can peak between 20 minutes and 30 minutes depending on the agent. In asthma, the duration of bronchodilator effect is about the same for ipratropium as for β agonists. In COPD, the duration is longer by 1 to 2 hours.³

Ipratropium bromide (Atrovent nasal spray) is also available for treatment of rhinopathies and rhinorrhea, including nonallergic perennial rhinitis, viral infectious rhinitis (colds), and allergic rhinitis, if intranasal corticosteroids fail to control symptoms.⁴ The nasal spray is available in two strengths, with a 0.03% solution delivering 21 μg/spray and the 0.06% solution delivering 42 μg/spray. The 0.03% strength is given as two sprays per nostril two or three times daily, and the 0.06% strength is given as two sprays per nostril three or four times daily. Optimal dosage varies. Intranasal ipratropium has been shown to reduce significantly the volume of nasal secretions and symptoms in patients with allergic rhinitis and in patients with nonallergic rhinitis.⁴ Side effects with the nasal spray are largely local and have included nasal dryness, itching, and epistaxis in a few patients. Dry mouth and dry throat have also occurred. Systemic symptoms such as blurred vision or urinary hesitancy are rare.

Ipratropium and albuterol (Combivent) is a combination MDI product, with the usual doses of each agent (18 μg/puff of ipratropium, 90 μg/puff of albuterol). The combination therapy has been shown to be more effective in stable COPD than either agent alone.⁵ Another agent, DuoNeb, is available as a combination of ipratropium (0.5 mg) and albuterol base (2.5 mg). Another option for the delivery of Combivent is the soft-mist, propellant-free, Respimat inhaler. As mentioned earlier, Respimat inhaler at the time of this edition is unavailable in the United States. The chlorofluorocarbon (CFC) version of Combivent will be removed from the market on December 31, 2013.

Glycopyrrolate is a quaternary ammonium derivative of atropine that, similar to ipratropium, does not distribute well across lipid membranes in the body. It is usually administered parenterally as an antimuscarinic agent during reversal of neuromuscular blockade, as an alternative to atropine, with fewer ocular or central nervous system (CNS) side effects. The injectable solution has been nebulized in a 1-mg dose for bronchodilation. Gal and colleagues ⁶ reported a comparison of glycopyrrolate with atropine and established dose-response curves. Glycopyrrolate has an onset of action of approximately 15 to 30 minutes, a peak effect at 0.5 to 1 hour, and a duration of approximately 6 hours. Although the injectable formulation of glycopyrrolate is used as a less expensive alternative to the Atrovent brand of ipratropium, it is not approved for inhalation. More recently in new research of asthma and COPD, glycopyrrolate as an inhaled agent currently under investigation (NVA-237) has found favor. In a small study, Hansel and coworkers⁷ found superiority over ipratropium in the protection of bronchospasm from methacholine.

Tiotropium bromide (Spiriva), a muscarinic receptor antagonist, is a long-acting bronchodilator. It is a quaternary ammonium compound structurally related to ipratropium. Similar to ipratropium, tiotropium is poorly absorbed after inhalation. Inhalation of a single dose gives a peak plasma level within 5 minutes, with a rapid decline to very low levels within 1 hour.⁸^,⁹ Tiotropium exhibits receptor subtype selectivity for M₁ and M₃ receptors. The drug binds to all three muscarinic receptors (M₁, M₂, and M₃) but dissociates much more slowly than ipratropium from the M₁ and M₃ receptors. This results in a selectivity of action on M₁ and M₃ receptors. Atropine and ipratropium block all three types of muscarinic receptors. The M₂ receptor is an autoreceptor inhibiting further release of acetylcholine, so that blockade can increase acetylcholine release and may offset the bronchodilating effect of atropine or ipratropium.⁸ In patients with COPD, tiotropium gives a bronchodilating effect for up to 24 hours with adequate dose. The effect of tiotropium can be seen for 32 hours; however, it dips between 16 hours and 24 hours owing to circadian rhythm. The drug also gives a prolonged, dose-dependent protection against inhaled methacholine challenge.¹⁰

! KEY POINT

Anticholinergic bronchodilators are specifically parasympatholytic, that is, antimuscarinic agents, blocking the effect of acetylcholine at the cholinergic (muscarinic) receptors on bronchial smooth muscle.

Several studies have examined the bronchodilating effect of various doses of tiotropium compared with placebo and ipratropium.10–12 A single dose of 18 μg inhaled once daily from a dry powder inhaler (DPI), the HandiHaler,¹³ provided significant bronchodilation for up to 24 hours, with a low side-effect profile. An increase of 15% from baseline forced expiratory volume in 1 second (FEV₁) occurred 30 minutes after inhalation, with a peak effect at about 3 hours. Improvement in FEV₁ was greater 3 hours after inhalation for tiotropium than for ipratropium. After a dose of tiotropium, the trough, or lowest, value for FEV₁ remained above that of ipratropium because of the prolonged action of tiotropium. Ipratropium had a more rapid onset of action than tiotropium, but after the initial dosing this difference loses relevance because tiotropium maintains a higher level of baseline bronchodilation. In a meta-analysis, Barr and associates¹⁴ found that tiotropium reduces COPD exacerbations and hospitalizations, improves quality-of-life symptoms, and may slow the decline in a patient’s FEV₁.

At the present time in the United States, tiotropium is available only as a DPI. However, as discussed earlier in the use of ipratropium and Combivent, the soft-mist, propellant-free Respimat inhaler is available outside the United States with tiotropium. At the time of this edition, no time table has been set for U.S. Food and Drug Administration (FDA) approval in this formulation.

Aclidinium bromide is a novel, long-acting, inhaled muscarinic antagonist currently being developed by Forest Laboratories as a maintenance treatment for COPD.¹⁵ This agent has shown potent antagonism of all muscarinic receptors, dissociating slowly at M₃ and a shorter time at M₂, indicating the potential to provide sustained bronchodilation that is similar in action to tiotropium.¹⁶ Aclidinium is rapidly hydrolyzed in human plasma, in contrast to ipratropium and tiotropium.¹⁶^,¹⁷ This rapid hydrolysis results in very low and transient systemic exposure, suggesting a reduced potential for systemic side effects.¹⁶^,¹⁷

Early clinical studies in healthy subjects have confirmed the low systemic bioavailability and favorable safety profile of single and multiple doses of aclidinium.¹⁸^,¹⁹ In a subsequent study, which included patients with moderate to severe COPD, aclidinium displayed long-lasting bronchodilation and was well tolerated.²⁰

! KEY POINT

The only approved anticholinergic agents for inhalation as an aerosol at this time are ipratropium (Atrovent), which is available as an MDI, an SVN solution, and an intranasal spray, and tiotropium (Spiriva), which is available only as a DPI.

Clinical pharmacology

Structure-activity relationships

Chemical structures of the two naturally occurring belladonna alkaloids, atropine and scopolamine (also called hyoscine), are illustrated in Figure 7-1. Atropine, including its sulfate (atropine sulfate), and scopolamine are both tertiary ammonium compounds that differ from each other only by an oxygen bridging the carbon-6 and carbon-7 positions. Quaternary ammonium derivatives of atropine include atropine, ipratropium, and tiotropium. Another quaternary atropine derivative, which has been administered experimentally as a bronchodilator by aerosol, is glycopyrrolate (Robinul) (not shown in Figure 7-1).

Figure 7-1 Chemical structures of anticholinergic (parasympatholytic) agents: tertiary compounds, such as atropine and scopolamine, and quaternary compounds, such as ipratropium and tiotropium.

Tertiary ammonium forms such as atropine sulfate or scopolamine are easily absorbed into the bloodstream, distribute throughout the body, and in particular cross the blood-brain barrier to cause CNS changes. Quaternary ammonium forms (e.g., ipratropium, tiotropium, and glycopyrrolate) are fully ionized and poorly absorbed into the bloodstream or CNS. As a result, the systemic side effects seen with aerosol administration of the tertiary ammonium atropine sulfate do not occur or are minimal with a quaternary ammonium such as ipratropium. Quaternary ammonium agents given by inhalation generally are poorly absorbed from the lung. They are not rapidly removed from the aerosol deposition site and do not cross the blood-brain barrier as atropine sulfate does, giving them a wider therapeutic margin in relation to side effects.

Pharmacologic effects of anticholinergic (antimuscarinic) agents

The general effects of cholinergic (muscarinic) stimulation and the corresponding effects produced by anticholinergic (antimuscarinic) action are listed in Table 7-2. Specific effects differ for tertiary and quaternary ammonium compounds because of their absorption differences as previously outlined for their structure-activity relationships. These effects and their differences are summarized in Table 7-3 and discussed subsequently.

TABLE 7-2

Comparison of Cholinergic Antagonism (Antimuscarinic Effects) with Cholinergic Effects (Muscarinic Effects)

CHOLINERGIC EFFECT	ANTICHOLINERGIC EFFECT
Decreased heart rate	Increased heart rate
Miosis (contraction of iris, eye)	Mydriasis (pupil dilation)
Contraction (thickening) of lens, eye	Cycloplegia (lens flattened)
Salivation	Drying of upper airway
Lacrimation	Inhibition of tear formation
Urination	Urinary retention
Defecation	Antidiarrheal or constipation
Secretion of mucus	Mucociliary slowing
Bronchoconstriction	Inhibition of constriction

TABLE 7-3

Pharmacologic Effects of Tertiary versus Quaternary Anticholinergic Agents Given by Inhaled Aerosol

	TERTIARY (ATROPINE)	QUATERNARY (IPRATROPIUM AND TIOTROPIUM)
Respiratory tract	Bronchodilation	Bronchodilation
	Decreased mucociliary clearance	Little or no change in mucociliary clearance
	Blockage of hypersecretion	Blockage of nasal hypersecretion
CNS	Altered CNS function (dose related)	No effect
Eye	Mydriasis	Usually no effect*
	Cycloplegia
	Increased intraocular pressure
Cardiac	Minor slowing of heart rate (small dose); increased heart rate (larger dose)	No effect
Gastrointestinal	Dry mouth, dysphagia; slows motility	Dry mouth
Genitourinary	Urinary retention	Usually no effect^†

CNS, Central nervous system.

^*Assumes aerosol is not sprayed into eye; use with caution in glaucoma.

^†Use with caution in prostatic enlargement or urinary retention.

Tertiary ammonium compounds

Tertiary compounds include atropine sulfate, scopolamine, and hyoscyamine sulfate. They are well absorbed across mucosal surfaces, and their effects increase with dose. Effects are summarized for these agents for the organ systems.

Respiratory tract effects.

Atropine sulfate, a prototype tertiary compound, inhibits and reduces mucociliary clearance, as shown by Groth and associates.²¹ Atropine seems to block hypersecretion stimulated by cholinergic agonists in both the lower airway and the nose (upper airway) more than basal secretion.²² Atropine relaxes airway smooth muscle, the basis for its use in asthma.