Drug Administration Phase

The drug administration phase describes the method by which a drug dose is made available to the body. Administering drugs directly to the respiratory tract uses the inhalation route, and the dose form is an aerosol of liquid solutions, suspensions, or dry powders. The most commonly used devices to administer orally or nasally inhaled aerosols are the metered dose inhaler (MDI), the small volume nebulizer (SVN), and the dry powder inhaler (DPI). Reservoir devices, including holding chambers with one-way inspiratory valves and simple, nonvalved spacer devices, are often added to MDIs to reduce the need for complex hand-breathing coordination and to reduce oropharyngeal impaction of the aerosol drug (see Chapter 36).

The advantages of treatment of the respiratory tract with inhaled aerosols are as follows:

Disadvantages of the delivery of inhaled aerosols in treating respiratory disease include the number of variables affecting the delivered dose and lack of adequate knowledge of device performance and use among patients and caregivers.³

Pharmacokinetic Phase

The pharmacokinetic phase of drug action describes the time course and disposition of a drug in the body based on its absorption, distribution, metabolism, and elimination. Inhaled bronchoactive aerosols are intended for local effects in the airway. Undesired systemic effects result from absorption and distribution throughout the body. One method of limiting distribution of inhaled aerosols is use of a fully ionized drug rather than a nonionized agent. A fully ionized drug is not absorbed across lipid membranes, whereas a nonionized drug is lipid-soluble and diffuses across cell membranes and into the bloodstream. Examples are ipratropium and atropine sulfate. Ipratropium is a fully ionized quaternary ammonium compound that diffuses poorly across lipid membranes. Atropine is poorly ionized and diffuses well, distributing throughout the body. As a result, atropine produces systemic side effects such as mydriasis (dilation of the pupils) and blurring of vision. The effects of ipratropium are largely local to the airway, and systemic effects are nonexistent or minimal.

An inhaled aerosol distributes to the lung by inhalation and the stomach through swallowing of drug that deposits in the oropharynx. The therapeutic effect of the aerosol drug is caused by the portion in the airway. Systemic effects are due to absorption of the drug from the airway and gastrointestinal (GI) tract. The ideal aerosol would distribute only to the airway with none reaching the stomach. The lung availability-to-total systemic availability ratio (L/T ratio) quantifies the efficiency of aerosol delivery to the lung:

< ?xml:namespace prefix = "mml" />L/T ratio=Lung availability/(Lung+GI availability)

This concept, proposed by Borgström⁴ and elaborated by Thorsson,⁵ is illustrated in Figure 32-1, showing delivery of albuterol by inhalation using an MDI and a DPI.

Pharmacodynamic Phase

The pharmacodynamic phase describes the mechanisms of drug action by which a drug molecule causes its effects in the body. Drug effects are caused by the combination of a drug with a matching receptor. Drug signaling mechanisms include the following:

The mechanisms of drug action are briefly described for each class of bronchoactive drug.

Airway Receptors and Neural Control of the Lung

Pharmacologic control of the airway is mediated by receptors found on airway smooth muscle, secretory cells, bronchial epithelium, and pulmonary and bronchial blood vessels. There are sympathetic (adrenergic) and parasympathetic (cholinergic) receptors in the lung. The terminology for drugs acting on these receptors is based on the usual neurotransmitter that acts on the receptor. The usual neurotransmitter in the sympathetic system is norepinephrine, which is similar to epinephrine, also known as adrenaline (Adrenalin). The usual neurotransmitter in the parasympathetic system is acetylcholine. The receptors responding to these neurotransmitters are termed adrenergic and cholinergic. Agonists (stimulating agents) and antagonists (blocking agents) that act on these receptors are given the following classifications:

Because cholinergic receptors exist at autonomic ganglia and at the myoneural junction in skeletal muscle, the terms muscarinic and antimuscarinic distinguish cholinergic agents whose action is limited to parasympathetic sites. Neostigmine is a cholinergic (indirect-acting) drug that increases receptor stimulation at both the myoneural junction and the parasympathetic sites. By contrast, atropine is an antimuscarinic agent, which blocks the action of acetylcholine only at the parasympathetic sites. Table 32-1 summarizes receptors and their effects for the cardiopulmonary system. A more detailed description of the autonomic nervous system and receptor subtypes is provided by Katzung and colleagues.²

Indications for Use

The general indication for use of an adrenergic bronchodilator is the presence of reversible airflow obstruction. The most common use of these agents clinically is to improve flow rates in asthma (including exercise-induced asthma), acute and chronic bronchitis, emphysema, bronchiectasis, cystic fibrosis (CF), and other obstructive airway states.

Mode of Action and Effects

Adrenergic bronchodilators can stimulate one or more of the following receptors, with the effects described:

Bronchodilation, through stimulation of beta-2 receptors, is the desired therapeutic effect. Both alpha-adrenergic and beta-adrenergic receptors are G protein–linked receptors. Figure 32-2 illustrates the mode of action for relaxation of airway smooth muscle when a beta-2 receptor is stimulated. The nature of the beta receptor and its activity is presented in detail in a review by Barnes.⁷

Adrenergic Bronchodilator Agents

Adrenergic bronchodilator agents represent the evolution of a drug class. Although all of these agents are adrenergic agonists, the differences among individual agents are due to their receptor preference (alpha-adrenergic, beta-1-adrenergic, beta-2-adrenergic) and their different pharmacokinetics as listed in Table 32-2. These differences determine the optimal clinical application of individual agents, as discussed subsequently. The adrenergic bronchodilators form three subgroups.

Short-Acting Noncatecholamine Agents

Because of their short duration of action and lack of beta-2 specificity, catecholamines were replaced with longer acting, beta-2-specific agents, including metaproterenol, pirbuterol, albuterol, and levalbuterol. Because their duration of action is approximately 4 to 6 hours, these drugs are more suited to maintenance therapy than catecholamines and can be taken on a four-times-daily schedule. However, their modest duration of action results in loss of bronchodilating effect overnight.

Single-Isomer Beta Agonists

Levalbuterol is approved as a single-isomer beta-2-selective agonist. Previous inhaled formulations of adrenergic bronchodilators all were synthetic racemic mixtures, containing both the (R)-isomer and the (S)-isomer in equal amounts. Levalbuterol is the pure (R)-isomer of racemic albuterol. Both stereoisomers of albuterol are shown in Figure 32-3 with the single-isomer (R-isomer) form of levalbuterol. Although the (S)-isomer is physiologically inactive on adrenergic receptors, there is accumulating evidence that the (S)-isomer is not completely inactive. Box 32-1 lists some of the physiologic effects of (S)-albuterol noted in the literature.^8–14 The effects noted antagonize the bronchodilating effects of the (R)-isomer and promote bronchoconstriction. In addition, the (S)-isomer is more slowly metabolized than the (R)-isomer.

Box 32-1   Effects and Characteristics of (S)-Isomer of Albuterol

• Increases intracellular calcium concentration in vitro⁸

• Activity is blocked by the anticholinergic atropine⁸

• Does not produce pulmonary or extrapulmonary beta-2-mediated effects⁹

• Enhances experimental airway responsiveness in vitro¹⁰

• Increases contractile response of bronchial tissue to histamine or leukotriene C₄ in vitro¹¹

• Enhances eosinophil superoxide production with interleukin-5 stimulation¹²

• Slower metabolism than (R)-albuterol in vivo¹³

• Preferential retention in the lung when inhaled by MDI (in vivo)¹⁴

Levalbuterol is available as a nebulization solution in three strengths: 0.31 mg/3 ml, 0.63 mg/3 ml, and 1.25 mg/3 ml. As a result of mixing of other inhaled agents, levalbuterol is also available as a concentrate of 1.25 mg/0.5 ml and an MDI. In a study by Nelson and associates,¹⁵ the 0.63-mg dose was found to be comparable to the 2.5-mg racemic albuterol dose in onset and duration. Side effects of tremor and heart rate changes were less with the single-isomer formulation. The 1.25-mg dose showed a higher peak effect on forced expiratory volume in 1 second (FEV₁) with an 8-hour duration compared with racemic albuterol. Side effects with this dose were equivalent to the side effects seen with racemic albuterol. An equivalent clinical response was seen with one-fourth of the racemic dose (0.63 mg) using the pure isomer, although the racemic mixture contains 1.25 mg of the (R)-isomer (half of the total 2.5-mg dose). A detailed review is available of levalbuterol and differences between the (R)-isomer and (S)-isomer of albuterol.¹⁶

Adverse Effects

Older adrenergic agents, such as isoproterenol, commonly caused tachycardia, palpitations, and an “adrenaline effect” of shakiness and nervousness. The newer, more beta-2-selective agents are safer and typically cause tremor as the main side effect. Other common side effects with the inhaled agents include headache, insomnia, and nervousness. Patients should be reassured that some tolerance to these effects does occur. Potential adverse effects with use of adrenergic bronchodilators include the following:

Inhalation results in fewer and less severe side effects than oral administration. Although tolerance develops to the bronchodilating effect, this is not a contraindication to use of the drugs, and relaxation of airway smooth muscle still occurs. Desaturation resulting from mismatching of with inhalation of the aerosol is not clinically significant and reverses quickly. Bronchospasm resulting from chlorofluorocarbon propellants can be prevented by changing to newer hydrofluoroalkane-propelled MDIs or a different aerosol delivery form.

The implication of beta-2-adrenergic agonists in deaths from asthma—termed the asthma paradox or the beta agonist controversy—remains debated.¹⁹ There is evidence of loss of a bronchoprotective effect with use of beta agonists, and patients should be cautioned to avoid asthma triggers.²⁰ The increased prevalence of asthma in general remains a troublesome and unresolved issue.

Assessment of Bronchodilator Therapy

Assessment of therapy with adrenergic bronchodilators should be based on the indication for the aerosol agent (presence of reversible airflow obstruction owing to primary bronchospasm or other obstruction secondary to an inflammatory response or secretions, either acute or chronic). With all aerosol drug therapy, basic vital signs (respiratory rate and pattern, pulse, breath sounds) should be assessed before and after treatment, especially for initial drug use, and the patient’s subjective reaction (complaints of breathing difficulty) should be assessed. Patients should be instructed in the correct use of the aerosol device used, with verification of correct use. Finally, the patient’s subjective reaction to the treatment should be monitored for any change in breathing effort. This assessment applies to all subsequent drug groups by aerosol and is not repeated for each class. The following specific actions are suggested to evaluate patient response to this class of drugs:

The following actions are suggested to evaluate patient response to long-acting beta agonists:

Note: Death has been associated with excessive use of inhaled adrenergic agents in severe acute asthma crises. Individuals using such drugs should be instructed to contact a physician or an emergency department if there is no response to the usual dose of the inhaled agent.

Because of the ongoing safety concerns of long-acting beta-2 agonists, the FDA is requiring changes on how long-acting beta-2 agonists are used in the treatment of asthma. As of June 2, 2010, the FDA suggests the following:

Indications for Use

Ipratropium bromide and tiotropium bromide are the only inhaled anticholinergic bronchodilators available in the United States. Table 32-3 lists the dosage forms and pharmacokinetics of ipratropium and tiotropium. Generally, anticholinergic agents have been found to be as effective as beta agonists in airflow improvement in COPD but less so in asthma. A nasal formulation of ipratropium is also available for relief of allergic and nonallergic perennial rhinitis, including the common cold.²¹