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Routes of Drug Delivery to the Lungs Drugs may be delivered to the lungs by oral or parenteral routes and also

by inhalation. The choice depends on the drug and on the respiratory disease. Inhaled Route Inhalation (Figure 363) is the preferred mode of delivery of many drugs with a direct effect on airways, particularly for asthma and COPD (Berger, 2009). It is the only way to deliver some drugs such as cromolyn sodium and anticholinergic drugs and is the preferred route of delivery for 2 agonists and corticosteroids to reduce systemic side effects. Antibiotics may be delivered by inhalation in patients with chronic respiratory sepsis (e.g., in cystic fibrosis). Inhalation is also used to facilitate systemic drug delivery in other diseases (e.g., to avoid daily injections with insulin; see Chapter 43). The major advantage of inhalation is the delivery of drug to the airways in doses that are effective with a much lower risk of systemic side effects. This is particularly important with the use of inhaled corticosteroids (ICS), which largely avoids systemic side effects. In addition, drugs such as inhaled bronchodilators have a more rapid onset of action than when taken orally so that more rapid control of symptoms is possible.

Figure 36-3. Schematic representation of the deposition of inhaled drugs (e.g., corticosteroids, 2 agonists). Inhalation therapy deposits drugs directly, but not exclusively, in the lungs. Distribution between lungs and oropharynx depends mostly on the particle size and the efficiency of the delivery method. Most material will be swallowed and absorbed, entering systemic circulation after undergoing the first-pass effect in the liver. Some drug will also be absorbed into the systemic circulation from the lungs.

Use of a large-volume spacer will reduce the amount of drug deposited on oropharynx, thereby reducing amount swallowed and absorbed from GI tract, thus limiting systemic effects. MDI, metered-dose inhaler. Particle Size The size of particles for inhalation is of critical importance in determining the site of deposition in the respiratory tract. The optimum size for particles to settle in the airways is 2-5 m mass median aerodynamic diameter (MMAD). Larger particles settle out in the upper airways, whereas smaller particles remain suspended and are therefore exhaled. There is increasing interest in delivering drugs to small airways, particularly in COPD and severe asthma (Sturton et al., 2008). This involves delivering drug particles of 1 m MMAD, which is now possible using drugs formulated in hydrofluoroalkane (HFA) propellant. Pharmacokinetics Of the total drug delivered, only 10-20% enters the lower airways with a conventional pressurized metered-dose inhaler (pMDI). The fate of the inhaled drug is poorly understood. Drugs are absorbed from the airway lumen and have direct effects on target cells of the airway. Drugs may also be absorbed into the bronchial circulation and then distributed to more peripheral airways. Whether drugs are metabolized in the airways is often uncertain, and there is little understanding of the factors that may influence local absorption and metabolism of inhaled drugs. Drugs with higher molecular weights tend to be retained to a greater extent in the airways. Nevertheless, several drugs have greater therapeutic efficacy when given by the inhaled route. The inhaled corticosteroid ciclesonide is a prodrug activated by esterases in the respiratory tract to the active principle des-ciclesonide. More extensive pulmonary distribution of a drug with a smaller MMAD increases alveolar deposition and thus is likely to increase absorption from the lungs into the general circulation resulting in more systemic side effects. Thus, although HFA pMDIs deliver more inhaled corticosteroid to smaller airways, there is also increased systemic absorption, so that the therapeutic ratio may not be changed.

Delivery Devices Several ways of delivering inhaled drugs are possible (Virchow et al., 2008). Drugs are propelled from a canister with the aid of a propellant, previously with a chlorofluorocarbon (Freon) but now replaced by a hydrofluoroalkane (HFA) that is "ozone friendly." These devices are convenient, portable, and typically deliver 100-400 doses of drug. It is necessary to coordinate inhalation with activation of the device, so it is important that patients are taught to use these devices correctly. Many patients find this difficult despite instruction. Spacer Chambers Large-volume spacer devices between the pMDI and the patient reduce the velocity of particles entering the upper airways and the size of the particles by allowing evaporation of liquid propellant. This reduces the amount of drug that impinges on the oropharynx and increases the proportion of drug inhaled into the lower airways. The need for careful coordination between activation and inhalation is also reduced because the pMDI can be activated into the chamber and the aerosol subsequently inhaled from the one-way valve. Perhaps the most useful application of spacer chambers is in the reduction of the oropharyngeal deposition of inhaled corticosteroids and the consequent reduction in the local side effects of these drugs. Large volume spacers also reduce the systemic side effects of drugs because less is deposited in the oropharynx, and therefore swallowed. It is the swallowed fraction of the drug absorbed from the GI tract that makes the greatest contribution to the systemic fraction. This is of particular importance in the use of certain inhaled steroids, such as beclomethasone dipropionate, which can be absorbed from the GI tract. Spacer devices are also useful in delivering inhaled drugs to small children who are not able to use a pMDI. Children as young as 3 years of age are able to use a spacer device fitted with a face mask. Dry Powder Inhalers Drugs may also be delivered as a dry powder using devices that scatter a fine powder dispersed by air turbulence on inhalation. These devices may be preferred by some patients (Chan, 2006) because careful coordination is not as necessary as with the pMDI, but some patients find that the dry powder is an irritant.

Children <7 years of age find it difficult to use a dry powder inhaler (DPI) because they may not be able to generate sufficient inspiratory flow. DPIs have been developed to deliver peptides and proteins, such as insulin (e.g., EXUBERA, AFRESA), systemically. Nebulizers Two types of nebulizer are available. Jet nebulizers are driven by a stream of gas (air or oxygen), whereas ultrasonic nebulizers use a rapidly vibrating piezo-electric crystal and thus do not require a source of compressed gas. The nebulized drug may be inspired during tidal breathing, and it is possible to deliver much higher doses of drug compared with pMDI. Nebulizers are therefore useful in treating acute exacerbations of asthma and COPD, for delivering drugs when airway obstruction is extreme (e.g., in severe COPD), for delivering inhaled drugs to infants and small children who cannot use the other inhalation devices, and for giving drugs such as antibiotics when relatively high doses must be delivered. Small handheld nebulizers (soft mist inhalers) are now also available. Oral Route Drugs for treatment of pulmonary diseases may also be given orally. The oral dose is much higher than the inhaled dose required to achieve the same effect (typically by a ratio of 20:1), so that systemic side effects are more common. When there is a choice of inhaled or oral route for a drug (e.g., 2 agonist or corticosteroid), the inhaled route is always preferable, and the oral route should be reserved for the few patients unable to use inhalers (e.g., small children, patients with physical problems such as severe arthritis of the hands). Theophylline is ineffective by the inhaled route and therefore must be given systemically. Corticosteroids may have to be given orally for parenchymal lung diseases (e.g., in interstitial lung diseases), although it may be possible in the future to deliver such drugs into alveoli using specially designed inhalation devices with a small particle size. Parenteral Route The intravenous route should be reserved for delivery of drugs in the severely ill patient who is unable to absorb drugs from the GI tract. Side effects are generally frequent due to the high plasma concentrations.