DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Delivery Devices
Several ways of delivering inhaled drugs are possible (Virchow
et al., 2008).
Pressurized Metered-Dose Inhalers. 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., β 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.
BRONCHODILATORS
Bronchodilator drugs relax constricted airway smooth
muscle in vitro and cause immediate reversal of airway
obstruction in asthma in vivo. They also prevent bronchoconstriction
(and thereby provide bronchoprotection).
Three main classes of bronchodilator are in
current clinical use:
• 2
Adrenergic agonists (sympathomimetics)
• Theophylline (a methylxanthine)
• Anticholinergic agents (muscarinic receptor antagonists)
Drugs such as cromolyn sodium, which prevent
bronchoconstriction, have no direct bronchodilator
action and are ineffective once bronchoconstriction has
occurred. Anti-leukotrienes (leukotriene receptor antagonists
and 5-lipoxygenase inhibitors) have a small bronchodilator
effect in some asthmatic patients and appear
to prevent bronchoconstriction. Corticosteroids, although
gradually improving airway obstruction, have no direct
effect on contraction of airway smooth muscle and are
not therefore considered to be bronchodilators.
2
ADRENERGIC AGONISTS
Inhaled 2
agonists are the bronchodilator treatment of
choice in asthma because they are the most effective
bronchodilators and have minimal side effects when
used correctly. Systemic, short-acting, and nonselective
agonists, such as isoproterenol (isoprenaline) or
metaproterenol, should only be used as a last resort.
Chemistry. The development of 2
agonists is based on substitutions
in the catecholamine structure of norepinephrine and epinephrine
(Chapter 12). The catechol ring consists of hydroxyl groups in the 3
and 4 positions of the benzene ring (Figure 36–4). Norepinephrine
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CHAPTER 36
PULMONARY PHARMACOLOGY