Airway Pharmacology

Pharmacodynamics

Pharmacodynamics refers to the properties of a drug at the site of action and its resulting effects, including the intensity of therapeutic and adverse effects. It describes a drug or drug class on the basis of mechanism of action, such as receptor binding or enzymatic action, and the subsequent effect of that action. The effect of a drug can be described on a molecular level, such as in the example of a G protein–coupled receptor creating a cascade of intracellular events or a sodium channel closing and altering resting ion conductance across the cell membrane. Alternatively, the effect can be described on a systemic basis, or by the therapeutic change effected by the drug’s action. Examples of this include a change in airway resistance with dilation of a respiratory bronchiole or numbing of the airway resulting from loss of sensory input with blockade of nerve conduction. Analysis of a drug’s effect based on the amount of drug given, or a dose-response relationship, is also under the scope of pharmacodynamics. Finally, description of drug action compared with other drugs also falls under the umbrella of pharmacodynamics. For example, classifying drugs as agonists, antagonists, or partial agonists at a receptor site is a pharmacodynamic concept.

Pharmacokinetics

Pharmacokinetics includes the absorption, distribution, metabolism, and excretion properties of a drug in relation to the body. Essentially, it describes where a drug goes when it is administered, or the volume of distribution. Drug delivery falls within these considerations, as does drug elimination from the body—clearance. A more granular view of pharmacokinetics would describe the complex processes of drug distribution and redistribution within the body, as well as the factors that govern how a drug molecule reaches its site of action and how that drug is removed from its site of action to terminate the effect. Drug distribution and redistribution require an intricate knowledge of how much drug is present in various sites in the body at a given time after administration, and, in fact, several complex mathematical models attempt to describe this idea in a very discrete manner. Finally, the physical aspects and molecular structure of a drug often play into its pharmacokinetics because this is one of the primary determinants of a drug’s ability to travel in the body. For example, a drug’s ability to cross a lipid membrane may be very important in determining its onset of action or the concentration in the blood required to initiate an effect.

Adverse Reactions, Side Effects, and Toxicity

With any administration of a drug, there are side effects, adverse reactions, and toxicity that must be taken into consideration. The first concept to introduce is that of local and systemic effects of drugs. For example, agents directly involved in airway management may have systemic considerations; conversely, systemic treatments may have effects on the airway. In fact, a drug administered with an intended effect may actually act in a completely remote area of the body to create that effect. This leads into the concept of side effects of drugs, which describes effects that a drug may have secondary to its intended therapeutic use. An example of this would be with sympathomimetic agents, which may be given with the intent of airway smooth muscle relaxation but have a separate effect of increased heart rate and blood pressure. This side effect of a drug may or may not be considered also to be an adverse reaction of the drug, which is an unintended effect with the potential to create harm or injury to a patient. Another example of an adverse reaction is a drug allergy; however, the two are not equivalent terms.

One way to describe a drug’s ability to create harm or adverse effects is the concept of toxicity. This describes the extent to which a drug can cause harm and is often related to the amount of drug in the body. Many drugs have an established toxicity level based on observation after clinical use. For example, lidocaine has the ability to create toxic effects at or above serum concentrations of 5 to 6 µg/mL. This introduces the concept of a therapeutic range of a drug, which is a conceptualization of the amount of drug that will create and maximize the intended therapeutic effect with minimal toxic side effects. Some drugs have a therapeutic range below a toxic concentration range, but some drugs create therapeutic effects at similar concentrations that create toxic effects. A situation in which administration of a drug simultaneously results in benefit and harm creates a dilemma for the practitioner in the drug prescribing process and requires special consideration. Unfortunately, this is frequently the case when managing the airway and in the perioperative period or with critically ill patients.

Anatomy

Anatomic considerations include age, body habitus, and posture. As individuals age, the cartilaginous structures of the airway continue to grow and increase in rigidity. Obesity, particularly in the cervical region, can restrict range of movement as well as decrease the volume of the upper airway. In the supine position, the effect of gravity is such that the tissue will tend to collapse on the airway, potentially creating a partial or complete obstruction. Similarly, the lower airway can be affected with changes in lung volumes and functional residual capacity.

The upper airway is most susceptible to anatomic change and loss of patency because of the complex muscle arrangements that coordinate function, such as passage of air, swallowing, and speech. ^, Activation of these muscles prevents collapse of the space with the negative pressure of inspiration. This concept will present itself in various forms when various drug classes are considered with their effects on neuromuscular function and upper airway patency.

Neuromuscular Function

The upper airway is primarily comprised of skeletal muscles that are innervated by motor neurons. This is not to say that the muscles are always and completely under voluntary control. In fact, the complex relationships between muscles for contraction and relaxation to maintain patency of the airway are controlled by the respiratory centers and, to some extent, by the arousal centers and reticular activating system. A phasic contraction and relaxation in the oropharynx and the glottic musculature is related to and controlled by the central respiratory control centers. Additionally, reflex arcs exist in response to mechanical and chemical stimuli that create coordinated contractions of the upper airway musculature to protect the airway.

The lower airway is primarily comprised of smooth muscle that is involuntary and under autonomic control. It also, however, has reflex activity that serves to protect the airway in the presence of noxious stimuli ^, and to prevent the aspiration of unwanted material into the lungs.

Hypoxia and hypercarbia serve to increase the respiratory drive, triggering the upper airway muscles, diaphragm, and accessory muscles of the lung to increase airway patency and function.

Autonomic Nervous System

Airway dynamics are controlled by the surrounding musculature, which provides either dilating or constricting effects. The autonomic nervous system is the principal regulator of airway tone. Environmental stressors, such as exercise, increase sympathetic nervous activity, which dilates the upper and lower airways.

The lower airway is where the autonomic system has the greatest influence. Adrenergic receptors are present in the lower airway; however, no sympathetic nerves actually innervate the smooth muscle fibers of the airway—rather, they are influenced by the sympathetic nervous system when there is an increase in circulating epinephrine. The resulting phenomenon is one of autonomic control by primarily vagal output ( Fig. 6.2 ). The effect of parasympathetic activity is of muscarinic activation, which leads to bronchoconstriction, increase in mucus production and secretion, and pulmonary vasodilation.

Another influence on lower airway musculature and function is a nonadrenergic, noncholinergic (NANC) system that may be mediated by nitric oxide (NO) and by-products as well as vasoactive intestinal peptide (VIP). This system is rather complex, but it is increasingly implicated in the development of airway inflammatory disease, cytokine release, and pathologic structural change in the airway.

Voluntary Regulation of Airway Patency

Upper airway patency is somewhat dependent on arousal, with the reticular activating system playing a role in the contraction of musculature and maintenance of patency. Sleep tends to have a countereffect by typically increasing airway resistance, whereas general anesthesia blunts the response of the sympathetic nervous system to external stimuli such as pain.

Voluntary activities that involve coordination of muscular activity include speech and swallowing. The use of the term voluntary is not to indicate that the muscles of the oropharynx are under voluntary control individually but that the central processing and output of that coordinated activity is under voluntary control. Indeed, it is rather easy to voluntarily swallow, but it is rather difficult to voluntarily contract one’s stylopharyngeus muscle. An exception to this rule in the upper airway is the tongue; its movements are largely under voluntary control to facilitate speech and swallowing. It does, however, undertake centrally controlled muscular contraction in coordination with the remainder of the pharyngeal apparatus.

Disease Affecting the Airway

Various pathologies, such as malignancy, genetic conditions, neuromuscular disease, infection, asthma, chronic obstructive pulmonary disease (COPD), restrictive lung disease, obesity, and obstructive sleep apnea (OSA), can affect the airway in a number of ways. Airway sensitivity, resistance, patency, and anatomy can be affected and must be considered when selecting a pharmacologic agent in the setting of these problems.