The Antitussive Action Of Opioids Blockade Of Cough Reflex

Each cough involves a complex reflex arc beginning with the stimulation of sensory nerves that function as cough receptors. There is evidence, primarily clinical, that the sensory limb of the reflex exists in and outside of the lower respiratory tract. Although myelinated, rapidly adapting pulmonary stretch receptors (RARs), also known as irritant receptors, are the most likely type of sensory nerve that stimulates the cough center in the brain, afferent C-fibers and slowly adapting pulmonary stretch receptors (SARs) also may modulate cough. RARS, C-fibers, and SARs have been identified in the distal esophageal mucosa; however, studies have not been performed to determine whether they can participate in the cough reflex. Although gastroesophageal reflux disease can potentially stimulate the afferent limb of the cough reflex by irritating the upper respiratory tract without aspiration and by irritating the lower respiratory tract by micro- or macroaspiration, there is evidence that strongly suggests that reflux commonly provokes cough by stimulating an esophageal-bronchial reflex. Each involuntary cough involves a complex reflex arch beginning with the stimulation of sensory nerves in the airway epithelium that function as "cough receptors." Efferent impulses from these receptors are conducted by means of the vagus nerve to the "cough center" in the brain stem. Because cough can be voluntarily suppressed, controlled, or initiated, there also can be afferent input from the cerebral cortex. The function of this "cough center" is to receive these impulses and produce a cough by activating efferent nervous pathways to the diaphragm and laryngeal, thoracic, and abdominal musculature. The possibility that there might be afferent input other than the vagus nerve and cerebral cortex was based on clinical observations described in case reports and a few animal studies [111].

Histologic studies of the respiratory tract in both animals and humans have revealed sensory nerve endings within the basal layer of the epithelium and between epithelial cells of the larynx, trachea, and bronchi [111]. These nerve endings are thought to be cough receptors. They contain neuropeptides, such as substance P and calcitonin-gene related peptide (CGRP), which mediate neurogenic inflammatory events in the airways. These sensory nerve endings have been found to be most numerous in the posterior wall of the trachea, at branching points of large airways, and less numerous in the more distal, smaller airways. None have been found beyond terminal bronchioles.

It is not known for certain which type of afferent nerve mediates cough. A model that summarizes the current understanding of cough is schematically depicted in the figure. It shows the myelinated, rapidly adapting pulmonary stretch receptors (RARs), also referred to as irritant receptors, as the most likely type of sensory nerve that stimulates the cough center in the brain. Both mechanical and chemical stimulation of RARs have been shown experimentally to cause cough. Another type of sensory nerve in the airways, C-fibers, may also participate in regulating cough. They are unmyelinated, vagal afferent fibers that may be activated by the same triggers as RARs. Their activation releases neuropeptides locally that may secondarily stimulate cough by activating RAR nerves. However; impulses transmitted by C-fibers alone probably do not stimulate cough, because experimental evidence has shown that they inhibit cough centrally in the brain. A third type of sensory nerve, the slowly adapting pulmonary stretch receptors (SARs), may modulate cough. Although these nerves do not directly respond to chemical and mechanical triggers, they do appear to be activated by the deep breath of a cough and may enhance cough by making the expiratory effort more forceful. In addition to mechanical and chemical stimuli, cough has been caused in animals by thermal and electrical provocation. The sites most sensitive to all stimuli are the larynx, trachea, and cannulae of the larger airways.

Outside of the lower respiratory tract, cough receptors have been demonstrated histologically only in the hypopharynx [111]. However, it has been inferred from clinical studies that sensory nerve endings subserving the cough reflex via the vagus nerve probably exist in the extemal auditory canals and eardrums, hypopharynx, pericardium, stomach, and esophagus, because stimulation of these sites has been reported to cause cough [111]. Based on the fact that cough can be voluntarily initiated, postponed, and/or suppressed, this provides evidence that there also can be afferent input from the cerebral cortex. In addition to directly stimulating cough by carrying impulses from cough receptors to the cough center, vagal afferents may indirectly provoke cough by another mechanism. They may stimulate neuro-transmitter release or mucus secretion from airway submucosal glands that, in turn, stimulate the cough reflex [111].

The existence of a discrete central cough center is controversial. What is known is that afferent pathways first relay impulses to an area in or near the nuc1eus tractus solitarius. These impulses then are integrated into a coordinated cough response in the medulla oblongata of the brain stem, probably separate from the medullary centers, which control breathing. Although electrical stimulation studies of different areas in the medulla have evoked cough in animals, suggesting that the cough center is diffusely located [111] a discrete cough center still may exist, because these electrical stimulations may have activated afferent pathways of the cough reflex.

The motor outputs trom the cough center are in the ventral respiratory group, with the nucleus retro-ambigualis sending impulses via motoneurons to the respiratory skeletal muscles and the nucleus ambiguus sending impulses to the larynx and bronchial tree. More specifically, the efferent impulses of the cough reflex are transmitted from the medulla to the expiratory musculature, through the phrenic nerve and other spinal motor nerves, and to the larynx through the recurrent laryngeal branches of the vagus nerves (Figure II-49).

Vagal efferents also innervate the tracheobronchial tree and mediate bronchocon-striction [111]. Although stimulation of cough and bronchoconstriction can be experimentally separated using nonpermeant anions to stimulate cough without bronchoconstriction, these two phenomena normally are activated simultaneously to facilitate the most effective cough. Bronchoconstriction may improve clearance of secretions by narrowing the cross-sectional area of the airways, thereby increasing the velocity of air leaving the patients lower respiratory tract during the expiratory phase of coughing [111]. Experimentally, it has been shown in animals that the efferent pathways of the cough reflex are anatomically distinct and separate from the efferent pathways of normal spontaneous ventilation.

Blockade of the cough reflex arch by means of opioids, known as the antitussive action, refers to the fact that they suppress this protective reflex. This is of benefit during anesthesia and/or in patients being artificially ventilated in the intensive care unit (ICU) because it results in the tolerance of an endotracheal tube. However, the antitussive potency differs significantly among the various opioids (Figure II-50).

The action is not related to a specific receptor site, because a stereoselective action of opioids in regard to their antitussive effect could not be demonstrated. In addition, reversal with the selective antagonist naloxone is less selective [112]. The mode of action is a blockade of the cough center within the brainstem. Three of the most commonly used suppressors of the cough reflex are hydrocodone, codeine and hydromorphone. All of them are characterized by low analgesic potency, they

Cough Receptors

Figure 11-49. Model for afferent limb of cough reflex in airways. Myelinated. rapidly adapting pulmonary stretch receptors (RARs) and unmyelinated C-fibers are sensory nerves that participate in the afferent limb of the cough reflex. Mechanical and chemical stimuli activate sensory nerve enelings in the epithelial layer. RARs appear to be the main type of sensory nerve stimulating cough centrally. Although C-fibers may inhibit cough centrally, neuropeptides released in the periphery upon stimulation of C-fibers may indirectly stimulate cough by activating RARs. Slowly adapting pulmonary stretch receptors (SARs) do not respond to irritant stimuli that initiate cough but may enhance cough centrally by making expiratory muscular effort more forceful

Figure 11-49. Model for afferent limb of cough reflex in airways. Myelinated. rapidly adapting pulmonary stretch receptors (RARs) and unmyelinated C-fibers are sensory nerves that participate in the afferent limb of the cough reflex. Mechanical and chemical stimuli activate sensory nerve enelings in the epithelial layer. RARs appear to be the main type of sensory nerve stimulating cough centrally. Although C-fibers may inhibit cough centrally, neuropeptides released in the periphery upon stimulation of C-fibers may indirectly stimulate cough by activating RARs. Slowly adapting pulmonary stretch receptors (SARs) do not respond to irritant stimuli that initiate cough but may enhance cough centrally by making expiratory muscular effort more forceful demonstrate a negligible dependence liability, and they are common components in DOC (drugs over the counter) cough medicine.

A similar antitussive potency, however, is also seen with the more potent opioids such as diamorphine, fentanyl or sufentanil. The latter are used in an opioid-based anesthetic regimen or in ICU patients who are in need of ventilatory support. When a potent opioid such as sufentanil is used, the patient is adapted much easier to the respiratory cycle of the ventilator resulting in lesser doses of additional sedative agents. Morphine in this regard has a much weaker antitussive activity while pethidine (meperidine) and all mixed agonist/antagonists are characterized by a negligible antitussive action (Figure II-50). It can be summarized that potent opioids also inherit a marked antitussive effect, while weak opioids and especially the mixed opioid analgesics are unable to sufficiently suppress the cough reflex.

During the induction of anesthesia, while injecting an intravenous bolus dose of a potent opioid such as fentanyl or sufentanil, often a cough reflex is initiated. Such

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Hydromorphone Hydrocodone Phennperi dine

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Methadone

Oextromoramide

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Peth id ine Pi ri t ramide Pentazoc ine

Figure II-50. Comparable potency of different opioids to induce an antitussive action at equianalgesic doses a reflex is induced by an increasing rate of binding of the ligand at the target site. While lower dosages first induce a stimulatory effect, later when sufficient receptor sites are occupied, this results in inhibition of the cough reflex.

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