Cough, Cold, and Allergy

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Chapter 12 Cough, Cold, and Allergy

Antitussives

Description

Antitussives constitute a heterogeneous class of compounds that inhibit cough through either a central or a peripheral mechanism, or a mixture of the two.

Prototype and Common Drugs

Centrally Acting

image Prototype: dextromethorphan
image Others: codeine, hydrocodone

Peripherally Acting

image Prototype: camphor and menthol
image Others: eucalyptus oil, benzonatate, levodropropizine

Moa (Mechanism of Action)

image Antitussives are cough suppressants. There are two ways to inhibit coughing: centrally and peripherally.
image Cough is normally produced through the stimulation of sensory receptors of the glossopharyngeal and vagus nerves, innervating the mucous membranes of the lower pharynx, larynx, trachea, and smaller airways of the respiratory system. The receptors then transmit the signal to the cough center in the brain, which then triggers a reflex motor response that results in contraction of the muscles to close the glottis (vocal cords) and contraction of the muscles of expiration. The result is a sudden increase in intrathoracic pressure, followed by relaxation of the vocal cords, resulting in rapid expulsion of air (Figure 12-1).
image Centrally acting agents such as dextromethorphan work by inhibiting the cough center in the brain, elevating the threshold for coughing. The exact mechanism by which they do this is still poorly understood. Dextromethorphan, for example, is an N-methyl-d-aspartate (NMDA) antagonist, although it is not known what contribution this has to its antitussive effects.
image Opiates such as codeine and hydrocodone also work through a central mechanism.
image Peripheral-acting agents work either by anesthetizing the local nerve endings or acting as demulcents. Demulcents have a soothing effect on the throat.
image

Figure 12-1

Pharmacokinetics

image Dextromethorphan has an onset of action of 15 to 30 minutes and a duration of 3 to 6 hours.
image Camphor and menthol are used topically or are inhaled through a vaporizer. When the medication is applied topically, the vapors are inhaled.

Indication

image Cough

Contraindications

image None of major significance

Side Effects

Dextromethorphan

image Drowsiness
image Nausea
image Dizziness

Opiates

Main side effects are sedation and constipation at the lower doses used to suppress cough. Several other side effects, many seen at higher doses or with chronic use, are reviewed in Chapter 21.

Important Notes

image Dextromethorphan was developed in an attempt to create a cough suppressant with the efficacy of codeine but with none of the central nervous system (CNS) side effects such as euphoria. Dextromethorphan therefore has little or no ability to induce euphoria and therefore is available without a prescription and without pharmacist consultation in most jurisdictions.
image However, very high doses of dextromethorphan can cause dissociative effects similar to those seen with phencyclidine (PCP). PCP and dextromethorphan are both NMDA antagonists, and this is believed to be why they share similar effects. The doses needed to achieve this effect with dextromethorphan are high enough to cause toxicities resulting in hypertension, tachycardia, and respiratory depression.
image Codeine can be an effective antitussive at lower doses than required for analgesia. Therefore some of the more important side effects of codeine, such as respiratory depression, can generally be avoided at the antitussive dose. The exception appears to be young children (≤5 years of age) who may be more sensitive to the respiratory depression. Codeine is therefore not recommended for children under the age of 2 and should be used with caution in children 2 to 5 years old.
image The use of cough and cold preparations in children, particularly combination products, has come under close scrutiny owing to concerns over deaths attributed to overdose. The use of multiple combination products facilitates overdose, as parents can be easily confused by the duplication of ingredients among products. In addition, the lack of clear evidence of efficacy of these products in young children has prompted many to question why they are used at all.
image The three most common causes of chronic cough include:

image Asthma
image Postnasal drip
image Gastroesophageal reflux

image Treatment of chronic cough must include investigations into the possible cause of the cough in addition to symptomatic treatment.

Evidence

Over-the-Counter Preparations for Acute Cough

image A 2008 Cochrane review (25 trials, N = 3492 participants) assessed the effects of over-the-counter (OTC) cough preparations for acute cough. Six trials in adults had variable results for antitussives versus placebo. Of the two trials involving expectorants, one showed benefit versus placebo whereas the other did not. In children, antitussives (two trials), antihistamines (two trials), antihistamine-decongestant combinations (two trials), and antitussive-bronchodilator combinations were no more effective than placebo. No trials were found of expectorants, but one trial showed benefit of a mucolytic versus placebo.

FYI Notes

image Paradoxically, when high-potency opioids are administered intravenously (so that they have a rapid increase in levels in the blood and brain), they can induce cough. This is common with the opioid called fentanyl, which is commonly used in conjunction with general anesthetics.
image Older-generation antihistamines (dexbrompheniramine, diphenhydramine) have also been used as antitussives with some success. The mechanism behind their use is not well understood. Other agents that have been used as cough suppressants include amitriptyline and baclofen.

Expectorants

Description

Expectorants comprise a heterogeneous collection of compounds that facilitate the removal of mucous from the respiratory tract.

Prototype and Common Drugs

image Prototype: guaifenesin
image Others: ammonium chloride, terpin hydrate, potassium iodide, iodinated glycerol

Moa (Mechanism of Action)

image Mucus serves as an airway lubricant and functions as a first level of immune defense. When mucus becomes thickened and/or dried out by infections, the functions of the mucus, including the clearing of infections, becomes impaired.
image Expectorants typically work by increasing the amount of fluid in the respiratory tract, which increases flow and clearance of local irritants as well as reducing the viscosity of mucus.
image It is not clear exactly how guaifenesin increases respiratory fluid, but it may be through a local irritant effect.

Pharmacokinetics

image Guaifenesin is most commonly available as an oral syrup.

Indication

image Loosening of mucus in upper respiratory tract infections

Contraindications

image Guaifenesin: none of major significance

Side Effects

image Guaifenesin: Generally well tolerated; side effects occur infrequently.

image Nausea: mechanism unknown
image Drowsiness: mechanism unknown
image Vomiting: typically only seen at high doses

Important Notes

image There has been a longstanding controversy over the use of expectorants. This is partly because of the limited data demonstrating their efficacy.
image The use of cough and cold preparations in children, particularly combination products, has come under close scrutiny because of concerns over deaths attributed to overdose. The use of multiple combination products facilitates overdose, as parents can be easily confused by the duplication of ingredients among products. In addition, the lack of clear evidence of efficacy of these products in young children has prompted many to question why they are used at all.
image Guaifenesin is the most widely used expectorant. Other agents that have been used as expectorants include ammonium chloride, which can cause acidosis in patients with renal failure; terpin hydrate, which can cause nausea and vomiting; potassium iodide, which has several side effects; and iodinated glycerol.

Evidence

Over-the-Counter Preparations for Acute Cough

image A 2008 Cochrane review (25 trials, N = 3492 participants) assessed the effects of OTC cough preparations for acute cough. Of the two trials involving expectorants, one showed benefit versus placebo whereas the other did not. In children, no trials were found of expectorants, but one trial showed benefit of a mucolytic versus placebo.

FYI Notes

image Guaifenesin is a derivative of guiacol, which is a constituent of guaiac resin from the wood of Guajacum officinale. Guiacol has been used in cough extracts in the past but has been largely supplanted by guaifenesin.

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