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.

Moa (Mechanism of Action)

Antitussives are cough suppressants. There are two ways to inhibit coughing: centrally and peripherally.

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).

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.

Opiates such as codeine and hydrocodone also work through a central mechanism.

Peripheral-acting agents work either by anesthetizing the local nerve endings or acting as demulcents. Demulcents have a soothing effect on the throat.

Figure 12-1

Pharmacokinetics

Dextromethorphan has an onset of action of 15 to 30 minutes and a duration of 3 to 6 hours.

Camphor and menthol are used topically or are inhaled through a vaporizer. When the medication is applied topically, the vapors are inhaled.

Indication

Contraindications

None of major significance

Side Effects

Dextromethorphan

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

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.

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.

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.

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.

The three most common causes of chronic cough include:

Gastroesophageal reflux

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

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

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.

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

Prototype: guaifenesin

Others: ammonium chloride, terpin hydrate, potassium iodide, iodinated glycerol

Moa (Mechanism of Action)

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.

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.

It is not clear exactly how guaifenesin increases respiratory fluid, but it may be through a local irritant effect.

Pharmacokinetics

Guaifenesin is most commonly available as an oral syrup.

Indication

Loosening of mucus in upper respiratory tract infections

Contraindications

Guaifenesin: none of major significance

Side Effects

Guaifenesin: Generally well tolerated; side effects occur infrequently.

Nausea: mechanism unknown

Drowsiness: mechanism unknown

Vomiting: typically only seen at high doses

Important Notes

There has been a longstanding controversy over the use of expectorants. This is partly because of the limited data demonstrating their efficacy.

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.

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

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

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.

Decongestants

Description

Decongestants are a heterogeneous class of compounds that are related by therapeutic use. These agents are typically available without a prescription.

Moa (Mechanism of Action) (Figure 12-2)

Nasal congestion occurs when the nasal passages become edematous, usually a result of an inflammatory response to an upper respiratory tract infection, an allergic response, or a response to chemical irritant

All decongestants are vasoconstrictors.

The main mechanism by which they reduce nasal congestion is by constricting precapillary blood vessels, which reduces capillary hydrostatic pressure, blood flow, and volume. Hydrostatic pressure is one of the forces that pushes plasma out of a blood vessel into the tissues, causing edema. Capillary permeability and oncotic pressure are the two other factors that influence the formation of tissue edema.

By reducing hydrostatic pressure, the outward force that pushes fluid out of the vessel becomes an inward force that drives fluid into the vessel. The net effect is to reduce leakage in blood vessels, therefore reducing congestion.

Through reduction of blood flow and volume, a smaller amount of fluid is made available to the leaky capillaries, and thus edema formation decreases as well.

The vasoconstriction is mediated by stimulation of α₁ receptors. These receptors are stimulated either by direct agonists or indirectly. Direct agonists tend to be analogs of norepinephrine, although with greater selectivity for the α₁ receptor.

Indirect agonists work by increasing levels of endogenous norepinephrine.

Figure 12-2

Pharmacokinetics

Decongestants come in either oral (pseudoephedrine) or topical (xylometazoline and oxymetazoline) formulations, or both (phenylephrine). The topical agents have a faster onset of action than the oral agents and have fewer systemic effects.

Pseudoephedrine has an onset of action of 30 minutes and a duration of 4 to 6 hours.

Indication

Nasal congestion

Contraindications

Concomitant use with monoamine oxidase inhibitors (MAOIs): Monoamine oxidase breaks down amines such as norepinephrine. Concomitant use of MAOIs with indirect-acting decongestants such as pseudoephedrine that increase norepinephrine can lead to excess norepinephrine and hypertensive crisis. MOAIs are used to treat depression and are not commonly used because newer agents have replaced them.

Severe hypertension and coronary disease: Decongestants all cause vasoconstriction, which may cause a dangerous rise in blood pressure in those with hypertension or may reduce coronary blood flow in patients with heart disease.

Side Effects

CNS stimulation: The phenylamines (phenylephrine, ephedrine, pseudoephedrine) share common structural features with amphetamine, and therefore they also stimulate the CNS. This manifests as:

Rhinitis medicamentosa: Rebound congestion is typically only seen with topical agents. This is a pharmacologic phenomenon that occurs with chronic use, secondary to changes in receptor density. Patients will find that their decongestant does not work as well, that their congestion is much worse when they miss a dose of the drug, or both. The net effect is that the patient finds that he or she is unable to discontinue the decongestant.

Increased blood pressure: Constriction caused by peripheral α₁ receptors leads to increased resistance and therefore increased blood pressure. This problem is more likely to be seen with oral agents and is usually a problem only in patients who have hypertension.

Urinary retention: Stimulation of α₁ receptors in the bladder leads to constriction of the urinary sphincter, restricting the flow of urine. This is typically a problem only in patients with preexisting urinary retention or in conditions such as enlarged prostate, in which patients are more prone to urinary retention.

Other side effects associated with adrenergic stimulation: Other effects include dry mouth and sweating.

Local (topical agents only): Local effects include stinging, burning, and dryness of the nasal mucosa.

Important Notes

Rhinitis medicamentosa is an uncomfortable complication of topical decongestant use. However, because it is a simple pharmacodynamic phenomenon, patients should inevitably improve once receptor densities have returned to their predrug state. This typically takes 1 to 2 weeks, and in the intervening period the patient may benefit from oral decongestants to get through the periods of severe congestion.

Vasoconstrictors have the greatest efficacy among decongestants; however, there are other agents that are used to relieve nasal congestion. Camphor, menthol, and eucalyptus oil are all considered to be relatively innocuous, although their efficacy in treating nasal congestion and the mechanism by which they exert their effects are not well studied.

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.

Evidence

Nasal Congestion in the Common Cold

A 2009 Cochrane review (seven trials, all in adults) assessed the efficacy of nasal decongestants in reducing symptoms of nasal congestion in adults and children with the common cold. There was a 6% decrease in subjective symptoms after a single oral dose of decongestant versus placebo. From a clinical standpoint, this is a small difference. With repeated use over 3 to 5 days, the benefit decreased to 4%. Only two trials reported safety measures, but in these two trials there was a small increased risk of insomnia versus placebo.

FYI Notes

Ephedrine is structurally related to the amphetamines. The main difference from a pharmacologic perspective is that ephedrine and pseudoephedrine have less effect on the CNS. Ephedrine is also used to raise heart rate and blood pressure, most commonly in anesthetized patients. It is given intravenously for this indication.

Although phenylpropanolamine is also supposed to have fewer CNS effects than amphetamine, its use in children has come under scrutiny because of CNS adverse effects such as agitation, irritability, and insomnia. Most jurisdictions have removed phenylpropanolamine from the market or severely restricted access to it.

Decongestants are available without a prescription in most jurisdictions. However, their use is often still monitored closely, as they have become drugs of abuse for their stimulant properties. Ephedrine and pseudoephedrine can also readily be converted into amphetamine derivatives such as methamphetamine (also known as crystal meth).

Pseudoephedrine is available in several different combination products with antitussives (dextromethorphan), expectorants (guaifenesin), and analgesics (acetaminophen).

H₁ Antagonists

Description

H₁ antagonists are agents that antagonize the allergic responses and other effects mediated by histamine. These are also known as antihistamines.

Moa (Mechanism of Action)

Histamine is mainly synthesized in mast cells and basophils of the immune system, enterochromaffin-like cells in gastric mucosa, and certain neurons that release it as a neurotransmitter.

H₁-receptor antagonists competitively antagonize histamine at these receptors, mitigating the immune response to an allergen.

Many of the first-generation antihistamines also possess anticholinergic activity. This might contribute to some of the side effects associated with these agents, but it also might contribute to their efficacy in the treatment of nausea.

Figure 12-3

Pharmacokinetics

Antihistamines vary in their ability to cross the blood-brain barrier. Second-generation agents penetrate much more slowly and in lower quantities compared with first-generation agents. This is one reason why second-generation agents are much less sedating than first-generation agents.

Fexofenadine is an active metabolite of terfenadine. Terfenadine was a very popular antihistamine before being withdrawn from the market over safety concerns (fatal arrhythmias). Fexofenadine is not metabolized further before being excreted unchanged.

Several of the first-generation antihistamines are also available in injectable forms.

Indications

Allergic rhinitis

Urticaria (swelling and itching) caused by allergy-related dermatologic disorders

Nasal symptoms associated with common cold

Nausea (first-generation agents)

Contraindications

None of major significance

For use in pregnancy, see Advanced section

Side Effects

Sedation: H₁ receptors in the CNS mediate wakefulness, so antagonism of these receptors leads to drowsiness. Some antihistamines also antagonize serotonin receptors, and this might also contribute to sedation.

Anticholinergic side effects (first-generation agents): dry mouth, urinary retention

Important Notes

Two factors appear to play a role in distinguishing sedating from nonsedating antihistamines. Aside from the pharmacokinetic property of being able to cross into the CNS, some antihistamines also antagonize serotonin (5-HT₂) receptors. For the agents that cross into the CNS, this contributes further to their sedating properties.

Antihistamines are not typically useful for life-threatening anaphylactic reactions, which are managed acutely with an injection of epinephrine. Antihistamines typically do not work quickly enough to be useful in these situations, but they also fail to address many of the most important characteristics of anaphylaxis, such as hypotension and bronchoconstriction. Although histamine elicits these life-threatening responses, it is believed that this is possibly mediated by another histamine receptor and therefore is not addressed through H₁ blockade.

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.

Evidence

For the Common Cold

A 2003 Cochrane review (32 trials, N = 8930 participants) assessed the effects of antihistamines in reducing nasal symptoms in patients with common cold. First-generation antihistamines were found to have a small effect on rhinorrhea and sneezing, but this was not considered to be clinically significant. First-generation agents also were associated with the side effect of sedation. Combinations of antihistamines and decongestants were not found to be effective in young children.

FYI Notes

Many of the first-generation antihistamines, particularly dimenhydrinate, are used off-label as sleep aids owing to their propensity for inducing sedation.

The efficacy and safety of second-generation antihistamines has been more thoroughly studied compared with first-generation agents.

Doxepin, which is classed as a tricyclic antidepressant, also possesses significant antihistamine activity. It is actually much more potent than most marketed antihistamines.

Sensitization of afferent nerve terminals is the reason why a mosquito bite stings and itches.

Name alert: Diphenhydramine and dimenhydrinate are also known in North America by their proprietary names Benadryl and Gravol, respectively.

Desloratadine is the active metabolite of loratadine.

Mast Cell Stabilizers

Description

Mast cell stabilizers inhibit allergic responses by preventing degranulation of mast cells. They are often referred to as chromones.

Prototype and Common Drugs

Prototype: cromolyn sodium

Others: nedocromil, lodoxamide

Moa (Mechanism of Action)

The degranulation of mast cells and eosinophils is an important step in the response to an allergen. Degranulation leads to release of a variety of proinflammatory factors, including histamine, leukotrienes, and various cytokines. These factors then act on tissues to elicit the classic signs of an allergic reaction.

Mast cell stabilizers work by preventing this degranulation from occurring. The mechanism by which they accomplish this is still not confirmed.

Mast cell stabilizers have a variety of other actions that may contribute to their efficacy. They suppress the actions of chemotactic factors on eosinophils, neutrophils, and monocytes, and they may reduce movement of leukocytes in asthmatic airways (Figure 12-4).

Figure 12-4

Pharmacokinetics

The chromones are generally delivered topically, either by the inhalational route or as drops for ophthalmic use. They have a very low oral bioavailability (1%); therefore any topical drug that happens to be swallowed will have minimal systemic effects.

Indications

Conditions with an allergic component:

Asthma (mild to moderate)

Systemic mastocytosis (excessive proliferation of mast cells in tissues—this is an extremely rare disorder)

Contraindications

None of major significance

Side Effects

Generally well tolerated

Side effects generally related to topical application

Cough from irritation of the throat

Nasal irritation—local irritation from sprays

Important Note

Cromolyn and related compounds do not posses bronchodilator activity and are therefore not useful in acute asthma attacks.

Evidence

Sodium Cromoglycate versus Placebo in Pediatric Asthma

A 2008 Cochrane review (23 trials, N = 1026 participants) examined the efficacy of sodium cromoglycate versus placebo in prophylactic treatment of pediatric asthma. Most of the studies had small sample sizes, and most were crossover studies, thus limiting confidence in the results. The authors concluded that there is insufficient evidence to be certain about the beneficial effects of sodium cromoglycate for this indication and in this population.

Sodium Cromoglycate versus Inhaled Corticosteroids in Chronic Asthma

A 2006 Cochrane review (17 trials, N = 1279 children; eight trials, N = 321 adults) compared inhaled corticosteroids with sodium cromoglycate in adults and children with chronic asthma. In children and adults, sodium cromoglycate was inferior to inhaled corticosteroids with respect to use of rescue bronchodilators and improved performance on pulmonary function tests. Sodium cromoglycate was also inferior with respect to improvement of symptoms, although in adults these improvements were significant only in crossover trials and not in those of parallel design. There were no differences in adverse effects between inhaled corticosteroids and sodium cromoglycate in either children or adults.

FYI Notes

The chromones are derived from the Ammi visnaga plant and have been used as spasmolytics for many centuries, dating back to ancient Egypt.

Applied Pharmacology