Question

Explain why all decongestant products should be used cautiously by people with hypertension, hyperthyroidism ,diabetes mellitus , cardiac disease , increased intraocular pressure or prostatic disease.

Answer 1

As the incidence of hypertension rises in concert with the obesity epidemic, pharmacists need to be prepared to counsel their hypertensive patients seeking relief from cold symptoms. First-line therapy for the common cold includes rest, adequate fluid intake, humidification for expectoration, and avoidance of others to minimize viral transmission.¹ However, beyond OTC pain relievers, decongestants are generally the pharmacologic agents of choice for congestion associated with the common cold. Decongestants are sympathomimetic agents that act primarily on alpha-adrenergic receptors, with some activity on beta-adrenergic receptors.² The alpha agonist activity causes vasoconstriction of the superficial blood vessels in the nasal mucosa, reducing edema, nasal congestion, and tissue hyperemia, and increasing nasal patency.² Decongestants not only cause constriction of nasal vessels; their systemic action is associated with insomnia, nervousness, tremor, urinary retention, loss of appetite, and cardiovascular side effects including increase in blood pressure, tachycardia, and palpitations.^1,2 Therefore, the FDA requires that the following warning be placed on both oral and topical decongestants: "Do not use this product if you have heart disease, high blood pressure, thyroid disease, diabetes, or difficulty in urination due to enlargement of the prostate gland, unless directed by a doctor."³

This article will focus on standards of care and medications used for nasal congestion, including oral and topical nasal decongestants and alternatives to decongestants. Table 1lists conservative, pooled information concerning absolute and relative contraindications and precautions for the agents discussed in this review. Table 2 provides limited, pooled, cardiovascular (CV) adverse event (AE) frequencies.

DECONGESTANTS
Oral Decongestants
Pseudoephedrine: Evaluative trials regarding oral decongestant use in hypertensive patients are quite limited. Recently Salerno et al.⁴ performed a meta-analysis (MA) of some pertinent available pseudoephedrine studies in an attempt to provide more conclusive information regarding the safety of these products in hypertensive patients. This MA included 24 studies with 1,285 patients and 45 total treatment arms. Thirty-one treatment arms used immediate-release (IR) formulations and 14 treatment arms used sustained-release (SR) formulations. Seven of the 45 arms investigated patients with treated, stable hypertension, and five arms investigated pseudoephedrine's effects on the normal BP elevation during exercise.⁴

Overall, there was a statistically significant 1-mmHg increase in systolic blood pressure (SBP) but no difference in diastolic blood pressure (DBP). Heart rate (HR) increased by approximately 3 beats per minute (bpm). Also, longer study durations were associated with a less pronounced effect on SBP. However, there was no such association with regard to DBP or HR.⁴

In the 31 IR treatment arms, there was a statistically significant 1.5-mmHg increase in SBP but no increase in DBP. HR increased by 2 bpm. There was a dose-response relationship for SBP, DBP, and HR.⁴ In the 14 SR arms, there was a statistically significant 4-to-5–bpm HR increase but no detected systolic or DBP difference.

When data from only controlled hypertensive patients (BP <140/90 mmHg) were analyzed, a statistically significant 1-mmHg increase in SBP was detected but no difference was found for DBP or HR. None of the five trials that included exercise testing revealed any statistically significant differences in SBP, DBP, or HR.⁴

Although the authors reported no clinically significant AEs, there were two patients whose mean arterial pressure (MAP) increased by 20 mmHg and there were 30 reported episodes of loss of BP control. MAP is calculated by multiplying DBP by 2 + SBP and then dividing this value by 3. DBP is counted twice as much as SBP because diastole accounts for two thirds of the cardiac cycle. Unfortunately, baseline MAP and BP were not provided.⁴

The authors concluded, "Pseudoephedrine modestly increases SBP and HR, with the greatest effects seen in IR formulations, higher doses, and shorter-term medication administration. Patients with stable, controlled hypertension do not seem to be at higher risk for BP elevation than other groups when given pseudoephedrine along with their antihypertensive medications."⁴ However, the authors noted BP elevations greater than 140/90 mmHg in 3% of patients, so "the risk-benefit ratio should be evaluated carefully before using sympathomimetic agents in at-risk individuals."⁴

Limitations of this MA included a relatively small evaluable sample size (n=1,260), inconsistent baseline BP data, low numbers of elderly patients, and inadequate information regarding confounding medications and/or conditions. Also, the authors pointed out that their result may have "overestimated the effect of pseudoephedrine" since the higher-quality studies of this MA "showed less pronounced effects on vital signs."⁴ Furthermore, none of the trials within this MA contained patients with uncontrolled hypertension.^4-6

Phenylephrine (AH-Chew D, Sudafed PE)
CV safety data are lacking, thus limiting the ability to make a recommendation for or against using this agent in controlled, hypertensive patients.

Topical Decongestants Requiring FDA Warning
The FDA mandates that topical decongestants include the same warning as stated for oral decongestants.^1,7,8 Communications received by the FDA have argued that systemic distribution of topical decongestants is so small as to have no effect on BP and HR.⁸ However, "the FDA examined the studies submitted by the correspondents and failed to find support for the assertion that topical products would be safe for patients with high blood pressure or heart disease."⁸ The FDA also found that "cardiovascular adverse reactions are among the most frequent AEs with topical nasal decongestants, exceeded only by rebound congestion," which generally occurs with more than 3–5 days of consistent use.⁸ The FDA concluded that "all sprays and drops produced bradycardia, tachycardia, hypertension, and hypotension."⁸This appears to be more of a problem with oxymetazoline than with phenylephrine.⁸ However, phenylephrine has a much shorter duration of action, dosed every 4 hours compared to oxymetazoline's twice daily dosing recommendation.^3,7

There are four case reports of CV adverse effects that warrant special mention. The first was in a 73-year-old male with a past medical history (PMH) of cerebellar degeneration and peripheral neuropathy who experienced bradycardia, hypotension, and syncope after using oxymetazoline nasal spray. This was attributed to a baroreceptor reflex impairment.⁹ The second case was in a 35-year-old male who experienced an ischemic stroke after using oxymetazoline nasal spray every 3 days for 20 years.¹⁰ The third case was of a 31-year-old female with a PMH including hiatal hernia, cigarette smoking, and remote marijuana use who experienced a thunderclap headache 20 minutes after using oxymetazoline. This patient had been using 2 to 3 sprays twice daily on a consistent basis. (A thunderclap headache has a sudden, severe onset and often happens before a severe intracranial vascular incident.) The headache resolved after discontinuation of oxymetazoline.¹¹ The last case warranting mention involved a 44-year-old male who had a thalamic hemorrhage with temporary left hemiparesis one day after naphazoline use. His BP was 190/120 mmHg upon presentation. He was discharged home on day 8 without the need for any BP medications. All motor deficits recovered.¹²

Topical Decongestants Not Requiring an FDA Warning
Levmetamfetamine (Vicks Inhaler) and propylhexedrine (Benzedrex) are two OTC nasal decongestants that are not mandated by the FDA to carry the warning. However, their roles are limited due to lack of comparable efficacy data relative to other sympathomimetic decongestants, limited duration of action, and abuse potential, including reports of medication extraction from the inhaler for intravenous and/or oral abuse.¹ Although levmetamfetamine is generally safe and effective for OTC use, propylhexedrine appears to cause headache, hypertension, nervousness, and tachycardia.¹

Various topical rubs and vapor agents containing menthols, camphor, and/or eucalyptus oil appear to be somewhat effective for improving congestion symptoms associated with the common cold.¹³ Topical rubs can be applied to the chest and/or throat, and vapor agents can be added to warm or hot vaporizers. As with topical levmetamfetamine and propylhexedrine, data regarding comparable efficacy relative to more traditional topical and oral nasal decongestants are lacking. However, if patients are not hypersensitive to the components of these agents, they can be beneficial in relieving nasal congestion and are safe for use in hypertensive patients.^13,14

Throat lozenges containing menthol appear to be no more effective than placebo lozenges when evaluated objectively; however, there are data supporting subjective efficacy in patients experiencing congestion symptoms from the common cold.^14-16

ALTERNATIVES TO DECONGESTANTS
Oral Antihistamines
Antihistamines are commonly used alternatives to decongestants. Although these agents have a negligible effect on congestion, they generally have a moderate effect on runny nose and a pronounced effect on sneezing and watery eyes, which also occur with the common cold.^17,18 Most of the data supporting these benefits were obtained from studies using first-generation antihistamines (FGAs).

Neither FGAs nor second-generation antihistamines (SGAs) adversely affect BP. Therefore, these agents may be used to help decrease runny nose in hypertensive patients who have no comorbidities. However, not all antihistamines are devoid of adverse cardiac effects, and in practice, we rarely treat patients with hypertension alone. Therefore, information regarding non-BP associated CV adverse effects follows.

First-Generation Antihistamines
Cardiotoxicity is more likely with FGAs than with SGAs.^17,19 The quinidine-like local anesthetic and anticholinergic properties appear to be responsible for the observed adverse cardiac effects, including tachycardia, electrocardiogram (ECG) changes, hypotension, and arrhythmias. "Although the relative risk of cardiotoxicity with these drugs is real (patients taking the drugs have an increased risk), the absolute risk is small (occurs in only a small number of people even when a large number of people take the drug). However, OTC FGAs have been shown to be associated with a higher rate of ventricular arrhythmias than the SGA terfenadine," withdrawn from the U.S. market due to its life-threatening QT interval prolonging effects.¹⁷ Also, cardiotoxicity is more likely with higher doses. Although cardiovascular effects are uncommon, FGAs should be used conservatively in patients with cardiac disease.²

Second-Generation Antihistamines
Based on current data, SGAs appear to pose a lower risk for drug interactions and cardiac side effects than FGAs.²⁰ However, CV effects are variable among the SGAs. It is important to consider agent-specific data and reports.

• Loratadine
There has been one case report of torsades de pointesand QT interval prolongation when loratadine was combined with amiodarone.²¹ This occurred in a 73-year-old female with a history of hypertension, hyperlipidemia, paroxysmal atrial fibrillation, and left ventricular hypertrophy (LVH) with diastolic dysfunction who was admitted to the hospital for syncope. She was taking chronic amiodarone 200 mg daily for atrial fibrillation. Other medications included cilazapril, pravastatin, and warfarin. She had been given loratadine 10 mg daily "a few days prior to admission … for a suspected allergic reaction."²¹ The authors of this report suggested "prior to prescribing loratadine concomitantly with a drug that may potentially prolong the QT interval, an ECG should be done and repeated several hours after ingestion of the first dose."²¹ If "an increase in QT interval or dispersion is noted, loratadine should be discontinued and rhythm monitoring initiated."²¹

There is some evidence of a statistically significant QT interval prolongation when loratadine 20 mg daily and nefazodone are used concomitantly. This interactive AE appears to be correlated with increased concentrations of loratadine.²⁰ According to the World Health Organization Collaborating Center for International Drug Monitoring at Uppsala, Sweden, there have been 57 reports of ventricular arrhythmias associated with loratadine. Twenty-seven of these reports did not mention other confounding or interacting drugs, and five of these patients died.²²

• Desloratadine (Clarinex)

Desloratadine is the active metabolite of loratadine. Although there have been reports of spontaneous adverse effects such as tachycardia and palpitations as listed in the product package insert, it does not appear that this agent causes QT interval prolongation.²³ Even when "administered alone in a higher dose or in combination with ketoconazole or erythromycin, no prolongation of the QT interval was observed."²⁰

• Fexofenadine (Allegra)

Fexofenadine is a noncardiotoxic water-soluble metabolite of terfenadine. "As far as its cardiological safety is concerned, fexofenadine has shown an excellent CV profile in clinical trials."²⁴ "No statistically significant increase in mean QT interval compared to placebo was observed in 714 seasonal allergic rhinitis patients given fexofenadine … in doses of 60 to 240 mg twice daily for two weeks."²⁵ A separate study of 432 patients receiving 180 mg for 14 days to three months supports this data.²⁵

There is one reported case of a 67-year-old male with hypertension and mild LVH who had QT interval prolongation after taking 180 mg daily for two months.²⁵ Although there was a temporal relationship between fexofenadine use and QT interval prolongation, there were several possible confounding contributors to the arrhythmia. This patient's age, history of hypertension, and recent withdrawal of antihypertensive therapy would be expected to increase his risk for QT interval prolongation and ventricular dysrhythmia. In addition, no continuous ECG monitoring was conducted. Given all of these limitations, the authors indicated it would be "unfair to draw conclusions on the basis of a single case report."²⁵

• Cetirizine (Zyrtec)

Cetirizine is the active metabolite of the sedating antihistamine hydroxyzine. At recommended doses, cetirizine has not caused QT interval prolongation.^19,26 Current data including pooled reports indicate that adverse CV events including cardiac failure, hypertension, palpitation, and tachycardia would be expected to occur in less than 2% of patients.²⁶

Topical Antihistamines
Azelastine (Astelin/Optivar)

Astelin is the intranasal topical formulation and Optivar is the ophthalmic topical formulation of azelastine. This agent does not appear to cause an increase in CV adverse event risk relative to placebo.^1,14

Miscellaneous Options
Saline Mist and Humidification
An isotonic saline mist is very safe and soothing for a dry and irritated nose. Humidification can also help loosen congestion and facilitate mucociliary clearance and expectoration.¹Evaporative or steam humidifiers appear to be preferred over cool mist humidifiers because the latter may be more likely to disseminate aerosols contaminated with allergens."²⁷However, all humidifiers must be cleaned regularly per manufacturer recommendations to minimize risk of exposure to contaminants, i.e., bacteria, protozoa or fungi. ^27-29

External Dilators

Breathe Right Nasal Strips are external nasal dilators worn over the bridge of the nose. As the cross-sectional area of the nasal valve determines nasal airway resistance, these strips open the nasal airway by applying approximately 25 grams of outward pulling force through two parallel plastic springs. A small, randomized controlled trial showed external dilators significantly increase the size of the nasal valve area and decrease the level of congestion in normal subjects.³⁰ As would be expected, symptoms recur after removal. The obvious major benefit of this option is no increased risk of CV adverse effects.

Conclusion
While pharmacists often answer questions concerning products for relief of common cold symptoms, selecting appropriate products for the patient with hypertension is a challenge. Unfortunately, there is no one product that can be recommended to provide safe and effective relief of nasal congestion in all patients with high blood pressure. In addition, such patients typically have comorbidities that also must be considered when choosing therapy. The information presented in this review will assist pharmacists in making safe and effective therapeutic recommendations for nasal congestion in their hypertensive patients.