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Decongestant Use in Hypertension

Charles T. Herring, PharmD, BCPS, CPP
Assistant Professor of Pharmacy Practice, Campbell University School of Pharmacy
Adult Medicine Team Clinical Pharmacist, Downtown Health Plaza of North Carolina
Baptist Medical Center, Winston-Salem, North Carolina

Kara Maryansky
Campbell University PharmD Candidate
Kathryn Trivette
Campbell University PharmD Candidate

Nathan Hemberg
Campbell University PharmD Candidate

7/20/2006

US Pharm. 2006;7:80-88.

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 1 lists 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."8 This 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 Centre 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.1 Evaporative or steam humidifiers appear to be preferred over cool mist humidifiers because the latter may be more likely to disseminate aerosols contaminated with allergens."27 However, 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.

References
1. Micromedex Web site. Available at: www.thomsonhc.com/home/dispatch (accessed November 13, 2005).
2. Clinical Pharmacology. Available at: cpip.gsm.com or cp.gsm.com/ (accessed November 13, 2005).
3. Code of Federal Regulations. Drugs for human use. Title 21, Volume 5, Chapter 1, subchapter D, revised as of April 1, 2005. Available at: www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=341.80 (accessed January 6, 2006).
4. Salerno SM, Jackson JL, Berbano EP. Effect of oral pseudoephedrine on blood pressure and heart rate: a meta-analysis. Arch Intern Med. 2005;165:1686-694.
5. Chua SS, Benrimoj SI, et al. A controlled clinical trial on the cardiovascular effects of single doses of pseudoephedrine in hypertensive patients. Br J Clin Pharmacol. 1989;28:369-72.
6. Coates ML, Rembold CM, et al. Does pseudoephedrine increase blood pressure in patients with controlled hypertension? J Fam Pract. 1995;40:22-26.
7. Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use. Federal Register Part 341:235-52. Available at: www.fda.gov/cder/otcmonographs/Allergy/Cold,Cough,Allergy(341).pdf (accessed January 24, 2006)
8. Pray SW. Blood pressure effects of nasal decongestants. U.S. Pharm. Available at: www.uspharmacist.com/oldformat.asp?url=newlook/files/cons/feb00cyp.htm. (accessed January 6, 2006).
9. Glazener F, Blake K, Gradman M. Bradycardia, hypotension, and near-syncope associated with Afrin (oxymetazoline) nasal spray. N Engl J Med. 1983;309:731.
10. Montalban J, Ibanez L, et al. Cerebral infarction after excessive use of nasal decongestants. J Neurol Neurosurg Psychiatry. 1989;52:541-543.
11. Loewen AHS, Hudon ME, Hill MD. Thunderclap headache and reversible segmental cerebral vasoconstriction associated with use of oxymetazoline nasal spray. Can Med Assoc J. 2004;171:593-594.
12. Zavala JAA, Pereira ER, et al. Hemorrhagic stroke after naphazoline exposition. Arch Neuropsychiatr. 2004;62:889-891.
13. Cohen BM, Dressler WE. Acute aromatics inhalation modifies the airways. Effects of the common cold. Respiration. 1982;43:285-293.
14. eFacts. Available at www.factsandcomparisons.com (accessed Nov. 15, 2005). 
15. Eccles R, Jawad MS, Morris S. The effects of oral administration of (-)-menthol on nasal resistance to airflow and nasal sensation of airflow in subjects suffering from nasal congestion associated with the common cold. J Pharm Pharmacol. 1990 Sep;42(9):652-654.
16. Eccles R, Morris S, Jawad MS. The effects of menthol on reaction time and nasal sensation of airflow in subjects suffering from the common cold. Clin Otolaryngol Allied Sci. 1990;39-42.
17. The Antihistamine Impairment Roundtable. First do no harm: managing antihistamine impairment in patients with allergic rhinitis. J Allergy Clin Immunol. 2003;111:5:S835-S842.
18. Health care guideline: rhinitis. Institute for Clinical Systems Improvement. May 2003. Available at www.icsi.org/display_file.asp?FileId=147&title=Chronic%20Rhinitis (pages 10 and 25 accessed January 9, 2006)
19. Chandler, C.  Drug class review on second-generation antihistamines: final report. November 2004. Available at www.oregon.gov/DAS/OHPPR/HRC/docs/AH_EPC.pdf  (accessed January 6, 2006).
20. Paakkari, I. Cardiotoxicity of new antihistamines and cisapride. Toxicol Lett. 2002;127:279-284.
21. Atar S, Freedberg NA, et al. Torsades de pointes and QT prolongation due to a combination of loratadine and amiodarone. Pacing Clin Electrophysiol. 2003;26:785-786.
22. Clark S. Dangers of nonsedating antihistamines. Lancet. 1997;349:1268.

23. Clarinex package insert. Available at www.spfiles.com/piclarinex.pdf (accessed November 12, 2005).
24. Allegra package insert. Available at products.sanofi-aventis.us/allegra/allegra.pdf (accessed November 12, 2005).
25. Dhar S, Hazra PK, et al. Fexofenadine-induced QT prolongation:  a myth or fact? Br J Dermatol . 2000;142:1260.
26. Zyrtec prescribing information. Available at www.pfizer.com/pfizer/download/uspi_zyrtec.pdf (accessed November 12, 2005).
27. Arundel AV, Sterling EM, Biggin JH, Sterling TD. Indirect health effects of relative humidity in indoor environments. Environ Health Perspect. 1986;65:351-361.
28. Assendelft AV, Forsen KO, Keskinen H, Alanko K. Humidifier-associated extrinsic allergic alveolitis. Scand J Work Environ Health. 1979;5:35-41.
29. Park JH, Spiegelman DL, et al. Predictors of airborne endotoxin in the home. Environ Health Perspect. 2001;109:859-864.
30. Latte J, Taverner D. Opening the nasal valve with external dilators reduces congestive symptoms in normal subjects. Am J Rhinol. 2005;19:215-219.
31. Lexi-Comp. Lexi-Drugs (Comp + Specialties). Available at www.lexi.com (accessed November 15, 2005.

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