The Effect Of Pseudoephedrine On Blood Pressure J Am Board Fam Pract: first published as 10.3122/jabfm.4.4.201 on 1 July 1991. Downloaded from In Patients With Controlled, Uncomplicated Hypertension: A Randomized, Double-Blind, Placebo-Controlled Trial

John G. Bradley, M.D., Ken]. Kallai~ Ph.D., John N. Dorsch, M.D., andJoan Fox, R.N.

Abslrtlet: Pseudoephedrine is frequendy used as a decongestant. Because of concern about 1be safety of pseudoephedrine in hypertensive patients, a clinical1rial was conducted to detennine whether blood pressure control was actuallya1fected by 1bis drug in a selected group of patients with hypertension. 1Wenty-nine patients wi1b controlled, uncomplicated hypertension, who received drug therapy and ranged in age from 25 to 50 years, were randomized to a treatment or a control group. Subjects took eI1ber 60 mg of pseudoephedrine or placebo capsules four times a day for 3 days. From 0800 hours until 2200 hours each day, the subjects obtained hourly blood pressure measurements using a porlable sphygmomanometer. An analysis of variance wi1b repeated measures was calculated to determine group differences for systolic and diastoUc readings. No statistically or clinically signiftcant differences were found. 1berapeu1ic: doses of pseudoephedrine did not adversely affect control of hypertension in 1bese selected patients. 0 Am Board Fam Pract 1991; 4:201-6.)

Pseudoephedrine, phenylpropanolamine, and in hypertensive patients. While no adverse effect phenylephrine are oral sympathomimetic agents was found,IO this study was uncontrolled, a com­ commonly used as decongestants in prescription bination of drugs was used, and patient compli­ and over-the-counter preparations. Long-stand­ ance was unverified. Only topical nasal adminis­ ing concern exists regarding their potential ad­ tration of phenylephrine has been studied in verse effect in hypertensive patients. This con­ hypertensive patients. In one double-blind study, cern is found in standard texts (e.g., American no elevation of blood pressure was found when Hospital Formulary Service-Drug Information), 1 doses exceeded therapeutic levels. 11 Researchers http://www.jabfm.org/ prescribing information, package labeling, and in other similar studies have failed to show in­ the literature.2,3 Given the ubiquity of the prob­ creased blood pressure resulting from nasally ad­ lems for which these drugs are used, the availabil­ ministered phenylephrine.2 ity of these drugs, and the high rate of hyperten­ Data from studies of oral pseudoephedrine sion in this country,4 sufficient information about given to persons with normal blood pressure have their effects in hypertensive patients is important. shown no clinical effect on blood pressures when Little data, however, are available. administered in amounts double or higher than on 2 October 2021 by guest. Protected copyright. Phenylpropanolamine, . while probably safe at the therapeutic dose.I2-I4 Isolated reports exist of recommended doses in persons with normal hypertensive crises or elevated blood pressure blood pressures,5-7 has been the subject of great measurements in patients taking pseudoephed­ concern.8,9 It has been evaluated in only one study rine, but these patients were taking overdoses or combination drugs.2 Two studies have assessed the effect of pseudo­ From the Department of Family and Community Medicine, ephedrine on blood pressure in hypertensive pa­ University of Kansas School of Medicine-Wichita, and the St. tients. Findings from one study showed no ad­ Joseph Medical Center Family Practice Residency, Wichita. Ad­ dress reprint requests to John G. Bradley, M.D., SIU Decatur verse effect, but the study was uncontrolled and Family Practice Residency, 1314 North Main, Suite 201, Deca­ combination drugs were used. IS The other study tur, IL 62526. was a crossover, double-blind trial using single This project was supported by grants from the American Acad­ emy of Family Physicians Foundation and the Family Health oral doses of pseudoephedrine. Statistically sig­ Foundation of Kansas. nificant elevations in blood pressure were found;

Pseudoephedrine and Hypertension 201 however, these elevations were not clinically sig­ Table 1. Antlhypertell8he Drup 'liken by die 25 Paden.. Completing J Am Board Fam Pract: first published as 10.3122/jabfm.4.4.201 on 1 July 1991. Downloaded from nificant based on the reported data. 16 die Study. The literature review and clinical experience Drug Number of support that pseudoephedrine at therapeutic Patients doses might be a safe drug in at least some Diuretics hypertensive patients. The efficacy of pseudo­ Hydrochlorothiazide 8 ephedrine as a nasal decongestant has been ChlorthaJidone 2 reported,13,17 and evaluations of its effect on Triamterene 2 hypertension have been called for by some Amiloride 2,3 authors. ~-Blockers The purpose of our study was to test the Atenolol 4 hypothesis that repeated maximal therapeutic Pindolol 2 doses of immediate-release oral pseudoephed­ Propranolol rine would not adversely affect control of uncom­ Angiotensin-converting enzyme inhibitors plicated hypertension in selected patients. The Lisinopril 7 study was undertaken in the hope that the Enalapril 3 findings would assist physicians with their recom­ Captopril mendations to hypertensive patients regarding pseudoephedrine. Calcium channel blockers Verapamil 2 Methods Diltiazem Twenty-nine persons were enrolled in the study Peripheral vasodilators after meeting eligibility requirements and provid­ Hydralazine ing informed consent. Sixteen were recruited Patients taking one antihypertensive drug 20* from a residency teaching practice, 7 from a pri­ Patients taking two antihypertensive drugs 4 vate practice, and 6 through an advertisement. Patient taking three antihypertensive drugs Four were eventually excluded from data analysis *Patients taking combination diuretics were counted in this (see below). group. To be eligible, subjects (1) had to have pre­ viously diagnosed hypertension; (2) had to be re­ sure control than those taking only one drug. The ceiving drug therapy; (3) had to have documented hypertension of all subjects appeared to be con­ http://www.jabfm.org/ office blood pressure measurements of 140/90 trolled, and blood pressure measurements met the mmHg or less on the day of enrollment and for at criteria for inclusion in the data analysis. least 1 month before enrollment (this criterion Subjects were randomized in a double-blind reflects the standard decision-making practice re­ fashion to a control or a treatment group. Placebo lated to hypertension control); (4) could range in (lactose) and 60-mg pseudoephedrine capsules

age from 18 to 50 years; (5) could not have his­ used in the investigation were manufactured on 2 October 2021 by guest. Protected copyright. tories of diabetes or cerebrovascular, cardiovascu­ by the hospital pharmacy. All capsules were lar, or peripheral vascular disease; and (6) had to identical and self-administered on 3 consecu­ be deemed reliable and compliant by their per­ tive days at 0800, 1200, 1600, and 2000 hours. sonal physician. A 60-mg dose to be taken four times a day Patients taking a-blockers or a combination of was used because it is the maximum rec­ a- and ~-blockers were excluded. With the ommended therapeutic dose. A 3-day study patient's permission, the subject's physician veri­ period was selected to provide adequate time for fied the patient's clinical data. steady-state serum levels and to enhance the like­ The number and type of antihypertensive lihood of any adverse effect on blood pressure drugs used by the 25 persons completing the control. study are shown in Table 1. The medical records Subjects were provided a. small portable os­ T11 of the 5 patients who were taking two or three cillometric sphygmomanometer (Marshall 85 ) antihypertensive drugs were reviewed to deter­ with automatic digital readout, and they were mine whether they experienced less blood pres- taught to obtain their own blood pressure meas-

202 JABFP July-August 1991 Vol. 4 No.4 urements according to American Heart Associa­ mmHg J Am Board Fam Pract: first published as 10.3122/jabfm.4.4.201 on 1 July 1991. Downloaded from tion guidelines. IS The technique for insuring ac­ 140 curacy of the sphygmomanometer had been re­ 130 ported previously. 19 Using this method,19 120 ____ Syetotlc: Pseudoephedrine sphygmomanometer measurements for the cur­ 110 _ Syo1oIIc: _ I _____ DtuIoIic: PMUdoephedrine 100 rent study were compared for accuracy simulta­ ___.- DiuIoIic:_ neously with those obtained from a standard cali­ brated wall-type mercury manometer. All 80 measurements from the Marshall85™ sphygmo­ 10 15 20 25 30 35 40 45 manometer were within 5 mmHg of those ob­ DAY 1 DAYZ DAY 3 tained from the mercury manometer. HOURLY MEASUREMENTS Subjects were given a I-page data form to re­ cord the exact time each capsule was taken and Figure 1. Average blood pressure measurements for values for each blood pressure measurement. eacll of the 4S hourly readings over 3 daJs. They were to measure and record their blood pressure measurements hourly from 0800 to 2200 readings. No differences were found for systolic on each of the 3 study days. Subjects were in­ (F = 1.0; df = 44) or diastolic (F = 1.17; df = 44) structed to notify the physician investigators im­ blood pressure measurements between the two mediately if their blood pressure exceeded 145 groups (P> 0.05). mmHg systolic or 94 mmHg diastolic. The sub­ Table 2 shows the means, ranges, and standard jects also were instructed to continue their regular deviations for systolic and diastolic blood pres­ prescription medications and normal activities sures for the pseudoephedrine and placebo during the trial. Compliance was assessed from groups. Mean scores reflect well-controlled blood the data form, history, and pill count at the end of pressures throughout the study. The range of the study period. A stipend was provided for pa­ measurements, however, exceeded the allowable tient participation. 145/94 mmHg established for safety. As mentioned, subjects were instructed to call Results the physician investigators immediately if the sys­ Twenty-five persons, ranging in age from 25 to 50 tolic pressure exceeded 145 mmHg or the dia­ years, completed the protocol and were included stolic pressure exceeded 94 mmHg. Of those in the data analysis. Two subjects (one in each of completing the study, 11 (5 in the pseudoephed­ http://www.jabfm.org/ the treatment and control groups) deviated suffi­ rine group and 6 in the placebo group) failed to ciendy from the protocol to be excluded. Two comply with these instructions. Of the 1125 others reported a blood pressure measurement hourly measurements, the allowable blood pres­ greater than 145/94 mmHg and were instructed sure level was exceeded 36 times (3.2 percent of to stop taking the study medication (one had total number of measurements). The systolic

taken only one capsule, and the second had taken measurement exceeded 145 mmHg on six occa­ on 2 October 2021 by guest. Protected copyright. six capsules). Both subjects continued to check sions (0.5 percent of total number of measure- their blood pressures hourly for 3 days and ap­ peared to have uncontrolled hypertension, even 'DIble 2. 'I1le MeaM, ...... ad SIud8I'd DevIIdoM for SyItoIic though they had several previously documented ad DlIllOIic Blood I'reIIIuft MaluremeIIII for PIeucIoepWri_ office blood pressure values that were well within (0 • 13) aad PlMebo (0 • 12) Grollpl. acceptable range. Both patients had been ran­ Blood Pressure Pseudoephedrine Placebo domized to the control group and were taking a mmHg mmHg placebo. Mean systolic 125 127 Figure 1 displays the average blood pressure Range 95-146 74-161 measurements of the pseudoephedrine and pla­ Standard deviation 9.4 11.2 cebo groups for each of the 45 hourly readings in Mean diastolic 79 80 the 3-day period. An analysis of variance with Range 55-111 53-111 repeated measures was calculated to determine Standard deviation 7.7 group differences for both systolic and diastolic 8.6

Pseudoephedrine and Hypertension 203 J Am Board Fam Pract: first published as 10.3122/jabfm.4.4.201 on 1 July 1991. Downloaded from ments). The diastolic measurement exceeded 94 trol in hypertensive patients. The study was de­ mmHg on 29 occasions (2.6 percent of total num­ signed to obtain infonnation that would be di­ ber of measurements). Both systolic and diastolic recdy applicable to the outpatient family practice measurements exceeded the allowable level on population. one occasion. All subjects were patients who had a high prob­ Of the 36 occasions of high blood pressure ability of having true hypertension. Antihyper­ measurements, 12 were reported by subjects tak­ tensive medications were not discontinued to ver­ ing pseudoephedrine and 24 were reported by ify the patients' hypertension. Hypertension subjects taking placebo (Table 3). The placebo control was based on office blood pressure meas­ group, therefore, had significandy more occa­ urements documented in the patient's chart and sions of high blood pressure measurements (X2 = taken at the time of enrollment. That both treat­ 4.5; df = 1; P < 0.05). Three occasions of a high ment and placebo groups experienced blood pres­ diastolic blood pressure and one occasion of high sures greater than 145/94 mmHg raises the ques­ systolic and diastolic blood pressure were re­ tion of whether it is appropriate to rely solely on ported by one subject in the placebo group. He office blood pressure measurements in therapeu­ was a fireman who recorded these measurements tic decision making, which is the current method during a 4-hour period while working at a fire. commonly used to assess hypertension control. Five persons in the pseudoephedrine group re­ Although this finding does not invalidate the con­ ported seven instances of side effects. The side clusions of the study because similar results oc­ effects included sleeplessness (2 subjects), de­ curred in both groups, it does point out the need creased appetite (2 subjects), a funny taste in the for further study of patients' ambulatory blood mouth, increased thirst, and dry mouth. No one pressure measurements as they relate to control in the placebo group reported side effects. of hypertension. The conclusions based on the results of this Discussion study are limited. Nevertheless, the subject selec­ The purpose of this study was to evaluate the tion procedures and the evaluation of the effect of effect of pseudoephedrine on blood pressure con- pseudoephedrine on hypertension control were

Table 3. Stuaaay ofPaden1l Who Reported Blood Pra8ures > 14~ IIIIIIIfg during the Study PerIod. *

Episodes of Elevated Highest Systolic Highest Diastolic http://www.jabfm.org/ Group Concurrent Medication(s) Blood Pressure Pressure mmHg Pressure mmHg Pseudoephedrine Pindolol 144 97 Pseudoephedrine Diltiazem 146 86 Pseudoephedrine Hydrochlorothiazide 135 95 Trimaterene Hydrochlorothiazide 7 135 Pseudoephedrine 99 on 2 October 2021 by guest. Protected copyright. Lisinopril Verapamil Pseudoephedrine Hydrochlorothiazide 2 144 97 Enalapril Placebo Hydrochlorothiazide 3 139 100 Placebo Lisinopril 2 140 99 Placebo Enalapril 7 142 105 Placebo Lisinopril 3 161 100 Hydralazine Placebo Chlorthalidone 6 148 111 Placebo Hydrochlorothiazide Triamterene 3 150 92 Captopril

*Highest systolic and highest diastolic measurements often did not occur together.

204 JABFP July-August 1991 Vol. 4 No.4 realistic and practical. We followed a reasonable and good office control may be an unrecognized J Am Board Fam Pract: first published as 10.3122/jabfm.4.4.201 on 1 July 1991. Downloaded from clinical decision-making process that physicians problem and an area for further investigation. It regularly use to determine whether a patient has also highlights the difficulty of comparing office hypertension and whether the patient's hyperten­ measurements with ambulatory measurements. sion is controlled. Nonnative ambulatory data are difficult to obtain, A wide range of antihypertensive medications and a certain percentage of ambulatory blood was used by patients in this study. All receiving pressures> 140/90 mmHg is probably nor­ a-blocker agents were specifically excluded, be­ mal.21,22 For this reason, we compared the blood cause of theoretic concern that pseudoephedrine pressures of the two study groups and did not would directly antagonize these drugs and, there­ investigate the potential change in blood pressure fore, be less safe. No other attempts were made to from the entry criteria (i.e., office measurements). control for the type of medications used. The results show that pseudoephedrine did not Conclusion adversely affect control of hypertension statisti­ Short-tenn administration of therapeutic doses cally or clinically. Whereas the number of sub­ of pseudoephedrine can be safe in a selected jects was small, the results suggest that, even with group of patients with controlled and uncompli­ a greater number, no clinically significant differ­ cated hypertension. It should not be assumed, ences would exist between the two groups. That however, that pseudoephedrine will have no effect the differences in group blood pressure measure­ on patients with untreated hypertension. No spe­ ments were small, that there were few occasions cific age generalizations can be made based upon of high blood pressure measurements, and that these data because of the small sample. Additional most blood pressure elevations> 145/94 mmHg study is required to determine the safety of were in the placebo group support this con­ pseudoephedrine in other populations of patients clusion. Further, elevations in blood pressure with hypertension. > 145/94 mmHg were generally not extreme. Our results differed slightly from those of Chua and colleagues16 who reported some eleva­ The authors acknowledge the valuable assistance of Dr. Ran­ dall V. Goering and Dr. Edward}. Hett in the completion of this tion of systolic blood pressure with one 60-mg project. dose of pseudoephedrine. They found no differ­ ences for diastolic blood pressures or mean arte­ rial pressures. Although the differences in systolic References http://www.jabfm.org/ 1. McEvoy GK, editor. AHFS drug infonnation. measurements were statistically significant, these Bethesda, MD: American Society of Hospital Phar­ differences did not appear to be clinically import­ macists; 1990:648-54. ant based on the data reported. The highest mean 2. Chua SS, Benrimoj SI. Non-prescription sympatho­ systolic pressure reported in this study was 134 mimetic agents and hypertension. Med Toxicol Ad­ verse Drug Exp 1988; 3:387-417. mmHg with pseudoephedrine and 131 mmHg 3. Radack K, Deck CC. Are oral decongestants safe in with placebo. The standard deviations for the hypertension? An evaluation of the evidence and a on 2 October 2021 by guest. Protected copyright. blood pressure measurements for each treatment framework for assessing clinical trials. Ann Allergy also were similar. Further, 9 of the 20 subjects 1986; 56:396-401. studied were treated with low-salt diet alone and 4. National High Blood Pressure Education Program, Coordinating Committee. The 1988 report of the were not receiving drug therapy.16 joint national committee on detection, evaluation, An additional note of interest in our study and treatment of high blood pressure. Bethesda, involved the two patients who were poorly MD: National Heart, Lung, and Blood Institute, controlled according to ambulatory measure­ 1988. (Nlli publication no 88-1088.) 5. Liebson I, Bigelow G, Griffiths RR, Funderburk FR. ments and were excluded from analysis. They Phenylpropanolamine: effects on subjective and car­ appeared to be controlled based on several office diovascular variables at recommended over-the­ blood pressure measurements; however, ambula­ counter dose levels. J Clin Pharmacol 1987; tory measurements strongly suggested otherwise. 27:685-93. 6. Blackburn GL, Morgan JP, Lavin PT, Noble R, Office measurements are generally believed to Funderburk FR, Isdim N. Determinants of the pres­ be higher than those taken elsewhere.2o The oc­ sor effect of phenylpropanolamine in healthy sub­ currence of ambulatory blood pressure elevations jects.JAMA 1989; 261:3267-72.

Pseudoephedrine and Hypertension 205 J Am Board Fam Pract: first published as 10.3122/jabfm.4.4.201 on 1 July 1991. Downloaded from 7. Goodman RP, Wright ]T ]r., Barlascini CO, moderate hypertensives. Curr Ther Res 1969; McKenney ]M, Lambert CM. The effect of 11:252-5. phenylpropanolamine on ambulatory blood pres­ 16. Chua SS, Benrimoj SI, Gordon RD, Williams G. A sure. Clin Pharmacol Ther 1986; 4Q: 144-7. controlled clinical trial on the cardiovascular effects 8. Bravo EL. Phenylpropanolamine and other over­ of single doses of pseudoephedrine in hypertensive the-counter vasoactive compounds. Hypertension patients. Br] Clin Pharmacol1989; 28:369-72. 1988; II(Suppl):II7-IO. 17. Empey DW, Bye C, Hodder M, Hughes DT. A dou­ 9. Pentel P. Toxicity of over-the-counter stimulants. ble-blind crossover trial of pseudoephedrine and ]AMA 1984; 252:1898-903. triprolidine, alone and in combination, for the treat­ 10. Unger DL, Unger L, Temple DE. Effect of an anti­ ment of allergenic rhinitis. Ann Allergy 1975; 34: asthmatic compound on blood pressure of hyperten­ 41-6. sive asthmatic patients. Ann Allergy 1967; 25 :260-1. 18. Kirkendall WM, Feinleib M, Freis ED, Mark AL. 11. Myers MG, lazzetta ]]. Intranasally administered Recommendations for human blood pressure deter­ phenylephrine and blood pressure. Can Med Assoc] mination by sphygmomanometers. Subcommittee 1982; 127:365-8. of the AHA Postgraduate Education Committee. 12. Drew CD, Knight GT, Hughes DT, Bush M. Circulation 1980; 62:1l46A-1l55A. Comparison of the effects of D-( - )-ephedrine and 19. Bradley ]G, Dorsch ]N, Kallail K], Chaney E], L-(+)-pseudoephedrine on the cardiovascular and Haskins R], Streit]G. The accuracy of the Marshall respiratory systems in man. Br ] Clin Pharmacol 85 oscillometric sphygmomanometer in the ambula­ 1978; 6:221-5. tory care setting. ] Am Board Fam Pract 1989; 2: 13. Empey DW, Young GA, Letley E,]ohn Ge, Smith 247-51. P, McDonnell KA, et al. Dose-response study of 20. Spence ]D. Pseudohypertension. In: Laragh ]H, the nasal decongestant and cardiovascular effects Brenner BM, editors. Hypertension: pathophysiol­ of pseudoephedrine. ] Clin Pharmacol 1980; 9: ogy, diagnosis and management. Vol. 2. New York: 351-8. Raven Press, 1990:14Q7-14. 14. Bye C, Hill HM, Hughes DTD, Peck AW. A com­ 21. Drayer]I, Weber MA, Nakamura DK. Automated parison of plasma levels of L( +)pseudoephedrine fol­ ambulatory blood pressure monitoring: a study in lowing different formulations, and their relation to age-related normotensive and hypertensive men. cardiovascular and subjective effects in man. Eur ] Am Heart] 1985; 109:1334-8. ClinPharmacol1975; 8:47-53. 22. Kennedy HL, Horan MJ, Sprague MK, Padgett NE, 15. Greening GK. The effect of an antihistamine­ Shriver KK. Ambulatory blood pressure in healthy pseudoephedrine drug on the blood pressure of normotensive males. Am Heart] 1983; 106:717-22. http://www.jabfm.org/ on 2 October 2021 by guest. Protected copyright.

206 JABFP July-August 1991 Vol. 4 No.4