The Acute Effect of Phenylpropanolarnine and Brompheniramine on Blood Pressure in Controlled Hypertension: A Randomized Double-blind Crossover Trial ALICE STOLLENWERK PETRULIS, MD, THOMAS F. IMPERIALE, MD, THEODORE SPEROFF, PhD Study objective: To d e t e r m i n e the acute effect o f phenylp r o p a n o l a m i n e , 75 m ~ a n d b r o m p h e n i r a m i n e , 12 n t ~ i n c o m b i n a t i o n ( P P A / B ) o n blood p r e s s u r e i n p a t i e n t s with controlled hypertension, u s i n g a m b u l a t o r y b l o o d p r e s s u r e m o n i t o r i n g (ABPM). Design: R a n d o m i z e d double-blind c r o s s o v e r t r i a l Setting: Outpatient clinic a t o n e medical center. Participants: 13 healthy volunteers aged 3 6 to 64 years, receiving medication f o r hypertension. Interventions: Following 24-hour baseline ABPM, particip a n t s were r a n d o m i z e d to receive eitherplacebo o r P P A / B every 12 h o u r s f o r three doses, while ABPM continued. After a 24-hour w a s h o u t period, all p a r t i c i p a n t s received the c r o s s o v e r regimem M e a s u r e m e n t s a n d m a i n results: No clinically i m p o r t a n t o r statistically significant difference was n o t e d f o r m e a n systolic a n d diastolic blood p r e s s u r e s d u r i n g the baseline (125/75), P P A / B (127/72), a n d p l a c e b o ( 1 2 6 / 7 3 ) p h a s e s o f the study. Within the f i r s t f o u r h o u r s o f treatmeng the m e a n c h a n g e i n systolic blood p r e s s u r e f r o m baseline between P P A / B a n d placebo p h a s e s w a s 1. 7 m m H g (95% CI --5.3 to 8. 7), a n d m e a n change in diastolic blood p r e s s u r e was 0.9 m m Hg (95% C I - - 1 . 6 to 3.5), excluding a firstdose p r e s s o r effect. Conclusion: When u s e d a s r e c o n n n e n d e d , PPA/B, a comm o n l y used over-the-counter cold medication, h a s n o sign i f i c a n t acute effect o n b l o o d p r e s s u r e i n p a t i e n t s with controlled hypertension. Key words: hypertension; sympathontimetics; p h e n y l p r o p a n o l a m i n e ; decongestants; b r o m p h e n i r a m i n e ; blood pressure. J GEN ~ MED 1991;6:503- 506.

PHENYLPROPANOLAMINE (PPA), a sympathomimetic agent, is used for treatment of the c o m m o n cold and for appetite suppression. The safety of this and other sympathomimetic decongestants in patients with hypertension is controversial. Isolated case reports o f complications include severe hypertension and intracerebral hemorrhage, but these reports have often inReceived from the Department of Medicine (ASP, TFI) and the Department of Epidemiology and Biostatistics (TS), Case Western Reserve University School of Medicine, and the Divisions of General Medicine and Nephrology, MetroHeahh Medical Center, Cleveland, Ohio. Presented at the annual meeting of the Society of General Internal Medicine, May 2 - 4 , 1990, Arlington, Virginia. Supported by funds from the Division of General Internal Medicine, MetroHealth Medical Center, Cleveland, Ohio. Address correspondence and reprint requests to Dr. Petrulis: MetroHealth Medical Center, 3395 Scranton Road, Cleveland, OH 44109.

volved dangerous drug interactions,t excessive doses, 2 or use o f a more potent isomer unavailable in the United States. 3 Clinical trials examining the effect of PPA on b l o o d pressure have shown conflicting results. In doses of 75 mg, PPA failed to cause a pressor effect in normotensive males. 4 However, in another investigation, 150 mg of PPA significantly elevated blood pressure in normotensive individuals, s A more recent randomized trial in patients with stable hypertension reported no overall effect of PPA, 25 mg, taken every four hours, but could not exclude an early, acute rise in blood pressure. 6 The purpose o f this study was to determine w h e t h e r the sustained-release formulation of PPA, 75 mg, and brompheniramine, 12 mg, a c o m m o n overthe-counter formulation (PPA/B; Dimetapp Extentabs", A. H. Robins Co., Richmond, VA) acutely affects blood pressure in patients with controlled hypertension. The study design was a randomized, double-blind, crossover trial. The study was p e r f o r m e d using an ambulatory b l o o d pressure monitor. This device automatically records multiple indirect blood pressure readings t h r o u g h o u t a 24-hour period. The advantages o f this t e c h n i q u e are the abilities: 1) to obtain n u m e r o u s readings without intrusion of normal daily activities and 2) to minimize the effect of " w h i t e coat" hypertension. 7

METHODS Eligible participants w e r e persons b e t w e e n 20 and 70 years of age with medication-controlled hypertension, recruited from the full-time employees of MetroHealth Medical Center. Exclusion criteria included poorly controlled coronary artery disease, indications for or hypersensitivity to PPA or brompheniramine, and concomitant use of a m o n o a m i n e oxidase inhibitor. On day 1, patients u n d e r w e n t baseline 24-hour ambulatory b l o o d pressure monitoring (ABPM) with a Suntech Accutracker II monitor (Suntech Medical Instruments, Inc., Raleigh, NC) beginning at 8:00 AM. On day 2, subjects w e r e randomized to receive one capsule of either PPA/B or placebo every 12 hours for three doses, while ABPM c o n t i n u e d until 4:00 PM of day 3 (32 hours total). Monitors were kept on for the entire 56 hours, with battery changes after 24 hours. After a 24503 TM

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hour washout period, the crossover treatment began on day 4 at 8:00 AM,with ABPM continuing until 4:00 PMof day 5. Monitors remained in place during the 32-hour treatment period, with battery changes at 24 hours. Placebo and medication capsules were devised by the pharmacy department at MetroHealth Medical Center. Opaque gelatin capsules contained either the sustained-release formulation of PPA/B (75 mg phenylpropanolamine and 12 mg brompheniramine) or a lactose-based placebo. Blood pressure was measured every 30 minutes for the 16 hours between 8:00 AM and midnight, and hourly from midnight to 8:00 AM. The units were checked daily for accuracy of blood pressure readings by comparison with readings obtained using a mercury sphygmomanometer. To evaluate compliance with the regimen, urine was obtained on days 3 and 5 and assayed for the presence of PPA. Urinary PPA levels were measured by Southgate Medical Laboratory, Cleveland, Ohio, using high-performance thin-layer chromatography. Sample size was calculated to detect a 10-mm-Hg increase in blood pressure from baseline with a power of 0.9 using a one-sided alpha of 0.05. To detect a change of 10 mm Hg in systolic blood pressure (SBP), the required sample size was ten; for diastolic blood pressure (DBP), the required sample size was seven. Thirteen patients were recruited for the study. There was no exclusion, and all patients completed the study protocol.

Data E d i t i n g Accutracker measurements were reviewed independently by two investigators (ASP and TFI) who were blinded to treatment sequence and phase. Readings were excluded from analysis for the following reasons: 1) technical problems such as major arm motion, or inadequate or weak Korotkoffsounds, and 2) predetermined reading errors such as pulse pressure

(SBP--DBP) < 20, SBP < 80 mm Hg, or DBP < 40 mm Hg. All remaining readings were coded and classified according to treatment sequence (PPA/B followed by placebo or placebo followed by PPA/B), phase of study (baseline, PPA/B, or placebo), and interval (4-hour daily or 8-hour nightly recordings). For the baseline phase (24 hours), there were five intervals: 8 AMto 12 noon, 12 noon to 4 PM, 4 PM tO 8 PM, 8 PM to 12 midnight, and 12 midnight to 8 AM. For the PPA/B and placebo phases, there were seven time intervals: the five intervals used in the baseline phase plus the intervals of 8 AMto 12 noon and 12 noon to 4 PM of the next day (32 hours total). Statistical

Analysis

Mean SBP and DBP and their standard errors were calculated for each phase and for each interval within a phase. Data were evaluated for treatment sequence effect, differences from baseline, and differences between PPA/B and placebo phases using analysis of variance with repeated measures. Ninety-five percent confidence intervals (CIs) were calculated for differences between PPA/B and placebo. The proportions of elevated readings (SBP > 160 mm Hg or DBP > 100 mm Hg) were compared among baseline, PPA/B, and placebo phases.

RESULTS Of the 13 participants, 11 were women, and six were black. The mean age was 48 years (range 36 to 64 years). The mean duration of hypertension was seven years (range 0.5 to 20 years). The antihypertensive agents used included diuretics (7), angiotensin-converting enzyme inhibitors (6), beta blockers (5), calcium channel blockers (1), and centrally acting alpha agonists (1). Seven participants were taking two antihypertensive medications. Comorbid conditions included polycystic kidney disease with normal renal function (1), sarcoidosis (1), and insulin-dependent diabetes mellitus (1). Concomitant medications included fluoxetine (1), metoclopramide (1), insulin (1), and postmenopausal hormonal replacement (1). Readings were excluded from analysis for technical reasons and for reading errors. Percentages of excluded readings were 29% for the baseline phase, 29% for the PPA/B phase, and 28% for the placebo phase. Analysis of the remaining readings showed no significant difference between PPA/B and placebo. No significant difference was noted for mean SBP and DBP among the baseline ( 1 2 7 / 7 5 ) , PPA/B ( 1 2 7 / 7 2 ) , or placebo ( 1 2 6 / 7 3 ) phases (Fig. 1). There was no significant difference in mean SBP or DBP for the six patients receiving PPA/B ( 1 3 0 / 7 1 ) followed by placebo ( 1 2 9 / 7 2 ) ,

JOURNALOFGENERALINTERNALMEDICINE,Volume 6 (November/December),

compared with the seven subjects receiving placebo (124/74) followed by PPA/B (125/74). These findings exclude a sequence effect. The overall difference between the mean SBPs of the PPA/B and placebo phases was 1.1 mm Hg (95% CI --2.0 to 4.2), and the overall difference between mean DBPs was 0.5 mm Hg (95% CI --2.1 to 3.2). Subgroup analyses of mean SBPs and DBPs by time intervals showed no significant difference among the baseline, PPA/B, and placebo phases (Fig. 2). For the first four hours of each phase, there was no difference in the mean SBP or DBP for the baseline (131/79), PPA/B (127/75), and placebo (125/14) phases. During the first interval of treatment, the mean difference between the SBPs in the PPA/B and placebo phases was 1.7 mm Hg (95% CI --5.3 to 8.7) and that between the DBPs was 0.9 mm Hg (95% CI --1.6 to 3.5). These findings exclude a first-dose effect. The proportions of blood pressure readings exceeding an SBP of 160 mm Hg and/or a DBP of 100 mm Hg during all intervals were no different for the baseline (17%), PPA/B (13%), and placebo (13%) phases. Proportions of readings exceeding 160 mm Hg SBP were 11%, 9%, and 10% for the baseline, PPA/B, and placebo phases, respectively. When readings exceeding a DBP of 90 mm Hg were considered, the proportions were 20% for the baseline phase, 12% for the PPA/B phase, and 14% for the placebo phase. There was no significant difference between the PPA/B and placebo phases for either SBP exceeding 160 mm Hg or DBP exceeding 90 mm Hg. Since the majority of hypertensive readings had originated from one participant, the data were reanalyzed excluding this participant. The repeat analysis for readings exceeding 160/100 mm Hg revealed the proportions to be 12%, 7%, and 6% for the baseline, PPA/B, and placebo phases, respectively. The proportions of readings exceeding an SBP of 160 mm Hg were 6%, 4%, and 4% for the baseline, PPA/B, and placebo phases, respectively. The proportions of readings exceeding a DBP of 90 mm Hg were 20%, 10%, and 14%. Again, there was no significant difference between the PPA/B and placebo phases for either SBP exceeding 160 mm Hg or DBP exceeding 90 mm Hg. Exclusion of this patient's values had no effect on the other results. Compliance with pill taking was confirmed by qualitative measurement of urinary PPA. Phenylpropanolamine was detected in urine samples only during treatment (PPA/B) phases and not during placebo phases.

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1991

major comorbid disease. The sample size of our trial had a sensitivity greater than 90% to detect a 10-mm-Hg change in blood pressure. Changes smaller than 10 mm Hg are likely to be of little clinical importance. Our results support the previously reported trial of Kroenke et al.,6 which demonstrated no significant hypertensive effect of PPA when monitored with ABPM. Both studies investigated well-controlled, mildly hypertensive patients in a randomized, double-blind crossover trial. The present study differed from that of Kroenke et al. by using the sustained-release form of PPA/B. In addition, ABPM was initiated prior to ingestion of the first capsule to evaluate for a first-dose pressor effect. Another recently reported randomized crossover trial using sustained release PPA4 also showed no significant difference in blood pressures when measured with ABPM, but involved only normotensive subjects. Limitations of this study include the limited generalizability of the results. A variable that might affect

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Petrulis et aL. DECONGESTANTSIN HYPERTENSION

generalizability is the type of participant. All subjects were employed, highly motivated, compliant individuals w h o had hypertension relatively well controlled with antihypertensive agents and w h o had no major c o m o r b i d illness. These results, therefore, may not apply to less compliant individuals, to nonpharmacologic control of b l o o d pressure, or to less well-controlled hypertension. In addition, the PPA c o m p o n e n t used was 7 5 mg of a sustained-release preparation. The results of this study do not apply to different doses and may not a p p l y to the immediate-release preparation.

CONCLUSION The results of this study suggest that the combination of PPA/B k n o w n as Dimetapp Extentabs has no significant acute effect on b l o o d pressure in patients with controlled hypertension w h e n used as recommended. Studies are needed to determine the true generalizability of these results b y investigating factors that may modify this effect, such as the specific dose and type of PPA, the use of c o n c o m i t a n t medications such as

nonsteroidal anti-inflammatory drugs, and the presence of c o m o r b i d conditions.

REFERENCES 1. LakeCR, ZalogaG, ClymerR, Quirk R, Chernow B. A double dose of phenylpropanolaminecausestransient hypertension.AmJMed. 1988;85:339-43. 2. Kase CS, Foster TE, Reed JE~ Spatz EL, Girgis GN. Intracerebral hemorrhage & phenylpropanolamine use. Neurology. 1987; 37:399-403. 3. HorowitzJD,LangwJ, HowesLG. Hypertensiveresponse induced by phenylpropanolamine in anorectic and decongestant prepara- tions. Lancet. 1980;i:60-1. 4. Goodman RP, Wright JT, Barlascini CO, McKenneyJM, Lambert CM. The effect of phenylpropanolamine on ambulatory blood pressure. Clin Pharmacol Ther. 1986;40:144-7. 5. lake CR, Zaloga G, BrayJ, Rosenberg D, Chernow B. Transient hypertension after two phenylpropanolamine diet aids and the effects of caffeine: a placebo-controlled follow-up study. Am J Med. 1989;86:427-32. 6. Kroenke K, Omori DM, SimmonsJO, Wood DR, Meier NJ. The safety of phenylpropanolamine in patients with stable hypertension. Ann Intern Med. 1989;111:1043-4. 7. NationalHigh BloodPressure Education ProgramWorkingGroup Report on Ambulatory Blood Pressure Monitoring. Arch Intern Med. 1990;150:2270-80.

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The acute effect of phenylpropanolamine and brompheniramine on blood pressure in controlled hypertension: a randomized double-blind crossover trial.

To determine the acute effect of phenylpropanolamine, 75 mg, and brompheniramine, 12 mg, in combination (PPA/B) on blood pressure in patients with con...
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