pharmacology and safety of phenylpropanolamine

Drug Development Research 22: 197-207 (1991)

Current Trends Review

Pharmacology and Safety of Phenylpropanolamine David A. Johnson

Cardiovascular Laboratow, Department of Nutrition, Harvard University, School of Public Health, Boston, Massachusetts

ABSTRACT INTRODUCTION THE PHARMACOLOGY OF PHENYLPROPANOLAMINE

History Pharmacodynamics Direct and Indirect Receptor Activation Effects on Vascular Tissue Cardiovascular Effects Summary

Animal Studies Concern Over Toxicity Reported Adverse Reactions Controlled Clinical Studies

SAFETY

CONCLUSION REFERENCES

Received final version August 28, 1990; accepted September 1, 1990.

Current address for reprint requests: David A. Johnson, Interneuron Pharmaceuticals, Inc., 1 Ledgemont Center, 99 Hayden Avenue, Lexington, MA 02173.

Abbreviations used: PPA, Phenylpropanolamine; BP, Blood Pressure; CNS, Central Nervous System; NE, Norepinephrine; OTC, Over-the-counter; NOR, Norephedrine; NORP, Norpseudoephedrine.

0 1991 Wiley-Liss, Ine.

198 Johnson

ABSTRACT

Johnson, D.A.: Pharmacology and safety of phenylpropanolamine. Drug Dev. Res. 22: 197-207. 1991.

Phenylpropanolamine (PPA) is a phenylethylamine found commonly in cough medicines, nasal decongestants, and over-the-counter (OTC) diet aids. Since its discovery more than 70 years ago, the pharmacology of this drug has periodically been reexamined as the result of advances in the understanding of the sympathetic nervous system and adrenergic receptor function. This review presents a brief overview of the pharmacology of PPA, with an emphasis on how the drug effects smooth muscle tissues. Additionally, since the safety of PPA has recently been called into question, research pertaining to its toxicity is also reviewed.

Key words: hypertension, partial agonist, alpha-adrenoceptors, anorexia, decongestant, smooth muscle

INTRODUCTION

From time to time well established drugs have been re-evaluated following advances in the understanding of how they work, the development of new applications, or increases in public consumption. Phenylpropanolamine, the racemic mixture of the enantiomers d- and 1-norephedrine (NOR), is a chemical analog of the endogenous sympathomimetic amines. One of the most frequently used drugs in the United States, PPA is found as a constituent ingredient of many non-prescription nasal decongestants, cold medications, and appetite suppressants. More recently, PPA has also been utilized in amphetamine look-alike or “street speed” preparations in combination with caffeine and/or ephedrine.

The intent of this review is first to present an overview of the pharmacology of PPA, emphasizing its cardiovascular activity. Second, the controversy surrounding the safety of PPA is addressed and research pertaining to its toxicity is reviewed (for a more comprehensive review of PPA, see Lasagna [1988] and Morgan et al. [1985].

THE PHARMACOLOGY OF PHENYLPROPANOLAMINE History

Phenylpropanolamine was first synthesized early in the century [Caliess, 1912; Rabe and Hallensleben, 1910; Mannich and Jacobsohn, 19101 and patented as a medication to induce mydriasis by Nagai [i913]. During the 1930’s the effects of PPA on blood pressure (BP) were investigated. In both animals and humans PPA could, with sufficient dosage, induce a pressor response when administered either intravenously [Hasama, 1930; Loman et al., 19391, or orally [Chen et al., 1929; Hartung and Munch, 19311. Oral activity was possible since PPA contains an alpha-methyl group as part of its structure, and therefore is not metabolically degraded by gastrointestinal enzymes like some of the other sympathomimetic amines.

Later, it was discovered that PPA also has significant anorectic activity. Moreover, PPA was effective without the central nervous system (CNS) side effects of insomnia or nervous- ness associated with d-amphetamine [Hirsch, 19391. It was found that PPA increased locomotor activity in rats only at extremely high doses [Schulte et al., 19411. Other work in rats [Tainter, 1944; Warren and Werner, 1946; Eisenberg and Maher, 19871 and mice [Fairchild and Alles, 19671 confirmed PPA had only weak or negligible stimulatory effects on the CNS. The mechanisms for PPA’s anorexic properties are not fully understood, but may be related to both central and peripheral actions.

Pharrnacodynarnics

The pharmacodynamics of PPA have been studied extensively in isolated tissues and whole animal preparations, as well as in clinical trials. In general, the activity of PPA is found

Phenylpropanolamine 199

to be relatively weak compared with the other sympathomimetic amines. As an example, PPA is 100 to 200 times less potent than epinephrine or norepinephrine (NE) at increasing heart rate or mean aterial pressure {Persson et al., 1973). However, the effects of PPA vary with the particular tissue involved.

In isolated tissue preparations of vas deferens from rats, PPA induced contractions with low potency [less than l/lOOO) and less than half the intrinsic activity (47 & 3.3%) of NE [Minneman et al., 19831. Of the partial adrenergic agonists tested, PPA had the lowest potency and intrinsic activity. The order of potency observed was; oxymetazoline > naphazoline > p-aminoclonidine > tramazoline > clonidine > ephedrine > PPA. According to Minneman, there was a significant pool of spare receptors for full adrenergic agonists, but not partial agonists such as PPA. Similar results with PPA were obtained from isolated preparations of human vas deferens [Ratnasooriya et al., 19791, but, PPA has also demonstrated intrinsic activity in other smooth muscle tissues equal to full agonists [Stevens et al., 19811.

Direct and Indirect Receptor Activation

The action of PPA may be mediated directly, by activation of post-junctional adrenoceptors; indirectly, by affecting the release and/or the reuptake of NE; or by a combination of both mechanisms. In isolated guinea pig atria, pretreatment with reserpine shifted the dose- response curve to the right, which suggests the effect of PPA is mediated at least partly through an indirect mechanism [Trendelenburg, 19631. In further support of the indirect activity of PPA in heart tissue, PPA inhibited the reuptake of NE in the isolated heart [Burgen and Iversen, 1965; Iversen, 1964; Levitt et al., 1974; Swamy et al., 19691.

In the cat nictitating membrane, however, the direct effects of PPA appear to predom- inate since neither reserpine pretreatment nor cocaine alter the contractions induced by PPA in this tissue [Trendelenburg, 1962a,b]. Furthermore, in other studies, reserpine did not alter the effects of PPA in rabbit isolated aortic strips [Persson et al., 19731. Therefore the investigations suggest that whether PPA acts directly or indirectly is to some extent dependent on the tissue being studied.

Effects on Vascular Tissue

In isolated aortic strips from rabbit, Persson et al. [1973] obtained dose-response- dependent contractions for PPA at concentrations ranging from 0.005 to 1.6 pg/ml (US0 to 1/80 as potent as NE). When responses were compared to tissues from animals pretreated with reserpine (5 mg/kg I.P.), there was no significant change in the response to PPA. These investigators also determined whether brompheniramine, a common antihistamine frequently found in combination with PPA in OTC cold medications, altered the vascular response to PPA. In doses up to 0.8 pgiml, the presence of brompheniramine had no effect on the contractions of submaximum doxes of PPA; however, higher doses of brompheniramine depressed the contractions induced by PPA in this preparation. Persson concluded that the contractile effect of PPA was probably mediated by direct interaction with postjunctional adrenoceptors and that the vascular responses to PPA would most likely not be affected by therapeutic doses of brompheniramine.

Stevens and Moulds [ 198 11, utilizing cumulative dose-response curves, conducted experiments on the activity of adrenergic agonists, including PPA, in strips from the common digital arteries of the second and third fingers and the dorsal metacarpal vein from cadavers 8 to 30 hrs after death. In arteries the agonist potency order was oxymetazoline > clonidine > epinephrine > naphazoline > norepinephrine > phenylephrine > methoxamine > PPA with a pD, value for PPA of 4.26 2 0.36. There was no significant difference seen in the potency of PPA between arteries and veins; however, the maximal response of PPA was 67% of that for NE. This result could be misleading, however, since in additional studies utilizing specific alpha-adrenoceptor antagonists, it was found that these tissues had a mixed population of

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postjunctional alpha,- and alpha,-adrenoceptors. Therefore, it was possible that the difference in response between NE and PPA could be related to differential activation of postjunctional receptor subtypes.

Cardiovascular Effects

Several studies have demonstrated that PPA administered intravenously could increase BP and reflexly decrease heart rate [Chen et a]., 1929; Loman et al., 1939; Persson, 19731. In isolated heart preparations, however, PPA (0.01-10 mg) increased heart rate [Liebman, 19611, the opposite of that observed in whole animal preparations in which vasoconstriction induced by PPA tended to slow heart rate via the baroreceptor reflex mechanism. Liebman suggested that the increased heart rate induced by PPA in the isolated heart could be the result of either direct beta adrenergic stimulation of the heart or perhaps indirect stimulation via the release of NE. The extent to which PPA acts at beta-adrenoceptors, however, is not well established. Moya-Huff and Maher [ 19871 demonstrated that PPA could lower BP in pithed rats pretreated with the vasoconstrictor angiotensin 11, indicating the existence of some beta- adrenoceptor activity.

The cardiovascular effects of PPA and related amines have more recently received a comprehensive examination in chloralose-urethane anesthetized rats and pithed rats [Moya- Huff et al., 1987; Moya-Huff and Maher, 19871. In these studies, PPA and its individual enantiomers IR,2S(-)-erythro and 1S,2R( +)-erythro NOR, or 1- and d- NOR, respectively, were effective pressor agents in cumulative dose-response tests, with the order of potency 1-NOR > dl-NOR >> d-NOR. The diastereomers of PPA, lS,2S(+)-threo, and lR, 2R(-)-threo, (d- and 1 -norpseudoephedrine; NORP), however did not show significant pressor responses in cumulative dose-response tests.

When animals were pretreated with reserpine to deplete neuronal stores of NE, the pressor responses of dl-NOR and d-NOR were unaffected, thus suggesting that these species acted via direct stimulation of postjunctional alpha-adrenoceptors rather than indirectly. There was, however, a small but significant displacement to the right by the cumulative dose- response curve in reserpine pretreated rats administered I-NOR, indicating some indirect activity which could be attributed to this compound. The primarily direct actions of PPA and its enantiomers were additionally confirmed by a lack of tachyphylaxis to repeated injections of each compound. Tachyphylaxis was seen, however, with d-NORP, a diastereomer of the norephedrines, suggesting that this species had significant indirect adrenergic activity [Moya- Huff et al., 19871.

By administering PPA and its enantiomers in the presence of specific adrenergic antagonists, activities at specific adrenoceptor subtypes could be determined. Alpha-adrenergic mediated vascular tone was most affected when alpha,-adrenoceptors were blocked with prazosin, while the effect of alpha, blockade by yohimbine was less pronounced. It was thus concluded that the primary vasoconstrictor activity of PPA and its enantiomers was mediated via postjunctional alpha,-adrenoceptors.

Beta,-adrenoceptor activity was determined by blocking alpha-adrenoceptors with phe- noxybenzamine and yohimbine, and beta, responses with ICI 118,551. It was found that heart rate in the pithed rat was increased with a rank order of potency of I-NOR > dl-NOR > d-NOR, with the response of dl; and d-NOR unaffected by pretreatment with reserpine, thus indicating mediation of the responses by the direct activation of beta,-adrenoceptors. There was, however, a significant shift to the right with 1-NOR, suggesting a mixed directiindirect response at beta-adrenoceptors with this species.

Beta, activity was determined by blocking alpha-adrenoceptor activity and then infusing angiotensin 11 to raise vascular tone. The results indicated relatively weak activity by PPA and its enantiomers at this adrenoceptor subtype, with the same rank order of potency seen for the other adrenoceptor subtypes.


Summary

In summary, PPA is a drug which is common in OTC decongestants and diet aids. When administered intravenously, and orally in high doses, PPA can increase BP in animals as well as humans; however, the lower therapeutic doses taken orally fail to stimulate the sympathetic nervous system enough to alter BP. Phenylpropanolamine affects smooth muscle and heart tissues directly by acting at adrenergic receptors and also indirectly by evoking the release of NE and/or blocking its reuptake. The major effect of PPA on smooth muscle tissues is the induction of contraction via alpha-adrenergic receptors.

SAFETY Animal Studies

The LD,, of PPA in laboratory animals varies from 50 mg/kg I.V. in rabbits [Warren and Werner, 19461 to 1538 mg/kg P.O. in rats [Groves, 19701. Several investigations, however, revealed that the combination of PPA and other drugs may increase overall toxicity. In one study using rats, Davis and Pinkerton 119721 found that atropine 0.4 mg/Kg. increased the toxicity of PPA administered intraperitoneally by a factor of 6. Other studies by Schlemmer et al. [ 19841 and Katz et al. [I9851 demonstrated potentiation of the lethality of PPA by caffeine in rats. In contrast, however, when PPA was tested in therapeutic doses with human volunteers in combination with caffeine [Silverman et al., 19801, no change in BP could be detected.

Concern Over Toxicity

Over the last several years, the safety of PPA has become a topic of some controversy. Previous to the 1970’s, there had been few reports of toxicity associated with the drug, and its use had been considered relatively safe. When PPA was introduced into the American market there had been no extensive testing procedure required for safety; therefore, the safety of PPA was based not on controlled clinical trials, but rather on the general experience of consumers over the decades.

In 1970, however, the use of amphetamine as an anorexic agent was banned by the FDA, and, consequently, the supply of amphetamine, which had been marketed illegally for its abuse potential, disappeared. As a result, the market for OTC diet control products containing PPA increased significantly. To fill the void for illicit stimulants, several fly-by-night companies began marketing amphetamine “look alikes” sold in capsules and tablets which resembled amphetamine; however, the major ingredients were most frequently a combination of caffeine, PPA, and/or ephedrine.

As the use of PPA in combination with other ingredients increased, so did the number of anecdotal reports of adverse reactions associated with its use. Concern grew with regard to the safety of PPA in combination with caffeine or other sympathomimetic agents. And finally, in 1983, the manufacture of drug formulations that contained PPA and caffeine was banned by the FDA. For a more comprehensive review, see Lasagna [ 19881.

Reported Adverse Reactions

It should be noted that it is frequently impossible to determine in cases of adverse reactions to any drug whether the reaction was caused by drug exposure in an otherwise healthy individual, whether it was precipitated by the drug under circumstances of underlying pathology, or whether the event was unfortunately coincidental to drug administration. Fol- lowing are representative examples of adverse reactions which have been associated with PPA.

Intracerebral hemorrhage. Probably the most severe adverse reaction associated with PPA is cerebral hemorrhage. In 1985 a report was published describing a 20-year-old woman who had taken Dexatrima in the recommended dosage (which at the time contained 50 mg PPA and 100 mg caffeine) over a period of 6 months. Her initial symptom was sudden onset

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of headache, and later right frontal intracerebral hemorrhage was confirmed by noncontrast CAT scan [Fallis and Fisher, 19851.

Hypertension. A number of cases report idiosyncratic episodes of hypertension following ingestion of PPA as an ingredient of combination cough and cold preparations. These hypertensive episodes occurred within a time period as short as 10 min following ingestion and persisted for 1 to 2 h [Gibson and Warrell, 1972; Peterson and Vasquez, 19731.

Psychotic reactions. Kane and Green [1966] report a case of a 35-year-old patient treated with PPA in doses of 50 mglday who developed a psychotic episode. The patient was noted to gradually develop a paranoid schizophrenia in association with disordered thinking, and delusions of grandiosity and persecution that were responsive to treatment with chlorpro- mazine. It was not clearly established, however, whether PPA was the cause of the psychotic episode.

Seizures. Chronic abuse of PPA (Triaminicol@) resulted in psychotic behavior and grand ma1 seizures in a 29-year-old female [Cornelius et al., 19841. The patient responded to treatment with diazepam, but seizure activity recurred when she was challenged with a single 50 mg dose of orally administered PPA.

Renal failure. Acute renal failure with tubular necrosis has been reported in a 25- year-old male following overdose with PPA [Duffy et al., 19811. The authors suggested the findings in this patient were similar to norepinephrine-induced acute renal failure in animals. A causal relationship, however, between PPA ingestion and renal failure could not be established.

Controlled Clinical Studies

In response to the number of reported cases of adverse reactions to drug formulations which contained PPA during the 1970’s and go’s, a number of investigations of the safety of PPA were carried out that included experiments in animals, as well as clinical trials utilizing normal healthy individuals and subjects who were obese and/or hypertensive. Other studies were performed to determine the safety of PPA alone and in combination with other drugs. The results from these investigations have to some degree, however, been conflicting. A relatively early study was performed in Australia using the diet-aid Trimoletsm sold in that country [Horowitz et al., 19791. In a double-blind cross-over trial, 16 healthy normotensive young adults were administered one Trimolets capsule, reported to be 85 mg PPA in a sustained- release formulation, or placebo on a given day. The results demonstrated a significant rise in both systolic and diastolic BP which persisted over 6 hrs, with a less marked, but still statistically significant increase in BP when measured from a standing position. In a follow-up study [Horowitz et al., 19801, 12 of 37 volunteer medical students developed a supine diastolic BP of 100 mm Hg or greater following administration of a single Trimolets capsule. These results were clouded, however, by uncertainty related to the identity of the active drug in the capsules. Available information indicated that the drug was not the racemic mixture, d,l-NOR, which was available as PPA in the United States, but possibly 85 mg of the free base of I-NOR. This enantiomer of PPA contain most of the activity related to BP [Moya-Huff and Maher, 19871; thus, the Australian preparation could posses a much higher potential to induce hypertension than products available in the United States. Additionally, this preparation did not prove to be sustained-release, but instead was immediate release. Unfortunately, the Trimolets studies continue to be referenced in the current literature as evidence of the potentially unsafe pressor activity of PPA.

Several recent clinical studies have been performed with PPA in the United States that report no adverse cardiovascular or CNS effects, while others report increased BP when administered to subjects in higher than recommended dosages. Two studies involved administering (in a double-blind cross-over design) a sustained-release preparation of PPA in doses of 75 mg, 150 mg, or 75 mg in combination with 400 mg caffeine, or placebo [Lake et al., 1988a, 19891. In the recommended dose of 75 mg sustained release PPA, there was no


significant increase in systolic or diastolic BP above placebo; yet in twice the recommended dose of 150 mg, there was a mean peak BP of 173 2 91103 2 4 mm Hg. Additionally, there was a significant increase in peak BP when 75 mg PPA was mixed with 400 mg caffeine. The significant increase in BP was only seen, however, when the subjects were supine. With the subjects standing, there was no significant difference in BP when compared with values before the drug was administered, or between PPA and placebo.

That the increases in BP associated with PPA seem to be related to orthostatic position is further supported by a study of 10 subjects who received 37.5 mg PPA. There was an increase in supine BP, yet no effect in sitting or standing BP [Pentel et al., 19851. This conclusion, however, may be somewhat misleading since the results of one subject may have significantly shifted the mean of a relatively small sample.

An investigation of the effects of PPA on sympathetic activity was also performed with acute (1 and 2 hr) and chronic (2 week) administration of a daily dose of 75 mg of sustained release PPA in 14 normal volunteers [Lake et al., 1988bl. Measurements of heart rate, BP, and plasma catecholamines were made with the subjects in supine and standing positions, and upon gripping a hand dynamometer for 5 mins. Two hours after the administration of PPA, but before exercise, there was a small but not clinically significant increase in systoiic BP (120 & 11 mm Hg compared to 117 2 11 mm Hg for placebo). Furthermore, there was a non-significant increase in BP during strenuous isometric exercise above control values, and similarly, a non-significant increase in circulating NE or epinephrine when compared to concentrations in blood taken before the administration of PPA. Thus, Lake was unable to demonstrate any clinically relevant changes in BP, pulse, or the concentration of plasma catecholamines, at rest or with exercise, associated with acute or chronic ingestion of PPA.

A recent study was published on the relationship between the serum concentration of PPA and cardiovascular effects in about 10 subjects [O’Connell et al., 19891. When in a double-blind cross-over protocol, subjects were administered PPA intravenously over a four hr period, they found a significant relationship between the serum concentration of PPA and BP of individual subjects, but no significant relationships within the group. These results were attributed to the large inter-subject variability of BP response to PPA and it was hypothesized that the variability could be related to differences in stereoisomer concentration and distribution among individuals. However, considering that the enantiomers of PPA have identical lipid solubilities and relatively little affinity for sympathetic amine uptake mechanisms, O’Connell’s hypothesis appears somewhat dubious. O’Connell concluded that the effect of phenylpropanolamine on BP could not be predicted on the basis of serum concentration alone.

Other studies demonstrate no change in BP following administration of PPA, either alone or in combination with caffeine. Three studies by Silverman et al. [1980], involving a total of 37 subjects, showed no changes in BP following administration of either 25 mg of PPA hydrochloride or 25 mg of PPA combined with 100 mg of caffeine.

In a double-blind cross-over investigation of the effect of 75 mg sustained-release PPA on ambulatory BP [Goodman et al., 19861, there was no pressor effect observed with PPA. Eighteen subjects were administered one 75 mg sustained-release capsule containing PPA or placebo each day for 7 days and BP was monitored on days 1 and 6 utilizing an ambulatory BP measuring device. The results demonstrated that the drug therapy had no effect on either systolic or diastolic pressure or on heart rate.

In a study of 150 subjects [Liebson et al., 19871, investigations were made into both cardiovascular and mood effects of PPA in dosages of 75 mg sustained-release and 25 mg immediate-release preparations. Over a single 12 hr period subjects were administered capsules 3 times in 4 hour intervals: one group received a 75 mg sustained-release tablet at their first dosing, and placebo at subsequent dosings, the second group received 25 mg immediate release PPA at each dosing period, while a third group received placebo at each dosing period. Blood pressures were taken in sitting, standing, and supine positions. The

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results demonstrated no significant effects of PPA on BP or pulse, whether the subjects were standing or supine; and furthermore, there were no significant differences between drug treatments on mood effects. In a subsequent study using a statistically more powerful cross-over design, there were small but statistically significant increases in all BP measurements except standing systolic BP with changes in BP against placebo that ranged from 0.82 mni Hg (standing systolic) to 3.37 mm Hg (supine diastolic). Other clinical trials by Saltzman et al. [1983] and Noble [1988] showed no change in BP with PPA administered in therapeutic doses.

Perhaps the most comprehensive study of BP effects of PPA was a multicenter double-blind placebo controlled examination of a group of 881 normotensive patients (including obese as well as normal weight subjects) administered 75 mg controlled-release PPA once a day or 25 mg immediate-release PPA 3 times a day. The results of the study found no clinically significant PPA related effects on BP with either dosage form [Blackburn et al., 19881.

There has been some concern whether PPA could be more hazardous to hypertensive individuals. The investigation of 26 mildly hypertensive patients by Omori et al. [ 19881 found no clinically significant increases in BP following administration of 25 mg PPA 4 times per day. Additionally, Bradley and Raines [ 19881 found no clinically significant changes in pulse or BP in 84 obese hypertensive patients administered the recommended doses of either immediate- or sustained-release PPA. Thus it appears from these studies that PPA does not present any additional risk to patients with controlled hypertension.

Because of the close structural similarity between amphetamine and PPA, and the use of PPA in combination with other drugs in the “pseudospeed look-alike’’ market, there has been concern for the possible abuse potential of PPA. In a retrospective study of 37 cases reported in Europe and North America between 1960 and 1988, Lake et al. [1988c] reviewed patients diagnosed with acute mania, paranoid schizophrenia, and organic psychosis following PPA ingestion. However, the etiology of these episodes remains clouded. Of 27 cases reported in North America, reactions tended to occur with PPA in combination with other drugs and/or in overdose situations and tended to involve patients with a past or family psychiatric history. It was concluded by the authors that psychiatric reactions to PPA were rare relative to the number of doses consumed, yet caution should be exercised in susceptible patients.

A study by Chait et al. [I9881 was performed to determine whether PPA had any reinforcing or subjective effects. Seventeen normal, healthy adults, aged 21-35 (eight males, nine females) were administered PPA in 25 or 75 mg dosages, d-amphetamine 5 mg, or placebo. The study utilized a discrete-trial choice procedure in which subjects first sampled placebo, then a dose of one of the drugs and were then allowed to choose between self- administration of drug or placebo on subsequent occasions. The relative frequency with which active drug was chosen was used to determine whether the drug had reinforcing activity. The results demonstrated reinforcing behavior with amphetamine, but not with PPA in the 25 mg dose; yet, in the 75 mg dose, PPA was chosen less frequently than placebo and was described as a “punisher.” Thus, it was concluded that PPA did not have amphetamine-like dependence potential.

A review was made of all cases of PPA ingestion received by the Hennepin Regional Poison Center in Minneapolis, MN between January 1985 and July 1986 [Larson and Rogers, 19861. Of the 92 cases received, hypertension developed in 14%. However, hypertension rarely occurred in patients receiving less than 10 mg/kg PPA, equivalent to almost 10 sustained-release capsules in a 70 kg adult. Drowsiness and tachycardia were the most commonly reported symptoms, which could be related to other active ingredients in the medications. In view of the results of the study, it was suggested that the current criteria used by that facility for medical referral may be too aggressive and may result in patients being seen in health care facilities with only mild symptoms of little consequence.


CONCLUSION

In summary, there have been a number of case reports of adverse reactions to PPA, some of which were severe. Furthermore, the results of several clinical trials show that PPA administered in greater than recommended doses could increase BP, especially when supine. Several of these studies were criticized, however, because of possible flaws involving ques- tions of 1) the actual ingredients of the drug being tested, 2) the time frame of the study, and 3) the technique used to measure BP. However, there was general agreement concerning the results of clinical investigations in the United States. That is: PPA administered in recommended dosages produces neither clinically significant cardiovascular effects nor euphoric or reinforcing CNS effects.

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pharmacology and safety of phenylpropanolamine

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