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Short Report

Introduction

Ephedra represents a mixture of different Ephe-

draceae family members. Its effects are due mainly to

the presence of alkaloids ephedrine and pseudoephe-

drine. Ephedrine alkaloids are a group of sympatho-

mimetic alkaloids extracted from the Ephedra genus

plants. There are over 40 species in Asia, Europe and

America. American species (E. sinica, E. intermedia, and E. equisetina) have the highest alkaloid content17.

Ephedrine alkaloids have a long history as tradition-

al folk medicines, especially among the Chinese. The

main alkaloid known as ephedrine was isolated for the

first time in 18853 and its purified form is used in mod-

ern medicine as a bronchodilator, decongestant and

vasopressor agent16.

In the recent years, many companies started market-

ing products containing Ephedra extract for weight

reduction and increased physical stamina. Medicines

for colds and cough relief have also been approved

for use. Ephedrine and its derivatives have become

very popular15 and are widely available without pre-

scription and even as dietary supplements. Following

the extensive application of ephedrine and its deriva-

tives, the reported cases of adverse reactions associ-

REVIEW OF THE DRUG SAFETY PROFILE AND PRESCRIPTION REGULATIONS OF MEDICINAL PRODUCTS CONTAINING EPHEDRINE AND PSEUDOEPHEDRINEV. Stoynova, I. Getov Faculty of Pharmacy, Medical University, Sofia

Key words: ephedrine, pseudoephedrine, adverse reactions, drug safety profileContact details: V. Stoynova, Faculty of Pharmacy, Medical University - Sofia, 2 Dunav St., Sofia,tel: +359 889 643 699, e-mail: veselinastoyneva@yahoo.com

Abstract: For over 2000 years, Ephedra has been used for treatment of bronchial asthma, colds and flu, chills, fever, hy-

perhydrosis, headaches, bone pains, nasal congestion, coughing, and sneezing. The pharmacological effects of Ephedra are

due mainly to its alkaloids ephedrine and pseudoephedrine. In the past decades, an alarming number of reports regarding

the adverse effects of Ephedra have been received. In Bulgaria, there are over 30 medicinal products registered to contain

ephedrine and pseudoephedrine. Most of them are for the treatment of colds, flu and coughing and are over-the-counter

products. On the other hand, the review of the safety database shows that there are over 2000 cases of adverse reactions, in-

cluding 8 death cases. The ephedrine and pseudoephedrine containing products are widely available and their uncontrolled

use may lead to serious adverse effects

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42

Medicinal Products Containing Ephedrine and Pseudoephedrine

ated with its use became more frequent. Based on the

emerging evidence for the risk of Ephedra application,

many national regulatory authorities are in the proc-

ess of reconsidering the approval of products contain-

ing Ephedra as dietary supplements and/or nonpre-

scription drugs.

Value, structure and pharmacology of ephedrine alkaloids

For over 2000 years, Ephedra has been used for

treatment of bronchial asthma, colds and flu, chills, fe-

ver, hyperhydrosis, headaches, bone pains, nasal con-

gestion, coughing, and sneezing13. In Eastern medi-

cine, stems of Ephedra (Ma-huang) are an essential

drug for the treatment of asthma and bronchitis.

World Health Organization defines the medicinal use

of Ephedra products for the treatment of nasal decon-

gestion caused by hay fever, common cold, rhinitis,

and sinusitis and as a bronchodilator in the treatment

of astma21.

Ephedra is a generic term for several sympathomi-

metic substances, including ephedrine, pseudoephe-

drine, norephedrine, methylephedrine, methylpseu-

doephedrine and phenylpropanolamine (synthetic,

racemic mixture of stereoisomers of norephedrine). All

these substances are isomers and have similar molecu-

lar structure that is substantially similar to ampheta-

mines and catecholamines. Ephedra is spread world-

wide and depending on the type, the used parts of

the plant (aerial part, stems, leaves or a combination

of all), method of collection, and techniques of ex-

tracting the alkaloids, the content of the ephedrine

alkaloids may vary considerably. There is a big con-

centration of ephedrine in the Asian species Ephedra cinica. The alkaloid content of Ephedra cinica is 1-3%,

as 40-90% of the alkaloids are ephedrine, and the rest

are pseudoephedrine, norephedrine and norpseu-

doephedrine. The pharmacological effects of Ephedra

are due mainly to the ephedrine content in it.

Ephedrine is a sympathomimetic which acts directly

and indirectly on the sympathetic nerves by increas-

ing the activity of noradrenaline in post-synaptic

α- and β-receptors. The presence of a direct effect on

α-receptors is unlikely and still controversial5,8.12. The ef-

fect on the central nervous system is limited because

ephedrine crosses the blood-brain barrier poorly and

thus it is not very effective. The bronchodilating ef-

fect of ephedrine is a result of relaxation of bronchial

smooth muscles by direct stimulation of β-adrenergic

receptors18. The bronchodilating therapeutic doses

ranged from 12.5 to 50 mg, administered three times

daily with a maximum daily dose between 120 mg and

150 mg.

In addition, the ephedrine alkaloids increase the

release of endogenous catecholamines. This addi-

tional effect of depletion of the endogenous stores of

catecholamines explains the tachyphylaxis noted on

repeated dosing. Increasing the dosage can induce

toxic effects, including peripheral vasoconstriction and

cardiac stimulation, leading to higher blood pressure

and increased heart rate, side effects of central nerv-

ous system, nervousness, restlessness, tremor, weak-

ness, irritability and insomnia. These effects aggravate

with the increasing of dosage, as extreme doses may

lead to nausea, vomiting, fever, palpitations, tachycar-

dia, hypertension, paranoid psychosis, convulsions and

coma16.

Ephedrine also decongests the nose, has a therapeu-

tic effect on nocturnal enuresis, diabetic neuropathic

edema, dysmenorrhea, narcolepsy and myasthenia

gravis. Ephedrine in combination with caffeine is

shown to support thermogenesis, weight loss and ac-

cumulation of muscle mass1.

Its metabolism is up to norephedrine (phenylpropa-

nolamine), which is responsible for the stimulating ef-

fects of ephedrine containing medicines on the central

nervous system.

Pseudoephedrine is the stereoisomer of ephedrine

in which two of the three chiral centers are different.

It has ephedrine-like effect but less inhibitory activity

and less adverse effects of the central nervous system.

Pseudoephedrine has less pronounced cardiac effects

but higher diuretic activity. Pseudoephedrine and its

salts are used orally for the symptomatic relief of na-

sal congestion. It is commonly combined with other

active substances in medicinal products for the treat-

ment of coughs and colds. Pseudoephedrine finds its

application for control of urinary retention and other

medical conditions14.

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43

Regulation of the ephedrine products

In Bulgaria, the current legislation prohibits the use

of certain parts of the plant Ephedra distachya (Normal

Ephedra) in dietary supplements and the drugs with

ephedrine and pseudoephedrine active substances

have various prescription and nonprescription status22.

The nonprescription bronchodilators and cold medi-

cines containing ephedrine are required to indicate

the concentration of each dose, the recommended

dose, potential adverse reactions and contraindica-

tions.

Until recently, the products sold as dietary supple-

ments have not been subject to regulation. Ephedra

products advertised for weight reduction, energy stim-

ulants and alternative psychotropic substances have

been sold for years without the compulsory labeling

for pharmacologically active substance, the potential

adverse effects, contraindications or recommended

doses. In fact, most products sold on the market con-

vince consumers that the product is safe because it

contains only a plant source of ephedrine. Others are

directly labeled wrongly and really contain ephedrine

and its derivatives in proportions that may repeatedly

exceed therapeutic doses. All these facts mislead the

consumers and require regulatory measures.

Drug safety profile and adverse reactions, associated with the use of ephedrine containing products

Over the years, the lack of warning labels for possi-

ble toxicity combined with the wrong concept of safe-

ty have increased the misuse and abuse of ephedrine

containing products. Messages for misuse and abuse

of all ephedrine products appear in the literature and

not just for those sold as dietary supplements. Mis-

used are also the prescription drugs such as decon-

gestants and bronchodilators. The expanding stock

and sale of herbal products, containing ephedrine and

its derivatives contribute to the increased prevalence

of adverse reactions.

Some reports about adverse effects of ephedrine

and pseudoephedrine in adults appeared in the medi-

cal literature even before 1982. As a sympathomimetic

with α- and β-agonist activity, the most common ad-

verse reactions are tachycardia, anxiety, restlessness

and insomnia. Tremor, dry mouth, impaired circula-

tion in the limbs, hypertension and cardiac arrhyth-

mias may also occur. Paranoid psychosis, delusions and

hallucinations are reported in overdosing. The adverse

reactions associated with the use of pseudoephedrine

are similar to those of ephedrine. Moreover, there are

cases of skin rash and urine retention14.

The first report of a fatal cerebral hemorrhage due to

misuse of ephedrine appeared as a formal case report

in neurology databases in 1983. It presented the case

of a 20-year-old man with cerebral hemorrhage and

internal bleeding of the small vessels2.

A year later (1985), another case report described

non-fatal intracerebral hemorrhage following the in-

take of a combination drug containing ephedrine,

phenylpropanolamine and caffeine11.

Despite these reports, most of the ephedrine prod-

ucts have been assessed as safe and effective bron-

chodilators in a monograph for OTC medicines in Oc-

tober 1986.

Between 1986 and 1993, several additional cases were

published in literature, reporting of ephedrine caused

hemorrhage and 3 cases of stroke related to ephe-

drine use. One of these reports presented a 37-year-

old man with stroke, who had taken ten tablets ephe-

drine daily for weight reduction - a dose equivalent to

approximately 150mg/daily dose9,19.

The U.S. Food and Drug Administration Agency has

attempted to legally restrict the indiscriminate use of

ephedrine containing products among the U.S. popu-

lation. Producers were obliged to take responsibility

and to provide the consumers with easily accessible

information about their products. Responsibility for

adverse reactions, however, is transferred from produc-

ers to regulatory institutions. Although the adverse

effects of ephedrine products are reported in litera-

ture, the relatively few fatalities cannot stop the grow-

ing sales and promotion of emerging new drugs and

supplements. Flooding advertisements are targeted to

adolescents and young people.

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44

The story continues as in October 1995, the Food

Advisory Committee at the FDA presented in the me-

dia more than 330 adverse reactions and 12 deaths

due to the use of ephedrine5.

In 1997, in response to the growing number of seri-

ous adverse reaction in the U.S., there was a sugges-

tion for banning products containing more than 8

mg ephedrine alkaloids and for strict labeling of low-

dosed dietary supplements. FDA also proposed the

captions of Ephedra containing products to include

obligatory warnings about possible risks such as heart

attack, stroke or death6.

At the same time, the biggest manufacturer of

ephedrine nutritional supplements Metabolife stated

officially several times that it was aware of the Ephe-

dra adverse effects and nevertheless it was “absolutely

safe”4. An investigation of a U.S. court revealed that

in the period 1997-2002, the company had received

over 13,000 reports of suspected adverse reactions,

involving approximately 2,000 serious adverse reac-

tions. Summary of Ephedra-related adverse reactions

published in 2000, presented several cases of sudden

cardiac death or severe disability that occurred after

the use of Ephedra in recommended dosage10.

In 2004, after numerous data on serious adverse re-

actions, FDA formally prohibited the sale of Ephedra as

a dietary supplement7.

A group of Boston cardiologists and pharmacolo-

gists examined in detail the cases of possible adverse

reactions associated with the use of Ephedra. Of ap-

proximately 900 reported cases of possible toxicity,

they defined 37 cases (23 women) associated with the

use of Ephedra, of which 16 with stroke, 10 with heart

attack and 11 with sudden death. The authors found

that in all cases the administered dose is consistent

with that recommended by the manufacturer. Most

157

77

187

351

25 33

123

31 29

449

353

62

127 150104

050

100150200250300350400450500

Figure 1. Distribution of cases with adverse reactions to Ephedra containing products, according to the affected organs and systems of the human organism

Medicinal Products Containing Ephedrine and Pseudoephedrine

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J Clin Med. 2010; 3(3):41-50

45

cases happened in relatively young adults - the aver-

age age of patients was 43 years.

Following a review of the database, at the begin-

ning of 2010 there were 421 adverse reactions regis-

tered from clinical trials and 1,793 from post-marketing

use, including 8 deaths – all associated with the use

of Ephedra products. The distribution of cases accord-

ing to the affected organs and systems is presented

in figure 1.

The increasing prevalence of adverse reactions is as-

sociated primarily with the consumption of ephedrine

and can be partly attributed to a misleading market-

ing. Factors for this trend are the poor labeling, the

widespread misconception about safety and the pres-

entation of ephedrine products as “natural alterna-

tives”.

The overviewed data and history on the misuse and

the adverse reactions lead to the conclusion that while

there are ephedrine products on the market, they are

going to be subject of misuse and abuse by the con-

sumers despite the selling and labeling regulations.

Review of Ephedra medicinal products approved for use of in Bulgaria

The review of the approved drugs on the Bulgar-

ian market is current as of the beginning of 2010 and

shows no registered products or active substances

containing norephedrine and norpseudoephedrine.

The medicinal products with active substances ephe-

drine and pseudoephedrine are 3523 and are present-

ed in Table 1.

The analysis shows that there are currently 17 ap-

proved medicinal products containing ephedrine and

ephedrine hydrochloride. Of these, 7 are nonprescrip-

tion (OTC) while the others are prescription drugs.

The approved medicinal products containing pseu-

doephedrine (16) and pseudoephedrine hydrochlo-

ride (2) are 18, 14 of which are nonprescription drugs.

Most of the medicinal products (33 out of 35 approved

at the time of the study) have therapeutic indications

for treating cough, nasal decongestion and relieving

the symptoms of colds and flu.

Conclusions

The overview analysis of the official BDA register for

medicinal products containing ephedrine alkaloids

shows that the majority of the drugs contain ephedrine

and pseudoephedrine as active substance. Most of the

medicinal products are nonprescription drugs making

them widely available and widely used for relieving

common conditions like colds and flu. On the other

hand, the review of the regulatory measures and the

safety profile indicates that the ephedrine derivatives

are not so safe. Some of them have many adverse

reactions and may cause life-threatening conditions,

especially in high risk patients.

The presented material of misuse, abuse and adverse

reactions suggests that the presence of ephedrine

containing medicinal products on the market as

nonprescription drugs is associated with higher risk

for the safety of the consumers, despite the way of

signing and labeling.

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Medicinal Products Containing Ephedrine and Pseudoephedrine

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