Pseudoephedrine (commonly as PSE) is a
sympathomimetic amine commonly used as a
decongestant. The salts
pseudoephedrine
hydrochloride and
pseudoephedrine sulfate
are found in many
over-the-counter preparations either
as single-ingredient preparations, or more commonly in combination
with
antihistamines,
paracetamol (acetaminophen) and/or
ibuprofen.
Sudafed is a
trademark for a common brand which
contains pseudoephedrine hydrochloride, though Sudafed PE does not.
Cirrus contains pseudoephedrine in conjunction with
cetirizine (an antihistamine).
Unlike antihistamines, which relieve multiple allergic symptoms by
acting as
antagonists at
histamine receptors, pseudoephedrine
primarily relieves
nasal congestion
commonly associated with
colds or
allergies.
The advantage of oral pseudoephedrine over topical nasal
preparations, such as
oxymetazoline,
is that it does not cause rebound congestion (
rhinitis medicamentosa); however, it
is more likely to cause adverse effects including
hypertension,
sweating,
and
anxiety.
Pseudoephedrine is being phased out as an over-the-counter drug in
some countries and replaced by less effective alternative
decongestants such as
phenylephrine,
due to pseudoephedrine's use as an ingredient in the manufacture of
methamphetamine. Internationally,
pseudoephedrine is listed as a Table I precursor under the
United Nations Convention Against Illicit Traffic in Narcotic Drugs
and Psychotropic Substances.
Chemistry
Pseudoephedrine is a
psychedelic phenethylamine, and a
diastereomer of
ephedrine. Pseudoephedrine is a
chiral molecule, meaning it occurs in
both "left-handed" and "right-handed" configurations which are not
superimposable.
Pseudoephedrine is the
International Nonproprietary
Name (INN) of the (1
S,2
S)- diastereomer of
ephedrine (which has 1
R,2
S- configuration). Other
names are (+)-pseudoephedrine and
D-pseudoephedrine.
L-Pseudoephedrine, also known as
(-)-(1
R,2
R)-pseudoephedrine or
(-)-pseudoephedrine, is the
optical
isomer of
D-pseudoephedrine. It has fewer
side-effects, fewer
central
nervous system (CNS) stimulatory effects, does not reduce to
D-
methamphetamine
(which is the enantiomer used as a recreational drug), and yet it
retains its efficacy as a decongestant. However, the patent holder
for
L-pseudoephedrine (Pfizer/Warner-Lambert) has
not yet sought or received government approval for its sale to the
public.
Mechanism of action
Pseudoephedrine is a
sympathomimetic
amine—that is, its principal mechanism of
action relies on its indirect action on the
adrenergic receptor system. While it may
have weak
agonist activity at α- and
β-adrenergic receptors, the principal mechanism is to cause the
release of endogenous
norepinephrine
(noradrenaline) from storage
vesicles in
presynaptic neurons. The
displaced noradrenaline is released into the neuronal
synapse where it is free to activate the
aforementioned
postsynaptic adrenergic
receptors.
These adrenergic receptors are located on the muscles lining the
walls of blood vessels. When activated by pseudoephedrine, the
muscles contract, causing the blood vessels to constrict
(vasoconstriction). These constricted blood vessels now allow less
fluid to leave the blood vessels and enter the nose, throat and
sinus linings, which results in decreased inflammation of nasal
membranes as well as decreased mucus production. Thus, by
constriction of blood vessels, mainly those located in the nasal
passages, pseudoephedrine causes a decrease in the symptoms of
nasal congestion.
The
vasoconstriction that
pseudoephedrine produces is believed to be principally an
α-adrenergic receptor response. While all sympathomimetic amines,
to some extent, have decongestant action, pseudoephedrine shows
greater selectivity for the nasal mucosa and a lower affinity for
central nervous system (CNS)
adrenergic-receptors than other sympathomimetic amines.
Vasoconstriction in the nasal mucosa shrinks swollen nasal mucous
membranes, reduces tissue
hyperemia,
edema, and nasal congestion. Other beneficial
effects may include increasing the drainage of
sinus secretions, and opening of obstructed
Eustachian tubes. The same
vasoconstriction action can also result in hypertension, which is a
noted side effect of pseudoephedrine.
Clinical uses
Indications
Pseudoephedrine is indicated for the treatment of:
Pseudoephedrine is also indicated for
vasomotor rhinitis, and as an adjunct to
other agents in the optimum treatment of
allergic rhinitis,
croup,
sinusitis,
otitis media, and
tracheobronchitis.
Pseudoephedrine is also used as first-line therapy of
priapism.
Erection is
largely a
parasympathetic
response, so the sympathetic action of pseudoephedrine may serve to
relieve this condition.
Treatment for
urinary
incontinence is an
off-label use
(aka "unlabeled use") for these medications.
Adverse effects
Common adverse drug reactions (ADRs) associated with
pseudoephedrine therapy include:
CNS stimulation, sleeplessness,
nervousness, excitability, dizziness and anxiety. Infrequent ADRs
include:
tachycardia and/or
palpitations. Rarely, pseudoephedrine therapy
may be associated with
hallucinations,
arrhythmias,
hypertension, seizures and
ischemic colitis; as well as severe skin
reactions known as recurrent pseudo-scarlatina, systemic contact
dermatitis, and nonpigmenting
fixed
drug eruption. Pseudoephedrine, particularly in high doses, may
also cause episodes of paranoid
psychosis.It has also been reported that
pseudoephedrine, amongst other
sympathomimetic agents, may be associated
with the occurrence of
stroke.
Precautions and contraindications
It is recommended that pseudoephedrine not be used in patients
with:
diabetes mellitus,
cardiovascular disease,
hypertension,
prostatic hypertrophy,
hyperthyroidism,
closed angle glaucoma and/or
pregnancy.
Patients who are prone to
anxiety or
panic attacks should use
pseudoephedrine with caution, as anxiety and restlessness are
common side effects, mostly due to the drugs stimulant
properties.
Since nasal congestion is considered to be a relatively minor
ailment, alternatives are preferred in patients with these
conditions. Appropriate alternatives may include topical
decongestants or
saline
sprays/instillations, depending on the patient's condition.
Contraindications for the use of pseudoephedrine include:
concomitant or recent (previous fourteen days)
monoamine oxidase inhibitor
(MAOI), or
selective serotonin
reuptake inhibitor (SSRI) therapy , severe or uncontrolled
hypertension, and/or severe coronary artery disease.
People with
bipolar disorder should
use care when taking pseudoephedrine, as it can cause
insomnia and thus trigger a
manic episode.
Chiral auxiliary
Both (R,R)- and (S,S)-pseudoephedrine are used as a
chiral auxiliary.Pseudoephedrine is reacted
with a
carboxylic acid,
acid anhydride, or
acyl chloride to give a pseudoephedrine
amide.
The α-proton of the carbonyl compound is easily deprotonated by a
non-nucleophilic base to give
the enolate, which can further react. The configuration of the
addition compound, such as with an
alkyl
halide, is directed by the methyl group. Thus, any addition
product will be anti to the methyl and syn with the
hydroxyl group.
The pseudoephedrine chiral auxiliary is subsequently removed by
cleaving the amide bond with an appropriate
nucleophile.
Manufacture
Although pseudoephedrine occurs naturally as an
alkaloid in certain plant species (for example, as
a constituent of extracts from the
ephedra
species, also known as
Ma Huang, in which
it occurs together with other isomers of
ephedrine), the majority of pseudoephedrine
produced for commercial use is derived from
yeast fermentation of
dextrose
in the presence of
benzaldehyde. In
this process, specialized strains of yeast (typically a variety of
Candida utilis or
Saccharomyces
cerevisiae) are added to large vats containing water,
dextrose and the enzyme
pyruvate
decarboxylase (such as found in
beets and
other plants). After the yeast has begun fermenting the dextrose,
the benzaldehyde is added to the vats, and in this environment the
yeast convert the precursor ingredients to
l-phenylacetylcarbinol (L-PAC). L-PAC
is then chemically converted to pseudoephedrine via reductive
amination.
The bulk
of pseudoephedrine is produced by commercial pharmaceutical
manufacturers in India
and China
, where
economic and industrial conditions favor the mass production of
pseudoephedrine for export.
Common brand names
The following are some brand names of medications containing
pseudoephedrine. Some of them no longer contain it and have
phenylephrine instead.
Alternative and illicit use
There have also been reports of off-label uses of pseudoephedrine
for its stimulant properties. Long-distance truck drivers and
sports athletes, for example, have reportedly used pseudoephedrine
as a stimulant to increase their state of alertness/awareness. It
is doubtful that pseudoephedrine would be of significant benefit,
except in sensitive individuals, because of its minimal effect in
the
central nervous system
(see Mode of Action above).
The similarity in chemical structure to the
amphetamines has made pseudoephedrine a
sought-after chemical precursor in the
illicit manufacture of
methamphetamine and
methcathinone. As a result of the increasing
regulatory restrictions on the sale and distribution of
pseudoephedrine, many pharmaceutical firms have reformulated, or
are in the process of reformulating medications to use alternative
decongestants, such as
phenylephrine.
Many retailers such as
Target,
Walgreens,
CVS, and
Winn-Dixie have created corporate
policies restricting the sale of pseudoephedrine-containing
products. Their policies restrict sales by limiting purchase
quantities and requiring a minimum age with proper identification.
These requirements are similar to and sometimes more stringent than
existing law. Internationally, pseudoephedrine is listed as a Table
I precursor under the
United Nations Convention Against Illicit Traffic in Narcotic Drugs
and Psychotropic Substances.
Sports
Pseudoephedrine was on the banned substances IOC list until 2004,
when the WADA list replaced the IOC list. On the WADA list,
pseudoephedrine is monitored, but not banned.
Andreea Răducan was stripped of her
gold medal at the
2000 Sydney
Olympics after testing positive. She took two pills given to
her by the team coach for a cold. Although she was stripped of the
overall gold medal, she kept her other medals, and, unlike in most
other doping cases, was not banned from competing again; only the
team doctor was banned for a number of years.
Ion Ţiriac, the president of the Romanian
Olympic Committee, resigned over the scandal.
Australia
Illicit diversion of pseudoephedrine in Australia has caused
significant changes to the way pseudoephedrine products are
regulated. As of
2006, all products containing
pseudoephedrine have been rescheduled as "Pharmacist Only
Medicines" (Schedule 3). As a result, a pharmacist must be directly
involved in every transaction involving the sale of pseudoephedrine
to members of the public, and such medicines will be kept behind
the counter, away from public access. Such measures are designed to
ensure that the medicines are needed for a legitimate purpose.
Pharmacists are also required to log the purchase with an online
database called
PROJECTSTOP. This
database records each purchase of pseudoephedrine products,
tracking the customers drivers license or 18+ card. This system was
put in place to stop drug mules driving from Sydney to Cairns (a
trip of 3000 km or 1875 mi) purchasing a small box of
pseudoephedrine at every pharmacy along the way. When the database
is used 3 modes of sale can be used. One allows the sale (as "no
match" was found), one denies the sale and the third, called a
safety sale, is when the product was sold under duress. Certain
preparations containing significantly high amounts of
pseudoephedrine are further restricted as "Prescription Only
Medicines" (Schedule 4).
As of
April 2007, the Australian
government is considering the prohibition of all medications
containing pseudoephedrine.
Most of the illicit PSE which is coming into Australia originates
from China or India. It comes via containers and mail parcels
concealed in other commercial packing such as coffee and tea. Since
Chinese manufacturers started colouring their PSE it is easily
identified by the Australian authorities. Most PSE comes via Viet
Nam or Cambodia. Vietnamese-chinese ethnic community is behind most
of the illegal importation. Due to the corrupt Chinese and
Vietnamese officials an illicit trade is being organised by the
Mafia.
Indian origin PSE is from Delhi and Chennai. Indian PSE does not
contain colouring like Chinese PSE. Indian PSE is mainly white
mixed with some camouflaging materials like plastic contaminants to
disguise it like curry powder.
Mexico
On November 23, 2007, the use and trade of Pseudoephedrine in
Mexico was made illicit, as it was argued that pseudoephedrine was
extremely popular as a precursor in the synthesis of
methamphetamine.
New Zealand
In New Zealand, from 15 October 2004, as a result of large
intercepts of pseudoephedrine and ephedrine, any product containing
these substances e.g. cold and flu medicines were classified as
Class C Part III (partially exempted) controlled drugs in the
Misuse of Drugs Act 1975. New Zealand Customs and police officers
are continuing to make large interceptions of precursor substances
believed to be destined for
methamphetamine production. On 9 October
2009 Prime Minister
John Key made
pseudoephedrine-based cold and flu tablets a prescription-only drug
and reclassified as a class 2B drug.
United Kingdom
In the UK pseudoephedrine is available on prescription or over the
counter under the supervision of a qualified pharmacist. As of
2009 UK pharmacies sell Sudafed
(pseudoephedrine hcl) in 12 tablet pack size containing 60 mg
per pill. There is not a major problem with pseudoephedrine
diversion in the UK.
United States
The
United States Congress
has recognized the use of pseudoephedrine in the illicit
manufacture of methamphetamine. In late
2005,
the
Committee
on Education and the Workforce heard testimony concerning
education programs and state legislation designed to curb the use
and manufacture of methamphetamine with pseudoephedrine-containing
products. State laws in Oregon and Kansas were particularly
influential in the proposed legislation. The
House passed the
Combat
Methamphetamine Epidemic Act of 2005 ("CMEA") as an
amendment to the renewal of the
Patriot
Act. Signed into law by president
George W. Bush
on March 6, 2006, the act amended
Title 21 of the United States
Code (21 USC 830) concerning the sale of
pseudoephedrine-containing products. The Federal statute included
the following requirements for merchants ("regulated seller") who
sell these products (pseudoephedrine is defined as a "
scheduled listed chemical product
under (45(A)):
- A retrievable record of all purchases identifying the name and
address of each party to be kept for two years.
- Required verification of proof of identity of all
purchasers
- Required protection and disclosure methods in the collection of
personal information
- Reports to the Attorney General of any
suspicious payments or disappearances of the regulated
products
- Required training of employees with regard to the requirements
of the CMEA; Retailer must self-certify as to training and
compliance
- Non-liquid dose form of regulated product may only be sold in
unit dose blister packs
- Regulated products are to be stored behind the counter or in a
locked cabinet in such a way as to restrict public access
- Daily sales of regulated products not to exceed 3.6 grams
without regard to the number of transactions
- 30 day (not monthly) sales limit not to exceed 7.5 grams if
sold by mail-order or "mobile retail vendor"
- 30 day purchase limit not to exceed 9 grams of pseudoephedrine
base in regulated products (misdemeanor possession offense under
for the individual who buys it)
Forty-one
individual states also have varying laws on the matter: Alabama
, Arizona
, Arkansas
, California
, Colorado
, Connecticut
, Delaware
, Florida
, Georgia
, Hawai'i
(as of May
1, 2009) Illinois
, Indiana
, Iowa
, Kansas
, Kentucky
, Louisiana
(as of August 15, 2009) Maryland
, Massachusetts
, Michigan
, Minnesota
, Missouri
, Montana
, Nevada
, New Hampshire
, New
Jersey
, New
York
, North
Carolina
, Ohio
, Oklahoma
, Pennsylvania
, Rhode
Island
, South
Dakota
, Tennessee
, Texas
, Utah
, Vermont
, Virginia
, West
Virginia
, Wisconsin
and Washington
have laws require pharmacies to sell
pseudoephedrine behind-the-counter and to collect personal
information from the purchaser. Oregon
requires a
prescription to purchase products containing
pseudoephedrine.
See also
References
External links
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