|Systematic (IUPAC) name|
|Trade names||Afrinol, Sudafed, Sinutab(UK)|
|Pregnancy cat.||B2 (AU) C (US)|
|Legal status||Pharmacist Only (S3) (AU) S3 (CA) P (UK) Behind the Counter (BTC) Rx only in Oregon and Mississippi (US)|
| (what is this?)
Pseudoephedrine (// or //; PSE) is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It may be used as a nasal/sinus decongestant, as a stimulant, or as a wakefulness-promoting agent.
The salts pseudoephedrine hydrochloride and pseudoephedrine sulfate are found in many over-the-counter preparations, either as a single ingredient or (more commonly) in combination with antihistamines, guaifenesin, dextromethorphan, and/or paracetamol (acetaminophen) or another NSAID (such as aspirin or ibuprofen).
- 1 Chemistry
- 2 Nomenclature
- 3 Synthesis
- 4 Mechanism of action
- 5 Medical uses
- 6 Other uses
- 7 National legislation
- 8 See also
- 9 References
In the outdated d/l system (+)-pseudoephedrine is also referred to as l-pseudoephedrine and (−)-pseudoephedrine as d-pseudoephedrine (in the Fisher projection then the phenyl ring is drawn at bottom).
Often the d/l system (with small caps) and the d/l system (with lower-case) are confused. The result is that the dextrorotary d-pseudoephedrine is wrongly named d-pseudoephedrine and the levorotary l-ephedrine (the diastereomer) wrongly l-ephedrine.
The IUPAC names of the two enantiomers are (1S,2S)- respectively (1R,2R)-2-methylamino-1-phenylpropan-1-ol. Synonyms for both are psi-ephedrine and threo-ephedrine.
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 converts the ingredients to the precursor l-phenylacetylcarbinol (L-PAC). L-PAC is then chemically converted to pseudoephedrine via reductive amination.
Mechanism of action
Pseudoephedrine is a sympathomimetic amine. Its principal mechanism of action relies on its indirect action on the adrenergic receptor system. The vasoconstriction that pseudoephedrine produces is believed to be principally an α-adrenergic receptor response.
While it may have weak or no 'direct' 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 postsynaptic adrenergic receptors. These adrenergic receptors are located on the muscles lining the walls of blood vessels. When these receptors are activated by noradrenaline, the muscles contract, causing the blood vessels to constrict (vasoconstriction). The 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.
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Pseudoephedrine is a stimulant, but it is well known for shrinking swollen nasal mucous membranes, so it is often used as a decongestant. It reduces tissue hyperemia, edema, and nasal congestion commonly associated with colds or allergies. 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.
Pseudoephedrine can be used either as oral or as topical decongestant. The advantage of oral pseudoephedrine over topical nasal preparations, such as oxymetazoline, is that it does not cause rebound congestion (rhinitis medicamentosa). However, due to its stimulating qualities, it is more likely to cause adverse effects, including hypertension, sweating, insomnia, and anxiety.
Pseudoephedrine is also used by some ADHD patients to self-medicate, due to its stimulant properties.
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Pseudoephedrine is indicated for the treatment of:
Pseudoephedrine is also used as a first-line prophylactic for recurrent priapism. Erection is largely a parasympathetic response, so the sympathetic action of pseudoephedrine may serve to relieve this condition.
Common adverse drug reactions (ADRs) associated with pseudoephedrine therapy include: CNS stimulation, insomnia, nervousness, excitability, dizziness and anxiety. Infrequent ADRs include: tachycardia or palpitations. Rarely, pseudoephedrine therapy may be associated with mydriasis (dilated pupils), 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 when combined with other drugs including narcotics, may also play a role in the precipitation of 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, severe or uncontrolled hypertension, severe coronary artery disease, prostatic hypertrophy, hyperthyroidism, closed angle glaucoma, or by pregnant women.
Since nasal congestion is considered to be a relatively minor ailment, alternatives are preferred in patients with these conditions. Appropriate alternatives may include saline sprays/instillations, depending on the patient's condition. Topical decongestants should be used with caution and for no longer than three days to avoid rhinitis medicamentosa.
The antihypertensive effects of methyldopa, mecamylamine, reserpine and veratrum alkaloids may be reduced by sympathomimetics. Beta-adrenergic antagonists may also interact with sympathomimetics. Increase of ectopic pacemaker activity can occur when pseudoephedrine is used concomitantly with digitalis. Antacids increase the rate of pseudoephedrine absorption, while kaolin decreases it.
Common brand names
- Actifed (made by GlaxoSmithKline) — previously contained pseudoephedrine, now contains phenylephrine.
- Aleve D (made by Bayer Healthcare) — contains 120 mg pseudoephedrine hydrochloride (also 240 mg naproxen).
- Allegra D (made by Sanofi Aventis) — contains 240 mg of pseudoephedrine hydrochloride (also 180 mg of fexofenadine).
- Allerclear-D (made by Kirkland Signature) — contains 240 mg of pseudoephedrine sulfate (also 10 mg of loratadine).
- Benadryl Plus (made by Johnson & Johnson) — contains 60 mg pseudoephedrine hydrochloride (also 8 mg acrivastine)
- Cirrus (made by UCB) — contains 120 mg pseudoephedrine hydrochloride (also 5 mg cetirizine).
- Claritin-D (made by MSD Consumer Care) — contains 120 mg of pseudoephedrine sulphate (also 5 mg of loratadine).
- Codral (made by Johnson & Johnson) — Codral Original contains pseudoephedrine, Codral New Formula substitutes pseudoephedrine for phenylephrine.
- Congestal (made by Sigma) — contains 60 mg pseudoephedrine hydrochloride (also 650 mg paracetamol and 4 mg chlorpheniramine).
- Contac (made by GlaxoSmithKline) — previously contained pseudoephedrine, now contains phenylephrine.
- Eltor (made by Sanofi Aventis) — contains pseudoephedrine hydrochloride.
- Mucinex D (made by Reckitt Benckiser) — contains 60 mg pseudoephedrine hydrochloride (also 1200 mg guaifenesin).
- Nurofen Cold & Flu (made by Reckitt Benckiser) — contains 30 mg pseudoephedrine hydrochloride (also 200 mg ibuprofen).
- Rhinex Flash (made by Pharma Product Manufacturing, Cambodia) — contains pseudoephedrine combined with paracetamol and triprolidine.
- Rhinos SR (made by Dexa Medica) — contains 120 mg of pseudoephedrine hydrochloride (also 5 mg loratadine).
- Sinufed (made by Trima) — contains 60 mg pseudoephedrine hydrochloride.
- Sudafed Decongestant (made by Johnson & Johnson) — contains 60 mg of pseudoephedrine hydrochloride.
- Theraflu (made by Novartis) — previously contained pseudoephedrine, now contains phenylephrine.
- Unifed (made by United Pharmaceutical Manufacturer, Jordan) — contains pseudoephedrine hydrochloride (also triprolidine and guaifenesin).
- Zyrtec-D 12 Hour (made by Johnson & Johnson) — contains 120 mg pseudoephedrine hydrochloride (also 5 mg of cetirizine).
There have been reports of off-label uses of pseudoephedrine for its stimulant properties. Long-distance truck drivers and athletes, for example, have reportedly used pseudoephedrine as a stimulant to increase their state of alertness/awareness.
Use to make methamphetamine
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, but less effective, decongestants, such as phenylephrine.
Many retailers, such as Target, Walgreens, CVS, Rite Aid, and Winn-Dixie in the USA, along with Boots in the UK, 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.
Pseudoephedrine was on the banned substances IOC list until 2004, when the WADA list replaced the IOC list. Although WADA initially only monitored pseudoephedrine, it is once again on the banned list starting January 1, 2010. Romanian gymnast 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.
Detection of use
Pseudoephedrine may be quantitated in blood, plasma or urine to monitor any possible performance-enhancing use by athletes, confirm a diagnosis of poisoning or assist in a medicolegal death investigation. Many commercial immunoassay screening tests directed at the amphetamines cross-react appreciably with pseudoephedrine, but chromatographic techniques can easily distinguish pseudoephedrine from other phenethylamine derivatives. Blood or plasma pseudoephedrine concentrations are typically in the 50–300 µg/l range in persons taking the drug therapeutically, 500–3000 µg/l in abusers or poisoned patients and 10–70 mg/l in cases of acute fatal overdosage.
Illicit diversion of pseudoephedrine in Australia has caused significant changes to the way the products are regulated. As of 2006[update], all products containing pseudoephedrine have been rescheduled as either "Pharmacist Only Medicines" (Schedule 3) or "Prescription Only Medicines" (Schedule 4), depending on the amount of pseudoephedrine in the product. A Pharmacist Only Medicine may only be sold to the public if a pharmacist is directly involved in the transaction. These medicines must be kept behind the counter, away from public access.
Pharmacists are also encouraged (and in some states required) to log purchases with the online database Project STOP. This system aims to prevent individuals from purchasing small quantities of pseudoephedrine from many different pharmacies.
As a result, many pharmacies simply no longer stock Sudafed (the common brand of pseudoephedrine cold/sinus tablets), opting instead to sell Sudafed PE, a phenylephrine product which is no more effective as a decongestant than placebo pills.
The Colombian government prohibited the trade of pseudoephedrine in 2010.
On November 23, 2007, the use and trade of pseudoephedrine in Mexico was made illicit, as it was argued that it was extremely popular as a precursor in the synthesis of methamphetamine.
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 announced pseudoephedrine-based cold and flu tablets would become prescription-only drugs and reclassified as a class B2 drug. The Misuse of Drugs Amendment Bill 2010 has not yet been finalised.
In the UK, pseudoephedrine is available over the counter under the supervision of a qualified pharmacist, or on prescription. In 2007, the MHRA reacted to concerns over diversion of ephedrine and pseudoephedrine for the illicit manufacture of methamphetamine by introducing voluntary restrictions limiting over the counter sales to one box containing no more than 720 mg of pseudoephedrine in total per transaction. These restrictions became law in April, 2008. However no form of ID is required.
The United States Congress has recognized that pseudoephedrine is used in the illegal manufacture of methamphetamine. In 2005, the Committee on Education and the Workforce heard testimony concerning education programs and state legislation designed to curb this illegal practice.
Attempts to control the sale of the drug date back to 1986, when federal officials at the Drug Enforcement Administration (DEA) first drafted legislation, later proposed by Senator Bob Dole, R-KS, that would have placed a number of chemicals used in the manufacture of illicit drugs under the Controlled Substances Act. The bill would have required each transaction involving pseudoephedrine to be reported to the government, and federal approval of all imports and exports. Fearing this would limit legitimate use of the drug, lobbyists from over the counter drug manufacturing associations sought to stop this legislation from moving forward, and were successful in exempting from the regulations created by the bill, all chemicals that had been turned into a legal final product, such as Sudafed.
Prior to the passage of the Combat Methamphetamine Epidemic Act of 2005, sales of the drug became increasingly regulated, as DEA regulators and pharmaceutical companies continued to fight for their respective positions. The DEA continued to make greater progress in their attempts to control pseudoephedrine as methamphetamine production skyrocketed, becoming a serious problem in the Western United States. When purity dropped, so did the number of people in rehab, and people admitted to emergency rooms with methamphetamine in their systems. However, this reduction in purity was usually short lived as methamphetamine producers eventually found a way around the new regulations.
Congress passed the Combat Methamphetamine Epidemic Act of 2005 ("CMEA") as an amendment to the renewal of the USA PATRIOT Act. Signed into law by president George W. Bush on March 6, 2006, the act amended 21 U.S.C. § 830, concerning the sale of pseudoephedrine-containing products. The law mandated two phases, the first needing to be implemented by April 8, 2006, and the second phase to be completed by September 30, 2006. The first phase dealt primarily with implementing the new buying restrictions based on amount, while the second phase encompassed the requirements of storage, employee training, and record keeping. Though the law was mainly directed at pseudoephedrine products it also applies to all over the counter products containing:ephedrine, pseudoephedrine, and phenylpropanolamine, their salts, optical isomers, and salts of optical isomers. Pseudoephedrine was defined as a "scheduled listed chemical product" under 21 U.S.C. § 802(45(A)). The act included the following requirements for merchants ("regulated sellers") who sell such products:
- Required 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
- Required 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. Retailers must self-certify as to training and compliance.
- The non-liquid dose form of regulated products may only be sold in unit dose blister packs
- Regulated products must be stored behind the counter or in a locked cabinet in such a way as to restrict public access
- Sales limits (per customer):
- Daily sales limit—must not exceed 3.6 grams of pseudoephedrine base without regard to the number of transactions
- 30-day (not monthly) sales limit—must not exceed 7.5 grams of pseudoephedrine base if sold by mail order or "mobile retail vendor"
- 30-day purchase limit—must not exceed 9 grams of pseudoephedrine base. (A misdemeanor possession offense under 21 U.S.C. § 844a for the person who buys it.)
In regards to the identification that may be used by an individual buying pseudoephedrine products the following constitute acceptable forms of identification:
- US passport
- Alien registration or permanent resident card
- Unexpired foreign passport with temporary I-551 stamp
- Unexpired Employment Authorization Document
- Driver's License or Government issued identification card (including Canadian driver's license)
- School ID with picture
- Voter's Registration card
- US Military Card
- Native American tribal documents
Most states also have laws regulating pseudoephedrine.
Alabama, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Hawai'i (as of May 1, 2009[update]) Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana (as of August 15, 2009[update]) Maryland, Massachusetts, Michigan, Minnesota, Missouri, Montana, Nebraska, Nevada, New Hampshire, New Jersey, New York, North Carolina, Ohio, Oklahoma, Pennsylvania, Rhode Island, South Dakota, Tennessee, Texas, Utah, Vermont, Virginia, Washington, West Virginia and Wisconsin have laws requiring pharmacies to sell pseudoephedrine "behind the counter" and to collect personal information from purchasers.
Oregon and Mississippi require a prescription for the purchase of products containing pseudoephedrine. Oregon reduced the number of methamphetamine lab seizures from 467 in 2004, (the final full year before implementation of the prescription only law), to a new low of 12 in 2009. Some municipalities in Missouri have enacted similar ordinances, including Washington, Union, New Haven, Cape Girardeau and Ozark. Certain pharmacies in Terre Haute, Indiana do so as well.
Another approach to controlling the drug on the state level which has been mandated by some state governments to control the purchases of their citizens is the use of electronic tracking systems, which require the electronic submission of specified purchaser information by all retailers who sell pseudoephedrine. Several states that have implemented tracking systems are: Tennessee, Kentucky, and Oklahoma. These states have had mixed results in reducing the number of methamphetamine laboratory seizures in their states. Prior to implementation of the system in Tennessee in 2005, methamphetamine laboratory seizures totaled 1,497 in 2004, but were reduced to 955 in 2005, and 589 in 2009. Kentucky's program was implemented statewide in 2008, but since statewide implementation, the number of laboratory seizures has actually increased. Oklahoma initially experienced success with their tracking system after implementation in 2006, as the number of seizures dropped in that year and again in 2007. However in 2008, seizures began rising again, and have continued to rise in 2009.
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