Pseudoephedrine

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Pseudoephedrine
Systematic (IUPAC) name
(1S,2S)-2-methylamino-1-phenylpropan-1-ol
Identifiers
CAS number 90-82-4
ATC code R01BA02
PubChem 7028
DrugBank APRD00634
ChemSpider 6761
Chemical data
Formula C10H15NO 
Mol. mass 165.23
Pharmacokinetic data
Bioavailability unknown
Metabolism hepatic (10–30%)
Half life 9–16 hours
Excretion 70-90% renal
Therapeutic considerations
Pregnancy cat.

B2(AU) ?(US)
Legal status

Pharmacist Only (S3)(AU) P(UK)
Routes oral

Pseudoephedrine (commonly abbreviated 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 modify the systemic histamine-mediated allergic response, pseudoephedrine only 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.

Pseudoephedrine is being phased out as an over-the-counter drug in some countries and replaced by less effective[1] alternative decongestants such as phenylephrine, due to pseudoephedrine's notable popularity as a precursor in the illicit synthesis 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.[2]

Contents

[edit] Chemistry

Pseudoephedrine is a 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 (1S,2S)- diastereomer of ephedrine (which has 1R,2S- configuration). Other names are (+)-pseudoephedrine and D-pseudoephedrine.[3]

L-Pseudoephedrine, also known as (-)-(1R,2R)-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.[citation needed] However, the patent holder for L-pseudoephedrine (Pfizer/Warner-Lambert)[4] has not yet sought or received government approval for its sale to the public. [5]

[edit] Mode 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.

[edit] Clinical uses

[edit] 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.[6]

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.[citation needed]

[edit] 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;[7] as well as severe skin reactions known as recurrent pseudo-scarlatina, systemic contact dermatitis, and nonpigmenting fixed drug eruption.[8] Pseudoephedrine, particularly in high doses, may also cause episodes of paranoid psychosis. [9] It has also been reported that pseudoephedrine, amongst other sympathomimetic agents, may be associated with the occurrence of stroke.[10]

[edit] 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.[7]

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 serotonin-specific reuptake inhibitor (SSRI) therapy , severe or uncontrolled hypertension, and/or severe coronary artery disease.[7]

People with bipolar disorder should use care when taking pseudoephedrine, as it can cause insomnia and thus trigger a manic episode.

[edit] Chiral auxiliary

Both (R,R)- and (S,S)-pseudoephedrine are used as a chiral auxiliary.[11] 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.

[edit] 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.[12]

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.[13]

[edit] Common brand names

The following are some brand names of medications containing pseudoephedrine. Some of them no longer contain it and have phenylephrine instead.

[edit] Alternative and illicit use

 This section is missing citations or needs footnotes. Please help add inline citations to guard against copyright violations and factual inaccuracies. (March 2009)

There have also been reports of off-label uses of pseudoephedrine for its stimulant properties. Some people, long-distance truck drivers and sports athletes for example, have reportedly used pseudoephedrine as a stimulant to increase their state of alertness/awareness.[weasel words] 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).[original research?]

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, Wal-Mart, 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.[2]

[edit] Sports

Pseudoephedrine is on the banned substances IOC list. 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, 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.[14][15]

[edit] United States federal law

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.[citation needed] 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 21 U.S.C. § 802(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 21 U.S.C. § 844a for the individual who buys it)

[edit] United States state law

Thirty-seven individual states also have varying laws on the matter: Alabama, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Illinois, Indiana, Iowa, Kansas, Kentucky, 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 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.

[edit] 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.

[edit] 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 1875mi) 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.[16]

[edit] 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.[citation needed] New Zealand Customs and police officers are continuing to make large interceptions of precursor substances believed to be destined for methamphetamine production.

[edit] United Kingdom

In the UK pseudoephedrine has only ever been available on prescription or over the counter[clarification needed], and as of 2007 pharmacies are required to sell only in limited pack sizes.[17]

[edit] See also

[edit] References

  1. ^ Hatton RC, et al. Efficacy and Safety of Oral Phenylephrine: A Systematic Review and Meta-Analysis. Ann Pharmacother. 2007 Mar;41(3):381-90. Epub 2007 Jan 30.
  2. ^ a b Microsoft Word - RedListE2007.doc
  3. ^ Edited by Reynolds JEF, ed (1989). Martindale: The complete drug reference (29th edition ed.). London: Pharmaceutical Press. ISBN 0-85369-210-6. 
  4. ^ U.S. Patent 6,495,529, (-)-Pseudoephedrine as a Sympathomimetic Drug, Warner-Lambert (2002)
  5. ^ (U.S. Patent 6,495,529 )
  6. ^ a b Bicopoulos D, editor. AusDI: Drug information for the healthcare professional, 2nd edition. Castle Hill: Pharmaceutical Care Information Services; 2002.
  7. ^ a b c Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
  8. ^ Vidal C, Prieto A, Pérez-Carral C, Armisén M (April 1998). "Nonpigmenting fixed drug eruption due to pseudoephedrine". Ann. Allergy Asthma Immunol. 80 (4): 309–10. PMID 9564979. 
  9. ^ Adco-Tussend
  10. ^ Cantu C, Arauz A, Murillo-Bonilla LM, López M, Barinagarrementeria F (July 2003). "Stroke associated with sympathomimetics contained in over-the-counter cough and cold drugs". Stroke 34 (7): 1667–72. doi:10.1161/01.STR.0000075293.45936.FA. PMID 12791938. 
  11. ^ Myers, A. G., et al, Pseudoephedrine as a Practical Chiral Auxiliary for the Synthesis of Highly Enantiomerically Enriched Carboxylic Acids, Alcohols, Aldehydes, and Ketones, J. Am. Chem. Soc., 1997, 119, 6460-6651.doi:10.1021/ja970402f
  12. ^ Oliver AL, Anderson BN, Roddick FA (1999). "Factors affecting the production of L-phenylacetylcarbinol by yeast: a case study". Adv. Microb. Physiol. 41: 1–45. PMID 10500843. 
  13. ^ Suo, Steve. Clamp down on shipments of raw ingredients. The Oregonian; 6 October 2004. From a version reprinted on a U.S. congressional caucus website.
  14. ^ http://assets.espn.go.com/oly/summer00/news/2000/0925/776388.html
  15. ^ http://web.archive.org/web/20010715112418/http://www.intlgymnast.com/news2000/oct3.html
  16. ^ "Govt considers banning pseudoephedrine products. 16/04/2007. ABC News Online". http://www.abc.net.au/news/newsitems/200704/s1898059.htm. Retrieved on 2007-10-31. 
  17. ^ Pseudoephedrine.co.uk

[edit] External links

v • d • e
Adrenergic agonists (models/most important in small caps)
α
β
Nonselective β
α and β
Epinephrine (α1+2, β1+2) · Norepinephrine (α1+2, β1) · Cirazoline · Etilefrine · Ephedrine · Pseudoephedrine
Indirect
presynaptic norepinephrine release: Amphetamine · Tyramine · Ephedrine  · Pseudoephedrine
norepinephrine reuptake inhibitor: Cocaine
v • d • e
Decongestants and other nasal preparations (R01)
Topical
Antiallergic agents,
excluding corticosteroids
Other nasal preparations
Systemic use:
Sympathomimetics
Phenylpropanolamine • Pseudoephedrine • Phenylephrine • Phenylpropylamine
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