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
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)
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 and/or ibuprofen. Consumers often referred to it by a product which contains pseudoephedrine, such as Sudafed, the trademark for a common brand of pseudoephedrine hydrochloride in North America, the United Kingdom and Australia, although Pfizer now sells products without pseudoephedrine under the Sudafed brand name.

Unlike antihistamines, which modify the systemic histamine-mediated allergic response, pseudoephedrine only relieves nasal congestion commonly associated with colds or allergies. However, some users report rapid and effective relief from other allergic symptoms, including itchy and/or watery eyes, which may not have been provided effectively by antihistamines.

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.

Contents

[edit] Chemistry

Pseudoephedrine is a phenethylamine, and a diastereomer of ephedrine. Pseudoephedrine is a chiral molecule, meaning it occurs as 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 (Reynolds, 1989).

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 enatiomer 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) has not yet sought or received government approval for its sale to the public. (U.S. Patent 6,495,529 )

[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 displace 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 activiated 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 mucous 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 hyperaemia, oedema, 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 use

[edit] Indications

Pseudoephedrine is indicated for the treatment of:

  • nasal congestion
  • sinus congestion
  • Eustachian tube congestion. (Bicopoulos, 2002)

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. (Bicopoulos, 2002)

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 unlabeled use for these medications. Unlabeled use means doctors can use the medication to treat a condition other than that for which it was first approved by the U.S. Food and Drug Administration (FDA). These medications are approved by the FDA for the treatment of nasal congestion caused by colds or allergies. However it has also been successful in treating stress incontinence by increasing the pressure (tension) exerted by the muscles of the bladder neck and the urethra, which helps retain the urine within the bladder.

[edit] Adverse effects

Common adverse drug reactions (ADRs) associated with pseudoephedrine therapy include: CNS stimulation, sleepiness, nervousness, excitability, dizziness, anxiety, and/or insomnia. Infrequent ADRs include: tachycardia and/or palpitations. Rarely, pseudoephedrine therapy may be associated with hallucinations, arrhythmias, hypertension, seizures, and ischemic colitis (Rossi, 2006).

It has also been reported that pseudoephedrine, amongst other sympathomimetic agents, may be associated with the occurrence of stroke (Cantu et al., 2003).

[edit] Precautions and contraindications

Pseudoephedrine should be used with caution in patients with: diabetes mellitus, cardiovascular disease, hypertension, prostatic hypertrophy, hyperthyroidism, closed angle glaucoma and/or pregnancy (Rossi, 2006).

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) therapy, severe or uncontrolled hypertension, and/or severe coronary artery disease (Rossi, 2006).

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.[1] Pseudoephedrine is reacted with a carboxylic acid, carboxylic anhydride, or acyl chloride to give a pseudoephedrine amide.

The α-proton of the carbonyl compound is easily deprotonated by a non-nucelophilic 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, inter alia). 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 (Oliver, 1999).

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 (Suo, 2004).

[edit] Misuse and illicit use

There have also been reports of off-label uses of pseudoephedrine for its stimulant properties. Some patients, long-distance truck drivers, and sports athletes for example, have reportedly used pseudoephedrine as a stimulant to increase their state of alertness/awakedness. 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).[citation needed] Nevertheless, such misuse of pseudoephedrine has been associated with stimulant dependence.[citation needed] 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, 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.[1]

[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[2]. The House passed the Combat Methamphetamine Epidemic Act of 2005 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 the US Code (21 USC 830) concerning the sale of pseudoephedrine containing products. The Federal statute included the following requirements for merchants who sell these products:

  • 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
  • Non-liquid dose form of regulated product may only be sold in unit dose blister packs
  • Regulated products are to be sold behind the counter or in a locked cabinet in such a way as to restrict access
  • Daily sales of regulated products not to exceed 3.6 grams without regard to the number of transactions
  • Monthly sales not to exceed 9 grams of pseudoephedrine base in regulated products

The law gives similar regulations to mail order purchases, except the monthly sales limit is only 7.5 grams.

[edit] United States State Law

Individual states also have varying laws on the matter, e.g. Alabama, California, Connecticut, Colorado, Delaware, Georgia, Florida, Illinois, Indiana, Iowa, Kansas, Massachusetts, Maryland, Michigan, Minnesota, Missouri, Montana, New Jersey, New York, North Carolina, Oklahoma, Pennsylvania, Rhode Island, Tennessee, Texas, Utah, Virginia, and Washington laws require pharmacies to sell pseudoephedrine behind-the-counter and to collect personal information from the purchaser. As of July 1, 2006 Oregon recognizes pseudoephedrine and all pseudoephedrine containing products as a Schedule III controlled substance, and requires a prescription to purchase them.

[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 seek identification from potential purchasers, and maintain a record of each transaction. Certain preparations containing significantly high amounts of pseudoephedrine are further restricted as "Prescription Only Medicines" (Schedule 4).

[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 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.

[edit] Brand names

  • Contac® (pseudoephedrine) - Has been discontinued as of 2007
  • Sudafed® (pseudoephedrine) - has an alternate phenylephrine HCl version, Sudafed® PE
  • Actifed® (triprolidine/pseudoephedrine) - will no longer contain pseudoephedrine by the end of 2006
  • Claritin-D® (loratadine/pseudoephedrine)
  • Clarinex-D® (desloratadine/pseudoephedrine)
  • Sinutab® (guaifenesin/pseudoephedrine)
  • Benylin® (pseudoephedrine)
  • Zyrtec-D® (certirizine/pseudoephedrine)
  • Allegra-D® (fexofenadine/pseudoephedrine)
  • Drixoral® (dexbrompheniramine/pseudoephedrine)
  • Mucinex-D® (guaifenesin/pseudoephedrine)
  • PediaCare® (pseudoephedrine/chlorpheniramine/dextromethorphan)
  • Pannaz® (pseudoephedrine/chlorpheniramine/methscopolamine)
  • Fludrex® (pseudoephedrine/dextromethorphan/triprolidine)
  • Solpa-Sinus® (pseudoephedrine/acetaminophen)
  • Tylenol-Sinus® (Phenylephrine/acetaminophen) - Many cold remedies like Tylenol Sinus no longer use pseudoephedrine due to its new legal status.

[edit] References

  1. ^ 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.
  • Bicopoulos D, editor. AusDI: Drug information for the healthcare professional, 2nd edition. Castle Hill: Pharmaceutical Care Information Services; 2002.
  • Cantu C, Arauz A, Murillo-Bonilla LM, Lopez M, Barinagarrementeria F. Stroke associated with sympathomimetics contained in over-the-counter cough and cold drugs. Stroke 2003;34(7):1667-72. PMID: 12791938
  • (1989) in Edited by Reynolds JEF: Martindale: The complete drug reference, 29th edition, London: Pharmaceutical Press. ISBN 0-85369-210-6. 
  • Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
  • Oliver AL, Anderson BN, Roddick FA. Factors affecting the production of L-phenylacetylcarbinol by yeast: a case study. Advances in Microbial Physiology. 1999;41:1-45. PMID: 10500843
  • 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.
  • U.S. Patent 6,495,529, (-)-Pseudoephedrine as a Sympathomimetic Drug, Warner-Lambert (2002).
  • Oregon House Bill 2485
  • WebMD [3]

[edit] See also

[edit] External links

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