Pseudoephedrine

Pseudoephedrine

File:Pseudoephedrine structure.png
Clinical data
Pregnancy category	B2 (Aust)
Routes of administration	oral
ATC code	R01BA02 (WHO)
Legal status
Legal status	Schedule 3/4 (Aust)
Pharmacokinetic data
Bioavailability	unknown
Metabolism	hepatic (10–30%)
Elimination half-life	9–16 hours
Excretion	70-90% renal
Identifiers
IUPAC name (1S,2S)-2-methylamino-1-phenylpropan-1-ol
CAS Number	90-82-4
PubChem CID	7028
DrugBank	APRD00634
CompTox Dashboard (EPA)	DTXSID0023537
ECHA InfoCard	100.001.835
Chemical and physical data
Formula	C10H15NO
Molar mass	165.23

Pseudoephedrine 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. It is often referred to by consumers as Sudafed, which is the trademark for a common brand of pseudoephedrine hydrochloride.

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.

Chemistry

Pseudoephedrine is a phenethylamine, and an isomer of ephedrine. 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) The enantiomer (-)-(1R,2R)-Pseudoephedrine has fewer side-effects, fewer central nervous system (CNS) stimulatory effects, does not reduce to d-methamphetamine, and yet retains its efficacy as a decongestant. However, the patent holder for (-)-Pseudoephedrine has not yet sought or received government approval for its sale to the public. (US Patent 6,495,529)

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.

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. (+)-(1S,2S)-pseudoephedrine shows far lower CNS activity than some other Ephedra alkaloids, such as ephedrine.

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.

Clinical use

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.

Adverse effects

Common adverse drug reactions (ADRs) associated with pseudoephedrine therapy include: CNS stimulation, sleepiness, nervousness, excitability, dizziness, 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)

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 or manic-depression should use care when taking pseudoephedrine, as it can cause insomnia and thus trigger a manic episode.

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)

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 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, due to its minimal effect in the central nervous system (see Mode of Action above). Nevertheless, such misuse of pseudoephedrine has been associated with stimulant dependence.

The similarity in chemical structure to the amphetamines has made pseudoephedrine a sought-after chemical precursor in the illicit manufacture of methamphetamine and methcathinone. United States federal law prohibits buying cold preparations containing pseudoephedrine in quantities greater than 3 packages in any 24-hour period. Individual states also have varying laws on the matter (e.g. Alabama, California, Delaware, Indiana, Kansas, Missouri, New Jersey, Oklahoma, Pennsylvania, Rhode Island, 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 requires a prescription to purchase pseudoephedrine due the passage of Oregon House Bill 2485. Various other legislatures around the world similarly restrict the sale of pseudoephedrine-containing products. Internationally, pseudoephedrine is listed as a Table I precursor under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances[1].

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.

Brand names

• Contac®
• Sudafed®
• Actifed®
• Claritin-D®
• Sinutab®
• Benylin®
• Zyrtec-D®
• Nurofen®

References

• 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
• Reynolds JEF, editor. Martindale: The extra pharmacopoeia, 29th edition. London: The Pharmaceutical Press; 1989. 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).
• Uttsehks, Gabe, PhD, Open Wide; Dangers of Pseudoephedrine, printed 1999 by Stalwart Press.
• Oregon House Bill 2485

See also

• Ephedrine
• Phenylephrine - a substitute used where pseudoephedrine sale is restricted by law
• Amphetamine
• Methamphetamine
• Methcathinone
• Phenethylamines

External links

• Pseudoephedrine (Systemic) monograph – from USP DI Advice for the Patient