Pseudoephedrine Explained

Watchedfields:changed
Verifiedrevid:464375838
Width:200px
Width2:200px
Tradename:Afrinol, Sudafed, Sinutab, others
Licence Eu:yes
Inn Ema:pseudoephedrine sulfate
Dailymedid:Pseudoephedrine
Pregnancy Au:B2
Routes Of Administration:By mouth
Class:Norepinephrine releasing agents; Sympathomimetics; Nasal decongestants; Psychostimulants
Atc Prefix:R01
Atc Suffix:BA02
Legal Au:S3
Legal Au Comment:Largely tracked nationwide via “Project STOP” to avoid purchases in large quantities.[1] Use of Project STOP is mandatory in all states and territories except Victoria and Tasmania[2] [3]
Legal Br:D1
Legal Br Comment:[4]
Legal Ca:OTC
Legal Ca Comment:Removed from the in 2024, for both combination and single ingredient preparations, on 1 Mar & 10 Jun 2024, respectively.[5]
Legal Uk:P
Legal Us:OTC
Bioavailability:~100%[6]
Protein Bound:21–29% [7] [8]
Metabolism:Not extensively metabolized
Metabolites:• Norpseudoephedrine
Onset:30minutes
Elimination Half-Life:5.4hours (range 3–16hours dependent on urine pH)
Duration Of Action:4–12hours[9]
Excretion:Urine

43–96% (unchanged)

Cas Number:90-82-4
Pubchem:7028
Drugbank:DB00852
Chemspiderid:6761
Unii:7CUC9DDI9F
Kegg:D08449
Chebi:51209
Chembl:1590
Synonyms:PSE; PDE; (+)-ψ-Ephedrine; ψ-Ephedrine; d-Isoephedrine; (1S,2S)-Pseudoephedrine; d-Pseudoephedrine; (+)-Pseudoephedrine; L(+)-Pseudoephedrine; Isoephedrine; (1S,2S)-α,N-Dimethyl-β-hydroxyphenethylamine; (1S,2S)-N-Methyl-β-hydroxyamphetamine
Iupac Name:(S,S)-2-methylamino-1-phenylpropan-1-ol
C:10
H:15
N:1
O:1
Smiles:O[C@@H](c1ccccc1)[C@@H](NC)C
Stdinchi:1S/C10H15NO/c1-8(11-2)10(12)9-6-4-3-5-7-9/h3-8,10-12H,1-2H3/t8-,10+/m0/s1
Stdinchikey:KWGRBVOPPLSCSI-WCBMZHEXSA-N

Pseudoephedrine, sold under the brand name Sudafed among others, is a sympathomimetic medication which is used as a decongestant to treat nasal congestion.[10] [11] [12] It has also been used off-label for certain other indications, like treatment of low blood pressure. At higher doses, it may produce various additional effects, including psychostimulant, appetite suppressant, and performance-enhancing effects. In relation to this, non-medical use of pseudoephedrine has been encountered. The medication is taken by mouth.

Side effects of pseudoephedrine include insomnia, increased heart rate, and increased blood pressure, among others.[13] Rarely, pseudoephedrine has been associated with serious cardiovascular complications like heart attack and hemorrhagic stroke. Some people may be more sensitive to its cardiovascular effects. Pseudoephedrine acts as a norepinephrine releasing agent, thereby indirectly activating adrenergic receptors. As such, it is an indirectly acting sympathomimetic. Pseudoephedrine significantly crosses into the brain, but has some peripheral selectivity due to its hydrophilicity. Chemically, pseudoephedrine is a substituted amphetamine and is closely related to ephedrine, phenylpropanolamine, and amphetamine.

Along with ephedrine, pseudoephedrine occurs naturally in ephedra, which has been used for thousands of years in traditional Chinese medicine.[14] It was first isolated from ephedra in 1889.[15] Subsequent to its synthesis in the 1920s, pseudoephedrine was introduced for medical use as a decongestant. Pseudoephedrine is widely available over-the-counter in both single-drug and combination preparations. Availability of pseudoephedrine has been restricted starting in 2005 as it can be used to synthesize methamphetamine. Phenylephrine has replaced pseudoephedrine in many over-the-counter oral decongestant products. However, oral phenylephrine appears to be ineffective as a decongestant.[16] [17]

Medical uses

Nasal congestion

Pseudoephedrine is a sympathomimetic and 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. Due to its stimulating qualities, however, the oral preparation is more likely to cause adverse effects, including urinary retention.[18] [19] According to one study, pseudoephedrine may show effectiveness as an antitussive drug (suppression of cough).[20]

Pseudoephedrine is indicated for the treatment of nasal congestion, sinus congestion, and Eustachian tube congestion.[21] 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.

Other uses

Amphetamine-type stimulants and other catecholaminergic agents are known to have wakefulness-promoting effects and are used in the treatment of hypersomnia and narcolepsy.[22] [23] [24] Pseudoephedrine at therapeutic doses does not appear to improve or worsen daytime sleepiness, daytime fatigue, or sleep quality in people with allergic rhinitis.[25] Likewise, somnolence was not lower in children with the common cold treated with pseudoephedrine for nasal congestion.[26] In any case, insomnia is a known side effect of pseudoephedrine, although the incidence is low. In addition, doses of pseudoephedrine above the normal therapeutic range have been reported to produce psychostimulant effects, including insomnia and reduced sense of fatigue.

There has been interest in pseudoephedrine as an appetite suppressant for the treatment of obesity.[27] However, due to lack of clinical data and potential cardiovascular side effects, this use is not recommended. Only a single placebo-controlled study of pseudoephedrine for weight loss exists (120mg/day slow-release for 12weeks) and found no significant difference in weight lost compared to placebo (-4.6kg vs. -4.5kg).[28] This was in contrast to phenylpropanolamine, which has been found to be more effective at promoting weight loss compared to placebo and has been more widely studied and used in the treatment of obesity.[29] [30]

Pseudoephedrine has been used limitedly in the treatment of orthostatic intolerance including orthostatic hypotension[31] and postural orthostatic tachycardia syndrome (POTS).[32] [33] [34] However, its effectiveness in the treatment of POTS is controversial. Pseudoephedrine has also been used limitedly in the treatment of refractory hypotension in intensive care units.[35] However, data on this use are limited to case reports and case series.

Pseudoephedrine is also used as a first-line prophylactic for recurrent priapism.[36] Erection is largely a parasympathetic response, so the sympathetic action of pseudoephedrine may serve to relieve this condition. Data for this use are however anecdotal and effectiveness has been described as variable.

Treatment of urinary incontinence is an off-label use for pseudoephedrine and related medications.[37] [38]

Available forms

See also: Azatadine/pseudoephedrine, Carbinoxamine/pseudoephedrine, Cetirizine/pseudoephedrine, Dexbrompheniramine/pseudoephedrine, Fexofenadine/pseudoephedrine, Pseudoephedrine/loratadine and Naproxen/pseudoephedrine.

Pseudoephedrine is available by itself over-the-counter in the form of 30 and 60mg immediate-release and 120 and 240mg extended-release oral tablets in the United States.[39] [40] [41] [42]

Pseudoephedrine is also available over-the-counter and prescription-only in combination with numerous other drugs, including antihistamines (acrivastine, azatadine, brompheniramine, cetirizine, chlorpheniramine, clemastine, desloratadine, dexbrompheniramine, diphenhydramine, fexofenadine, loratadine, triprolidine), analgesics (acetaminophen, codeine, hydrocodone, ibuprofen, naproxen), cough suppressants (dextromethorphan), and expectorants (guaifenesin).

Pseudoephedrine has been used in the form of the hydrochloride and sulfate salts and in a polistirex form. The drug has been used in more than 135 over-the-counter and prescription formulations. Many prescription formulations containing pseudoephedrine have been discontinued over time.

Contraindications

Pseudoephedrine is contraindicated 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. The safety and effectiveness of nasal decongestant use in children is unclear.[43]

Side effects

Common side effects with pseudoephedrine therapy may include central nervous system (CNS) stimulation, insomnia, nervousness, restlessness, excitability, dizziness, and anxiety. Infrequent side effects 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 non-pigmenting fixed drug eruption.[44] [45] Pseudoephedrine, particularly when combined with other drugs including narcotics, may also play a role in the precipitation of episodes of paranoid psychosis.[46] It has also been reported that pseudoephedrine, among other sympathomimetic agents, may be associated with the occurrence of hemorrhagic stroke and other cardiovascular complications.[47]

Due to its sympathomimetic effects, pseudoephedrine is a vasoconstrictor or pressor agent (increases blood pressure), a positive chronotrope (increases heart rate), and a positive inotrope (increases force of heart contractions). The influence of pseudoephedrine on blood pressure at clinical doses is controversial. A closely related sympathomimetic and decongestant, phenylpropanolamine, was withdrawn due to associations with markedly increased blood pressure and incidence of hemorrhagic stroke. There has been concern that pseudoephedrine may likewise dangerously increase blood pressure and thereby increase the risk of stroke, whereas others have contended that the risks are exaggerated. Besides hemorrhagic stroke, myocardial infarction, coronary vasospasm, and sudden death have also rarely been reported with sympathomimetic ephedra compounds like pseudoephedrine and ephedrine.

A 2005 meta-analysis found that pseudoephedrine at recommended doses had no meaningful effect on systolic or diastolic blood pressure in healthy individuals or people with controlled hypertension.[48] Systolic blood pressure was found to slightly increase by 0.99mmHg on average and heart rate was found to slightly increase by 2.83bpm on average. Conversely, there was no significant influence on diastolic blood pressure, which increased by 0.63mgHg. In people with controlled hypertension, systolic hypertension increased by a similar degree of 1.20mmHg. Immediate-release preparations, higher doses, being male, and shorter duration of use were all associated with greater cardiovascular effects. A small subset of individuals with autonomic instability, perhaps in turn resulting in greater adrenergic receptor sensitivity, may be substantially more sensitive to the cardiovascular effects of sympathomimetics. Subsequent to the 2005 meta-analysis, a 2015 systematic review and a 2018 meta-analysis found that pseudoephedrine at high doses (>170mg) could increase heart rate and physical performance with larger effect sizes than lower doses.

A 2007 Cochrane review assessed the side effects of short-term use of pseudoephedrine at recommended doses as a nasal decongestant. It found that pseudoephedrine had a small risk of insomnia and this was the only side effect that occurred at rates significantly different from placebo. Insomnia occurred at a rate of 5% and had an odds ratio (OR) of 6.18. Other side effects, including headache and hypertension, occurred at rates of less than 4% and were not different from placebo.

Tachyphylaxis is known to develop with prolonged use of pseudoephedrine, especially when it is re-administered at short intervals.

There is a case report of temporary depressive symptoms upon discontinuation and withdrawal from pseudoephedrine.[49] The withdrawal symptoms included worsened mood and sadness, profoundly decreased energy, a worsened view of oneself, decreased concentration, psychomotor retardation, increased appetite, and increased need for sleep.

Pseudoephedrine has psychostimulant effects at high doses and is a positive reinforcer with amphetamine-like effects in animals including rats and monkeys.[50] [51] [52] However, it is substantially less potent than methamphetamine or cocaine.

Overdose

The maximum total daily dose of pseudoephedrine is 240mg. Pseudoephedrine may produce sympathomimetic and psychostimulant effects with overdose. These may include sedation, apnea, impaired concentration, cyanosis, coma, circulatory collapse, insomnia, hallucinations, tremors, convulsions, headache, dizziness, anxiety, euphoria, tinnitus, blurred vision, ataxia, chest pain, tachycardia, palpitations, increased blood pressure, decreased blood pressure, thirstiness, sweating, difficulty with urination, nausea, and vomiting. In children, symptoms have more often included dry mouth, pupil dilation, hot flashes, fever, and gastrointestinal dysfunction. Pseudoephedrine may produce toxic effects both with use of supratherapeutic doses but also in people who are more sensitive to the effects of sympathomimetics. Misuse of the drug has been reported in one case at massive doses of 3,000 to 4,500mg (100–150×30-mg tablets) per day, with the doses gradually increased over time by this individual. No fatalities due to pseudoephedrine misuse have been reported as of 2021. However, death with pseudoephedrine has been reported generally.

Interactions

Concomitant or recent (previous 14days) monoamine oxidase inhibitor (MAOI) use can lead to hypertensive reactions, including hypertensive crisis, and should be avoided. Clinical studies have found minimal or no influence of certain MAOIs like the weak non-selective MAOI linezolid and the potent selective MAO-B inhibitor selegiline (as a transdermal patch) on the pharmacokinetics of pseudoephedrine.[53] [54] [55] [56] This is in accordance with the fact that pseudoephedrine is not metabolized by monoamine oxidase (MAO). However, pseudoephedrine induces the release of norepinephrine, which MAOIs inhibit the metabolism of, and as such, MAOIs can still potentiate the effects of pseudoephedrine.[57] No significant pharmacodynamic interactions have been found with selegiline, but linezolid potentiated blood pressure increases with pseudoephedrine. However, this was deemed to be without clinical significance in the case of linezolid, though it was noted that some individuals may be more sensitive to the sympathomimetic effects of pseudoephedrine and related agents. Pseudoephedrine is contraindicated with MAOIs like phenelzine, tranylcypromine, isocarboxazid, and moclobemide due to the potential for synergistic sympathomimetic effects and hypertensive crisis. It is also considered to be contraindicated with linezolid and selegiline as some individuals may react more sensitively to coadministration.

Concomitant use of pseudoephedrine with other vasoconstrictors, including ergot alkaloids like ergotamine and dihydroergotamine, linezolid, oxytocin, ephedrine, phenylephrine, and bromocriptine, among others, is not recommended due to the possibility of greater increases in blood pressure and risk of hemorrhagic stroke. Sympathomimetic effects and cardiovascular risks of pseudoephedrine may also be increased with digitalis glycosides, tricyclic antidepressants, appetite suppressants, and inhalational anesthetics. Likewise, greater sympathomimetic effects of pseudoephedrine may occur when it is combined with other sympathomimetic agents. Rare but serious cardiovascular complications have been reported with the combination of pseudoephedrine and bupropion.[58] [59] Increase of ectopic pacemaker activity can occur when pseudoephedrine is used concomitantly with digitalis. The antihypertensive effects of methyldopa, guanethidine, mecamylamine, reserpine, and veratrum alkaloids may be reduced by sympathomimetics like pseudoepehdrine. Beta blockers like labetalol may reduce the effects of pseudoephedrine.[60] [61]

Urinary acidifying agents like ascorbic acid and ammonium chloride can increase the excretion of and thereby reduce exposure to amphetamines including pseudoephedrine, whereas urinary alkalinizing agents including antacids like sodium bicarbonate as well as acetazolamide can reduce the excretion of these agents and thereby increase exposure to them.[62]

Pharmacology

Pharmacodynamics

Pseudoephedrine is a sympathomimetic agent which acts primarily or exclusively by inducing the release of norepinephrine.[63] [64] Hence, it is an indirectly acting sympathomimetic. Some sources state that pseudoephedrine has a mixed mechanism of action consisting of both indirect and direct effects by binding to and acting as an agonist of adrenergic receptors. However, the affinity of pseudoephedrine for adrenergic receptors is described as very low or negligible. Animal studies suggest that the sympathomimetic effects of pseudoephedrine are exclusively due to norepinephrine release.[65] [66]

Monoamine release by pseudoephedrine and related agents (nM)[67]
Compound data-sort-type="number" !data-sort-type="number" !data-sort-type="number" !Ref
Dextroamphetamine (S(+)-amphetamine) 6.6–7.2 5.8–24.8 698–1765 [68] [69]
12.4 18.5 2366
43.1–72.4 236–1350 >10000
218 2104 >10000
Dextromethamphetamine (S(+)-methamphetamine) 12.3–13.8 8.5–24.5 736–1291.7 [70]
Levomethamphetamine (R(–)-methamphetamine) 28.5 416 4640
(+)-Phenylpropanolamine ((+)-norephedrine) 42.1 302 >10000
(–)-Phenylpropanolamine ((–)-norephedrine) 137 1371 >10000
Cathine ((+)-norpseudoephedrine) 15.0 68.3 >10000
30.1 294 >10000
(–)-Pseudoephedrine 4092 9125 >10000
Pseudoephedrine ((+)-pseudoephedrine) 224 1988 >10000
The smaller the value, the more strongly the substance releases the neurotransmitter. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds.

Pseudoephedrine induces monoamine release in vitro with an of 224nM for norepinephrine and 1,988nM for dopamine, whereas it is inactive for serotonin.[71] [72] [73] As such, it is about 9-fold selective for induction of norepinephrine release over dopamine release. The drug has negligible agonistic activity at the α1- and α2-adrenergic receptors (Kact >10,000nM). At the β1- and β2-adrenergic receptors, it acts as a partial agonist with relatively low affinity (β1 = Kact = 309μM, = 53%; β2 = 10μM; = 47%).[74] It was an antagonist or very weak partial agonist of the β3-adrenergic receptor (Kact = ; = 7%). It is about 30,000 to 40,000times less potent as a β-adrenergic receptor agonist than (–)-isoproterenol.

Pseudoephedrine's principal mechanism of action relies on its action on the adrenergic system.[75] [76] The vasoconstriction that pseudoephedrine produces is believed to be principally an α-adrenergic receptor response.[77] Pseudoephedrine acts on α- and β2-adrenergic receptors, to cause vasoconstriction and relaxation of smooth muscle in the bronchi, respectively.[75] [76] α-Adrenergic receptors are located on the muscles lining the walls of blood vessels. When these receptors are activated, 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. Activation of β2-adrenergic receptors produces relaxation of smooth muscle of the bronchi,[75] causing bronchial dilation and in turn decreasing congestion (although not fluid) and difficulty breathing.

Pseudoephedrine is less potent as a sympathomimetic and psychostimulant than ephedrine.[78] Clinical studies have found that pseudoephedrine is about 3.5- to 4-fold less potent than ephedrine as a sympathomimetic agent in terms of blood pressure increases and 3.5- to 7.2-fold or more less potent as a bronchodilator. Pseudoephedrine is also said to have much less central effect than ephedrine and to be only a weak psychostimulant.[79] Blood vessels in the nose are around five times more sensitive than the heart to the actions of circulating epinephrine (adrenaline), which may help to explain how pseudoephedrine at the low doses used in over-the-counter products can produce nasal decongestion with minimal effects on the heart. Compared to dextroamphetamine, pseudoephedrine is about 30 to 35times less potent as a norepinephrine releasing agent and 80 to 350times less potent as a dopamine releasing agent in vitro.

Pseudoephedrine is a very weak reversible inhibitor of monoamine oxidase (MAO) in vitro, including both MAO-A and MAO-B (Ki = 1,000–5,800μM).[80] It is far less potent in this action than other agents like dextroamphetamine and moclobemide.

Pharmacokinetics

Absorption

Pseudoephedrine is orally active and is readily absorbed from the gastrointestinal tract. Its oral bioavailability is approximately 100%. The drug reaches peak concentrations after 1 to 4hours (mean 1.9hours) in the case of the immediate-release formulation and after 2 to 6hours in the case of the extended-release formulation. The onset of action of pseudoephedrine is 30minutes.

Distribution

Pseudoephedrine, due to its lack of polar phenolic groups, is relatively lipophilic. This is a property it shares with related sympathomimetic and decongestant agents like ephedrine and phenylpropanolamine. These agents are widely distributed throughout the body and cross the blood–brain barrier. However, it is said that pseudoephedrine and phenylpropanolamine cross the blood–brain barrier only to some extent and that pseudoephedrine has limited central nervous system activity, suggesting that it is partially peripherally selective. The blood–brain barrier permeability of pseudoephedrine, ephedrine, and phenylpropanolamine is reduced compared to other amphetamines due to the presence of a hydroxyl group at the β carbon which decreases their lipophilicity.[81] As such, they have a greater ratio of peripheral cardiovascular to central psychostimulant effect. Besides entering the brain, these substances also cross the placenta and enter breast milk.

The plasma protein binding of pseudoephedrine has been reported to be approximately 21 to 29%. It is bound to α1-acid glycoprotein (AGP) and albumin (HSA).

Metabolism

Pseudoephedrine is not extensively metabolized and is subjected to minimal first-pass metabolism with oral administration. Due to its methyl group at the α carbon (i.e., it is an amphetamine), pseudoephedrine is not a substrate for monoamine oxidase (MAO) and is not metabolized by this enzyme.[82] It is also not metabolized by catechol O-methyltransferase (COMT). Pseudoephedrine is demethylated into the metabolite norpseudoephedrine to a small extent. Similarly to pseudoephedrine, this metabolite is active and shows amphetamine-like effects. Approximately 1 to 6% of pseudoephedrine is metabolized in the liver via N-demethylation to form norpseudoephedrine.

Elimination

Pseudoephedrine is excreted primarily via the kidneys in urine. Its urinary excretion is highly influenced by urinary pH and is decreased when the urine is acidic and is increased when it is alkaline.

The elimination half-life of pseudoephedrine on average is 5.4hours and ranges from 3 to 16hours depending on urinary pH. At a pH of 5.6 to 6.0, the elimination half-life of pseudoephedrine was 5.2 to 8.0hours. In one study, a more acidic pH of 5.0 resulted in a half-life of 3.0 to 6.4hours, whereas a more alkaline pH of 8.0 resulted in a half-life of 9.2 to 16.0hours. Substances that influence urinary acidity and are known to affect the excretion of amphetamine derivatives include urinary acidifying agents like ascorbic acid and ammonium chloride as well as urinary alkalinizing agents like acetazolamide.[83]

A majority of an oral dose of pseudoephedrine is excreted unchanged in urine within 24hours of administration. This has been found to range from 43 to 96%. The amount excreted unchanged is dependent on urinary pH similarly to the drug's half-life, as a longer half-life and duration in the body allows more time for the drug to be metabolized.

The duration of action of pseudoephedrine, which is dependent on its elimination, is 4 to 12hours.

Pseudoephedrine has been reported to accumulate in people with renal impairment.[84] [85] [86]

Chemistry

Pseudoephedrine, also known structurally as (1S,2S)-α,N-dimethyl-β-hydroxyphenethylamine or as (1S,2S)-N-methyl-β-hydroxyamphetamine, is a substituted phenethylamine and amphetamine derivative. It is a diastereomer of ephedrine.

Pseudoephedrine is a small-molecule compound with the molecular formula C10H15NO and a molecular weight of 165.23g/mol.[87] [88] It has an experimental log P of 0.89, while its predicted log P values range from 0.9 to 1.32.[89] The compound is relatively lipophilic,[90] but is also more hydrophilic than other amphetamines. The lipophilicity of amphetamines is closely related to their brain permeability.[91] For comparison to pseudoephedrine, the experimental log P of methamphetamine is 2.1,[92] of amphetamine is 1.8,[93] of ephedrine is 1.1,[94] of phenylpropanolamine is 0.7,[95] of phenylephrine is -0.3,[96] and of norepinephrine is -1.2.[97] Methamphetamine has high brain permeability, whereas phenylephrine and norepinephrine are peripherally selective drugs.[98] The optimal log P for brain permeation and central activity is about 2.1 (range 1.5–2.7).[99]

Pseudoephedrine is readily reduced into methamphetamine or oxidized into methcathinone.

Nomenclatures

The dextrorotary (+)- or d- enantiomer is (1S,2S)-pseudoephedrine, whereas the levorotating (−)- or l- form is (1R,2R)-pseudoephedrine.

In the outdated system (+)-pseudoephedrine is also referred to as pseudoephedrine and (−)-pseudoephedrine as pseudoephedrine (in the Fisher projection then the phenyl ring is drawn at bottom).[100] [101]

Often the 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 pseudoephedrine and the levorotary l-ephedrine (the diastereomer) wrongly 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.

Pseudoephedrine is the of the (+)-form, when used as pharmaceutical substance.[102]

Detection in body fluids

Pseudoephedrine may be quantified in blood, plasma, or urine to monitor any possible performance-enhancing use by athletes, confirm a diagnosis of poisoning, or to assist in a medicolegal death investigation. Some 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 to 300μg/L range in persons taking the drug therapeutically, 500 to 3,000μg/L in people with substance use disorder involving pseudoephedrine or poisoned patients, and 10 to 70mg/L in cases of acute fatal overdose.[103] [104]

Manufacturing

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.[105]

The bulk of pseudoephedrine is produced by commercial pharmaceutical manufacturers in India and China, where economic and industrial conditions favor its mass production for export.[106]

History

Pseudoephedrine, along with ephedrine, occurs naturally in ephedra.[107] This herb has been used for thousands of years in traditional Chinese medicine. Pseudoephedrine was first isolated and characterized in 1889 by the German chemists Ladenburg and Oelschlägel, who used a sample that had been isolated from Ephedra vulgaris by the Merck pharmaceutical corporation of Darmstadt, Germany.[108] It was first synthesized in the 1920s in Japan. Subsequently, pseudoephedrine was introduced for medical use as a decongestant.

Society and culture

Generic names

Pseudoephedrine is the generic name of the drug and its and, while pseudoéphédrine is its and pseudoefedrina is its .[109] [110] [111] [112] Pseudoephedrine hydrochloride is its and in the case of the hydrochloride salt; pseudoephedrine sulfate is its in the case of the sulfate salt; pseudoephedrine polistirex its in the case of the polistirex form; and d-isoephedrine sulfate is its in the case of the sulfate salt. Pseudoephedrine is also known as Ψ-ephedrine and isoephedrine.

Brand names

The following is a list of consumer medicines that either contain pseudoephedrine or have switched to a less-regulated alternative such as phenylephrine.

Recreational use

Over-the-counter pseudoephedrine has been misused as a psychostimulant.[116] Six case reports and one case series of pseudoephedrine misuse have been published as of 2021. There is a case report of self-medication with pseudoephedrine in massive doses for treatment of depression.[117]

Use in exercise and sports

Pseudoephedrine has been used as a performance-enhancing drug in exercise and sports due to its sympathomimetic and stimulant effects.[118] [119] Because of these effects, pseudoephedrine can increase heart rate, elevate blood pressure, improve mental energy, and reduce fatigue, among other performance-enhancing effects.

A 2015 systematic review found that pseudoephedrine lacked performance-enhancing effects at therapeutic doses (60–120mg) but significantly enhanced athletic performance at supratherapeutic doses (≥180mg). A subsequent 2018 meta-analysis, which included seven additional studies, found that pseudoephedrine had a small positive effect on heart rate (= 0.43) but insignificant effects on time trials, perceived exertion ratings, blood glucose levels, and blood lactate levels. However, subgroup analyses revealed that effect sizes were larger for heart rate increases and quicker time trials in well-trained athletes and younger participants, for shorter exercise sessions with pseudoephedrine administered within 90minutes beforehand, and with higher doses of pseudoephedrine. A dose–response relationship was established, with larger doses (>170mg) showing greater increases in heart rate and faster time trials than with smaller doses (≤170mg) (= 0.85 for heart rate and = -0.24 for time trials, respectively). In any case, the meta-analysis concluded that the performance-enhancing effects of pseudoephedrine were marginal to small and likely to be lower in magnitude than with caffeine. It is relevant in this regard that caffeine is a permitted stimulant in competitive sports.

Pseudoephedrine was on the International Olympic Committee's (IOC) banned substances list until 2004, when the World Anti-Doping Agency (WADA) list replaced the IOC list. Although WADA initially only monitored pseudoephedrine, it went back onto the "banned" list on 1 January 2010.[120]

Pseudoephedrine is excreted through urine, and concentration in urine of this drug shows a large inter-individual spread; that is, the same dose can give a vast difference in urine concentration for different individuals.[121] Pseudoephedrine is approved to be taken up to 240 mg per day. In seven healthy male subjects this dose yielded a urine concentration range of 62.8 to 294.4 microgram per milliliter (μg/mL) with mean ± standard deviation 149 ± 72 μg/mL.[122] Thus, normal dosage of 240 mg pseudoephedrine per day can result in urine concentration levels exceeding the limit of 150 μg/mL set by WADA for about half of all users.[123] Furthermore, hydration status does not affect urinary concentration of pseudoephedrine.[124]

List of doping cases

Manufacture of amphetamines

Its membership in the amphetamine class 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, pharmaceutical firms have reformulated medications to use alternative compounds, particularly phenylephrine, even though its efficacy as an oral decongestant has been demonstrated to be indistinguishable from placebo.[134]

In the United States, federal laws control the sale of pseudoephedrine-containing products.[135] Retailers in the US have created corporate policies restricting the sale of pseudoephedrine-containing products.[136] [137] Their policies restrict sales by limiting purchase quantities and requiring a minimum age and government issued photographic 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.[138]

Legal status

Australia

Illicit diversion of pseudoephedrine in Australia has caused significant changes to the way the products are regulated., 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.[139]

As a result, some pharmacies no longer stock Sudafed, the common brand of pseudoephedrine cold/sinus tablets, opting instead to sell Sudafed PE, a phenylephrine product that has not been proven effective in clinical trials.[134] [140]

Belgium

Several formulations of pseudoephedrine are available over-the-counter in Belgium.[141]

Canada

Health Canada has investigated the risks and benefits of pseudoephedrine and ephedrine/Ephedra. Near the end of the study, Health Canada issued a warning on their website stating that those who are under the age of 12, or who have heart disease and may have strokes, should avoid taking pseudoephedrine and ephedrine. Also, they warned that everyone should avoid taking ephedrine or pseudoephrine with other stimulants like caffeine. They also banned all products that contain both ephedrine (or pseudoephedrine) and caffeine.[142]

Products whose only medicinal ingredient is pseudoephedrine must be kept behind the pharmacy counter. Products containing pseudoephedrine along with other medicinal ingredients may be displayed on store shelves but may be sold only in a pharmacy when a pharmacist is present.[143] [144]

Colombia

The Colombian government prohibited the trade of pseudoephedrine in 2010.[145]

Estonia

Pseudoephedrine is an over-the-counter drug in Estonia.[146]

Finland

Pseudoephedrine medicines can only be obtained with a prescription in Finland.[147]

Japan

Medications that contain more than 10% pseudoephedrine are prohibited under the Stimulants Control Law in Japan.[148]

Mexico

On 23 November 2007, the use and trade of pseudoephedrine in Mexico was made illegal as it was argued that it was extremely popular as a precursor in the synthesis of methamphetamine.[149]

Netherlands

Pseudoephedrine was withdrawn from sale in 1989 due to concerns about adverse cardiac side effects.[150]

New Zealand

Since April 2024, pseudoephedrine has been classified as a restricted (pharmacist-only) drug in the Misuse of Drugs Act 1975 which allows the purchase of medicines containing pseudoephedrine from a pharmacist without a prescription.[151]

Pseudoephedrine, ephedrine, and any product containing these substances, e.g. cold and flu medicines, were first classified in October 2004 as Class C Part III (partially exempted) controlled drugs, due to being the principal ingredient in methamphetamine.[152] New Zealand Customs and police officers continued 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.[153] The law was amended by The Misuse of Drugs Amendment Bill 2010, which passed in August 2011.[154]

On 24 November 2023, the recently-formed National-led coalition government announced that the sale of cold medication containing pseudoephedrine would be allowed (as part of the coalition agreement between the National and ACT parties).[155]

Turkey

In Turkey, medications containing pseudoephedrine are available with prescription only.[156]

United Kingdom

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.[157] No form of ID is required.

United States

Federal

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, 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 all chemicals that had been turned into a legal final product, such as Sudafed.[158]

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. This reduction in purity was usually short lived, however, as methamphetamine producers eventually found a way around the new regulations.[159]

Congress passed the Combat Methamphetamine Epidemic Act of 2005 (CMEA) as an amendment to the renewal of the USA Patriot Act.[160] Signed into law by president George W. Bush on 6 March 2006, the act amended, concerning the sale of pseudoephedrine-containing products. The law mandated two phases, the first needing to be implemented by 8 April 2006, and the second to be completed by 30 September 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.[161] 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.[161] Pseudoephedrine was defined as a "scheduled listed chemical product" under (45(A)). The act included the following requirements for merchants ("regulated sellers") who sell such products:

The requirements were revised in the Methamphetamine Production Prevention Act of 2008 to require that a regulated seller of scheduled listed chemical products may not sell such a product unless the purchaser:[162]

State

Most states also have laws regulating pseudoephedrine.[163] [164] [165]

The states of Alabama, Arizona, Arkansas, California, Colorado, Delaware, Florida, Georgia, Hawaii Idaho, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana, Massachusetts, Michigan, Minnesota, Mississippi, Missouri, Montana, Nebraska,[166] Nevada, New Jersey, North Carolina, Ohio, Oklahoma, Oregon, Pennsylvania, South Dakota, Tennessee, Texas, Utah, Vermont, Virginia, Washington, West Virginia and Wisconsin have laws requiring pharmacies to sell pseudoephedrine "behind the counter". Though the drug can be purchased without a prescription, states can limit the number of units sold and can collect personal information from purchasers.[167]

The states of Oregon and Mississippi previously required a prescription for the purchase of products containing pseudoephedrine. However as of 1 January 2022 these restrictions have been repealed.[168] [169] The state of Oregon reduced the number of methamphetamine lab seizures from 448 in 2004 (the final full year before implementation of the prescription only law).[170] to a new low of 13 in 2009.[171] The decrease in meth lab incidents in Oregon occurred largely before the prescription-only law took effect, according to a NAMSDL report titled Pseudoephedrine Prescription Laws in Oregon and Mississippi.[167] The report posits that the decline in meth lab incidents in both states may be due to other factors: "Mexican traffickers may have contributed to the decline in meth labs in Mississippi and Oregon (and surrounding states) as they were able to provide ample supply of equal or greater quality meth at competitive prices". Additionally, similar decreases in meth lab incidents were seen in surrounding states, according to the report, and meth-related deaths in Oregon have dramatically risen since 2007. Some municipalities in Missouri have enacted similar ordinances, including Washington,[172] Union,[173] New Haven,[174] Cape Girardeau[175] and Ozark.[176] Certain pharmacies in Terre Haute, Indiana do so as well.[177]

Another approach to controlling the drug on the state level 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. Thirty-two states now require the National Precursor Log Exchange (NPLEx) to be used for every pseudoephedrine and ephedrine OTC purchase, and ten of the eleven largest pharmacy chains in the US voluntarily contribute all of their similar transactions to NPLEx. These states have seen dramatic results in reducing the number of methamphetamine laboratory seizures. 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.[171] Kentucky's program was implemented statewide in 2008, and since statewide implementation, the number of laboratory seizures has significantly decreased.[171] 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. In 2008, however, seizures began rising again, and have continued to rise in 2009.[171]

NPLEx appears to be successful by requiring the real-time submission of transactions, thereby enabling the relevant laws to be enforced at the point of sale. By creating a multi-state database and the ability to compare all transactions quickly, NPLEx enables pharmacies to deny purchases that would be illegal based on gram limits, age, or even to convicted meth offenders in some states. NPLEx also enforces the federal gram limits across state lines, which was impossible with state-operated systems. Access to the records is by law enforcement agencies only, through an online secure portal.[178]

Research

Pseudoephedrine has been studied in the treatment of snoring.[179] However, data are inadequate to support this use.

A study has found that pseudoephedrine can reduce milk production in breastfeeding women.[180] [181] This might have been due to suppression of prolactin secretion. Pseudoephedrine might be useful for lactation suppression.

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