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Pseudoephedrine, sold under the brand name Sudafed among others, is a sympathomimetic medication which is used as a decongestant to treat nasal congestion. It has also been used off-label use for certain other indications, like treatment of hypotension. 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, elevated heart rate, increased blood pressure, restlessness, dizziness, anxiety, and dry mouth, among others. 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. It is the (1 S,2 S)-enantiomer of β-hydroxy- N-methylamphetamine.
Along with ephedrine, pseudoephedrine occurs natural product in ephedra, which has been used for thousands of years in traditional Chinese medicine. It was first chemical isolate from ephedra in 1889. Subsequent to its synthesis in the 1920s, pseudoephedrine was introduced for medical use as a decongestant. Pseudoephedrine is widely available over-the-counter (OTC) in both single-drug and combination drug dosage form. 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. In 2022, the combination with brompheniramine and dextromethorphan was the 265th most commonly prescribed medication in the United States, with more than 1million prescriptions. In 2022, the combination with loratadine was the 289th most commonly prescribed medication in the United States, with more than 500,000 prescriptions.
Pseudoephedrine can be used either as oral or as topical decongestant. Due to its psychostimulant qualities, however, the oral preparation is more likely to cause adverse effects, including urinary retention. According to one study, pseudoephedrine may show effectiveness as an antitussive drug (suppression of Cough medicine).
Pseudoephedrine is indicated for the treatment of nasal congestion, sinus congestion, and Eustachian tube congestion. 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.
There has been interest in pseudoephedrine as an appetite suppressant for the treatment of obesity. However, due to lack of clinical data and potential cardiovascular side effects, this use is not recommended. Only a single placebo-controlled trial 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). 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.
Pseudoephedrine has been used limitedly in the treatment of orthostatic intolerance including orthostatic hypotension and postural orthostatic tachycardia syndrome (POTS). 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. However, data on this use are limited to and case series.
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. 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.
Pseudoephedrine is also available over-the-counter and prescription-only combination drug with numerous other drugs, including (acrivastine, azatadine, brompheniramine, cetirizine, chlorpheniramine, clemastine, desloratadine, dexbrompheniramine, diphenhydramine, fexofenadine, loratadine, triprolidine), (acetaminophen, codeine, hydrocodone, ibuprofen, naproxen), cough suppressants (dextromethorphan), and (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.
Due to its sympathomimetic effects, pseudoephedrine is a vasoconstrictor and 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 cardiac arrest 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. 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 dysautonomia, 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 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 drug withdrawal from pseudoephedrine. The withdrawal symptoms included worsened mood and sadness, profoundly decreased mental 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. However, it is substantially less potent than methamphetamine or cocaine.
Concomitant use of pseudoephedrine with other , including 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. (2025). 9781461474944, Springer New York. ISBN 9781461474944 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. like labetalol may reduce the effects of pseudoephedrine.
Acidifier like ascorbic acid and ammonium chloride can increase the excretion of and thereby reduce exposure to amphetamines including pseudoephedrine, whereas urinary alkalinizing agents including like sodium bicarbonate as well as acetazolamide can reduce the excretion of these agents and thereby increase exposure to them.
Pseudoephedrine induces monoamine release in vitro with an of 224nM for norepinephrine and 1,988nM for dopamine, whereas it is inactive for serotonin. 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%). 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. The vasoconstriction that pseudoephedrine produces is believed to be principally an α-adrenergic receptor response. Pseudoephedrine acts on α- and β2-adrenergic receptors, to cause vasoconstriction and relaxation of smooth muscle in the bronchi, respectively. 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 the smooth muscle of the bronchi, 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. 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. 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). It is far less potent in this action than other agents like dextroamphetamine and moclobemide.
The plasma protein binding of pseudoephedrine has been reported to be approximately 21 to 29%. It is bound to orosomucoid (AGP) and albumin (HSA).
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 acidifier like ascorbic acid and ammonium chloride as well as urinary alkalinizing agents like acetazolamide.
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. (1998). 9780444828187, Elsevier. ISBN 9780444828187
Pseudoephedrine is a small molecule compound with the molecular formula C10H15NO and a molecular weight of 165.23g/mol. It has an experimental log P of 0.89, while its predicted log P values range from 0.9 to 1.32. The compound is relatively lipophilic, but is also more hydrophilic than other amphetamines. The lipophilicity of amphetamines is closely related to their brain permeability. For comparison to pseudoephedrine, the experimental log P of methamphetamine is 2.1, of amphetamine is 1.8, of ephedrine is 1.1, of phenylpropanolamine is 0.7, of phenylephrine is -0.3, and of norepinephrine is -1.2. Methamphetamine has high brain permeability, whereas phenylephrine and norepinephrine are peripherally selective drugs. The optimal log P for brain permeation and central activity is about 2.1 (range 1.5–2.7).
Pseudoephedrine is readily redox into methamphetamine or oxidized into methcathinone.
In the outdated (+)-pseudoephedrine is also referred to as pseudoephedrine and (−)-pseudoephedrine as pseudoephedrine (in the Fischer projection then the phenyl ring is drawn at bottom).
Often the system (with small caps) and the (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 (1 S,2 S)- respectively (1 R,2 R)-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. Proposed International Non-Proprietary Names (Prop. I.N.N.): List 11 WHO Chronicle, Vol. 15, No. 8, August 1961, pp. 314–20
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.
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 lactic acid levels. However, subgroup analyses revealed that 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.
Pseudoephedrine is excreted through urine, and the 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. 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. 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. Furthermore, hydration status does not affect the urinary concentration of pseudoephedrine.
In the United States, federal laws control the sale of pseudoephedrine-containing products. Retailers in the US have created corporate policies restricting the sale of pseudoephedrine-containing products. 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.
Pharmacists are also encouraged (and in some states required) to log purchases with the online database Project STOP.
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.
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.
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. 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. The law was amended by The Misuse of Drugs Amendment Bill 2010, which passed in August 2011.
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).
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 several 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.
Before 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 its 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.
Congress 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 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 the 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 (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:
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, 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.''
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. 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) to a new low of 13 in 2009. 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. 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, 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 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. Before the 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, and since statewide implementation, the number of laboratory seizures has significantly decreased. Oklahoma initially experienced success with its 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.
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.
A study has found that pseudoephedrine can reduce lactation in breastfeeding women. This might have been due to suppression of prolactin secretion. Pseudoephedrine might be useful for lactation suppression.
Research
Pseudoephedrine has been studied in the treatment of snoring. However, data are inadequate to support this use.
Categories: Amphetamine Alkaloids, Anorectics, Anti-obesity Drugs, Antihypotensive Agents, Beta-hydroxyamphetamines, Cardiac Stimulants, Decongestants, Drugs Acting On The Cardiovascular System, Drugs Acting On The Nervous System, Drugs In Sport, Enantiopure Drugs, Ergogenic Aids, Euphoriants, Methamphetamine, Methamphetamines, Norepinephrine Releasing Agents, Peripherally Selective Drugs, Stimulants, Sympathomimetics, Traditional Chinese Medicine, Wakefulness-promoting Agents, World Anti-doping Agency Prohibited Substances
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