Clinical data | |||
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Trade names | Benzedrex, Obesin, Dristan Inhaler, and others | ||
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AHFS/Drugs.com | Monograph | ||
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Routes of administration | Medical: Intranasal (inhaler) and oral Recreational: Oral and parenteral routes | ||
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Pharmacokinetic data | |||
Elimination half-life | 4 ± 1.5 hours | ||
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CompTox Dashboard (EPA) | |||
ECHA InfoCard | 100.002.673 | ||
Chemical and physical data | |||
Formula | C10H21N | ||
Molar mass | 155.285 g·mol−1 | ||
3D model (JSmol) | |||
Chirality | Racemic mixture | ||
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Propylhexedrine, commonly sold under the brand name Benzedrex, is an alkylamine primarily utilized as a topical nasal decongestant. [1] Its main indications are relief of congestion due to colds, allergies, and allergic rhinitis. [2]
Propylhexedrine is used to treat acute nasal congestion related to the common cold, allergies and hay fever. For nasal congestion, the dosage is listed as four inhalations (two inhalations per nostril) every two hours for adults and children 6–12 years of age. Each inhalation delivers 0.4 to 0.5 milligrams (400 to 500 μg) in 800 millilitres of air. [2] [3] Use is not to exceed three days. [2]
Historically, it has also been used for weight loss in oral tablet preparations at doses ranging from 5 to 30 milligrams. [4] No medications containing propylhexedrine are currently approved for weight loss in any country since roughly 1976. [5] [6]
Propylhexedrine should not be used if a MAOI has been used in the past 14 days or is currently in use by a person. [7]
Unlike other topical decongestants, propylhexedrine is not required to carry a warning against use in individuals with hypertension. [8]
Propylhexedrine is contraindicated in individuals under six years old. [9] There is at least one case of reported accidental poisoning resulting from a child's access to a propylhexedrine product. [10]
When used as an inhaler, the most common adverse effects warned about for propylhexedrine are temporary discomfort (e.g., stinging or burning sensations) or rebound congestion. [2] The sharing of propylhexedrine inhalers may spread infection. [2] The occurrence of these adverse effects is uncommon as propylhexedrine is generally recognized as safe and effective. [11] However, the use of propylhexedrine products in manners not intended by their labeling can result in severe adverse effects not typically encountered in therapeutic settings. [12] [13] [14] The outcomes of improperly using propylhexedrine products can include hospitalization, disability, or even death. [11] Public health agencies such as the FDA have advised propylhexedrine products only be used in the manners directed on their label. [11]
Reports of overdoses from propylhexedrine have been documented, but they are uncommon. [15] Most instances of overdoses attributed to propylhexedrine have been the result of improper use of a propylhexedrine product in a manner not intended by its labeling for (non-medical) recreational purposes. [12] As noted by the FDA, the most common symptoms of propylhexedrine overdose are the following: "...[R]apid heart rate, agitation, high blood pressure, chest pain, tremor, hallucinations, delusions, confusion, nausea, and vomiting." [12] The use of propylhexedrine products in manners inconsistent with their labeling has proven fatal in some cases. [16] [17] Propylhexedrine products are considered to be safe and effective if used as intended. [12] Regardless, medical attention should be sought in the case of suspected overdose. [18]
As referred to earlier, most of propylhexedrine's interactions with other medications have to do with its ability to constrict blood vessels. This means that propylhexedrine may interact adversely with certain stimulants, bronchodilators, sympathomimetics, nasal decongestants, and antidepressants. Caution should be exercised when administering propylhexedrine concurrently with other medicines. [19]
Propylhexedrine works mainly as an adrenergic agonist, when used at therapeutic doses in an inhaler dosage form. [19] This restricts the blood vessels in the nose and reduces swelling; thereby, the product relieves nasal congestion. [20] At higher doses, propylhexedrine affects the central nervous system as a norepinephrine–dopamine releasing agent. [21] Propylhexedrine likely exerts such effects in a manner similar to related alkylamines such as cyclopentamine, methylhexanamine, and tuaminoheptane. [22] [23] [24] In addition, propylhexedrine further releases monoamines through TAAR1 agonism and VMAT2 inhibition. [19] Propylhexedrine also exhibits antihypotensive effects. [25]
Propylhexedrine undergoes metabolism via N-demethylation, C-oxidation, N-oxidation, dehydration, and hydrolysis to form various metabolites such as norpropylhexedrine, cyclohexylacetoxime, cyclohexylacetone, and 4-hydroxypropylhexedrine. [26]
Freebase propylhexedrine is a volatile, oily liquid at room temperature. The slow evaporation of freebase propylhexedrine allows it to be administered via inhalation. [28] The evaporation of the freebase also accounts for the limited shelf-life of propylhexedrine inhalers. Many of the salts of propylhexedrine are stable, clear to off-white crystalline substances that readily dissolve in water. [29]
Propylhexedrine is similar in chemical structure to phenylethylamines. Phenylethylamines and substituted phenethylamines are found in the core of many trace amines and sympathomimetic drugs. The main difference is the presence of an alicyclic cyclohexyl group instead of the aromatic phenyl group of a phenethylamine.
Propylhexedrine is a chiral compound. The active ingredient contained in Benzedrex inhalers is racemic (RS)-propylhexedrine as the free base. [30] (S)-Propylhexedrine, also known as levopropylhexedrine, is believed to be the more biologically active isomer of the two. [31] The dextrorotatory counterpart, which is mainly unused, is dextropropylhexedrine.
Propylhexedrine can be synthesized from cyclohexylacetone through the reductive amination of an intermediary imine over an aluminum-mercury amalgam in the presence of a hydrogen source. [32]
However, propylhexedrine is more commonly prepared by the catalytic hydrogenation of methamphetamine over Adams' catalyst. This transforms methamphetamine's phenyl ring to a cyclohexyl moiety. [33]
Due to its structure, administration of propylhexedrine can lead to false-positives for phenethylamine-derivatives on urinalysis panels. [34] Propylhexedrine can be differentiated upon further analysis. [35]
Propylhexedrine's medical use as a decongestant evolved from desires to find safer alternatives to previous agents. [36] After searching for such an agent, Dr. Glenn E. Ullyot patented propylhexedrine as a decongestant in 1948. This patent was issued for benefit of Smith, Kline & French. [37] Before it was sold nationally in the United States, propylhexedrine underwent market trials in California. These market trials began on July 15, 1949. [38] Propylhexedrine (under the brand-name Benzedrex) was first introduced into interstate commerce on August 4, 1949. [39]
Approval for use in the United Kingdom soon followed in 1956. [15] Later, approval for use in Canada was granted in 1998. [40] In 2023, B. F. Ascher & Co. decreased the amount of propylhexedrine in the Benzedrex inhaler from its historic 250 milligrams down to 175 milligrams. [41]
Barbexaclone, an anticonvulsant containing propylhexedrine, was used in Turkey until its withdrawal from the market in 2009. Barbexaclone's former niche in Turkish medicine is now largely-occupied by levetiracetam. [42]
The manufacture of propylhexedrine products for therapeutic use is typically performed based on guidelines established in government regulations and pharmacopeia monographs. [43] [3]
The illicit manufacture or diversion of propylhexedrine by clandestine chemists for use as a recreational drug has been documented in academic literature. [35] Similar to when opioids are manufactured clandestinely for recreational use, it is unlikely that propylhexedrine produced by clandestine chemists adheres to the standards for purity, identity, and strength required of therapeutic products. [44]
Propylhexedrine was placed under international control by the Convention on Psychotropic Substances in 1985. This action was reversed in 1991. [45]
Propylhexedrine was long reported to be a Schedule V substance in Canada. [48] In 2023, this status changed and propylhexedrine has since been removed from Schedule V. [49]
Propylhexedrine is regulated as a prescription medicine in Germany. [50] Initially, propylhexedrine products (namely Obesin) were available over-the-counter. However, this changed in the 1970s and propylhexedrine is now regulated as a prescription product in Germany. [5]
It was formerly a Class C substance in the United Kingdom, but was deregulated in 1995. [51] Propylhexedrine was used recreationally during a brief period in the 1970s after increased government regulation on earlier decongestants due to misuse. [52]
On the 4th of April 1988, propylhexedrine was designated a controlled substance (Schedule V) in the United States. [53] This was done to satisfy U.S. compliance with an international treaty. However, in 1991, this action was reversed and propylhexedrine was removed from control under the Controlled Substances Act. This was based on the opinion of the Drug Enforcement Administration that propylhexedrine did not warrant control. [54] The substance has remained unregulated under the Controlled Substances Act in the United States ever since. Furthermore, pursuant to DEA regulations, certain Benzedrex inhalers are specifically exempt from the Controlled Substances Act. [55] [56] Propylhexedrine remains regulated under the laws of several U.S. states. These states include the states of Alaska, [57] Arizona, [58] Florida, [59] Georgia, [60] Idaho, [61] Kansas, [62] and Rhode Island. [63]
Multiple public health agencies (most notably within the United States) have warned against the recreational use of propylhexedrine and advised for its use only as directed by a product's labeling; nonetheless it has been reported, through the literature as early as 1959, that propylhexedrine products have been used for recreational purposes. [64] Recreational use is potentially fatal, its risks are magnified when administering the substance through injection means, and the adverse effects of recreational propylhexedrine are more severe when compared to related substances. [65] [66] [67] The undesirable side effects of propylhexedrine at recreational doses are less tolerable compared to other substances that produce similar effects; consequently, making propylhexedrine less desirable for recreational use. [18] [68] [16] The fact that propylhexedrine is less potent than comparable substances has also limited recreational use. [69] [70] Even in areas with prevalent substance use, the use of propylhexedrine was reported as non-significant. [15] The recreational use of nasal decongestant, [68] [71] anorectic, [64] and anticonvulsant preparations [72] have all been reported. The recreational use of propylhexedrine products has been on the rise since the early 2000s. [21]
In 2021, the United States Food & Drug Administration issued the following warning [12] in regard to recreational use of propylhexedrine products in manners inconsistent with their labeling:
"...[T]he abuse and misuse of the over-the-counter (OTC) nasal decongestant propylhexedrine can lead to serious harm such as heart and mental health problems. Some of these complications, which include fast or abnormal heart rhythm, high blood pressure, and paranoia, can lead to hospitalization, disability, or death....Propylhexedrine is safe and effective when used as directed."
That same year, the Indian Health Service issued the following statement [13] in reference to the recreational use of propylhexedrine products:
"Only use propylhexedrine according to the instructions on the package label. Do not use it in ways other than inhalation. Seek medical attention immediately for by calling [emergency services] or Poison Control...for anyone using propylhexedrine who experiences [the following.] [These following reactions are] [s]evere anxiety or agitation, confusion, hallucinations, or paranoia[,] [r]apid heartbeat or abnormal heart rhythm[,] [or] [c]hest pain or tightness[.]"
A year later, in 2022, the U.S. Army published the following guidance [14] on propylhexedrine. The guidance states that recreational use of propylhexedrine is not permissible by service-members, can open its participants up to disciplinary action, and carries potentially fatal risks:
"When disciplining a member for suspected use of any drug, it is important to consult [legal counsel] on how to proceed, [according to the Office of Drug Demand Reduction]...This is especially important when the evidence supporting discipline consists of scientific reports and data that may require special assistance in their interpretation. In cases involving [propylhexedrine], legal consultation is highly recommended."
Summarily, the Food & Drug Administration, Indian Health Service, and U.S. Army all advise individuals not to use propylhexedrine products for recreational purposes.
Propylhexedrine, under the brand name Benzedrex, is sold online by retailers such as Amazon, eBay, and Walmart. [30] Propylhexedrine has been sold in some countries as an anorectic or as part of an anticonvulsant preparation; however, such products are not sold freely to consumers and require a physician's prescription.
Propylhexedrine, as a nasal decongestant, is currently marketed under the trade name Benzedrex. The name Benzedrex was initially trademarked by Smith, Kline & French in 1944. [73] The brand was passed onto Menley James Laboratories (through a subsidiary, NuMark Laboratories) in 1990, and was finally acquired by B. F. Ascher & Co. in 1998. [74] [75]
Propylhexedrine was also sold in inhaler form by Whitehall Laboratories under the Dristan brand name as an inhaler. [76] In January 1966, propylhexedrine replaced mephentermine as the active ingredient in the product. [77] The Dristan inhaler has since been discontinued. Furthermore, Wyeth was acquired by Pfizer in 2009. All products currently sold under the Dristan brand are manufactured by Foundation Consumer Brands; Foundation Consumer Brands acquired the Dristan brand in 2020. [78] Foundation Consumer Brands is itself owned by Kelso & Company.
Propylhexedrine has also seen use in Europe as an appetite suppressant, under the trade name Obesin. [38] Obesin has been referenced in literature dating back to the 1950s. [10] [64] Obesin was manufactured by Fahlberg-List in East Germany from 1958 to around 1976. The discontinuation of Obesin was the result of increased regulatory restrictions on over-the-counter anorectics. These restrictions began to be imposed in 1974. [5] Fahlberg-List itself dissolved in 1995.
Propylhexedrine is a component in the anticonvulsant preparation barbexaclone. Its S-isomer (levopropylhexedrine or L-propylhexedrine) is bonded with phenobarbital for the purpose of offsetting the barbiturate-induced sedation. [38] Barbexaclone has been known under the brand name of Maliasin, manufactured by Abbott Laboratories, as early as 1965. [79] [80] Maliasin has also been manufactured by Knoll Pharmaceuticals; Knoll is a company acquired by Abbott Laboratories. In 2010, Abbott discontinued sale of its barbexaclone preparation in many countries. [81]
Levopropylhexedrine (the more active optical isomer of propylhexedrine) has been used as an appetite suppressant under the brand name Eventin. Eventin's use has been documented as early as 1958. [82]
Dextromethorphan, or DXM, a common active ingredient found in many over-the-counter cough suppressant cold medicines, is used as a recreational drug and entheogen for its dissociative effects. It has almost no psychoactive effects at medically recommended doses. However, dextromethorphan has powerful dissociative properties when administered in doses well above those considered therapeutic for cough suppression. Recreational use of DXM is sometimes referred to in slang form as "robo-tripping", whose prefix derives from the Robitussin brand name, or "Triple Cs", which derives from the Coricidin brand whose tablets are printed with "CC+C" for "Coricidin Cough and Cold". However, this brand presents additional danger when used at recreational doses due to the presence of chlorpheniramine.
Pseudoephedrine (PSE) is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It may be used as a nasal/sinus decongestant, as a stimulant, or as a wakefulness-promoting agent in higher doses.
Xylometazoline, also spelled xylomethazoline, is a medication used to reduce symptoms of nasal congestion, allergic rhinitis, and sinusitis. Use is not recommended for more than seven days. Use is also not recommended in those less than three months of age and some say not less than 6 years of age. It is used directly in the nose as a spray or drops.
Cold medicines are a group of medications taken individually or in combination as a treatment for the symptoms of the common cold and similar conditions of the upper respiratory tract. The term encompasses a broad array of drugs, including analgesics, antihistamines and decongestants, among many others. It also includes drugs which are marketed as cough suppressants or antitussives, but their effectiveness in reducing cough symptoms is unclear or minimal.
A decongestant, or nasal decongestant, is a type of pharmaceutical drug that is used to relieve nasal congestion in the upper respiratory tract. The active ingredient in most decongestants is either pseudoephedrine or phenylephrine. Intranasal corticosteroids can also be used as decongestants and antihistamines can be used to alleviate runny nose, nasal itch, and sneezing.
Dihydrocodeine is a semi-synthetic opioid analgesic prescribed for pain or severe dyspnea, or as an antitussive, either alone or compounded with paracetamol (acetaminophen) or aspirin. It was developed in Germany in 1908 and first marketed in 1911.
Nicotine replacement therapy (NRT) is a medically approved way to treat people with tobacco use disorder by taking nicotine through means other than tobacco. It is used to help with quitting smoking or stopping chewing tobacco. It increases the chance of quitting tobacco smoking by about 55%. Often it is used along with other behavioral techniques. NRT has also been used to treat ulcerative colitis. Types of NRT include the adhesive patch, chewing gum, lozenges, nose spray, and inhaler. The use of multiple types of NRT at a time may increase effectiveness.
Phenylephrine is a medication used as a decongestant for uncomplicated nasal congestion, used to dilate the pupil, used to increase blood pressure, and used to relieve hemorrhoids. It can be taken by mouth, as a nasal spray, given by injection into a vein or muscle, or applied to the skin.
Oxymetazoline, sold under the brand name Afrin among others, is a topical decongestant and vasoconstrictor medication. It is available over-the-counter as a nasal spray to treat nasal congestion and nosebleeds, as eyedrops to treat eye redness due to minor irritation, and as a prescription topical cream to treat persistent facial redness due to rosacea in adults. Its effects begin within minutes and last for up to six hours. Intranasal use for longer than three days may cause congestion to recur or worsen, resulting in physical dependence. It is estimated that 700,000 people in Norway could be dependent on nasal sprays.
Tiletamine is a dissociative anesthetic and pharmacologically classified as an NMDA receptor antagonist. It is related chemically to ketamine. Tiletamine hydrochloride exists as odorless white crystals.
Levomethamphetamine is the levorotatory (L-enantiomer) form of methamphetamine. Levomethamphetamine is a sympathomimetic vasoconstrictor that is the active ingredient in some over-the-counter (OTC) nasal decongestant inhalers in the United States.
Testosterone enanthate is an androgen and anabolic steroid (AAS) medication which is used mainly in the treatment of low testosterone levels in men. It is also used in hormone therapy for transgender men. It is given by injection into muscle or subcutaneously usually once every one to four weeks.
4-Methylaminorex is a stimulant drug of the 2-amino-5-aryloxazoline class that was first synthesized in 1960 by McNeil Laboratories. It is also known by its street name "U4Euh" ("Euphoria"). It is banned in many countries as a stimulant.
A drug is any chemical substance that when consumed causes a change in an organism's physiology, including its psychology, if applicable. Drugs are typically distinguished from food and other substances that provide nutritional support. Consumption of drugs can be via inhalation, injection, smoking, ingestion, absorption via a patch on the skin, suppository, or dissolution under the tongue.
Prolintane is a stimulant and norepinephrine-dopamine reuptake inhibitor developed in the 1950s. Being an amphetamine derivative, it is closely related in chemical structure to other drugs such as pyrovalerone, MDPV, and propylhexedrine and it has a similar mechanism of action. Many cases of prolintane abuse have been reported.
Tapentadol, brand names Nucynta among others, is a centrally acting opioid analgesic of the benzenoid class with a dual mode of action as an agonist of the μ-opioid receptor and as a norepinephrine reuptake inhibitor (NRI). Analgesia occurs within 32 minutes of oral administration, and lasts for 4–6 hours.
Embutramide is a potent analgesic and sedative drug that is structurally related to GHB. It was developed by Hoechst A.G. in 1958 and was investigated as a general anesthetic agent, but was found to have a very narrow therapeutic window, with a 50 mg/kg dose producing effective sedation and a 75 mg/kg dose being fatal. Along with strong sedative effects, embutramide also produces respiratory depression and ventricular arrhythmia. Because of these properties, it was never adopted for medical use as an anesthetic as it was considered too dangerous for this purpose. Instead it is used for euthanasia in veterinary medicine, mainly for the euthanization of dogs.
Methylhexanamine is an indirect sympathomimetic drug invented and developed by Eli Lilly and Company and marketed as an inhaled nasal decongestant from 1948 until it was voluntarily withdrawn from the market in the 1980s.
Substituted amphetamines are a class of compounds based upon the amphetamine structure; it includes all derivative compounds which are formed by replacing, or substituting, one or more hydrogen atoms in the amphetamine core structure with substituents. The compounds in this class span a variety of pharmacological subclasses, including stimulants, empathogens, and hallucinogens, among others. Examples of substituted amphetamines are amphetamine (itself), methamphetamine, ephedrine, cathinone, phentermine, mephentermine, tranylcypromine, bupropion, methoxyphenamine, selegiline, amfepramone (diethylpropion), pyrovalerone, MDMA (ecstasy), and DOM (STP).
Methiopropamine (MPA) is an organic compound structurally related to methamphetamine. Originally reported in 1942, the molecule consists of a thiophene group with an alkyl amine substituent at the 2-position. It appeared for public sale in the UK in December 2010 as a "research chemical" or "legal high", recently branded as Blow. It has limited popularity as a recreational stimulant.