Propylhexedrine

Propylhexedrine, sold under the brand name Benzedrex among others, is an alkylamine primarily utilized as a topical decongestant. Its main indications are relief of congestion due to colds, allergies, and allergic rhinitis. Propylhexedrine was first used medically in 1949, with the release of Benzedrex by Smith, Kline & French, and it has been used, mainly within the United States, since then.

Medical use 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 mg (400 to 500 μg) in 800 mL of air. Use is not to exceed three days. Historically, it has also been used for weight loss in oral tablet preparations at a dose of 25 mg. No medications containing propylhexedrine are currently approved for weight loss in any country since roughly 1976.

Contraindications Propylhexedrine should not be used if a MAOI has been used in the past 14 days or is currently in use by a person. Unlike other topical decongestants, propylhexedrine is not required to carry a warning against use in individuals with hypertension. Propylhexedrine is not recommended in individuals younger than six years of age. There is at least one case of reported accidental poisoning resulting from child access to a propylhexedrine product.

Adverse effects 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. The sharing of propylhexedrine inhalers may spread infection. The occurrence of these adverse effects is uncommon as propylhexedrine is generally recognized as safe and effective. 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. The outcomes of improperly using propylhexedrine products can include hospitalization, disability, or even death. Public health agencies such as the Food and Drug Administration (FDA) have advised propylhexedrine products only be used in the manners directed on their label.

Overdose Reports of overdoses from propylhexedrine have been documented, but they are uncommon. 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. 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." The use of propylhexedrine products in manners inconsistent with their labeling has proven fatal in some cases. Propylhexedrine products are considered to be safe and effective if used as intended. Regardless, medical attention should be sought in the case of suspected overdose.

Interactions Most of propylhexedrine's interactions with other medications have to do with its ability to constrict blood vessels. Propylhexedrine's most serious interaction is with monoamine oxidase inhibitors (MAOIs), which are contraindicated. Monoamine oxidase inhibitors are used, albeit uncommonly, as an antidepressant. Nonetheless, caution should be exercised when administering propylhexedrine concurrently with other medicines.

Pharmacology

Mechanism of action Propylhexedrine works mainly as an adrenergic agonist, when used at therapeutic doses in an inhaler dosage form. This restricts the blood vessels in the nose and reduces swelling; thereby, it relieves nasal congestion. At higher doses, propylhexedrine affects the central nervous system as a norepinephrine–dopamine releasing agent (NDRA). Propylhexedrine likely exerts such effects in a manner similar to related alkylamines such as cyclopentamine, methylhexanamine, and tuaminoheptane. Propylhexedrine also exhibits antihypotensive effects.

Pharmacokinetics

Propylhexedrine undergoes metabolism via N-demethylation, C-oxidation, N-oxidation, dehydrogenation, and hydrolysis to form various metabolites such as norpropylhexedrine, cyclohexylacetoxime, cyclohexylacetone, and 4-hydroxypropylhexedrine.

Chemistry

Freebase propylhexedrine is a volatile, oily liquid at room temperature. The slow evaporation of freebase propylhexedrine allows it to be administered via inhalation. 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. 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. (S)-Propylhexedrine, also known as levopropylhexedrine, is the more biologically active isomer of the two. The dextrorotatory counterpart, which is mainly unused, is dextropropylhexedrine.

Synthesis 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.

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.

The selective synthesis of enantiopure levopropylhexedrine can be accomplished through the initial Wenker synthesis of an intermediate aziridine followed by catalytic hydrogenation.

Detection in bodily fluids Administration of propylhexedrine can lead to false positives for phenethylamine derivatives on urinalysis panels. Propylhexedrine can be differentiated upon further analysis.

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