Ephedrine

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Ephedrine

Ephedrine (EPH) is a sympathomimetic amine commonly used as a decongestant and to treat hypotension associated with regional anaesthesia. Chemically, it is an alkaloid derived from various plants in the genus Ephedra (family Ephedraceae). It is usually marketed as the ephedrine hydrochloride and ephedrine sulfate.

In traditional Chinese medicine, the herb ma huang (Ephedra sinica) contains ephedrine as its principal active constituent. The same is true of other herbal products containing extracts from Ephedra species. Nagayoshi Nagai was the first one to isolate ephedrine from Ephedra vulgaris in 1885. The substance called soma mentioned in old Hindu books such as the Rig Veda, may have been ephedra extract.

Chemistry

Ephedrine exhibits optical isomerism and has two chiral centres. By convention the enantiomers with opposite stereochemistry around the chiral centres are designated ephedrine, while pseudoephedrine has same stereochemistry around the chiral carbons. That is, (1R,2R)- and (1S,2S)-enantiomers are designated pseudoephedrine; while (1R,2S)- and (1S,2R)-enantiomers are designated ephedrine.

The isomer which is marketed is (-)-(1R,2S)-ephedrine. Reynolds JEF, editor. Martindale: The extra pharmacopoeia, 29th edition. London: The Pharmaceutical Press; 1989. ISBN 0-85369-210-6

As with other phenylethylamines, it is also somewhat chemically similar to methamphetamine, although the amphetamines are more potent and have additional biological effects.

Ephedrine may also be referred to as: (αR)-α-α-[1-(methylamino)ethylbenzyl alcohol, or L-erythro-2-(methylamino)-1-phenylpropan-1-ol. Ephedrine hydrochloride has a melting point of 187-188°C. Budavari S, editor. The Merck Index: An encyclopedia of chemicals, drugs, and biologicals, 12th edition. Whitehouse Station: Merck

Mode of action

Ephedrine is a sympathomimetic amine - that is, its principal mechanism of action relies on its indirect action on the adrenergic receptor system, which is part of the sympathetic nervous system or SNS. Whilst it may have weak agonist activity at α- and β-adrenergic receptors, the principal mechanism is to displace noradrenaline from storage vesicles in presynaptic neurons. The displaced noradrenaline is released into the neuronal synapse where it is free to activate the postsynaptic adrenergic receptors.

Clinical use

Indications

Ephedrine was once widely used as a topical decongestant and as a bronchodilator in the treatment for asthma. It continues to be used for these indications, although its popularity is waning due to the availability of more effective agents for these indications which exhibit fewer adverse effects Joint Formulary Committee. British National Formulary, 47th edition. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2004. ISBN 0-85369-854-9. The role in nasal congestion has largely been replaced by more potent α-adrenergic receptor agonists (e.g. oxymetazoline). Similarly the role of ephedrine in asthma has been almost entirely replaced by β₂-adrenergic receptor agonists (e.g. salbutamol). Ephedrine continues to be used intravenously in the reversal of hypotension from spinal/epidural anaesthesia . It is also used in other hypotensive states, including overdose with ganglionic blocking agents, antiadrenergic agents, or other medications that lower blood pressure Bicopoulos D, editor. AusDI: Drug information for the healthcare professional, 2nd edition. Castle Hill: Pharmaceutical Care Information Services; 2002.. It can be used in narcolepsy and nocturnal enuresis.

In traditional Chinese medicine, ephedrine has been used in the treatment of asthma and bronchitis for centuries Ford MD, Delaney KA, Ling LJ, Erickson T, editors. Clinical Toxicology. Philadelphia: WB Saunders; 2001. ISBN 0-72165-485-1 Research Laboratories; 1996. ISBN 0-91191-012-3.

An ECA stack is a component found in thermogenic weight loss pills, composed of ephedrine, caffeine and aspirin working to speed up the metabolism and thus cause food energy to burn faster. The ECA stack is a popular supplement taken by body builders before workouts due to the increased amount of energy and alertness.

For many years, the US Coast Guard recommended ephedrine together with an equal 25 mg dose of promethazine to its sailors to combat seasickness. Promethazine manages nausea and ephedrine fights the ensuing drowsiness. Commonly referred to as the Coast Guard cocktail, ephedrine may still be available for prescription for this purpose.

Adverse effects

Adverse drug reactions (ADRs) are more common with systemic administration (e.g. injection) compared to topical administration (e.g. nasal instillations). ADRs associated with ephedrine therapy include :

Cardiovascular: tachycardia, bradycardia, arrhythmias, angina pain, vasoconstriction with hypertension, vasodilation with hypotension,
Dermatological: flushing, sweating
Gastrointestinal: nausea, vomiting, anorexia
Genitourinary: micturition difficulty, urine retention
Nervous system: anxiety, restlessness, confusion, psychoses, insomnia
Respiratory: dyspnea
Miscellaneous: dizziness, headache, tremor, hypersalivation, changes in blood glucose concentration, death

Ephedrine has been reported to cause physical dependence after excessive long-term use. This is particularly true with oral forms of ephedrine, since parenteral administration is unlikely to occur over long periods Mayne Pharma. Ephedrine sulfate injection DBL (Approved Product Information). Melbourne: Mayne Pharma; 2004..

Precautions/contraindications

Ephedrine should be used in caution in patients with inadequate fluid replacement, depletion of noradrenaline stores, hypoxia, hypercapnia, acidosis, hypertension, hyperthyroidism, prostatic hypertrophy, diabetes mellitus, cardiovascular disease, during delivery if maternal BP > 130/80 mmHg, and lactation .

Contraindications for the use of ephedrine include: closed angle glaucoma, phaeochromocytoma, asymmetric septal hypertrophy (idiopathic hypertrophic subaortic stenosis), concomitant or recent (previous 14 days) monoamine oxidase inhibitor (MAOI) therapy, general anaesthesia with halogenated hydrocarbons (particularly cyclopropane or halothane), tachyarrhythmias or ventricular fibrillation, hypersensitivity to ephedrine, and psychoneurosis .

Recreational and illicit use

Anecdotal reports have suggested that ephedrine helps studying, thinking, or concentrating to a greater extent than caffeine. Some students and some white-collar workers have used ephedrine (or Ephedra-containing herbal supplements) for this purpose, as well as some professional athletes and weightlifters. It is common for many athletes to use stimulants while exercising. Such misuse of ephedrine has been associated with stimulant dependence, as well as deaths from heatstroke in athletes and circulatory problems such as aortic aneurysm in weightlifters.

As a phenylethylamine, ephedrine has a similar chemical structure to amphetamines. Ephedrine can be used in the synthesis of methamphetamine by chemical reduction; this has made ephedrine a highly sought-after chemical precursor in the illicit manufacture of methamphetamine. The most popular method for reducing ephedrine to methamphetamine is similar to the Birch reduction, in that it uses anhydrous ammonia and lithium metal in the reaction. The second most popular method uses red phosphorus, iodine, and ephedrine in the reaction.

Through oxidation, ephedrine can be easily synthesized into methcathinone. Ephedrine is listed as a Table I precursor under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances http://www.incb.org/pdf/e/list/red.pdf.

Legality in USA

Ephedrine itself has never been illegal. In 1997, the FDA proposed a regulation on ephedra (the herb from which ephedrine is obtained), which limited an ephedra dose to 8mg with no more than 24mg per day. This proposed rule was then withdrawn in 2000 because "concerns regarding the agency's basis for proposing a certain dietary ingredient level and a duration of use limit for these products." In 2004, the FDA created a ban on ephedrine alkaloids that are marketed for reasons other than asthma, colds, allergies, other disease, or traditional Asian use. Products such as VasoPro's ephedrine HCL contains Guaifenesin, which thins the mucus in the air passages and makes it easier to clear the airway, and thus is sold as a bronchodilator. In 2005, the US Federal District Court determined that the FDA did not have proper evidence that low dosages of ephedrine alkaloids are actually unsafe. The current legal status for ephedrine is ambiguous depending on how the FDA interprets the district court ruling, but regardless, ephedrine sold for other purposes is still legal. However, currently purchasing is limited and records are kept of how much ephedrine is purchased, with the specifics varying from state to state. Although the FDA claims that their ruling is a result from several deaths from people taking large doses, some people believe that it is only because ephedrine is one of the key ingredients for creating crystal meth, and that is the reason the FDA limits the total quantity one can purchase.

References

External links

Alkaloids | Amphetamines | Sympathomimetic amines | Stimulants

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