ephedrine - Chemistry, Mode of action, Clinical use

A drug with similar actions to adrenaline, used as a nasal decongestant. Earlier, it was also used in the treatment of asthma and low blood pressure.

Ephedrine is commonly used as a stimulant, appetite suppressant, concentration aid, decongestant and to treat hypotension associated with regional anaesthesia.

In traditional Chinese medicine, the herb ma huang (Ephedra sinica) contains ephedrine as its principal active constituent.

Chemistry

Ephedrine exhibits optical isomerism and has two chiral centres.

Ephedrine may also be referred to as: (αR)-α-[(1S)-1-(methylamino)ethyl]benzenemethanol, α-[1-(methylamino)ethyl]benzyl alcohol, or L-erythro-2-(methylamino)-1-phenylpropan-1-ol.

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.

Ephedrine's mechanism of action on neurotransmission in the brain is wide.

Because of ephedrine's ability to potentiate dopamine neurotransmission it is thought to have addictive properties by some researchers.

While ephedrine's role in the serotonin system is less understood there is preliminary documentation of clinically significant agonism at excitory serotonin receptors, perhaps as a downstream response to the large release of norepinephrine in the nucleus accumbens (commonly referred to as the "pleasure center" of the brain).

Clinical use

Indications

Ephedrine was once widely used as a topical decongestant and as a bronchodilator in the treatment for asthma. Similarly the role of ephedrine in asthma has been almost entirely replaced by β2-adrenergic receptor agonists (e.g. Ephedrine continues to be used intravenously in the reversal of hypotension from spinal/epidural anaesthesia .

In traditional Chinese medicine, ephedrine has been used in the treatment of asthma and bronchitis for centuries .

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.

For many years, the US Coast Guard recommended ephedrine together with an equal 25 mg dose of promethazine to its sailors to combat seasickness. ADRs associated with ephedrine therapy include :

Cardiovascular: tachycardia, cardiac arrhythmias, angina pain, vasoconstriction with hypertension Dermatological: flushing,acne vulgaris Gastrointestinal: nausea, appetite loss, anorexia Genitourinary: increased urine output due to increased blood flow Nervous system:restlessness, confusion, insomnia, mild euphoria, mania/hallucinations (rare except in previously existing psychiatric conditions), delusions, formication (may be possible, but lacks documented evidence) paranoia, hostility, confusion, panic, stereotypical behaviour ('obsessive compulsive' or repetitive tasks such as cleaning, grooming, organizing items arbitrarily) agitation Respiratory: dyspnea, pulmonary edema Miscellaneous: dizziness, headache, tremor, hyperglycemic reactions

The approved maximum daily dosage of ephedrine for use as a bronchodilator is 150mg, as specified on the packaging of the bronchodilator and expectorant combination, Bronkaid, made by Bayer pharmaceuticals.

Ephedrine can also lead to damage of the brain receptors over a period of large usage this is because of its constant action on the nuerochemicals.

Contraindications

Ephedrine should not be used in conjunction with certain antidepressants, namely SNRIs (Selective norepinephrine re-uptake inhibitors), as this increases the risk of the above symptoms due to excessive serum levels of norepinephrine.

Wellbutrin is an example of an antidepressant with an amphetamine-like structure similar to ephedrine. It should not be used with ephedrine as it may increase the liklihood of the above side effects.

Ephedrine should be used in caution in patients with inadequate fluid replacement, impaired adrenal function, hypoxia, hypercapnia, acidosis, hypertension, hyperthyroidism, prostatic hypertrophy, diabetes mellitus, cardiovascular disease, during delivery if maternal BP >

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 or other stimulants, and psychoneurosis (bipolar disorder, severe depression, obsessive compulsive disorder, etc.)

Ephedrine should NOT be used at any time during pregnancy unless specifically indicated by a qualified physician and ONLY when other options are unavailable.

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.

As a phenylethylamine, ephedrine has a similar chemical structure to amphetamines. Ephedrine can be used in the synthesis of methamphetamine by chemical reduction; 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.

Through oxidation, ephedrine can be easily synthesized into methcathinone.

Ephedrine has been reported to cause both physical and psychological dependence after excessive long-term use.

Neurotoxicity of Ephedrine

As a sympathomimetic agent similar in structure and activity to amphetamines, there has been a dispute over whether ephedrine produces some of the same neurodegenerative effects.

Several studies have recently compared the quantities of such neurotransmitters as serotonin, dopamine, glutamate, and adrenaline after concurrent administration of ephedrine and various amphetamine-like agents. The results showed that ephedrine has a reduced neurotoxic effect on dopamine than its amphetamine counterparts.

Ephedrine increases serum dopamine levels minimally in comparison with an equivalent dose of dextroamphetamine (Adderall®). This supports the general consensus that ephedrine has more of a peripheral action on the sympathetic nervous system, whereas amphetamines appear to cross the blood brain barrier more freely and tend to have a stronger central action.

Legality in USA

Ephedrine itself has never been illegal. In 1996, 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. 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. On April 14th, 2005, the US Federal District Court ruled that the FDA did not have proper evidence that low dosages of ephedrine alkaloids are actually unsafe, but on August 17, 2006, the U.S. Court of Appeals for the Tenth Circuit in Denver upheld the FDA's final rule declaring all dietary supplements containing ephedrine alkaloids adulterated, and therefore illegal for marketing in the United States. 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.