Ephedrine


Ephedrine is a central nervous system stimulant and sympathomimetic agent that is often used to prevent low blood pressure during anesthesia. It has also been used for asthma, narcolepsy, and obesity but is not the preferred treatment. It is of unclear benefit in nasal congestion. It can be taken by mouth or by injection into a muscle, vein, or just under the skin. Onset with intravenous use is fast, while injection into a muscle can take 20minutes, and by mouth can take an hour for effect. When given by injection, it lasts about an hour, and when taken by mouth, it can last up to four hours.
Common side effects include trouble sleeping, anxiety, headache, hallucinations, high blood pressure, fast heart rate, loss of appetite, and urinary retention. Serious side effects include stroke and heart attack. While probably safe in pregnancy, its use in this population is poorly studied. Use during breastfeeding is not recommended. Ephedrine works by inducing the release of norepinephrine and hence indirectly activating the α- and β-adrenergic receptors. Chemically, ephedrine is a substituted amphetamine and is the -enantiomer of β-hydroxy-N-methylamphetamine.
Ephedrine was first isolated in 1885 and came into commercial use in 1926. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication. It can normally be found in plants of the Ephedra genus. Over-the-counter dietary supplements containing ephedrine are illegal in the United States, with the exception of those used in traditional Chinese medicine, where its presence is noted by má huáng.

Medical uses

Ephedrine is a non-catecholamine sympathomimetic with cardiovascular effects similar to those of adrenaline : increased blood pressure, heart rate, and contractility. Like pseudoephedrine, it is a bronchodilator, with pseudoephedrine having considerably less effect.
Ephedrine may decrease motion sickness, but it has mainly been used to decrease the sedating effects of other medications used for motion sickness.
Ephedrine is also found to have quick and long-lasting responsiveness in congenital myasthenic syndrome in early childhood and also even in adults with a novel COLQ mutation.
Ephedrine is administered by intravenous boluses. Redosing usually requires increased doses to offset the development of tachyphylaxis, which is attributed to the depletion of catecholamine stores.

Weight loss

Ephedrine promotes modest short-term weight loss, specifically fat loss, but its long-term effects are unknown. In mice, ephedrine is known to stimulate thermogenesis in the brown adipose tissue, but because adult humans have only small amounts of brown fat, thermogenesis is assumed to take place mostly in the skeletal muscle. Ephedrine also decreases gastric emptying. Methylxanthines such as caffeine and theophylline have a synergistic effect with ephedrine for weight loss. This led to the creation and marketing of compound products. One of them, known as the ECA stack, contains ephedrine with caffeine and aspirin. It is a popular supplement taken by bodybuilders seeking to cut body fat before a competition.
A 2021 systematic review found that ephedrine taken in doses from 60 mg to 150mg, with or without caffeine, for 4 to 24 weeks led to a weight loss greater than placebo, raised heart rate, and reduced LDL and raised HDL, with no statistically significant difference in blood pressure.

Available forms

Ephedrine is available as a prescription-only pharmaceutical drug in the form of an intravenous solution, under brand names including Akovaz, Corphedra, Emerphed, and Rezipres as well as in generic forms, in the United States. It is also available over-the-counter in the form of 12.5 and 25mg oral tablets for use as a bronchodilator and as a 0.5% concentration nasal spray for use as a decongestant. The drug is additionally available in combination with guaifenesin in the form of oral tablets and liquids. Ephedrine is provided as the hydrochloride or sulfate salt in pharmaceutical formulations.

Contraindications

Ephedrine should not be used in conjunction with certain antidepressants, namely norepinephrine–dopamine reuptake inhibitors, as this increases the risk of symptoms due to excessive serum levels of norepinephrine.
Bupropion is an example of an antidepressant with an amphetamine-like structure similar to ephedrine, and it is an NDRI. Its action bears more resemblance to amphetamine than to fluoxetine in that its primary mode of therapeutic action involves norepinephrine and to a lesser degree dopamine, but it also releases some serotonin from presynaptic clefts. It should not be used with ephedrine, as it may increase the likelihood of side effects.
Ephedrine should be used with 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 blood pressure is >130/80 mmHg, and during lactation.
Contraindications for the use of ephedrine include: closed-angle glaucoma, phaeochromocytoma, asymmetric septal hypertrophy, concomitant or recent monoamine oxidase inhibitor therapy, general anesthesia with halogenated hydrocarbons, tachyarrhythmias or ventricular fibrillation, or hypersensitivity to ephedrine or other stimulants.
Ephedrine should not be used at any time during pregnancy unless specifically indicated by a qualified physician and only when other options are unavailable.

Side effects

Ephedrine is a potentially dangerous natural compound; as of 2004 the US Food and Drug Administration had received over 18,000 reports of adverse effects in people using it.
Adverse drug reactions are more common with systemic administration compared to topical administration. ADRs associated with ephedrine therapy include
of ephedrine may result in sympathomimetic symptoms like tachycardia and hypertension.

Interactions

Ephedrine with monoamine oxidase inhibitors like phenelzine and tranylcypromine can result in hypertensive crisis.

Pharmacology

Pharmacodynamics

Ephedrine, a sympathomimetic amine, acts on part of the sympathetic nervous system. The principal mechanism of action relies on its indirect stimulation of the adrenergic receptor system by increasing activation of α- and β-adrenergic receptors via induction of norepinephrine release. The presence of direct interactions with α-adrenergic receptors is unlikely but still controversial. L-ephedrine, and particularly its stereoisomer norpseudoephedrine has indirect sympathomimetic effects and due to its ability to cross the blood–brain barrier, it is a CNS stimulant similar to amphetamines, but less pronounced, as it releases norepinephrine and dopamine in the brain.

Pharmacokinetics

Absorption

The oral bioavailability of ephedrine is 88%. The onset of action of ephedrine orally is 15 to 60minutes, via intramuscular injection is 10 to 20minutes, and via intravenous infusion is within seconds.

Distribution

Its plasma protein binding is approximately 24 to 29%, with 5 to 10% bound to albumin.

Metabolism

Ephedrine is largely not metabolized. Norephedrine is an active metabolite of ephedrine formed via N-demethylation. About 8 to 20% of an oral dose of ephedrine is demethylated into norephedrine, about 4 to 13% is oxidatively deaminated into benzoic acid, and a small fraction is converted into 1,2-dihydroxy-1-phenylpropane.

Elimination

Ephedrine is eliminated mainly in urine, with 60% excreted unchanged.
The elimination half-life of ephedrine is 6hours. Its duration of action orally is 2 to 4hours and via intravenous or intramuscular injection is 60minutes.
The elimination of ephedrine is dependent on urinary pH.

Chemistry

Ephedrine, or --ephedrine, also known as -β-hydroxy-N-methyl-α-methyl-β-phenethylamine or as -β-hydroxy-N-methylamphetamine, is a substituted phenethylamine and amphetamine derivative. It is similar in chemical structure to phenylpropanolamine, methamphetamine, and epinephrine. It differs from methamphetamine only by the presence of a hydroxyl group. Chemically, ephedrine is an alkaloid with a phenethylamine skeleton found in various plants in the genus Ephedra. It is most usually marketed as the hydrochloride or sulfate salt.
It has an experimental log P of 1.13, while its predicted log P values range from 0.9 to 1.32. The lipophilicity of amphetamines is closely related to their brain permeability. For comparison to ephedrine, the experimental log P of methamphetamine is 2.1, of amphetamine is 1.8, of pseudoephedrine is 0.89, 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.
Ephedrine hydrochloride has a melting point of 187−188°C.
The racemic form of ephedrine is racephedrine -ephedrine; dl-ephedrine;. A stereoisomer of ephedrine is pseudoephedrine. Derivatives of ephedrine include methylephedrine, etafedrine, cinnamedrine, and oxilofrine. Analogues of ephedrine include phenylpropanolamine and metaraminol.
The presence of an N-methyl group decreases binding affinities at α-adrenergic receptors, compared with norephedrine. Ephedrine, though, binds better than N-methylephedrine, which has an additional methyl group at the nitrogen atom. Also, the steric orientation of the hydroxyl group is important for receptor binding and functional activity.