Ephedrine
Discover related
5 sources
Mechanism of action
Ephedrine is a direct and indirect sympathomimetic amine. As a direct effect, ephedrine activates alpha-adrenergic and beta-adrenergic receptors. As an indirect effect, it inhibits norepinephrine reuptake and increases the release of norepinephrine from vesicles in nerve cells. These actions combined lead to larger quantities of norepinephrine present in the synapse for more extended periods of time, increasing stimulation of the sympathetic nervous system. Ephedrine acts as an agonist of alpha-1, beta-1 and beta-2-adrenergic receptors. The stimulation of alpha-1-adrenergic receptors causes the constriction of veins and a rise in blood pressure, the stimulation of beta-1-adrenergic receptors increases cardiac chronotropy and inotropy, and the stimulation of beta-2-adrenergic receptors causes vasodilation and bronchodilation.
Ephedrine alkaloids are members of a large family of sympathomimetic compounds that include dobutamine and amphetamine. Members of this family increase blood pressure and heart rate by binding to alpha- and beta-adrenergic receptors present in many parts of the body, including the heart and blood vessels. These compounds are called sympathomimetics because they mimic the effects of epinephrine and norepinephrine, which occur naturally in the human body. In addition to their direct pharmacological effects, many of these compounds also stimulate the release of norepinephrine from nerve endings. The release of norepinephrine further increases the sympathomimetic effects of these compounds, at least transiently.
Ephedrine does not contain a catechol moiety, and it is effective after oral administration. The drug stimulates heart rate and cardiac output and variably increases peripheral resistance; as a result, ephedrine usually increases blood pressure. Stimulation of the alpha-adrenergic receptors of smooth muscle cells in the bladder base may increase the resistance to the outflow of urine. Activation of beta-adrenergic receptors in the lungs promotes bronchodilation.
Ephedrine stimulates both alpha- and beta-adrenergic receptors. It is believed that beta-adrenergic effects result from stimulation of the production of cyclic adenosine 3',5'-monophosphate (AMP) by activation of the enzyme adenyl cyclase, whereas a-adrenergic effects result from inhibition of adenyl cyclase activity. In contrast to epinephrine, ephedrine also has an indirect effect by releasing norepinephrine from its storage sites. With prolonged use or if doses are given frequently, ephedrine may deplete norepinephrine stores in sympathetic nerve endings and tachyphylaxis may develop to the cardiac and pressor effects. Tachyphylaxis to the bronchial effects of the drug may also occur, but it is not the result of norepinephrine depletion.
Pharmacodynamics
Ephedrine increases blood pressure by stimulating heart rate and cardiac output and variably increasing peripheral resistance. It causes bronchodilation due to the activation of beta-adrenergic receptors in the lungs. By stimulating alpha-adrenergic receptors in bladder smooth muscle cells, ephedrine also increases the resistance to the outflow of urine. The therapeutic window of ephedrine is wide, as patients can be given doses of 5mg up to 50mg. Patients should be counselled regarding the pressor effects of sympathomimetic amines and the risk of tachyphylaxis. Also, the use of ephedrine for hypotension prophylaxis is associated with a higher risk of hypertension, compared to when ephedrine is used to treat hypotension.
Pharmacokinetics
Half-life
Oral ephedrine has a plasma elimination half life of approximately 6 hours, but there is a large degree of inter-patient variability.
...serum half-life of 2-3 hr.
Ephedrineis eliminated in the urine largely as unchanged drug, with a t1/2 of 3-6 hrs.
Absorption
Oral ephedrine reaches an average Cmax of 79.5ng/mL, with a Tmax of 1.81h, and a bioavailability of 88%.
Ephedrine is mainly eliminated in the urine. Approximately 60% is eliminated as the unmetabolized parent compound, 13% as benzoic acid conjugates, and 1% as 1,2-dihydroxypropylbenzene.
Oral ephedrine has an average volume of distribution of 215.6L.
Oral ephedrine has a clearance of 23.3L/h but there is a high degree of inter-patient variability.
Placental transfer of ephedrine occurs at 70% of the maternal blood levels. Ephedrine is also excreted in breast milk.
Up to 95% of an oral dose may be excreted in the urine within 24 hours. The urinary excretion of ephedrine is pH-dependent due to the presence of an ionizable group in the ephedrine molecule and is increased in acidic urine. In alkaline urine, excretion is reduced to 20 to 35% of the dose.
Metabolism
Ephedrine is largely unmetabolized in the body. Ephedrine can be N-demethylated to norephedrine, or demethylated and deaminized to benzoic acid conjugates and 1,2-hydroxypropylbenzene.
... After /volunteers (n=3 for each drug) consumed a single clinical dose of ephedrine (EPH), pseudoephedrine (PEPH), phenylpropanolamine (PPA), methylephedrine (MEPH) or cathine/..., urine samples were subjected to tert-butyl-methyl-ether (TBME) extraction and trifluoroacetic acid (TFAA) derivatization before gas chromatography-mass spectrometry (GC-MS) analysis. Most ephedrines were excreted unchanged in urine, including EPH (40.9%), PEPH (72.2%), and PPA (59.3%). However, only a relatively small amount of MEPH (15.5%) was excreted unchanged in urine. In addition, a trace amount of PPA (1.6%) and cathine (0.7%) was found to be the metabolites of EPH and PEPH, respectively. Urinary EPH, PEPH, and PPA reached peaks at 2-6 hr and disappeared in urine at approximately 24-48 hr post-administration. For MEPH, the peaks of excretion extended from 4 to 12 hr post-administration and were undetectable at approximately 48 hr. A single clinical dose of EPH (25 mg) may exceed threshold level (10 ug/mL) in sport drug testing if the urine samples are tested within approximately 8 hr post-administration. However, a single dose of MEPH (20 mg) never reached the threshold value (10 ug/mL).
The metabolism of ephedrine in humans, dogs and several species of rodents proceeds primarily by three reactions; aromatic hydroxylation, N-demethylation, and oxidative deamination. The extent to which ephedrine is metabolized and the major metabolites vary quantitatively between species. The extent of aromatic hydroxylation is greatest in rats, followed by rabbits, guinea pigs, and dogs, with no aromatic hydroxylation observed in humans. N-demethylation of ephedrine is greatest in rabbits followed by dogs, guinea pigs, rats, and humans. Deamination is greatest in rabbits, followed by humans and rats. Ephedrine, 8-20%, is metabolized in humans by N-demethylation to /phenylpropanolamin/ PPA. A total of 4-13% of an oral dose of ephedrine undergoes oxidative deamination yielding 1-phenylpropan-1,2-diol and further side-chain oxidation to benzoic acid and hippuric acid.
Yields L-norephedrine and phenylglycol in rabbits. /from table/
Route of Elimination: mainly renal
Half Life: 3-6 hours
Protein binding
(-) Ephedrine is 4.9±0.3% bound to human serum albumin and (+) Ephedrine is 6.9±1.4% bound to human serum albumin.
Fact-sheets from PsychonautWiki. Harm-reduction reference only — not medical advice.