Ephedrine: effect on the liver and kidneys

When speaking of the risks of ephedrine, the heart and blood pressure are the first things mentioned. However, the liver and kidneys are also involved: the kidneys eliminate the bulk of the substance, and the literature describes ephedrine stones, acute kidney injury and cases of toxic hepatitis from ephedra-containing supplements. The editorial team examined what of this is well documented and what remains isolated observations.

The path of ephedrine through the body

Ephedrine is well absorbed from the gastrointestinal tract and almost completely enters the systemic circulation. Unlike many drugs, it does not undergo intensive "first-pass" metabolism through the liver, so its oral bioavailability is high. The peak blood concentration occurs about one to two hours after taking a tablet.

The metabolism of ephedrine is relatively minor. A small part of the dose is converted in the liver by N-demethylation into norephedrine (phenylpropanolamine) and other metabolites. The larger part of the substance is eliminated by the kidneys unchanged. That is why, of the two organs this article considers, the main "working" load falls on the kidneys.

The half-life of ephedrine averages a few hours, but depends substantially on the pH of the urine. In acidic urine elimination is accelerated, in alkaline urine it is slowed. Impaired kidney function, in turn, prolongs the presence of ephedrine in the body and can intensify its cardiovascular effects.

It is important to distinguish a direct toxic effect on an organ from an indirect one — through elevated blood pressure, vasospasm, overheating or dehydration. For ephedrine the second mechanism is probably much more important: renal complications most often arise where sympathomimetic stimulation is superimposed on intense exertion and fluid deficit.

The kidneys: elimination and ephedrine stones

The most specific renal complication of ephedrine is urolithiasis, in which the stones consist of ephedrine itself and its metabolites. Such calculi have been described in people who long consumed large amounts of ephedrine or products with ma-huang (the Chinese name for ephedra). In the literature of the 1990s this phenomenon was called "ephedrine nephrolithiasis".

One of the first case series was published by Powell and colleagues in 1998 in the American Journal of Kidney Diseases under the telling title "Ma-huang strikes again". Later, in laboratories analyzing the composition of stones, ephedrine calculi began to be detected more often than expected — mainly in people who took ephedra as part of weight-loss supplements or as a stimulant.

The mechanism is linked to the fact that at high concentrations in the urine ephedrine and norephedrine can crystallize, especially if the person drinks little water. Such stones are poorly visible on ordinary X-rays, so they are often diagnosed with ultrasound or CT, and the exact composition is established only after analysis of the removed calculus.

Clinically, an ephedrine stone manifests the same as any other: renal colic, blood in the urine, sometimes infection. The key difference is in the cause: without stopping ephedrine use, stones can form again. So, with an atypical stone composition, urologists clarify which supplements and drugs the patient took.

Acute kidney injury and rhabdomyolysis

The second group of renal risks is linked not to the direct action of ephedrine but to situations in which it amplifies other factors. Ephedrine raises body temperature and thermogenesis, constricts some blood vessels and raises blood pressure. In combination with heat, dehydration and exhausting workouts, this creates conditions for rhabdomyolysis — the breakdown of muscle cells.

During rhabdomyolysis the protein myoglobin enters the blood, is filtered by the kidneys and can clog the tubules, causing acute kidney injury. In reports on the side effects of ephedra supplements, cases of rhabdomyolysis and acute kidney failure have been described, although establishing the role of ephedrine specifically among other factors is not always possible.

Another mechanism is malignant arterial hypertension. Sharp rises in blood pressure against a background of stimulants damage the small blood vessels of the kidneys. In people with already existing hypertensive nephropathy or chronic kidney disease, ephedrine increases the risk of progression, and because of its slowed elimination its effects last longer.

Practical "red flags" that should prompt urgent medical attention:

• severe muscle pain after training combined with darkening of the urine (the color of tea or cola);
• a sharp decrease in the amount of urine, swelling, weakness;
• pain in the lower back or side with wave-like intensification, blood in the urine;
• very high blood pressure with headache, nausea, vision disturbance.

The liver: what is known about hepatotoxicity

Ephedrine itself is not considered a classic hepatotoxic drug: at medical doses, which are used in anesthesiology, no clinically significant liver damage has been described. However, with herbal products the situation is more complicated. The LiverTox database of the US National Institutes of Health contains a separate section on ephedra, which presents published cases of acute hepatitis.

One of the early descriptions is the article by Nadir and colleagues (1996) about acute hepatitis in a patient who took a Chinese herbal product with ma-huang. Later other reports appeared, in particular about severe liver damage against the background of multi-component weight-loss supplements containing ephedra.

The main problem of interpretation is the complexity of the composition. Products with ephedra often contained dozens of ingredients, including other plant extracts, caffeine, aspirin or thyroid hormones. Establishing which component caused the liver damage is impossible in most cases, so a causal link specifically with ephedrine remains unproven.

An indirect effect on the liver is possible through hyperthermia: heat stroke and severe rhabdomyolysis are not infrequently accompanied by a sharp rise in liver enzymes. In this case the liver suffers as one of the target organs of systemic overheating, not through the direct toxicity of the molecule.

Monitoring organ function

During medical use of ephedrine (usually a single dose, in a hospital) special monitoring of the liver and kidneys is not needed if the patient has no known diseases. In people with chronic kidney disease the doctor takes into account the slowed elimination and monitors blood pressure more carefully.

But if a person has long consumed ephedrine or ephedra products outside medical supervision, a basic laboratory assessment helps to notice problems in time. The minimum set is creatinine with a calculation of the glomerular filtration rate, a general urine test, ALT, AST, bilirubin and, in case of muscle pain, creatine kinase.

If stones are suspected, a kidney ultrasound is informative, and if necessary, a CT scan. If a stone has passed or been removed, an analysis of its composition may reveal ephedrine — an important clue for the doctor and a reason to review supplement use.

Prevention here is simple: refusing uncontrolled use of stimulants, sufficient fluid intake, caution when training in the heat. People with diseases of the kidneys, liver or hypertension should discuss any drugs containing ephedrine or pseudoephedrine with a doctor.

Editorial conclusions

The kidneys are the main route of ephedrine elimination, and it is precisely with them that the best-documented organ complications are associated: ephedrine stones and damage against a background of rhabdomyolysis, hyperthermia or severe hypertension.

As for the liver, the evidence is weaker: isolated cases of hepatitis from multi-component herbal products with ephedra have been described, but a causal link specifically with ephedrine has not been established.

The greatest risk to both organs is created not by the molecule itself at a medical dose, but by the combination of prolonged uncontrolled use, dehydration, heat and other stimulants.

We also recommend reading our articles on the interaction of ephedrine with other drugs, on tests during the medical use of ephedrine, and on the effect of yohimbine on the liver and kidneys.

References

1. Powell T, Hsu FF, Turk J, Hruska K. Ma-huang strikes again: ephedrine nephrolithiasis. Am J Kidney Dis. 1998;32(1):153–159.
2. Nadir A, Agrawal S, King PD, Marshall JB. Acute hepatitis associated with the use of a Chinese herbal product, ma-huang. Am J Gastroenterol. 1996;91(7):1436–1438.
3. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Ephedra. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases.
4. Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med. 2000;343(25):1833–1838.
5. Shekelle PG, Hardy ML, Morton SC, et al. Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: a meta-analysis. JAMA. 2003;289(12):1537–1545.
6. U.S. Food and Drug Administration. Akovaz (ephedrine sulfate injection): prescribing information.