Prepared by Dr Maria Pak
A 19-year-old man presented to the ED. The patient is an employee in a nutritional supplement store. He states that he took an herbal supplement intended for energy and weight loss. He states that he only ingested a single pill. Shortly after ingestion, he began experiencing palpitations and chest pain. His chest pain is pleuritic in nature, severity of 5/10, diffusely located over his chest with no radiation, and exacerbated by movement and breathing.
Hospital course: The patient was admitted to the ICU service. He was started on an esmolol drip, which was later switched to propanolol. It was found that the ingested supplements contained clenbuterol and tamoxifen. His CPK was elevated to the level of rhabdomyolysis. Rhabdomyolysis was treated with IVF hydration. CPK and creatinine gradually trended down. Lactic acidosis also resolved. Cardiology was consulted for the elevated troponin, and 2D-echo showed mild LVH and impaired relaxation. He was continued on beta-blocker therapy and troponin gradually trended down. His hypotension and tachycardia resolved by hospital day 6. He was discharged on hospital day 8.
Anabolic steroids have been used by strength athletes for almost five decades in order to improve performance by increasing muscle mass and strength. Among the numerous documented toxic and hormonal effects of AAS, attention has been focused especially on the cardiovascular effects during recent years. Increases in blood pressure and peripheral arterial resistance are known from experimental studies, but there are also effects on the heart muscle, primarily left ventricular hypertrophy with restricted diastolic function. Severe cardiac complications such as cardiac insufficiency, ventricular fibrillation, ventricular thromboses, myocardial infarction, or sudden cardiac death in individual strength athletes with acute steroid abuse have also been reported.
More recently, beta-agonists have been used as anabolic agents to increase body weight and build muscle strength. Clenbuterol [4-amino-(t-butylamino)methyl-3,5-dichlorobenzyl alcohol] is a β2-adrenergic receptor agonist that has been shown to have a significant effect on muscle metabolism in a variety of muscle atrophy models, including hind-limb suspension atrophy, starvation induced atrophy, and denervation induced atrophy. Additionally, clenbuterol is known to induce a significant repartitioning effect by increasing the growth of skeletal muscle at the expense of fat tissues in most livestock species. It is licensed as a bronchodilator for use in human medicine in Spain and other countries in the European Community. It is also used as bronchodilator and tocolytic for the treatment of respiratory disease in horses and cattle and to relax the uterus in cows at parturition. Clenbuterol causes regression in body lipids, muscle growth, and weight gain and has been illegally used in the past as a growth promoter in young cattle.
β1-adrenoceptors are found in many areas of the body including the heart, kidney, white adipose tissue and the brain, where, in particular, high concentrations are found in the pineal gland. Receptors in the heart mediate positive chronotropic and inotropic responses; those in the kidney control renin release from the juxtaglomerular apparatus, whereas those in adipose tissue control lipolysis. In the brain, β1-adrenoceptors control the secretion of melatonin from the pineal gland and also appear to have a role in mood alterations. In blood vessels, β2-adrenoceptors have classically been considered to be dominant but in a number of arteries, including the coronary, mesenteric and saphenous, β1-adrenoceptors also mediate vasodilatation
Prolonged activation of β1-adrenoceptors has deleterious effects on the heart. For example, the use of xamoterol as an inotropic agent is associated with increased mortality, and transgenic mice with relatively mild cardiac over expression of β1- adrenoceptors rapidly develop cardiac failure. Chronic activation of cardiac β1- adrenoceptors is associated with apoptosis of cardiomyocytes. This may be a significant factor in the greatly increased risk of heart failure in people taking cocaine or amphetamines and in the success associated with the use of β-adrenoceptors antagonists for the treatment of cardiac failure.
β2-adrenoceptors have a wider distribution than β1-adrenoceptors and control a wide variety of functions in the body. They also mediate positive inotropic and chronotropic effects in the heart. The human heart has a significant (up to 40% of total β- adrenoceptors) population of β2-adrenoceptors. In the lung, the activation of β2- adrenoceptors causes not only a bronchodilator effect but also reduces the release of bronchoconstrictor mediators and increases the release of surfactants and mucus. β2- adrenoceptors mediate a powerful vasodilator effect in small coronary blood vessels and skeletal muscle blood vessels. Other effects seen in skeletal muscle include increased growth and speed of contraction, glycogenolysis and tremor. In the pancreas, there is an increase in both insulin and glucagon secretion, and glycogenolysis in the liver is increased.
The β3- adrenoceptor is widely distributed in the gut, brain, genitourinary tract, uterus and white and brown adipose tissue. The presence of the receptor in fat stimulated activity in the pharmaceutical industry to develop anti-obesity and anti-diabetic β3- adrenoceptor agonists that has so far been a success in rodents but not in humans.
A major target for many illicitly used drugs in sport is the β2-adrenoceptor that is found in the heart, lungs and skeletal muscle where it controls rate and force, relaxes tone and stimulates growth. β2-adrenoceptor agonists are powerful bronchodilators, anabolic agents and, in combination with corticosteroids, powerfully enhance their anti-inflammatory actions.
A survey of 113 cases of clenbuterol poisoning cases in Spain in 1992 showed that more than half of those afflicted presented symptoms of tachycardia, muscle tremors, nervousness, myalgia, and headache. Exposure and onset ranged from 15 minutes to 6 hours . The duration of symptoms varied between 90 minutes and 6 days.
Clenbuterol influences cell metabolism by combining with β2-adrenergic receptors and by increasing the cAMP concentration in cells. In adipocytes, stimulation of β-adrenergic receptors increases cyclic AMP levels and activates protein kinase A (PKA), which stimulates lipolysis by phosphorylating hormone-sensitive lipase and perilipin.
Adipose accumulation decreases dramatically by clenbuterol administration. In this study pigs treated with clenbuterol had a lean meat percentage increase by 2%, the back fat thickness was reduced by ~0.2 cm, and the loin muscle area was reduced by 4.7 cm2. This effect increased with the age of the pigs. Clenbuterol produces specific protein anabolic effects in skeletal muscle in addition to lipolysis in adipose tissue. The clenbuterol thickened the pig muscle fibers and reduced the sizes of the pig adipocyte cells. Histological sections and global evaluation of gene expression after administration of clenbuterol in pigs identified profound changes in adipose cells. With clenbuterol stimulation, adipose cell volumes decreased and their gene expression profile changed, which indicate some metabolism processes have been also altered. These findings indicate that some metabolic processes, such as DNA transcription, protein translation and protein translocation, were enhanced in the adipose cells by clenbuterol stimulation.
However, data has revealed that clenbuterol is also capable of inducing significant myocyte apoptosis and necrosis in the heart and slow-twitch soleus muscle of rats. Furthermore, the onset of myocyte death occurs at doses lower than those commonly used to demonstrate the hypertrophic effects of this agent
The skeletal myocyte death induced by administration of clenbuterol to whole animals in vivo is mediated by overstimulation of the myocyte β2-AR4. When administered in vivo, clenbuterol also stimulates the β2-AR of the sympathetic nerve terminals, which augments their release of norepinephrine, and the β2-AR of the peripheral vasculature, which results in a reflex tachycardia. These neuromodulatory effects may act synergistically, increasing the release of norepinephrine from the sympathetic varicosities, which induces cardiomyocyte death through the β1-AR pathway
Administration of clenbuterol induced significant and clearly discernible myocyte death in the heart and slow-twitch soleus muscle. Bolus injection of doses as low as 10 μg.kg-1 of clenbuterol induces significant myocyte death in the heart and soleus muscle of rats. In response to sustained exposure to an agonist, β-AR desensitization and downregulation occur resulting in tachyphylaxis. However, because of clenbuterol’s long plasma half-life and the fact that it accumulates in specific tissue compartments, particularly the heart, it is difficult to predict whether chronic administration would be more or less myotoxic than a bolus injection.
The patient above was treated with beta-blocker therapy. Mcclennan et al performed a study on the effects of clenbuterol and propanolol n muscle mass. They found that in animals treated with clenbuterol and propranolol, the changes in body weight and body composition observed in animals treated with clenbuterol alone were abolished. The Beta-blocking agent also abolished the effects of clenbuterol on both muscle growth and protein synthesis rate. However, the study showed that the effects of clenbuterol on muscle cyclic AMP, lactate and glycogen concentrations were still detectable after twice-daily injection of the drug for 7 days. The dose of propranolol employed in the study was able to inhibit the effects of clenbuterol on cardiac, fat and liver mass and on energy expenditure.
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Filed under: Sherwin's Critical Care