Corticosteroids B Spoelhof and SD Ray, Manchester University College of Pharmacy, Fort Wayne, IN, USA Ó 2014 Elsevier Inc. All rights reserved. This article is a revision of the previous edition article by Prathibha S. Rao, volume 1, pp 669–670, Ó 2005, Elsevier Inc. l
effects. There are two classes of corticosteroids, glucocorticoids and mineralocorticoids that have predominant effects on metabolic and electrolyte processes, respectively. Beyond the carbohydrate, protein, and lipid metabolism; water and electrolyte management; corticosteroids also exert effects by regulating normal function of the cardiovascular, immune, kidney, skeletal, endocrine, and nervous systems. Furthermore, in part
Name: Corticosteroids Chemical Abstracts Service Registry Number: 8001-02-3 Ò Ò l Synonyms: Cortisone; Prednisone (Deltasone , Orasone ); Ò Ò Dexamethasone (Decadron ); Hydrocotisone (Cortef , Ò Ò Westcort ); Aldosterone; Fludrocotrisone (Florinef ) l Molecular Formula: Varies depending on agent l Chemical Structure: l
OH O
O CH3
HO
HO
OH
CH3
H
CH3
OH
H H
H
H
F
OH
H3C
H
O
O
Fludrocortisone
Cortisol/Hydrocortisone
O O HO
OH
CH3
HO H
CH3 H O
H
O
CH3
OH CH3
H F
H
OH
H
O
Aldosterone
Dexamethasone
Background Addison first described in the mid-nineteenth century that destruction of the adrenal glands led to fatal outcomes. Further studies identified the adrenal cortex as a chief regulator of metabolic, water, and electrolyte homeostasis, and by the 1930s, the structure of several compounds important in glucose metabolism had been described. Nearly a century later, research by Kendall and colleagues led to the discovery of cortisone as an effective antiinflammatory agent for patients with rheumatoid arthritis. Corticosteroids are a broad class of both endogenous and exogenous compounds that exert a wide range of physiological
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due to the physiological responses during times of survival and noxious stimuli, corticosteroids have been termed the stress hormones.
Mechanisms of Action General Mechanism of Action Corticosteroids exert their physiological effects via activation of either glucocorticoid receptor (GR) or the mineralocorticoid receptor (MR) in target tissues to alter the expression of corticosteroid-responsive genes. For example, the GR in the cell cytoplasm binds with steroid ligands to form hormone–receptor
Encyclopedia of Toxicology, Volume 1
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Corticosteroids
complexes that eventually translocate to the cell nucleus. These complexes bind to specific DNA sequences and alter their expression. The complexes may induce the transcription of mRNA leading to synthesis of new proteins. Though less studied than glucocorticoids, mineralocorticoids have a similar mechanism of action in gene regulation.
Antiinflammatory Mechanism of Action Lipocortin, a protein known to inhibit PLA2a is one such protein that is upregulated and thereby blocks the synthesis of prostaglandins, leukotrienes, and platelet activating factor (PAF). Glucocorticoids also inhibit the production of other mediators including amino acids metabolites such as cyclooxygenase, cytokines, the interleukins, adhesion molecules, and enzymes such as collagenase.
Metabolic Mechanism of Action In order to provide a mode of preservation for highly energydependent organ systems such as heart and brain tissues, glucocorticoids lead to increased serum glucose levels. Though poorly understood peripheral uptake of glucose is inhibited, it leads to decreased glucose utilization. Furthermore, gluconeogenesis is stimulated by inducing the transcription of enzymes such as phosphoenolpyruvate carboxykinase, fructose-1,6biphosphatase, and glucose-6-phosphatase.
Electrolyte Homeostasis Mechanism of Action Aldosterone is the prototypical mineralocorticoid. MRs located on the distal tubule and collecting duct upregulate sodium potassium pumps to increase reabsorption of sodium within the nephron. As a result, potassium and hydrogen ions are excreted and water is retained.
Available Agents and Routes of Administration Corticosteroids are available as a variety of dosage forms. Oral administration can be facilitated via tablet, capsules, or liquid preparations. Furthermore, several commercially available
Table 1
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devices exist for administration of dry powder, nebulized, and aerosolized drug. Corticosteroids can be topically applied as solutions, foams, shampoos, creams, ointments, and suspensions to the skin, eyes, or ears. Suppositories for rectal administrations and parenteral preparations for intramuscular or intravenous administration also exist. These preparations are available as either over-the-counter or prescription only. In addition, they may also be supplied in combination with other therapeutic agents (ciprofloxacin, nystatin).
Uses Synthetic pharmaceutical drugs with corticosteroid-like effect are used in a variety of conditions, ranging from brain tumors to skin diseases. Dexamethasone and its derivatives are almost pure glucocorticoids, while prednisone and its derivatives have some mineralocorticoid action in addition to the glucocorticoid effect. Fludrocortisone (Florinef) is a synthetic mineralocorticoid. Hydrocortisone (cortisol) is available for replacement therapy, e.g., in adrenal insufficiency and congenital adrenal hyperplasia. See Table 1 for relative dosing and antiinflammatory/mineralocorticoid activity. The most common use for corticosteroids today is for their antiinflammatory effects. Both oral and topical agents are used as treatment options for patients with conditions such as contact dermatitis. Autoimmune disorders or other inflammatory diseases such as ulcerative colitis, Crohn’s disease, temporal arteritis, systemic lupus erythematosus, or multiple sclerosis can all be treated with oral or intravenous therapy. National treatment guidelines recommend the use of inhaled corticosteroids as maintenance therapy for patients with mild persistent asthma and a short course of oral therapy for moderate or severe persistent asthma. Corticosteroids have been widely used in treating people with traumatic brain injury. A systematic review identified 20 randomized controlled trials and included 12 303 participants, compared patients who received corticosteroids with patients who received no treatment. The authors recommended people with traumatic brain injury should not be routinely treated
Relative dosing and potency of select corticosteroids
Short-acting Cortisone Hydrocortisone
Approximate equivalent dose (mg)
Relative antiinflammatory potency
Relative mineralocorticoid potency
Half-life plasma (min)
25 20
0.8 1
0.8 1
30 90
Intermediate-acting Methylprednisolone Prednisolone Prednisone Triamcinolone
4 5 5 4
5 4 4 5
0 0.8 0.8 0
180 200 60 300
Long-acting Betamethasone Dexamethasone
0.75 0.75
25 25–30
0 0
100–300 100–300
Mineralocorticoids Fludrocortisone
–
10
125
Asare, K., 2007. Diagnosis and treatment of adrenal insufficiency in the critically ill patient. Pharmacotherapy 27 (11), 1512–1528.
200
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Corticosteroids
with corticosteroids, as it may lead to increased mortality. Furthermore, a Cochrane review found limited evidence for the use of methylprednisolone in spinal cord injury patients. If used, it must be given within 8 h of initial injury and continued for 24–48 h. Corticosteroids can also be given during moments of adrenal insufficiency. Addison’s disease is a disorder in which endogenous production of corticosteroids is either limited or completely ceased. This can occur for many reasons such as Hypothalamic–pituitary–adrenal axis (HPAA) suppression, moments of overt and high stress such as septic shock, or genetic abnormalities.
Side Effects and Adverse Reactions The potent effect of corticosteroids can result in serious side effects, which mimic Cushing’s disease, a malfunction of the adrenal glands resulting in an overproduction of cortisol. The list of potential side effects is long and includes: increased appetite and weight gain; deposits of fat in chest, face, upper back, and stomach; water and salt retention leading to swelling and edema; high blood pressure; diabetes; black and blue marks; slowed healing of wounds; osteoporosis; cataracts; acne; muscle weakness; thinning of the skin; increased susceptibility to infection; stomach ulcers; increased sweating; mood swings; psychological problems such as depression; and adrenal suppression and crisis. Side effects can be minimized by following doctor’s orders and keeping to the lowest dose possible. It is also important to avoid self-regulation of the dosage, either by adding more or stopping the medication without a schedule.
Acute and Short-Term Toxicity Human Acute exposure of methylprednisolone has been associated with seizure activity and cardiac dysrhythmias such as atrial fibrillation, myocardial infarction, asystole, and sudden death. Patients may develop hypertension, electrolyte abnormalities, and increased glucose following acute exposure.
Chronic Toxicity (or Exposure) Animal Animal Chronic exposure to high serum levels of corticosterone induced a significant impairment of inhibitory avoidance learning in rats. In another study, corticosterone elevated over a period of 21 days impaired the formation of a longer-term form of memory, most likely reference memory. Impairments in spatial working memory were seen only after longer durations of corticosterone administration.
Human Chronic administration leads to hypothalamic–pituitary– adrenal axis suppression. Chronic exogenous administration
of corticosteroids provides a negative feedback to decrease corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) release by the hypothalamus and the pituitary, respectively. When the exogenous steroids are removed, an Addisonian state is induced and patients may develop an Addison’s crisis characterized by hypoglycemia, low blood pressure, and several electrolyte derangements. Fluid and electrolyte disturbances, hypertension, hyperglycemia, and glycosuria of acute toxicity may also occur. It also increases the susceptibility to infections including tuberculosis; causes peptic ulcers, osteoporosis, behavioral disturbances, posterior subcapsular cataracts, growth arrest, Cushing’s habitus, ‘buffalo hump,’ enlargement of supraclavicular fat pads, ‘central obesity,’ striae, ecchymoses, acne, and hirsutism.
Genotoxicity Very few studies with the natural or synthetic corticosteroids have been published. Data on cortisol and corticosterone are not available. Data on hydrocortisone are minimal. There is weak evidence that dexamethasone could have clastogenic and sister-chromatid exchange (SCE)-inducing potential.
Toxicokinetics Generally, the biological half-lives of corticosteroids can be classified as short (8–12 h), intermediate (12–36 h), or long (36–72 h). See Table 1 for relative half-lives of various corticosteroids. Cortisone and cortisol are examples of short-lived corticosteroids. Prednisone, prednisolone, and triamcinolone are of the intermediate class. Dexamethasone and b-methasone are associated with the longer-lived class. The adrenocortical steroids and their synthetic congeners require a double bond in the 4,5 position and a ketone group at C3 for biological activity. The reduction of the 4,5 double bond, resulting in an inactive compound, occurs by both hepatic and extrahepatic metabolisms. Glucocorticoids are absorbed systemically from sites of local administration in amounts that may be sufficient to suppress the HPAA. Following absorption, w90% of cortisol (or its synthetic analogs) is reversibly bound to plasma proteins, primarily corticosteroid binding globulin, and albumin. Only the unbound portion is available to exert physiological and pharmacological effects. At very high steroid concentrations, protein-binding capacity may be exceeded. Most of the ring A-reduced metabolites can be conjugated at the 3-hydroxyl position with sulfate or glucuronic acid forming water-soluble metabolites enhancing excretion by the kidney.
Agents That Affect Corticosteroids There are several agents that affect corticosteroids throughout the body. Ketoconazole, for example, is an antifungal but at high doses inhibits the cholesterol side chain cleavage preventing steroids synthesis. Similar agents that block steroids production have been identified such as aminoglutethimide,
Corticosteroids
Table 2
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Representative toxins that are known to deregulate corticosteroid homeostasis in vivo
Name of the compound
Model system
Reference
Aflatoxin B1 Chlordane Cadmium Ethanol
Rat liver Rat Rat DBA/2J (D2) mice
MPTP TCDD
Mice C57BL/6N mice
Pratt, R.M., 1985. Environ. Health Perspect. 61, 35–40. Cassidy, R.A., Toxicol. Appl. Pharmacol. 126 (2), 326–337. Singh, P.K., et al., 2012. Drug Chem. Toxicol. 35 (2), 167–177. Ford, M.M., et al., 2013. Psychoneuroendocrinology S0306-4530(13) 00228-X. Ben-Shaul, Y., et al., 2006. Eur. J. Neurosci. 23 (11), 2915–2922. Kensler, T.W., et al., 1976. Biochim. Biophys. Acta 437 (1), 200–210.
metyrapone, trilostane, and abiraterone. Mifepristone at high doses blocks the GRs. There are also two commercially available agents, spironolactone and eplerenone, that are used as mild diuretics in hypertension and heart failure. They act by antagonizing mineralocorticoid activity. Table 2 describes several other agents that act upon the homeostasis of corticosteroids in the body.
Clinical Management Acute overdose probably would not result in toxicity. Should oral overdosage occur, standard emergency and supportive care procedures should be followed. If anaphylaxis should occur, epinephrine may be given as 0.3–0.5 ml (0.3–0.5 mg) subcutaneously of a 1:1000 solution for adults and children should receive 0.01 mg kg 1. Administrations of benzodiazepines for seizures are recommended. If chronic toxicity should occur, it is important to reduce the dosage of corticosteroid to a minimal maintenance dose at the first sign of toxicity. Because of the risk that patients have developed HPAA suppression, it is important to taper corticosteroids and not abruptly discontinuing them. Debate exists about the length and dosage required to develop HPAA suppression and proper tapering techniques. Tapering should be guided based on clinical symptoms of withdrawal.
during pregnancy revealed two instances of cleft palate, eight stillbirths, one spontaneous abortion, and 15 premature births. Another study reported two cases of cleft palate in 86 births. Occurrence of cleft palate in these studies is higher than in the general population but could have resulted from the underlying diseases as well as from the steroids. Other fetal abnormalities that have been reported following glucocorticoid administration in pregnant women include hydrocephalus and gastroschisis. Women should be instructed to inform their physicians if they become or wish to become pregnant while receiving glucocorticoids. If glucocorticoids must be used during pregnancy or if the patient becomes pregnant while taking one of these drugs, the potential risks should be carefully considered.
Routes of Exposure The National Institute for Occupational Safety and Health statistically estimated that 30 657 workers (17 738 of these are females) are potentially exposed to dexamethasone in the United States. Occupational exposure to dexamethasone may occur through dermal contact with this compound at workplaces where dexamethasone is produced or used.
See also: Anabolic Steroids; Lipid Peroxidation.
Population at Risk Glucocorticoids should be used with caution in patients with hypothyroidism or cirrhosis, because such patients often show exaggerated response to the drugs. Glucocorticoids should be used with caution in psychotic patients or patients with hypertension or congestive heart failure, patients with recent myocardial infarction, in patients with viral infections or bacterial infections not controlled by antiinfectives, in patients with active or latent peptic ulcer, diverticulitis, nonspecific ulcerative colitis (if there is a probability of impending perforation, abscess, or other pyogenic infection), and in those with recent intestinal anastomoses. Glucocorticoids may cause fetal damage when administered to pregnant women. One retrospective study of 260 women who received pharmacological dosages of glucocorticoids
Further Reading Asare, K., 2007. Diagnosis and treatment of adrenal insufficiency in the critically ill patient. Pharmacotherapy 27 (11), 1512–1528. Bracken, M.B., 2012. Steroids for acute spinal cord injury. Cochrane Database Syst. Rev. 1, CD001046. Barshes, N.R., Goodpastor, S.E., Goss, J.A., 2004. Pharmacologic immunosuppression. Front. Biosci. 9, 411–420. McEvoy, G.K. (Ed.), 2007. American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD, pp. 3034–3035. Miller, L.W., 2002. Cardiovascular toxicities of immunosuppressive agents. Am. J. Transplant. 2, 807–818. Nikkanen, H.E., Shannon, M.W., 2007. Endocrine toxicology. In: Shannon, M.W., Borron, S.W., Burns, M.J. (Eds.), Haddad and Winchester’s Clinical Management of Poisoning and Drug Overdose, fourth ed. Saunders Elsevier, Philadelphia, PA (Chapter 16).
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Takeda, Y., Tomino, Y., 2004. Immunosuppressive therapy for nephrotic syndrome and strategy for adverse side effects from that therapy. Nihon Rinsho 62, 1875–1879. Ventura, M.T., Buquicchio, R., Cecere, R., et al., 2013. Anaphylactic reaction after the concomitant intravenous administration of corticosteroids and gastroprotective drugs: two case reports. J. Biol. Regul. Homeost. Agents 27 (2), 589–594. Williams, J.S., Williams, G.H., 2003. 50th anniversary of aldosterone. J. Clin. Endocrinol. Metab. 88 (6), 2364–2372. Weissman, D.E., Dufer, D., Vogel, V., Abeloff, M.D., 1987. Corticosteroid toxicity in neuro-oncology patients. J. Neurooncol. 5 (2), 125–128.
Relevant Websites http://arthritis.about.com/cs/steroids/a/corticosteroids.htm – Arthritis & Joint Conditions at About.com: Facts about corticosteroids. http://www.merckvetmanual.com – The Merck Veterinary Manual. http://umm.edu/health/medical/ency/articles/corticosteroids-overdose – University of Maryland Medical Center.