Steroid allergy


Corticosteroids are a class of chemicals that includes steroid hormones naturally produced in the adrenal cortex of vertebrates and analogues of these hormones that are synthesized in laboratories. Corticosteroids are involved in a wide range of physiological processes, including stress response, immune response, and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior.

Some common natural hormones are corticosterone (), cortisone (, 17-hydroxy-11-dehydrocorticosterone) and aldosterone.

Biosynthesis

The corticosteroids are synthesized from cholesterol within the adrenal cortex. Most steroidogenic reactions are catalysed by enzymes of the cytochrome P450 family. They are located within the mitochondria and require adrenodoxin as a cofactor (except 21-hydroxylase and 17α-hydroxylase).

Aldosterone and corticosterone share the first part of their biosynthetic pathway. The last part is mediated either by the aldosterone synthase (for aldosterone) or by the 11β-hydroxylase (for corticosterone). These enzymes are nearly identical (they share 11β-hydroxylation and 18-hydroxylation functions), but aldosterone synthase is also able to perform an 18-oxidation. Moreover, aldosterone synthase is found within the zona glomerulosa at the outer edge of the adrenal cortex; 11β-hydroxylase is found in the zona fasciculata and zona glomerulosa.

Classification

By chemical structure

In general, corticosteroids are grouped into four classes, based on chemical structure. Allergic reactions to one member of a class typically indicate an intolerance of all members of the class. This is known as the "Coopman classification",[2] after S. Coopman, who defined this classification in 1989.[3]

The highlighted steroids are often used in the screening of allergies to topical steroids.[4]

Group A — Hydrocortisone type

Hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, and prednisone (Short- to medium-acting glucocorticoids).

Group B — Acetonides (and related substances)

Triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, and halcinonide.

Group C — Betamethasone type

Betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, and fluocortolone.

Group D — Esters

Group D1 — Halogenated (less labile)

Hydrocortisone-17-valerate, halometasone, alclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate, and fluprednidene acetate.

Group D2 — Labile prodrug esters

Hydrocortisone-17-butyrate, hydrocortisone-17-aceponate, hydrocortisone-17-buteprate, and prednicarbate.

By route of administration

Topical steroids

Main article: Topical steroid

For use topically on the skin, eye, and mucous membranes.

Topical corticosteroids are divided in potency classes I to IV,

Inhaled steroids

for use to treat the nasal mucosa, sinuses, bronchii, and lungs.[5] This group includes:

There is also a combination preparation (trade name Advair), containing fluticasone propionate and salmeterol xinafoate (a long-acting bronchodilator).[6] It is approved for children over 12 years old.

Oral forms

Such as prednisone and prednisolone.[7]

Systemic forms

Available in injectables for intravenous and parenteral routes.[7]

Uses of corticosteroids

Synthetic pharmaceutical drugs with corticosteroid-like effects 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.

Synthetic glucocorticoids are used in the treatment of joint pain or inflammation (arthritis), temporal arteritis, dermatitis, allergic reactions, asthma, hepatitis, systemic lupus erythematosus, inflammatory bowel disease (ulcerative colitis and Crohn's disease), sarcoidosis and for glucocorticoid replacement in Addison's disease or other forms of adrenal insufficiency.[8] Topical formulations are also available for the skin, eyes (uveitis), lungs (asthma), nose (rhinitis), and bowels. Corticosteroids are also used supportively to prevent nausea, often in combination with 5-HT3 antagonists (e.g. ondansetron).

Typical undesired effects of glucocorticoids present quite uniformly as drug-induced Cushing's syndrome. Typical mineralocorticoid side-effects are hypertension (abnormally high blood pressure), hypokalemia (low potassium levels in the blood), hypernatremia (high sodium levels in the blood) without causing peripheral edema, metabolic alkalosis and connective tissue weakness.[9] There may also be impaired wound healing or ulcer formation because of the immunosuppressive effects.

Clinical and experimental evidence indicates that corticosteroids can cause permanent eye damage by inducing central serous retinopathy (CSR, also known as central serous chorioretinopathy, CSC). A variety of steroid medications, from anti-allergy nasal sprays (Nasonex, Flonase) to topical skin creams, to eye drops (Tobradex), to prednisone have been implicated in the development of CSR.[10][11]

Corticosteroids have been widely used in treating people with traumatic brain injury.[12] A systematic review identified 20 randomised controlled trials and included 12,303 participants, then compared patients who received corticosteroids with patients who received no treatment. The authors recommended people with traumatic head injury should not be routinely treated with corticosteroids.[13]

History

First known use was in 1944.[14] Tadeusz Reichstein together with Edward Calvin Kendall and Philip Showalter Hench were awarded the Nobel Prize for Physiology and Medicine in 1950 for their work on hormones of the adrenal cortex, which culminated in the isolation of cortisone.[15]

Corticosteroids have been used as drug treatment for some time. Lewis Sarett of Merck & Co. was the first to synthesize cortisone, using a complicated 36-step process that started with deoxycholic acid, which was extracted from ox bile.[16] The low efficiency of converting deoxycholic acid into cortisone led to a cost of US $200 per gram. Russell Marker, at Syntex, discovered a much cheaper and more convenient starting material, diosgenin from wild Mexican yams. His conversion of diosgenin into progesterone by a four-step process now known as Marker degradation was an important step in mass production of all steroidal hormones, including cortisone and chemicals used in hormonal contraception.[17] In 1952, D.H. Peterson and H.C. Murray of Upjohn developed a process that used Rhizopus mold to oxidize progesterone into a compound that was readily converted to cortisone.[18] The ability to cheaply synthesize large quantities of cortisone from the diosgenin in yams resulted in a rapid drop in price to US $6 per gram, falling to $0.46 per gram by 1980. Percy Julian's research also aided progress in the field.[19] The exact nature of cortisone's anti-inflammatory action remained a mystery for years after, however, until the leukocyte adhesion cascade and the role of phospholipase A2 in the production of prostaglandins and leukotrienes was fully understood in the early 1980s.

Side-effects

Side effects such as cutaneous addiction with the development of uncomfortable and unsightly dermatoses, can occur with just one 15 g tube of moderate steroid over a period of one year.[20]

Use of corticosteroids has numerous side-effects, some of which may be severe:

  • Neuropsychiatric: steroid psychosis,[21] and anxiety,[22] depression. Therapeutic doses may cause a feeling of inappropriate well-being ("steroid euphoria").[23] The neuropsychiatric effects are partly mediated by sensitization of the body to the actions of adrenaline. Therapeutically, the bulk of corticosteroid dose is given in the morning to mimic the body's diurnal rhythm; if given at night, the feeling of being energized will interfere with sleep. An extensive review is provided by Flores and Gumina.[24]
  • Cardiovascular: Corticosteroids can cause sodium retention through a direct action on the kidney, in a manner analogous to the mineralocorticoid aldosterone. This can result in fluid retention and hypertension.
  • Metabolic: Corticosteroids cause a movement of body fat to the face and torso, resulting respectively in "moon face" and "buffalo hump". and away from the limbs. Due to the diversion of amino-acids to glucose, they are considered anti-anabolic, and long term therapy can cause muscle wasting [25]
  • Endocrine: By increasing the production of glucose from amin-acid breakdown and opposing the action of insulin, corticosteroids can cause hyperglycemia,[22] insulin resistance and diabetes mellitus,.[22] By inhibition of the action of sex steroids, they can cause erectile dysfunction, hypogonadism and amenorrhoea.
  • Skeletal: Steroid-induced osteoporosis imay be a side-effect of long-term corticosteroid use. While cases of colitis have been reported, corticosteroids are therapeutically employed when the colitis has an auto-immune nature, e.g., ulcerative colitis and Crohn's disease.
  • Gastro-intestinal: While the evidence for corticosteroids causing peptic ulceration is relatively poor except for high doses taken for over a month,[26] the majority of doctors as of 2010 still believe this is the case, and would consider protective prophylactic measures.[27]
  • Eyes: chronic use may predispose to cataract and retinopathy.
  • Vulnerability to infection: By suppressing immune reactions (which is one of their main reasons for their use in allergies), steroids may cause infections to flare up, notability candidiasis[28]
  • Pregnancy: Corticosteroids have a low but significant teratogenic effect, causing a few birth defects per 1,000 pregnant women treated. Corticosteroids are therefore contraindicated in pregnancy.[29]

Safety

Corticosteroids were voted Allergen of the Year in 2005 by the American Contact Dermatitis Society.[30]

See also

References

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