Prednisone is a synthetic glucocorticoid drug, a corticosteroid derived from cortisone that acts as an anti-inflammatory and immunosuppressive agent. It is a prodrug: after it is taken, the liver converts it into its active form, prednisolone. Because it affects many tissues at once, it is prescribed for a wide range of conditions, and its benefits are closely balanced against its systemic side effects.
Chemistry and pharmacology
Prednisone has the molecular formula C21H26O5 and a molar mass of about 358 g/mol. Structurally it resembles cortisone, from which it differs by one additional double bond in ring A of the steroid skeleton. Cortisone and its close cousin prednisone (with an additional double bond) are widely used anti-inflammatory agents, but their use must be monitored carefully because they can suppress the immune system.
Prednisone is first metabolized in the liver to its active form, prednisolone, a glucocorticoid agonist corticosteroid. Prednisolone carries most of the glucocorticoid activity, so pharmacological discussion of prednisone usually refers to the effects of prednisolone. The drug is taken by mouth as a tablet or liquid, and it can also be given by intramuscular injection.
Mechanism of action
Prednisolone enters cells and binds the glucocorticoid receptor (GR), a ligand-activated transcription factor of the nuclear receptor family. In the absence of glucocorticoid, GR resides in the cytoplasm and associates with chaperone proteins such as hsp90 and hsp70. The binding of hormone causes a conformational change in GR, leading to its translocation to the nucleus, where it exerts its transcriptional control activity. The receptor-ligand complex acts in two broad ways. In transrepression, the complex suppresses genes that drive the synthesis of inflammatory cytokines and other proteins, which is the principal source of the anti-inflammatory effect. As the intranuclear concentration of glucocorticoids increases, a second process named transactivation starts. Although this mechanism stimulates the transcription of some inhibitory genes, it mainly mediates the activation of gluconeogenesis, insulin resistance, skin atrophy, and the inhibition of bone formation.
Several downstream effects have been described. Glucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit phospholipase A2, which decreases the formation of arachidonic acid derivatives; they inhibit NF-Kappa B and other inflammatory transcription factors; they promote anti-inflammatory genes like interleukin-10. Dose matters: lower doses of corticosteroids provide an anti-inflammatory effect, while higher doses are immunosuppressive. Estimates of receptor occupancy suggest that the use of low doses of prednisone (≤7.5 mg/day) is associated with a progressive saturation up to 50% of the cGR. At higher doses, up to 100 mg/day, the predominant effect is transactivation, which is linked to a larger share of adverse effects.
Prednisone also has weak mineralocorticoid activity. It retains sodium and water in the kidney, which can lead to hypertension. In addition, prednisone will suppress ACTH production and endogenous glucocorticoids, meaning that the body's own cortisol production is reduced during treatment.
Clinical uses
Prednisone is used for conditions that involve inflammation, immune overactivity, or certain hormonal and malignant disorders. Its indications are commonly grouped by organ system. Prednisone is a glucocorticoid indicated to treat or manage many conditions, including endocrine disorders, rheumatic disorders, collagen diseases, dermatologic diseases, allergies, ophthalmic (eye) diseases, respiratory diseases, hematologic disorders, neoplastic diseases (cancers), edematous states, and gastrointestinal diseases.
Representative examples include rheumatoid arthritis, lupus, asthma exacerbations, inflammatory bowel disease, and multiple sclerosis relapses. Its uses include allergies and allergic reactions, anemia, asthma, bursitis, dermatitis, endocrine disorders such as adrenal insufficiency or congenital adrenal hyperplasia, eye inflammation, lung diseases such as sarcoidosis or aspiration pneumonia, lupus and nephrotic syndrome, and MS exacerbations. In hematologic malignancies, corticosteroids are part of many chemotherapy regimens for leukemia and lymphoma. The mechanism of their anticancer effect is incompletely understood: prednisone presumably induces killing of hematopoietic cancer cells through interaction with the glucocorticoid receptor and the induction of apoptosis, and multiple mechanisms exist whereby tumor cells of hematopoietic origin resist steroid-induced killing.
Adverse effects
The side-effect profile depends strongly on dose and duration. Side effects that can occur with short term use include sodium and water retention with associated hypertension, peptic ulcer with possible perforation and hemorrhage, increased susceptibility to infections, emotional instability, insomnia, increased appetite, weight gain, acne and hyperglycemia. Such effects are typical of short courses. With longer use, the spectrum widens: cataracts, increased intraocular pressure and associated glaucoma, development of a "cushingoid" state, compression fractures, menstrual irregularities, suppression of growth in children, secondary adrenocortical and pituitary unresponsiveness particularly in times of stress as in trauma, surgery or illness, osteoporosis and muscle wasting.
Two effects are particularly important clinically. The first is hyperglycemia, which is driven by gluconeogenesis and insulin resistance. The second is HPA-axis suppression. Long-term use of prednisone may cause the body's adrenal glands to stop making as much cortisol. This is known as adrenal insufficiency. Adrenal insufficiency can get worse if the body is under stress because of fever, surgery, or trauma. For this reason, treatment is usually stopped gradually rather than abruptly after prolonged use. Because prednisone also dampens immune defenses, serious side effects include reduced adrenal gland function and increased risk of infections.
Specific populations face distinct risks. In children, growth suppression is a known concern. Prednisone also has direct effects on the stomach: it can stimulate secretion of acid in the stomach and it also has a direct effect on the lining of the stomach.
History
The development of prednisone followed the discovery of cortisone and related hormones. Cortisone was identified in the 1930s by Edward C. Kendall at the Mayo Clinic, who shared the 1950 Nobel Prize for physiology or medicine for his work. Cortisone and the related hydrocortisone were used clinically soon after. The first successful use of hydrocortisone, the first glucocorticoid to be synthesized, was in 1948, when it was used to suppress the clinical manifestations of rheumatoid arthritis.
Natural glucocorticoids had a drawback: their strong mineralocorticoid action caused fluid retention and high blood pressure. Work at Schering Corporation addressed this. Prednisone was developed in the 1950s by Arthur Nobile and co-workers at Schering. The key step was microbial oxidation. The discovery of prednisone involved the innovative use of the bacterium Corynebacterium simplex to oxidize cortisone. The modification to the cortisone structure reduced the mineralocorticoid effects, mitigating side effects like fluid retention. Schering researchers reported that prednisone and prednisolone, developed in 1954 at the Schering Corporation, have three to five times the potency of cortisone, and less mineralocorticoid effect.
Patent and regulatory milestones are dated differently across sources. One account states that the drug was patented in 1954 and received FDA approval in February 1955. A different account gives the introduction date as the mid-1960s, which likely refers to a later marketing phase. Manufacturing history also involves other companies. Upjohn scientists had earlier developed microbial fermentation for cortisone, and Upjohn (together with Pharmacia) biochemically converted cortisone into the more potent steroid prednisone via bacterial fermentation. The development of microbial steroid transformations is also considered a foundation of the modern steroid drug industry. The discovery of prednisone and prednisolone heralded a new area of chemical synthesis, creating a multibillion dollar industry based on the use of microbes to manufacture drugs.
Limitations and ongoing research
The central challenge of corticosteroid therapy is separating the wanted anti-inflammatory action from the unwanted metabolic and hormonal effects. It is important to develop highly potent and selective glucocorticoids to reduce the unwanted side effects. Researchers have also noted that localizing the effects to the region of inflammation (e.g., the lungs) would minimize the systemic side effects.
Response to glucocorticoids is also variable. In leukemia, resistance to glucocorticoids is considered to be one of the most important factors in the prognosis of leukemia. Long-term immunosuppression, the need for careful monitoring, and the risk of adrenal suppression mean that prednisone remains a drug whose use is weighed case by case. The drug is still widely prescribed more than seventy years after the initial discovery of cortisone's effects.
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