Vaxcel Methylprednisolone Mechanism of Action

Pharmacology: Mechanism of Action: Glucocorticoids diffuse across cell membranes and complex with specific cytoplasmic receptors. These complexes then enter the cell nucleus, bind to DNA (chromatin), and stimulate transcription of mRNA and subsequent protein synthesis of various enzymes thought to be ultimately responsible for the numerous effects of glucocorticoids after systemic use. Glucocorticoids not only have an important influence on inflammatory and immune processes, but also affect the carbohydrate, protein and fat metabolism. They also act on the cardiovascular system, the skeletal muscles and the central nervous system.
Effect on the inflammatory and immune process: The anti-inflammatory, immunosuppressive and anti-allergic properties of glucocorticoids are responsible for most of the therapeutic applications. These properties lead to the following results: Reduction of the immunoactive cells near the inflammation focus; Reduced vasodilation; Stabilization of the lysosomal membranes; Inhibition of phagocytosis; Reduced production of prostaglandins and related substances. A dose of 4mg methylprednisolone has the same glucocorticosteroid (anti-inflammatory) effect as 20mg hydrocortisone. Methylprednisolone has only a minimal mineralocorticoid effect (200mg methylprednisolone are equivalent to 1mg desoxycorticosterone).
Effect on carbohydrate and protein metabolism: Glucocorticoids have a protein catabolic action. The liberated amino acids are converted into glucose and glycogen in the liver by means of the gluconeogenesis process. Glucose absorption in peripheral tissues decreases, which can lead to hyperglycemia and glucosuremia, especially in patients who are prone to diabetes.
Effect on fat metabolism: Glucocorticoids have a lipolytic action. This lipolytic activity mainly affects the limbs. They also have a lipogenetic effect which is most evident to chest, neck and head. All this leads to a redistribution of the fat deposits. Maximum pharmacologic activity of corticosteroids lags behind peak blood levels, suggesting that most effects of the drugs result from modification of enzyme activity rather than from direct actions by the drugs.
Pharmacokinetics: In vivo, cholinesterases rapidly hydrolyse methylprednisolone sodium succinate to free methylprednisolone. In man, methylprednisolone forms a weak dissociable bond with albumin and transcortin. Approximately 40 to 90% of the drug is bound. Intravenous infusions with 30mg/kg, administered over 20 minutes or 1g administered over 30 to 60 minutes lead after approximately 15 minutes to peak methylprednisolone plasma levels of nearly 20lg/ml. About 25 minutes after an intravenous bolus injection of 40mg peak methylprednisolone plasma levels of 34lg/100ml after some 120 minutes. Intramuscular injections give lower peak values than intravenous injections. With I.M. injections plasma values persist for a longer period, with the result that both administration patterns lead to equivalent quantities of methylprednisolone. The clinical importance of these small differences is probably minimal when we consider the mechanism of action of glucocorticoids. A clinical response is usually observed 4 to 6 hours after administration. In the treatment of asthma, the first beneficial results can already be perceived after 1 or 2 hours. The plasma half-life of methylprednisolone sodium succinate is 2.3 to 4 hours and appears to bear no relation to the administration pattern. Methylprednisolone is a glucocorticoid with a medium-term activity. It has a biological half-life of 12 to 36 hours. The intracellular activity of glucocorticoids results in a clear difference between plasma half-life and pharmacological half-life. Pharmacological activity persists after measurable plasma levels have disappeared. The duration of anti-inflammatory activity of glucocorticoids approximately equals the duration of hypothalamic-pituitary-adrenal (HPA) axis suppression. Metabolism of methylprednisolone occurs via hepatic routes qualitatively similar to that of cortisol. The major metabolites are 20 beta-hydroxymethylprednisolone and 20 beta-hydroxy-6 alpha-methylprednisone. The metabolites are mainly excreted in the urine as glucuronides, sulfates and unconjugated compounds. Following I.V. administration of 14C labeled methylprednisolone, 75% of the total radioactivity was recovered in the urine in 96 hours, 9% was recovered in human feces after 5 days and 20% in the bile.