Pharmacology: Properties: DEPO-MEDROL is a sterile aqueous suspension of the synthetic glucocorticoid methylprednisolone acetate. It has a strong and prolonged anti-inflammatory, immunosuppressive and anti-allergic activity. DEPO-MEDROL can be administered I.M. for a prolonged systemic activity as well as in situ for a local treatment. The prolonged activity of DEPO-MEDROL is explained by the slow release of the active substance.
Pharmacodynamics: Methylprednisolone acetate has the general properties of the glucocorticoid methylprednisolone but is less soluble and less readily metabolised, which explains its prolonged activity.
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 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 4.4 mg methylprednisolone acetate (4 mg methylprednisolone) has the same glucocorticosteroid (anti-inflammatory) effect as 20 mg hydrocortisone. Methylprednisolone has only a minimal mineralocorticoid effect (200 mg methylprednisolone are equivalent to 1 mg 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 on chest, neck and head. All this leads to a redistribution of the fat deposits.
Maximum pharmacologic activity of glucocorticoids lays behind peak blood levels, suggesting that most effects of the drugs result from modification of enzyme activity rather than from direct actions by the drug.
Pharmacokinetics: Methylprednisolone acetate is hydrolised to its active form by serum cholinesterases. In man, methylprednisolone forms a weak dissociable bond with albumin and transcortin. Approximately 40 to 90% of the drug is bound. 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. I.M. injections of 40 mg/ml give after approximately 7.3 ± 1 hour (Tmax) methylprednisolone serum peaks of 1.48 ± 0.86 μg/100 ml (Cmax). The half-life is in this case 69.3 hours. After a single I.M. injection of 40 to 80 mg methylprednisolone acetate, duration of HPA axis suppression ranged from 4 to 8 days. An intra-articular injection of 40 mg in both knees (total dose: 80 mg) gives alter 4 to 8 hours methylprednisolone peaks of approximately 21.5 μg/100 ml. After intra-articular administration methylprednisolone acetate diffuses from the joint into systemic circulation over approximately 7 days, as demonstrated by the duration of the HPA axis suppression and by the serum methylprednisolone values.
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. These conjugation reactions occur principally in the liver and to some extent in the kidney.