methylprednisolone methylprednisolone methylprednisolone (depo-medrol, medrol, solu-medrol) is a synthetic glucocorticoid, primarily prescribed for its anti-inflammatory and immunosuppressive effects. it is either used at low doses for chronic illnesses or used concomitantly at high doses during acute flares. methylprednisolone and its derivatives can be administered orally or parenterally. methylprednisoloneclinical datatrade namesmedrol, depo-medrol (as acetate), solu-medrol (as succinate), othersother names6α-methylprednisolone; 11β,17,21-trihydroxy-6α-methyl-δ1-progesterone; 11β,17,21-trihydroxy-6α-methylpregna-1,4-diene-3,20-dioneahfs/drugs.commonographmedlineplusa682795license data us dailymed: methylprednisolone us fda: methylprednisolone pregnancycategory au: a; c (acetate suspension) routes ofadministrationby mouth, im (as acetate), ia (as acetate), iv (as succinate, suleptanate)atc coded07aa01 (who) d07ac14 (who), d10aa02 (who), h02ab04 (who), d07ca02 (who), s01ca08 (who), h02bx01 (who), s03ca07 (who)legal statuslegal status uk: pom (prescription only) us: ℞-only eu: rx-only pharmacokinetic dataprotein binding78%metabolismliver primarily, kidney, tissues; cyp3a4elimination half-life1.8–2.6 hoursexcretionurineidentifiers iupac name (1s,2r,8s,10s,11s,14r,15s,17s)-14,17-dihydroxy-14-(2-hydroxyacetyl)-2,8,15-trimethyltetracycloheptadeca-3,6-dien-5-one cas number83-43-2 ypubchem cid6741iuphar/bps7088drugbankdb00959 ychemspider6485 yuniix4w7zr7023keggd00407 ychebichebi:6888 ychemblchembl650 ycomptox dashboard (epa)dtxsid7023300 echa infocard100.001.343 chemical and physical dataformulac22h30o5molar mass374.477 g·mol−13d model (jsmol)interactive imagemelting point228 to 237 °c (442 to 459 °f)solubility in water1.20x10+2 mg/ml (20 °c) smiles o=c\1\c=c/4(/c(=c/1)(c)c24(o)c3((o)(c(=o)co)cc23)c)c inchi inchi=1s/c22h30o5/c1-12-8-14-15-5-7-22(27,18(26)11-23)21(15,3)10-17(25)19(14)20(2)6-4-13(24)9-16(12)20/h4,6,9,12,14-15,17,19,23,25,27h,5,7-8,10-11h2,1-3h3/t12-,14-,15-,17-,19+,20-,21-,22-/m0/s1 ykey:vhrsudsxcmqtma-pjhhcjlfsa-n y (verify) regardless of route of administration, methylprednisolone integrates systemically as exhibited by its effectiveness to quickly reduce inflammation during acute flares. it is associated with many adverse reactions that require tapering off the drug as soon as the disease is under control. serious side effects include iatrogenic cushing's syndrome, hypertension, osteoporosis, diabetes, infection, and skin atrophy. chemically, methylprednisolone is a synthetic pregnane steroid hormone derived from hydrocortisone and prednisolone. it belongs to a class of synthetic glucocorticoids and more generally, corticosteroids. it acts as a mineralocorticoid and glucocorticoid receptor agonist. in comparison to other exogenous glucocorticoids, methylprednisolone has a higher affinity to glucocorticoid receptors than to mineralocorticoid receptors. glucocorticoid's name was derived after the discovery of their involvement in regulating carbohydrate metabolism. the cellular functions of glucocorticoids, such as methylprednisolone, are now understood to regulate homeostasis, metabolism, development, cognition, and inflammation. they play a critical role in adapting and responding to environmental, physical and emotional stress. methylprednisolone was first synthesized and manufactured by the upjohn company (now pfizer) and fda approved in the united states in october 1957. in 2020, it was the 161st most commonly prescribed medication in the united states, with more than 3 million prescriptions. methylprednisolone is also on the world health organization's list of essential medicines for its effects against lymphoid leukemia. pharmacodynamics methylprednisolone is a synthetic glucocorticoid (gcs) that exhibits pleiotropic effects on a variety of physiological mechanisms. however, they have been prescribed extensively for their effects on inflammation and immunity. the effects of synthetic glucocorticoids, such as methylprednisolone, is dependent on its association with intracellular glucocorticoid receptors (grs), and to a lesser extent, mineralocorticoid receptors (mrs). grs are widely distributed in contrast to mrs that show a restricted tissue distribution. by this mechanism, the ligand-bound receptor translocate to the nucleus and modulate gene expression. the signal transduction pathway of glucocorticoids (methylprednisolone): genomic and non-genomic effects. signal transduction in the absence of endogenous or synthetic gcs, monomeric grs are located in the cytoplasm and form multiprotein complexes with heat shock proteins (hsps), immunophilins, and other chaperones such as src, and p23. the gr acts in a ligand-dependent manner, with the complex holding the gr in an inactive form with high specificity for the ligand. when methylprednisolone from the plasma or interstitial fluid diffuses passively across the cell membrane, it binds to the gr inducing a conformational change and gc-gr dimerization. it was previously thought that this conformational change was necessary to dissociate the multiprotein complex to allow the ligand bound receptor to translocate to the nucleus. however, recent studies have indicated that chaperones play a role in nuclear import. the now active methylprednisolone-gr complex can either transduce non-genomic changes in the cytoplasm or translocate to the nucleus and regulate transcriptional activity of target genes by direct, tethering or composite mechanisms. genomic signaling genomic mechanisms, regardless of which type, elicit responses with a slow onset and a slow dissipation. this is attributed to the duration of mrna transcription and translation. glucocorticoids have the ability to regulate roughly 100 to 1000 genes with specificity to cell-type. three major mechanisms have described how the mp-gr complex alter gene expression by either binding to dna or transcription modulators. one mechanism of genomic signaling occurs when the mp-gr complex directly binds to dna sequences called glucocorticoid response elements (gres). gres are located in regulatory regions of target genes and mediate their transactivation or transrepression. for example, the activation of lipocortin 1 (anax1) negatively interferes with the production of prostaglandins and leukotrienes, known pro-inflammatory signals. likewise, negative gres (ngres) are responsible for repressing genes involved in immune cell activation. post transcriptional modifications post translational modifications (ptms) also contribute to methylprednisolone signaling and can produce genomic and non-genomic effects. the gr has contains several sites for phosphorylation, sumoylation, ubiquitination, and acetylation that primarily occurs after intracellular methylprednisolone binding to the gr. ptms modulate many functions including nuclear translocation, strength and duration of receptor signaling and cofactor interaction. a specific example is the deacetylation by histone deacetylase 2 (hdace) was necessary for transrepression of nf-κb. non-genomic signaling the mechanisms of non-genomic signaling are distinct from genomic signaling, yet mediate similar pathways and provide therapeutic relevance. these mechanisms are characterized as having a rapid onset (less than 15 minutes), because they do not rely on time-consuming transcription or translation and are not modified by inhibitors of transcription. methylprednisolone induced non-genomic signaling is classified by three mechanisms: (1) cytoplasmic glucocorticoid receptor (cgr)-mediated non-genomic effects, (2) membrane-bound glucocorticoid receptor (mgr) non-genomic effects, and (3) physiochemical interactions with cellular membranes (non-specific non-genomic effects). proteins that dissociate from the activated gc-cgr complex, initiate intracellular transcription-independent mechanisms. it is evidence that dissociated src is responsible for inhibiting the release of arachidonic acid (aa) from cell membrane phospholipids. aa is required for the synthesis of inflammatory mediators (prostaglandins and leukotrienes) and thus aa inhibition mediates several important pathways such as cellular growth, metabolism and inflammation. previous studies identified mgrs in lymphoma cells, but it wasn't until 2004 that mgrs were identified in human peripheral mononuclear cells. the prevalence of mgrs ranges per cell type, with the highest concentration in b lymphocytes at up to 12.3%, up to 9.2% in monocytes, and absent from t lymphocytes. studies have shown a positive correlation between the mgr-positive cells and disease related activity. there are no proven signaling pathways associated with mgr at this time. some researchers hypothesize that high disease activity activates mgr expression and upon administering methylprednisolone, creates a negative feedback loop by inducing apoptosis. high concentrations of methylprednisolone intercalate in plasma and mitochondrial cellular membranes. this association changes physiochemical properties of the membrane; activating membrane proteins, altering cellular functions and ultimately influencing cation transport through the plasma membrane and stimulating the proton leak across the inner mitochondrial membrane. hindered oxidative phosphorylation compromises atp production, a major energy source for cellular energy metabolism and immune function. in vivo studies of con-a stimulated thymocytes (in rats) and human immune cells that were administered high doses of methylprednisolone has been shown to inhibit respiration in a dose-dependent manner, inhibit plasma calcium and sodium uptake, and increase cytoplasmic calcium concentration. the summative process is as follows: methylprednisolone intercalates in the plasma membrane, causes physiochemical changes, activates membrane proteins that inhibit plasma calcium and sodium uptake (mimicking an energy deficit state). atp consumption drops (resembled by inhibited respiration), resulting in protein permeability at the inner mitochondrial membrane and uncoupling of oxidative phosphorylation. of notable importance, dna/rna synthesis was not hindered. the dependency of house keeping cells and immune cells on atp, results in immunosuppression during atp deficit. specific immune functions effected by this process are cytokinesis, migration, phagocytosis, antigen processing and presenting, antibody synthesis, cytotoxicity and regulation. the hpa regulation of the hpa axis the activation of the hypothalamic-pituitary axis (hpa) stimulates the production of endogenous glucocorticoids within the adrenal cortex. the hpa interprets stimuli (stress, inflammation and circadian cues) and transduces a corresponding physiochemical response. glucocorticoids released in the blood, serve as a messenger by binding to glucocorticoid receptors in a wide distribution across the body, including the hpa itself. thus, the physiological range of gcs is monitored by the negative feedback loop gcs exert on any portion of the hpa. methylprednisolone structurally and functionally mimics endogenous corticoids and will act upon the hpa in a similar fashion. pharmacokinetics methylprednisolone (medrol), methylprednisolone acetate (depo-medrol) and methylprednisolone succinate (solu-medrol), respectively. methylprednisolone is approved for oral and parenteral administration. methylprednisolone (medrol) for oral administration is available in a tablet formulation in 2 mg, 4 mg, 8 mg, 16 mg or 32 mg strengths. both methylprednisolone acetate (depo-medrol) and methylprednisolone succinate (solu-medrol) are approved for intramuscular injection. depo-medrol is additionally approved for intralesional, intra-articular, and soft tissue injections. depo-medrol is available as sterile aqueous solution in 20 mg/ml, 40 mg/ml, or 80 mg/ml strengths. solu-medrol is the only derivative of methylprednisolone that is approved for intravenous infusion, as the sterile powder is soluble in water and can be mixed with a diluent. strengths vary from 40 mg to 2g. synthetic glucocorticoids are similar to endogenous steroids in metabolism, but differ in affinity for glucocorticoid and mineralocorticoid receptors, affinity for protein-binding, rate of elimination, and metabolic products. oral methylprednisolone is readily absorbed from the gastrointestinal tract with a bioavailability of 89.9%. in contrast to endogenous gcs, methylprednisolone does not bind to the glycoprotein transcortin (corticosteroid binding globulin, cbg) but does have moderate protein binding to albumin. thus, pharmacokinetics of methylprednisolone is linear and show no dose dependency. patients exhibiting low albumin concentrations are at risk for adverse effects during glucocorticoid therapy. oral methylprednisolone has a moderate distribution into tissue at 1.38l/kg. methylprednisolone is primarily eliminated by hepatic metabolism and renal excretion of metabolites; with renal excretion of unchanged methylprednisolone at only 1.3–9.2%. methylprednisolone can be interconverted with methylprednisone. hepatic metabolism is mediated by 11 beta-hydroxysteroid dehydrogenases (11-hsd) and 20-ketosteroid reductases. methylprednisolone undergoes renal excretion of hydrophilic inactive metabolites, including 20-carboxymelthylprednisolone and 6-hydroxy-20-hydroxymethylprednisolone. characteristics of natural and synthetic glucocorticoids. 1activity is relative to hydrocortisone synthetic glucocorticoid equivalent dose (mg) anti-inflammatory activity1 mineralocorticoid activity1 biological half life (hrs)