Hydrocortisone

Absorption

Oral hydrocortisone at a dose of 0.2-0.3mg/kg/day reached a mean Cmax of 32.69nmol/L with a mean AUC of 90.63h*nmol/L A 0.4-0.6mg/kg/day dose reached a mean Cmax of 70.81nmol/L with a mean AUC of 199.11h*nmol/L. However, the pharmacokinetics of hydrocortisone can vary by 10 times from patient to patient.
Topical hydrocortisone cream is 4-19% bioavailable[8546995] with a Tmax of 24h.
Hydrocortisone retention enemas are have a bioavailability of 0.810 for slow absorbers and 0.502 in rapid absorbers. Slow absorbers take up hydrocortisone at a rate of 0.361±0.255/h while fast absorbers take up hydrocortisone at a rate of 1.05±0.255/h.
A 20mg IV dose of hydrocortisone has an AUC of 1163±277ng*h/mL.

Toxicity

Data regarding acute overdoses of glucocorticoids are rare. Chronic high doses of glucocorticoids can lead to the development of cataract, glaucoma, hypertension, water retention, hyperlipidemia, peptic ulcer, pancreatitis, myopathy, osteoporosis, mood changes, psychosis, dermal atrophy, allergy, acne, hypertrichosis, immune suppression, decreased resistance to infection, moon face, hyperglycemia, hypocalcemia, hypophosphatemia, metabolic acidosis, growth suppression, and secondary adrenal insufficiency. Overdose may be treated by adjusting the dose or stopping the corticosteroid as well as initiating symptomatic and supportive treatment.

Description

Hydrocortisone, also called cortisol, is a glucocorticoid produced by the adrenal glands. It has many physiological functions, including fighting inflammation. Synthetic hydrocortisone is sold over the counter as a topical anti-inflammatory and anti-itch agent.
T. Reichstein in 1937 and H. L. Mason et al. in 1938 isolated hydrocortisone from adrenal glands. (Reichstein was awarded the 1950 Nobel Prize in Medicine or Physiology for his work on adrenal cortex hormones.) Its?first synthesis?was reported by N. L. Wendler and co-workers in 1950.
Hydrocortisone is also called “the stress hormone”: It is released by the adrenal glands as a response to stress or fear. So expect your hydrocortisone level to increase on Halloween!

Chemical properties

crystalline white powder

Originator

Hydrocortone,MSD,US,1952

The Uses of Hydrocortisone

Cortisol, or Hydrocortisone, is a steroid hormone, more specifically a glucocorticoid, produced by the zona fasciculata of the adrenal gland. Cortisol is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat, protein and carbohydrate metabolism.

The Uses of Hydrocortisone

Principle glucocorticoid hormone produced by adrenal cortex. An anti-inflammatory hormone.

The Uses of Hydrocortisone

glucocorticoid, antiinflammatory

Indications

Otic solutions are indicated for infections of the external auditory canal caused by susceptible organisms and with inflammation. Hydrocortisone tablets are indicated for certain endocrine, rheumatic, collagen, allergic, ophthalmic, respiratory, hematologic, neoplastic, edematous, gastrointestinal, and other conditions. A hydrocortisone enema is indicated for ulcerative colitis, a topical ointment with antibiotics is indicated for corticosteroid responsive dermatoses with infections, and a topical cream with acyclovir is indicated to treat cold sores. Oral granules of hydrocortisone are used as a replacement therapy for Adrenocortical Insufficiency (AI) in children under 17 years of age.

Background

Hydrocortisone, or cortisol, is a glucocorticoid secreted by the adrenal cortex. Hydrocortisone is used to treat immune, inflammatory, and neoplastic conditions. It was discovered in the 1930s by Edward Kendall and named Compound F, or 17-hydroxycorticosterone.
Hydrocortisone was granted FDA approval on 5 August 1952.

What are the applications of Application

Hydrocortisone is a primary glucocorticoid and anti-inflammatory agent

Definition

ChEBI: A C21-steroid that is pregn-4-ene substituted by oxo groups at positions 3 and 20 and hydroxy groups at positions 11, 17 and 21. Cortisol is a corticosteroid hormone or glucocorticoid produced by zona fasciculata of the adrenal cortex, which is a part of the adrenal gland. It is usually referred to as the "stress hormone" as it is involved in response to stress and anxiety, controlled by corticotropin-releasing hormone (CRH). It increases blood pressure and blood sugar, and reduces immun responses

Indications

Hydrocortisone (Cortizone, Cortaid, Anusol-HC, Hytone, LactiCare-HC, Sarnol HC, Penecort, Texacort, and many other branded products) may be purchased as a generic drug.

Manufacturing Process

The following example from US Patent 2,602,769 illustrates the preparation of 17-hydroxycorticosterone (compound F) from 11-desoxy-17- hydroxycorticosterone (compound S). A medium was prepared from 0.5% peptone, 2% dextrose, 0.5% soybean meal, 0.5% KH2PO4, 0.5% sodium chloride and 0.3% yeast extract in tap water. To 200 ml of this sterilized medium was added an inoculum of the vegetative mycella of Cunninghamella blakesleeana. The spores had first been transferred from a sport slant to a broth medium and the broth medium was aerobically incubated at 24°C for 24 to 72 hours in a .reciprocating shaker until the development of vegetative growth. The inoculated medium containing added vegetative mycella of Cunninghamella blakesleeana was incubated for 48 hours at 24°C following which was added 66 mg of compound S, 11-desoxy-17-hydroxycorticosterone in solution in a minimum of ethanol, and incubation was maintained for 7 hours at 24°C. The beer containing steroid was diluted with 800 ml of acetone, shaken 1 hour on a reciprocating shaker and filtered. The cake was suspended in 500 ml of acetone, shaken another hour and again filtered. The filtrates were combined and the acetone was volatilized under reduced pressure at 50°C. Acetone was then added, if necessary, to bring the concentration to 20% acetone and this resulting aqueous acetone solution was extracted five times each with one-third volume of Skellysolve B petroleum ether to remove fatty materials. These extracts were back washed two times with one-tenth volume of 20% aqueous acetone and the washings were added to the main acetone extract.
The combined acetone extracts were extracted six times with one-fourth volume of ethylene dichloride and the ethylene dichloride extract was evaporated under vacuum to leave the steroid residue. This steroid residue was taken up in a minimum of methylene chloride and applied to the top of a column packed with 30 grams of silica which had been previously triturated with 21 ml of ethylene glycol. Then various developing mixtures, saturated with ethylene glycol, were passed over the column. Cuts were made as each steroid was eluted as determined by the lowering of the absorption of light at 240 nm on the automatic chromatographic fraction cutter.
Band Solvent Tube No. (60ml) Crude Solids (mg)
1 Cyclohexane 1-4 11
2 Cyclohexane-methylene chloride 3:1 5-13 6.4 compound S
3 Cyclohexane-methylene chloride 1:1 14-16 3.0
4 Cyclohexane-methylene chloride 2:3 17-23 6.0 compound E
5 Cyclohexane-methylene chloride 1:4 24-38 12.2 compound F
6 Methylene chloride 39-59 4.8
A 7.7 mg portion of band 5 was taken up in a minimum of acetone and refrigerated until crystals separated. This cold acetone mixture was centrifuged and the supernatant liquid removed by pipette. To the remaining crystals, a few drops of ice-cold ether-acetone, three to one mixture, were added, shaken, recentrifuged and the supernatant wash liquid removed by pipette. The ether-acetone wash was repeated. The resulting crystals were dried under vacuum yielding 3.3 mg of pure compound F, 17- hydroxycorticosterone.

brand name

Acticort (Baker Norton); Ala-Cort (Del Ray); Cetacort (Healthpoint); Colocort (Paddock); Cort- Dome (Bayer); Cortef (Pharmacia & Upjohn); Cortenema (Solvay Pharmaceuticals); Cortril (Pfizer); Dermacort (Monarch); Dermacort (Solvay Pharmaceuticals); Eldecort (Valeant); Epicort (Bluline); Flexicort (Westwood- Squibb); Glycort (Heran); Hi-Cor (C & M); Hydro-Rx (X Gen); Hydrocortone (Merck); Hytone (Dermik); Hytone (Sanofi Aventis); Nutracort (Healthpoint); Penecort (Allergan); Proctocort (Monarch); Stie-Cort (Stiefel); Synacort (Medicis); Texacort (Sirius).

Therapeutic Function

Glucocorticoid

General Description

Hydrocortisone, 11β,17,21-trihydroxypregn-4-ene-3,20-dione, is the primary natural GCin humans. Despite the large number of synthetic GCs, hydrocortisone,its esters, and its salts remain a mainstay ofmodern adrenocortical steroid therapy and the standard forcomparison of all other GCs and MCs . It isused for all the indications mentioned previously.

Health Hazard

Cortisol Increases (1) protein catabolism (excepting liver) gluconeogenesis; (2) carbohydrate anabolism (liver); (3) blood sugar; (4) glucose absorption; (5) brain excitation; (6) spread of infections; (7)urinary glucose and nitrogen; (8) stress tolerance; (9) lactation; (10) water diuresis.
Regulates general adaptation syndrome, water balance, blood pressure, and hormone release.
Decreases (1) fat anabolism; (2) growth rate; (3) inflammation; (4) eosinophils; (5) lymphocytes; (6) antigen sensitivity; (7) respiratory quotient; (8) ketosis; (9) wound healing; (10) skin pigmentation; (11)RBC hemolysis.

Biological Activity

hydrocortisone is a main glucocorticoid secreted by the adrenal cortex.

Contact allergens

Hydrocortisone is the principal glucocorticoid hor- mone produced by the adrenal cortex and is used topi- cally or systemically. It belongs to the allergenic A group. Marker of allergy is tixocortol pivalate.

Biochem/physiol Actions

Product does not compete with ATP.

Mechanism of action

Hydrocortisone exhibits anti-shock, anti-allergy, and anti-inflammatory action. It raises sugar content in the blood, increases potassium secretion, and lowers sodium excretion from the body. It exhibits anti-metabolic action and reduces histamine synthesis in the body.

Pharmacokinetics

Hydrocortisone binds to the glucocorticoid receptor leading to downstream effects such as inhibition of phospholipase A2, NF-kappa B, other inflammatory transcription factors, and the promotion of anti-inflammatory genes. Hydrocortisone has a wide therapeutic index and a moderate duration of action. Patients should stop taking the medication if irritation or sensitization occurs.

Clinical Use

Hydrocortisone is endogenous, and it has both glucocorticoid and mineralocorticoid activity. It is the fundamental structure by which the glucocorticoid and mineralocorticoid activities of all other corticosteroids are judged. Functional groups that are essential for both mineralocorticoid and glucocorticoid activity include the pregnane skeleton with an all-trans backbone, the ring A-en-one system (?4 -3-one ring A) and the 17β-ketol side chain (C-20-keto-C-21-hydroxy). The glucocorticoid activity is enhanced by the C-11 and C-17 hydroxyl groups. Hydrocortisone can be used to treat severe asthmatic attacks that do not respond to conventional treatment. It is available as various ester forms.

Safety Profile

Poison by

Synthesis

Hydrocortisone, 11|?,17|á,21-trihydroxypregn-4-en-3,20-dione (27.1.8), is synthesized in various ways and from various compounds containing a steroid skeleton. According to one of them, hydrocortisone is synthesized from dextropregnenolone. The double bond between C16 and C17 of dextropregnenolone is oxidized using hydrogen peroxide in a base, forming an epoxide 27.1.1. Interacting this with hydrobromic acid opens the epoxide ring, forming 16-bromo-17-hydroxydextropregnenolone (27.1.2). The resulting bromo derivative undergoes debromination by hydrogen using a palladium on carbon catalyst, and then the secondary hydroxyl group undergoes esterification using formic acid in the presence of p-toluenesulfonic acid, giving 3-formyloxy-17-hydroxydextropregnenolone (27.1.3). The resulting 3-formyloxy- 17-hydroxydextropregnenolone undergoes bromination by bromine, which results in bromination of the C4¨CC5 double bond and the methyl group of acetyl moiety, which forms a tribromo derivative 27.1.4. Reacting the product with sodium iodide results in dehalogenation of the resulting vicinal dibromide, during which the double bond is simultaneously shifted into the position between carbon atoms C5 and C6 that gives the bromoketone 27.1.5. This is reacted with potassium acetate and then with acetic anhydride in the presence of p-toluenesulfonic acid, forming a diacetate 27.1.6. Taking into account that unlike acetates, formates are easily oxidized and give exactly the same products as do the corresponding alcohols, the resulting diacetate is oxidized in an Oppenauer oxidation reaction, using aluminum isopropoxide and cyclohexanone as a hydrogen acceptor. During this, isomerization of the double bond into the primary position between C4 and C5 simultaneously takes place, forming a stable, conjugated vinylketone, after which the acetyl protection of both hydroxyl groups is hydrolyzed using potassium hydroxide, giving 17-hydroxy-11-deoxycorticosterone (27.1.7). This undergoes microbiological oxidation at position C1, forming the desired hydrocortisone (27.1.8). Side reactions of microbiological oxidation using the very same microorganisms can cause hydroxylation of steroids in different positions, using easily accessible progesterone as an initial substance.

Veterinary Drugs and Treatments

Because of its rapid effect and relatively high mineralocorticoid effect, hydrocortisone sodium succinate (Solu-Cortef?) is the most commonly used form of this medication when an acute glucocorticoid/ mineralocorticoid effect is desired (e.g., acute adrenal insufficiency). Corticosteroids have not been shown beneficial in treating hypovolemic shock, but low dose glucocorticoids probably reduce mortality associated with septic shock.
Glucocorticoids have been used in an attempt to treat practically every malady that afflicts man or animal, but there are three broad uses and dosage ranges for use of these agents. 1) Replacement of glucocorticoid activity in patients with adrenal insufficiency, 2) as an antiinflammatory agent, and 3) as an immunosuppressive. Among some of the uses for glucocorticoids include treatment of: endocrine conditions (e.g., adrenal insufficiency), rheumatic diseases (e.g., rheumatoid arthritis), collagen diseases (e.g., systemic lupus), allergic states, respiratory diseases (e.g., asthma), dermatologic diseases (e.g., pemphigus, allergic dermatoses), hematologic disorders (e.g., thrombocytopenias, autoimmune hemolytic anemias), neoplasias, nervous system disorders (increased CSF pressure), GI diseases (e.g., ulcerative colitis exacerbations), and renal diseases (e.g., nephrotic syndrome). Some glucocorticoids are used topically in the eye and skin for various conditions or are injected intra-articularly or intra-lesionally. The above listing is certainly not complete.

Metabolism

Hydrocortisone is metabolised to 6-beta hydrocortisol via CYP3A, 5-beta tetrahydrocortisol via 3-oxo-5-beta-steroid 4-dehydrogenase, 5-alpha tetrahydrocortisol via 3-oxo-5-alpha-steroid 4-dehydrogenase 2, cortisone via Corticosteroid 11-beta-dehydrogenase isozyme 1 and Corticosteroid 11-beta-dehydrogenase isozyme 2, and glucuronide products. Cortisone is further metabolized to tetrahydrocortisone and dihydrocortisol.

storage

Store at RT

Purification Methods

Recrystallise hydrocortisone from EtOH or isoPrOH. It is bitter tasting and has UV with max at 242 nm (log 4.20). Its solubility at 25o is: H2O (0.28%), EtOH (1.5%), MeOH (0.62%), Me2CO (0.93%), CHCl3 (0.16%), propylene glycol (1.3%) and Et2O (0.35%). It gives an intense green colour with conc H2SO4. [Wendler et al. J Am Chem Soc 72 5793 1950, Beilstein 8 IV 3422.]