Triamcinolone

Description

A natural extension of corticoid research involved examination of compounds containing both a 9α-fluoro group and a double bond between positions 1 and 2. Triamcinolone (9-fluoro-11β, 16α, 17, 21-tetrahydroxypregna- 1,4-diene-3,20-dione), introduced in 1958, combines the structural features of a ?1 -corticoid and a 9α-fluoro corticoid. As mentioned previously, the 9α-fluoro group increases the anti-inflammatory potency, but it also markedly increases the mineralocorticoid potency. This is undesirable if the drug is to be used internally for the treatment of rheumatoid arthritis. By inserting a 16α-hydroxy group into the molecule, one can decrease the mineralocorticoid activity.

Chemical Properties

White, crystalline powder. Insoluble in water; slightly soluble in usual organic solvents; soluble in dimethylformamide.

Originator

Kenacort,Squibb,US,1958

Uses

A glucocorticoid, antiasthmatic (inhalant); antiallergic (nasal).

Uses

Triamcinolone is a glucocorticoid. Triamcinolone is used as an antiasthmatic (inhalant); antiallergic (nasal).

Indications

Intralesional bleomycin, a cytotoxic drug that inhibits DNA synthesis, is effective for all varieties of recalcitrant warts. Various concentrations of the drug have been used, although the total dose must be carefully tracked over time to avoid potential systemic toxicity.

Definition

ChEBI: A C21-steroid hormone that is 1,4-pregnadiene-3,20-dione carrying four hydroxy substituents at positions 11beta, 16alpha, 17alpha and 21 as well as a fluoro substituent at position 9. sed in the form of its 16,17-acetonide to treat various skin infections.

Manufacturing Process

Preparation of δ1,4-Pregnandiene-9α-fluoro-11β,16α,17α,21-Tetrol-16,21- Diacetate: An agar slant of Corynebacterium simplex was washed with 5 ml of sterile saline and the spore suspension added to 100 ml of Trypticase soy broth in a 500 ml Erlenmeyer. The mixture was incubated at 32°C for 8 hr and 1 ml was used to inoculate 10 flasks, each containing 100 ml of Trypticase soy broth. The flasks were incubated with shaking at 32°C for 16 hr. 20 mg δ4- pregnene-9α-fluoro-11β,16α,17α,21-tetrol-3,20-dione16,21-diacetate dissolved in 2 ml ethanol was added and the flasks pooled. This solution was extracted several times with methylene chloride, washed with saturated saline and evaporated under reduced pressure. The residue was dissolved in methanol, treated with activated charcoal, filtered through diatomaceous earth and reevaporated to afford 277 mg of oil and acetylated overnight.
Paper strip chromatography showed approximately equal amounts of substrate and a more polar product (δ1,4-pregnadiene-9α-fluoro-11β,16α,17α,21-tetrol- 3,20-dione 16,21-diacetate) together with very small amounts of two less polar products. Partition chromatography of 0.25 gram of the residue (diatomaceous earth column; system: 2 parts ethyl acetate, 3 parts petroleum ether (90° to 100°C), 3 parts methanol and 2 parts water) separated the less polar products and the substrate. The desired most polar product remained on the column and was eluted with 500 ml of methanol. The residue (90 mg) from the evaporated methanol was repartitioned on diatomaceous earth [system: 3 parts ethyl acetate, 2 parts petroleum ether (90° to 100°C), 3 parts methanol, and 2 parts water] and the cut containing the desired product (determined by ultraviolet absorption spectrum) was evaporated under reduced pressure to afford 18 mg of solid.
Crystallization from acetone-petroleum ether gave 13 mg of colorless needles of δ1,4-pregnadiene-9α-fluoro-11β,16α,17α,21-tetrol-3,20-dione16,21- diacetate; melting point (Kofler block) about 150° to 240°C with apparent loss of solvent at 150°C. Recrystallization from acetone-petroleum ether did not alter the melting point.
Preparation of δ1,4-Pregnadiene-9α-Fluoro-11β,16α,17α,21-Tetrol-3,20-Dione: A solution of 100 mg of δ1,4-pregnadiene-9α-fluoro-11β,16α,17α,21-tetrol- 3,20-dione16,21-diacetate was dissolved in 10 ml of methanol and cooled to 0°C. After flushing with nitrogen, a solution of 35 mg of potassium hydroxide in 2 ml of methanol was added to the steroid solution. After standing at room temperature for 1 hour, the solution was neutralized with glacial acetic acid and evaporated under a nitrogen atmosphere to a white solid. Water was added, and after cooling, the product was filtered and washed with water to afford 52 mg of δ1,4-pregnadiene-9α-fluoro-11β,16α,17α,21-tetrol-3,20-dione, melting point 246° to 249°C. Three crystallizations from acetone-petroleum ether gave 29 mg of the tetrol, melting point 260° to 262.5°C according to US Patent 2,789,118.

Therapeutic Function

Glucocorticoid

Biochem/physiol Actions

Triamcinolone is a synthetic glucocorticoid agonist; induces gene expression and apoptosis; inhibits prostaglandin synthesis; impairs tumor necrosis factor (TNF)-α-induced degradation of κB-α; potentiates the differentiation-inducing effects of bone morphogenetic proteins (BMP-2, -4, -6).

Clinical Use

Triamcinolone to be used topically is generally dispensed as its more potent and lipophilic acetonide, a 16α,17α-methylenedioxy cyclic ketal or isopropylidene derivative. It is effective in the treatment of psoriasis and other corticoid-sensitive dermatologic conditions. Topically, triamcinolone acetonide is a more potent derivative of triamcinolone and is approximately eight times more active than prednisolone.

Side effects

Even though triamcinolone has an apparently decreased tendency to cause salt and water retention and edema and may induce sodium and water diuresis, it causes other unwanted side effects, including anorexia, weight loss, muscle weakness, leg cramps, nausea, dizziness, and a general toxic feeling.

Safety Profile

Poison by subcutaneous route.An experimental teratogen. Other experimentalreproductive effects. Human mutation data reported.When heated to decomposition it emits toxic fumes of F??.An anti-inflammatory and antiallergic agent.

Synthesis

Triamcinolone, 9a-fluoro-11b,16a,17,21-tetrahydroxypregna-1, 4-dien-3,20-dione (27.1.61), differs from dexamethsone in terms of chemical structure in that the a methyl group at C16 is replaced with a hydroxyl group. It is synthesized from the 21-O-acetate of hydrocortisone 27.1.17. In the first stage, both carbonyl groups of this compound undergo ketalization by ethylene glycol. Next, the hydroxyl group in the resulting diketal 27.1.53 is replaced with chlorine using thionyl chloride, and the product undergoes dehydrochlorination using an alkaline, during which the 21-O-acetyl group also is hydrolyzed. Acetylating the hydroxyl group once again with acetic anhydride gives a triene 27.1.54. Reacting this with osmium tetroxide gives the vicinal diol 27.1.55. The secondary hydroxyl group at C16 of this product undergoes acetylation by acetic anhydride in pyridine, which forms the diacetate 27.1.56. Treating the product with N-bromoacetamide in chloric acid gives a bromohydrin (27.1.57), which upon reaction with potassium acetate is transformed to an epoxide (27.1.58). Opening of the epoxide ring, using hydrofluoric acid, gives the corresponding 9-fluoro-11-hydroxy derivative 27.1.59. Upon microbiological dehydrogenation, the C1¨CC2 bond is oxidized to a double bond, forming triamcinolone acetate (27.1.60), the acetyl group of which is hydrolyzed, forming the desired triamcinolone (27.1.61).

Drug interactions

Potentially hazardous interactions with other drugs
Aldesleukin: avoid concomitant use.
Antibacterials: metabolism accelerated by rifamycins; metabolism possibly inhibited by erythromycin; concentration of isoniazid possibly reduced.
Anticoagulants: efficacy of coumarins and phenindione may be altered.
Antiepileptics: metabolism accelerated by carbamazepine, fosphenytoin, phenobarbital, phenytoin and primidone.
Antifungals: increased risk of hypokalaemia with amphotericin - avoid; metabolism possibly inhibited by itraconazole and ketoconazole.
Antivirals: concentration possibly increased by ritonavir.
Ciclosporin: rare reports of convulsions in patients on ciclosporin and high-dose corticosteroids.
Cobicistat: concentration of triamcinolone possibly increased.
Diuretics: enhanced hypokalaemic effects of acetazolamide, loop diuretics and thiazide diuretics.
Vaccines: high dose corticosteroids can impair immune response to vaccines; avoid with live vaccines.

Metabolism

Triamcinolone is metabolised largely hepatically but also by the kidney and is excreted in urine. The main metabolic route is 6-beta-hydroxylation; no significant hydrolytic cleavage of the acetonide occurs.