Triamcinolone potency

The natural compounds cortisol [50-23-7], cortisone [53-06-5], and corticosterone [50-22-6] vary only slightly in stmctures and pharmacologic properties (see Steroids). The synthetic analogues inmore modem practice, prednisolone [52438-85-4], dexamethasone [50-02-2], triamcinolone [124-94-7], and betamethasone have greater antiinflammatory potency, and their effects on sodium retention tend to be less severe. 

Two further communications [31,32] reported that prednisolone stearoylglycollate, in substantial doses, was the least potent anti-inflammatory steroid (among the representative series studied) with respect to pituitary-adrenal inhibition. The order of increasing suppressive potency in this test was prednisolone stearoylglycollate, prednisolone, triamcinolone, dexamethasone, betamethasone. Techniques used in the comparative evaluations included the metyrapone test and gas-liquid chromatography. 

Hydroxylation or methylation at the 16 position of a-fluoroprednisolone to give triamcinolone, dexam-ethasone, or betamethasone increases antiinflammatory potency and drastically diminishes sodium-retaining... 

Topical preparations usually contain relatively insoluble steroids, such as clobetasol propionate, triamcinolone acetonide, or triamcinolone diacetate. Side effects of this mode of drug application are usually milder and more transient than those seen after systemically administered steroids. However, potent topical corticosteroids, such as clobetasol propionate (Temovate), can suppress adrenal function when used in large amounts for a long time, especially when the skin surface is denuded or when occlusive dressings are employed. Since the high potency topical preparations carry a higher risk of local side effects, their use should be held in reserve. 

The 9,11 olefin in the intermediate (25-4) is next converted to the 9a-fluoro-11(3-hydroxy derivative (26-1) by the customary scheme. The additional unsaturation in ring A is then introduced by means of selenium dioxide to afford triamcinolone (26-2). Reaction of that compound with acetone converts the 16,17 diol to an acetal to afford triamcinolone acetonide (26-3) [21]. The latter is approximately 50 times more potent than cortisone in animal models the free glycol interestingly shows only a 2.5-fold increase in potency over the cortisone in the same model. 

There is a suggestion that the incidence of myopathy is greatest during treatment with compounds that are fluori-nated at the 9-alpha position, such as triamcinolone, but this may simply reflect its general potency. In children, the risk of effects on muscles is relatively high. 

Research teams at Glaxo then undertook the synthesis of derivatives of betamethasone that might afford superior local anti-inflammatory and anti-allergic effectiveness. Using McKenzie and Stoughton s [21] new human-based pharmacologic test that could identify with ease the relative topical potency of steroid inflammatory compounds, a series of 17-esters of betamethasone prepared by Elks [22] was evaluated. This resulted in compounds with new standards of topical potency such as triamcinolone acetonide and fluocinolone acetonide. It was then discovered, that potency peaked with betamethasone-17-valerate and betamethasone-17,21-dipropionate, which were between four- and ten-fold more potent than the standard. 

There are three aerosolized corticosteroid preparatioias available in MDI formulation for administration to horses via the Equine AeroMask beclometasone dipropionate, fluticasone propionate and flunisolide (Table 16.2). In terms of the relative potency, fluticasone is more potent than beclometasone, which is more potent than flunisolide, which is equipotent to triamcinolone. Using dexamethasone as the standard (1.0), the relative glucocorticoid receptor affinity of the common corticosteroids is flunisolide 1.9, triamcinolone 2.0, beclometasone (active metabolite) 13.5 and fluticasone propionate 22.0 (Barnes et al 1998). The pulmonary residence time of the aerosolized corticosteroids is determined by the lipophilicity of each drug. Flunisolide has intermediate water solubility (lOmg/ml), simitar to... 

The ICSs beclomethasone dipropionate, budesonide, flunisolide, fluticasone propionate, and triamcinolone acetonide that are currently available for use are compared and listed in Table 26-12. The ICSs have pharmacokinetic differences that result in different topical/ systemic activity. Most evidence is consistent with log-linear dose-response curves for both indirect and direct responses. The log-linear nature of the dose-response curve for corticosteroid activity raises the issue of how much of a difference in dose (or lung delivery) or potency is detectable. The dose-response curves for the ICSs are relatively flat primarily because all the measures used to assess efficacy (lung function, BHR, symptoms, and as-needed short-acting inhaled /32-agonist use) are downstream events from the anti-inflammatory activity. In general, it takes a fourfold difference in potency or dose to detect clinically significant differences. The table of comparative doses (see Table 26-12) is based on extensive comparative clinical trials. Clinical comparative doses take into consideration potency differences as well as lung delivery differences from the various devices. 

A natural extension of corticoid research involved examination of compounds containing both a 9a-fluoro group and a double bond between positions 1 and 2. Triamcinolone (9-fluoro-11 (3, 16a, 17, 21-tetrahydroxypregna-1,4-diene-3,20-dione), introduced in 1958, combines the structural features of a A -corticoid and a 9a-fluoro corticoid (Fig. 33.10). As mentioned previously, the 9a-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 16a-hydroxy group into the molecule, one can decrease the mineralocorticoid activity. 

On a weight-for-weight basis, the antirheumatic potency of triamcinolone is greater than that of prednisolone (-20%) and approximately the same as that of methylprednisolone. Initial improvement following administration of triamcinolone is similar to that noted with other compounds. Reports in the literature, however, indicate that the percentage of patients maintained satisfactorily for long periods has been distinctly smaller than that with prednisolone. 

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