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Injectable corticosteroids are synthetic analogues of the adrenal glucocorticoid cortisol (hydrocortisone). Cortisol is produced by the zona reticularis of the adrenal cortex. Corticosteroids have an effect at the cellular level, with modulation of the transcription of a large number of genes. They act directly on nuclear steroid receptors. They reduce the production of a variety of pro-inflammatory mediators and increase the production of anti-inflammatory mediators.


Corticosteroids are a class of steroid hormones that are released by the adrenal cortex. The class includes glucocorticoids and mineralocorticoids. However in general use, corticosteroids generally refers to glucocorticoids.


The hypothalamic-pituitary-adrenal axis (HPA) controls the release of glucocorticoids. Corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) released from the hypothalamus act on the anterior pituitary to stimulate the secretion of adrenocorticotrophin hormone (ACTH). ACTH then stimulates the adrenal cortex to release glucocorticoids. As well as this feed-forward mechanism, there are also negative feedback mechanisms whereby glucocorticoids inhibit the release of ACTH and CRH.

Glucocorticoids are synthesised rapidly following ACTH stimulation because they can't be pre-synthesised and stored in the adrenal glands. They are synthesised from cholesterol in a process called steroidogenesis.

Glucocorticoids are released by the adrenal glands with a circadian profile. This circadian profile is upregulated by the hypothalamic-pituitary-adrenal axis (HPA). Cortisol levels peak in the mornings and are lowest at night.

While the systemic level of glucocorticoids is maintained by synthesis in the adrenal glands, the tissue and cellular availability is maintained through various mechanisms

  • Ample protein binding which results in 95% of glucocorticoids being in an inactive form in the normal state. 80-90% of circulating glucocorticoids are bound to corticosteroid binding globulin (CBG), and 5-15% are bound to albumin. Therefore the accessibility of cortisol is regulated by the level of CBG.
  • At the cellular level the tissue-specific metabolic enzyme 11β-hydroxysteroid dehydrogenase 2 (11β-HSD 2) rapidly inactivates glucocorticoids by converting cortisol to cortisone. In contrast, 11β-HSD 1 converts the inactive precursor cortisone to bioactive cortisol. In this manner, cortisone acts as a reservoir.

Most synthetic glucocorticoids do not bind to CBD and are not metabolised by 11β-HSD 2.

Molecular Structure

The structure-activity relationship of adrenocorticosteroids. Light lines and letters indicate structural features common to compounds having anti-inflammatory action. Bold lines and letters indicate modifications that enhance or suppress characteristic activities.[1]

The first corticosteroid used for its anti-inflammatory effect was Cortisone. The structure was modified to increase the glucocorticoid potency and reduce the mineralocorticoid potency with the synthesis of prednisolone and methylprednisolone. In a number of currently available compounds, the mineralocorticoid electrolyte effects are now of no serious consequence, even at the highest doses used. Further advancements included fluorination (e.g. dexamethasone).

In all compounds the effects on inflammation and metabolism of carbohydrates and protein have paralleled one another. The effects on inflammation and metabolism are likely mediated by the same type of receptor.

Changes in the molecular structure can cause changes in biological potency. This can be due to alterations in absorption, protein binding, rate of metabolic transformation, rate of excretion, ability to traverse membranes, and intrinsic effectiveness of the molecule at its site of action. Modifications of the pregnane nucleus has been used for therapeutic value.

Ring A. The 4,5 double bond and the 3-keton are both necessary for typical adrenocorticosteroid activity. Prednisone and prednisolone introduce a 1,2 double bond. This enhances the carbohydrate-regulating potency resulting in an enhanced ratio with respect to its sodium-retaining potency. Prednisolone is also metabolised more slowly than cortisol.

Ring B. 6α substitution has unpredictable effects. For cortisol, 6α methylation increases its anti-inflammatory, nitrogen-wasting, and sodium-retaining effects. While 6α-methylprednisolone has a slightly greater anti-inflammatory potency and less electrolyte-regulating potency compared to prednisolone. Fluorination in the 9α position enhances all biological activities of the corticosteroids, apparently due to electron-withdrawing effect on the 11-beta-hydroxy group.

Ring C. Oxygen function at C 11 is indispensable for its significant anti-inflammatory and carbohydrate-regulating potency (cortisol vs 11-dexoxycortisol). However this is not necessary for its high sodium-retaining potency (desoxycorticosterone)

Ring D. 16-Methylation or hydroxylation eliminates the sodium-retaining effect but only slightly modifies potency on metabolism and inflammation

All currently used anti-inflammatory steroids are 17α-hydroxy compounds. 17-desoxy compounds (cortisol vs corticosterone) may have some carbohydrate-regulating and anti-inflammatory effects but full action requires the 17α-hydroxy substituent. All natural corticosteroids and most of the active synthetic analogues have a 21-hydroxy group. This is required for significant sodium-retaining activity, but some glycogenic and anti-inflammatory effects may occur without it.


Cortisol metabolism has been studied extensively. It is generally assumed that other related compounds have similar metabolism. Cortisol has a plasma half-life of around 1.5 hours. The metabolism and half-life of corticosteroids is greatly slowed down with the presence of a 1,2 double bond or a fluorine atom. Laboratories measure urinary cortisol and metabolites with the reduced ring A as "17-hydroxycorticosteroids." These compounds and those where the ketone at carbon 20 has been reduced are included in the group "17-ketogenic steroids." Urinary metabolites that have lost their side chain are included in the "17-ketosteroids." It is estimated that the liver metabolises at least 70% of secreted cortisol.

Dose Equivalency

Glucocorticoid Approximate Equivalent Dose (mg)
Cortisol 20
Cortisone 25
Hydrocortisone 20
PrednisoneLink to NZF: 833 5
Prednisolone 5
MethylprednisoloneLink to NZF: 3843 4
TriamcinoloneLink to NZF: 10068 4
BetamethasoneLink to NZF: 10065 0.6-0.75
DexamethasoneLink to NZF: 10066 0.75

Mechanism of Action

Glucocorticoids act through both genomic and non-genomic mechanisms.

Classical Genomic Action

Glucocorticoids are lipophilic and hence can easily pass through plasma membranes. The genomic action is mediated through glucocorticoid receptors to stimulate tissue specific gene expression. This process usually takes hours or days.

  • Transrepression: There is a resultant decrease in the production of proinflammatory mediators (e.g. IL-1, IL-2, tumour necrosis factor, prostaglandins) is called transrepression and this is thought to account for most of the anti-inflammatory effect.
  • Transactivation: There is also an increased expression of regulatory proteins (including anti-inflammatory), termed transactivation, and this is thought to be the cause of many of the adverse effects.

Annexin A1 (also known as lipocortin 1) is a potentially important mediator regulated by glucocorticoids that contributes to resolving inflammation by various complex mechanisms including the reduction of neutrophil recruitment and the promotion of clearance of apoptotic cells by macrophages.

Some ongoing therapeutic research questions include whether Annexin A1 based pharmacological interventions could be as effective as exogenous glucocorticoids with fewer side effects,[2] and developing selective glucocorticoid receptor agonists to minimise transactivation.

Non-genomic action

Some of the anti-inflammatory effects seen clinically occur much too fast to be explained purely from the genomic mechanism of action. For example in croup, nebulised corticosteroid administration causes a rapid clinical effect, possibly due to non-genomic effects through increased α and β adrenergic activity.[3]

There are a variety of rapid nongenomic mechanisms through which glucocorticoids have an effect. These involve changing the function of membrane-associated proteins, nongenomic effects mediated by cytosolic glucocorticoid receptors, and effects that are dependent on membrane-bound glucocorticoid receptors.[4]


There may be a direct chondroprotective effect on cartilage metabolism, for example it promotes the production of articular surfactant. There may also be a direct analgesic effect.

Choice for Injection

There is limited evidence to help guide the choice of a specific glucocorticoid for injection. Depot formulations stay at the injection site displaying mostly local effects, but some system effect can happen. The choice is largely based on availability, cost, and versatility. At the time of writing, the funded corticosteroids for depot injections are dexamethasone, methylprednisolone, and triamcinolone. Betamethasone is also available but is only partially funded. Dexamethasone is available on medical practitioner supply order, but only 5 vials at a time. Many practitioners tend to use particulate corticosteroids (like triamcinolone) for joint and soft tissue injections, and non-particulate corticosteroids (like dexamethasone) injections where there is a rare risk of serious vascular injury like spinal injections.

Side Effects

Injection therapy is relatively safe. Side-effects include post-injection flare of pain, subcutaneous atrophy and/or skin depigmentation, bleeding, steroid 'chalk' or 'paste' found in surgery, soft-tissue calcification, steroid arthropathy, tendon rupture and atrophy, delayed soft tissue healing, infection, nerve damage, transient paresis, needle fracture, facial flushing, increased systemic glucose levels, uterine bleeding, suppression of the hypothalamic-pituitary axis, allergic reaction, pancreatitis, nausea, dysphoria, acute psychosis, myopathy, posterior subcapsular cataracts.

Post-injection Flare

A post-injection flare is increased pain (grater than 2 or more points on a 0 to 10 scale) within 24 hours following a steroid injection. There is a wide range of reported incidences, potentially up to one third of patients, and it tends to last 1-5 days. The mechanism is an irritant effect of steroid crystals, e.g. triamcinolone and methylprednsolone. Microcystalline aggregates of steroid induce an inflammatory response. A flare does not affect the overall response to the steroid and doesn't predict the long term outcome from the injection. If the pain is increasing after 24 hours then consider infection.

Further Reading

  • Open access in depth review article: Ramamoorthy, Sivapriya, and John A Cidlowski. “Corticosteroids: Mechanisms of Action in Health and Disease.” Rheumatic diseases clinics of North America vol. 42,1 (2016): 15-31, vii. doi:10.1016/j.rdc.2015.08.002 Full Text


  1. Liddle 1961, Clinical Pharmacology and Therapeutics
  2. Sugimoto MA, Vago JP, Teixeira MM, Sousa LP. Annexin A1 and the Resolution of Inflammation: Modulation of Neutrophil Recruitment, Apoptosis, and Clearance. J Immunol Res. 2016;2016:8239258. doi: 10.1155/2016/8239258. Epub 2016 Jan 13. PMID: 26885535; PMCID: PMC4738713.
  3. Husby, S et al. “Treatment of croup with nebulised steroid (budesonide): a double blind, placebo controlled study.” Archives of disease in childhood vol. 68,3 (1993): 352-5. doi:10.1136/adc.68.3.352
  4. Stahn C, Buttgereit F. Genomic and nongenomic effects of glucocorticoids. Nat Clin Pract Rheumatol. 2008 Oct;4(10):525-33. doi: 10.1038/ncprheum0898. Epub 2008 Sep 2. PMID: 18762788.