What is the connective tissue toxicity of Glucocorticoids?
Glucocorticoids are a group of steroid hormones, which are secreted by the two adrenal glands that sit like hats, one on top of each kidney.
Each one has an inner layer called the medulla and an outer layer called the cortex.
The adrenal cortex secretes different corticosteroid hormones: like glucocorticoids under the control of adrenocorticotropic hormone, or ACTH.
Normally the hypothalamus, located at the base of the brain, secretes corticotropin releasing hormone, known as CRH, which stimulates the anterior pituitary gland to secrete adrenocorticotropic hormone, known as ACTH.
ACTH then travels to the pair of adrenal glands and binds to the ACTH receptors on adrenocortical cells.
This causes the adrenocortical cells to release the glucocorticoids from the zona fasciculata, which have powerful anti-inflammatory and metabolic effects.
These glucocorticoids have a negative feedback effect on the hypothalamic-pituitary-adrenal axis, meaning excess corticosteroids suppress the release of both CRH and ACTH into the circulation.
Now, once made, glucocorticoids enter the circulation and travel via the blood to reach the target cells.
Steroids are lipophilic molecules, so they cross the cell membrane, enter inside the cell, and bind with a cytoplasmic receptor protein, called a ‘glucocorticoid receptor’.
Now, this ‘glucocorticoid-receptor complex’ undergoes some structural changes, which allow them to enter inside the nucleus and bind with the ‘glucocorticoid response elements’ or GRE on the chromatin.
Now, this induces transcription of specific mRNA that’s used to synthesize different proteins, which in turn modifies various cell functions and metabolic effects in the body.
With regard to the immune response, cortisol promotes an overall anti- inflammatory state by inhibiting the two main products of inflammation - prostaglandins and leukotrienes - as well as inhibiting interleukin-2 production by white blood cells.
Now, for cellular metabolism, cortisol promotes overall catabolic effects on the body.
In peripheral adipose tissue, cortisol triggers lipolysis, which is the breakdown of fats into free fatty acids.
In the muscles, cortisol stimulates proteolysis, which is the breakdown of proteins into amino acids.
Often these free fatty acids and amino acids serve as a substrate for gluconeogenesis - a process where the liver cells produce new glucose molecules from non-carbohydrate sources like amino acids and free fatty acids.
High cortisol levels also increase insulin resistance in tissues, which means that insulin becomes less effective at moving glucose into cells, leading to an increase in blood glucose levels.
The increased glucose level also stimulates the release of more insulin.
The end result is we have a lot more glucose in the blood which can be used as fuel during times of stress!
Now let’s switch gears and focus on synthetic glucocorticoids.
Synthetic glucocorticoids in our body produce the same effect as endogenous cortisol; but, they also increase the number of neutrophils in the blood!
Let’s put it this way.
Glucocorticoids decrease the production of a protein that enables neutrophils to attach to the endothelial lining of the blood vessel.
As a result, neutrophils detach from the endothelial lining and enter the circulation.
This process is also known as “demargination”.
At the same time, these medications also decrease lymphocyte, monocyte, basophil, eosinophil counts.
Now, based on the duration of action, synthetic glucocorticoids can be classified into three groups.
The first group includes short-acting glucocorticoids with duration of action of 8 - 12 hours.
Cortisone and hydrocortisone fall under this group.
Cortisone is taken orally and in the liver, it requires conversion to hydrocortisone, therefore it is not active when used in topical forms.
On the other hand, hydrocortisone is chemically identical to cortisol and can be taken orally, intravenously, or intramuscularly.
It then enters inside the circulation, goes to the target cells, and very rapidly takes effect, but only for a short duration of time.
That’s why hydrocortisone is the drug of choice in acute adrenal insufficiency. Hydrocortisone is also available in topical forms.
The second group are intermediate-acting glucocorticoids with duration of action of 12 - 36 hours.
PredniSONE, prednisoLONE, methylPREDNISolone, and triamcinolone fall under this group. Prednisone is taken orally, while prednisolone has peroral, intravenous, and topical use.
Next, methylprednisolone can be taken orally, intravenously, intramuscularly, or intra-articularly; while triamcinolone has oral, intramuscular, topical, and intra-articular use.
In comparison to short-acting glucocorticoids, intermediate-acting glucocorticoids are almost 4 to 5 times more potent- meaning a lesser dose is needed to produce the desired response.
Finally, the third group includes ong-acting glucocorticoids with duration of action 36 - 72 hours.
Betamethasone and dexamethasone fall under this group and they can be taken orally; injected into a vein, muscle, or joint.
In addition, dexamethasone can be used topically.
Finally, these medications are 25 times more potent than short-acting glucocorticoids.
Now, the clinical use of glucocorticoids can be subdivided into several groups.
First, glucocorticoids are used in the treatment of adrenal conditions which are characterized by low corticosteroid levels in the body, such as primary adrenal insufficiency, also known as Addison disease.
With Addison disease, the underlying problem is due to damage to the adrenal glands themselves.
Another condition is congenital adrenal hyperplasia, which is characterized by genetic defects that prevent the synthesis of specific enzymes that make cortisol.
Now, to treat these conditions we use short-acting glucocorticoids, which are in this case, also referred to as physiologic replacement therapy.
Physiologic replacement therapy should mimic the normal physiologic diurnal pattern, meaning that in the morning individuals should receive the largest dose, and later in the afternoon a smaller dose.
In addition, a life-threatening adrenal crisis, which is also known as the Addisonian crisis or acute adrenal insufficiency, is treated with hydrocortisone due to its rapid effect.
Next, glucocorticoids are used as anti-inflammatory/immunosuppressive therapy in individuals with asthma; conditions with autoimmune and inflammatory components, such as rheumatoid arthritis, Crohn disease, ulcerative colitis, acute multiple sclerosis exacerbation, and idiopathic thrombocytopenic purpura; and in inflammatory conditions of skin, eye, ear or nose, like eczema, allergic conjunctivitis, or rhinitis.
Also, these medications are used to treat hypersensitivity states, such as severe allergic reactions; and prevent graft-versus-host disease.
Furthermore, betamethasone can be given to pregnant women before birth to speed up fetal lung maturation.
Finally, glucocorticoids are used in neoplastic conditions as adjuvant therapy, due to their anti-lymphocytic effect, which is characterized by a decreased clonal expansion of T and B lymphocytes.
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