Glucocorticoids

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Introduction0:00–0:24

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.

Physiology0:24–1:49

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.The most important glucocorticoid in humans is cortisol, and it’s generally released during times of stress, like during an illness or starvation.

Cortisol1:49–3:29

Cortisol helps to regulate both the immune response as well as cellular metabolism like gluconeogenesis. 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. And because this is similar to what happens in people with diabetes, this effect of cortisol is called diabetogenic.
The end result is we have a lot more glucose in the blood which can be used as fuel during times of stress! Finally, cortisol also plays a role in maintaining blood pressure levels, since it up-regulates alpha1 adrenergic receptors in blood vessels, which causes vasoconstriction.

Synthetic Glucocorticoids3:29–4:05

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.

Short-Acting Glucocorticoids4:05–4:58

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.

Intermediate-Acting Glucocorticoids4:58–5:41

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 long-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.

Long-Acting Glucocorticoids5:41–6:09

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.

Indications6:09–8:37

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.
Next, we have miscellaneous conditions which include chemotherapy-induced vomiting, hypercalcemia, and mountain sickness.
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.
This makes them effective in the treatment of hematopoietic cancers, such as acute lymphocytic leukemia, Hodgkin lymphoma, and non-Hodgkin lymphomas.
Finally, it’s important to note that dexamethasone is commonly used to relieve cerebral edema in individuals with metastatic or primary brain tumors.
Moreover, dexamethasone is a very potent medication and often causes marked suppression of the hypothalamic-pituitary-adrenal axis, even if given in a low dose- meaning dexamethasone provides a negative feedback to the pituitary gland, which leads to suppression of ACTH secretion.

Overnight Dexamethasone Suppression Test8:37–10:14

This in turn, lowers the natural production of cortisol.Due to this, it’s used in the overnight dexamethasone suppression test, where it’s used to diagnose the presence of Cushing syndrome.
Cushing syndrome is an endocrine disorder caused by too much cortisol production. It could be caused by Cushing disease where a pituitary adenoma overproduces ACTH.
Symptoms include obesity, where the extra adipose tissue tends to build up between the shoulders leading to a buffalo hump; in the trunk, causing truncal obesity; and in the face, causing moon facies.
Hyperglycemia and diabetes often result from the increased gluconeogenesis and insulin resistance. Muscle weakness and skin stretch marks can occur due to protein breakdown.
Hypertension, osteoporosis, and increased risk of bacterial and fungal infections are also common problems caused by excessive cortisol.
Now, when a person is suspected to have Cushing syndrome, they are given a low dose of dexamethasone, which suppresses ACTH production in the pituitary gland.
Normally, that should cause a decrease in serum cortisol levels, but if Cushing syndrome is caused by endogenous cortisol production, then the cortisol level should remain unchanged.
High cortisol levels determine the test as positive and it proves the presence of Cushing syndrome. Side effects of all the synthetic glucocorticoids are rare when administered for physiologic replacement therapy but the risk increases in individuals who are receiving high doses for a prolonged period of time.

Side Effects10:14–12:25

These side effects are pretty similar to Cushing syndrome, since they act just like the cortisol produced by the adrenal glands.
When we get these symptoms from an outside source, it’s called iatrogenic Cushing syndrome. This is actually more common than regular Cushing’s syndrome, since glucocorticoids are frequently used to treat fairly common conditions like rheumatoid arthritis and asthma.
Other side effects include fluid and electrolyte disturbance, such as fluid retention, hypertension, and hypokalemia; endocrine side effects, such as hyperglycemia, diabetes, and suppression of hypothalamic-pituitary-adrenal axis, which can lead to adrenocortical atrophy.
Next, since they cause immunosuppression, they are associated with an increased risk of infection and impaired wound healing.
In addition, glucocorticoids can cause musculoskeletal side effects, which include myopathy and avascular necrosis of femoral and humeral heads, but also osteoporosis and pathological fractures because they decrease osteoblast activity and increase osteoclast activity.
Finally, individuals treated with glucocorticoids can complain about psychiatric disturbances, such as depression, insomnia, psychosis, and mood swings; but they can also develop peptic ulcers and cataracts.
Also, glucocorticoids cause inhibition of growth in children. Now, it’s important to note that individuals that are treated with long-term glucocorticoid therapy should receive additional “stress doses” to prevent adrenal crisis.
“Stress doses” are commonly used before or after surgery, or during severe illness. Moreover, individuals taking long-term glucocorticoid therapy can take a doubled daily dose every other day to prevent the suppression of hypothalamic-pituitary-adrenal (HPA) axis and eventual adrenocortical atrophy.
This way of taking glucocorticoid therapy is also known as the alternate-day therapy or short ADT.Now, we’ve made a mnemonic to help you remember some of the hard to remember facts related to the synthetic glucocorticoids.

Memory Palace12:25–15:37

To start, let’s think of a crazy three-story apartment, where each level has only one room, and the room size decreases as we go towards the top.
So the long duration glucocorticoids gets the room at the bottom; the intermediate in the middle; and the short duration at the top.
Okay, since most of our glucocorticoids contain “-sone,” in their names, we’ll have sons representing these medications.
So on the top floor we’ll have hydrocortisone, which will be represented by a boy in a pool, playing water polo. For indications, have him play water polo against Thomas Edison who’s holding a light bulb.
Now, mixing electricity and water is dangerous, which helps you remember that hydrocortisone is used to treat the life- threatening Addisonian crisis.
He also has a bunch of rashes all over, to represent this medication’s topical uses. Okay on the next floor down, we have the intermediate duration glucocorticoids.
So here, we have three medications with “pred” in them, so let’s dress up three boys in predatory shark costumes, to represent predniSONE, prednisoLONE, and methylPREDNISolone.
Now, their room is on fire, so one of them is putting it out with a fire extinguisher to represent their anti- inflammatory properties.
Another one is eating one of the misbehaving white blood cells that set the fire to help you remember they can be used for autoimmune diseases.
Finally, methylPREDNISolone is connected to an IV line/holding tablet (alternative: predniSONE holding a white tablet) to help you remember it can be used in respiratory emergencies like asthma exacerbations.
Okay, let’s go to the last room which represents the long duration glucocorticoids. So here we have a boy named Dexter who’s doing math, for dexamethasone.
Helping him is another boy, with a betta fish on his shirt, and he represents BETAmethasone. They are calculating the force needed to crush different materials for his experimental trash compactor, which represents that it’s used to diagnose Cushing syndrome.
The misbehaving white blood cells also spread to this floor and are setting fire to the room, so they can also be used to treat the same conditions as the intermediate duration glucocorticoids.
Finally, the boy in the betta shirt is carrying a baby, so you know that it’s the preferred medication for pregnancy.Now, let’s head out of the building for the side effects.
We have a trash compactor outside for iatrogenic Cushing syndrome, which is caused by glucocorticoids not produced inside the body.
So to help you remember some of the symptoms, let’s put some stuff in this trash compactor: there’s a buffalo with a fat torso, wearing a smiling moon mask to represent buffalo hump, truncal obesity, and moon facies.
We can put a blood pressure cuff wrapped around a bone with holes in it, for hypertension and osteoporosis. There’s an obese man eating a candy bar to represent hyperglycemia and diabetes.
There’s bacteria climbing around him to represent an increased risk for infections. Finally, there’s a very sad man, representing psychiatric problems like depression.
He’s sad because he’s in a trash compactor, but also because he’s eyes are cloudy white, representing cataracts, and his stomach is leaking acid to remind you of peptic ulcers.

Review15:37–16:35

All right, as a quick recap. Based on the duration of action, synthetic glucocorticoids are subdivided into three groups: short-acting glucocorticoids (8 - 12 hours), which include cortisone and hydrocortisone; intermediate-acting glucocorticoids (12 - 36 hours), which include PredniSONE, prednisoLONE, methylPREDNISolone, and triamcinolone; and long-acting glucocorticoids (36 - 72 hours), such as betamethasone and dexamethasone.
Glucocorticoids can be used as the physiologic replacement therapy in adrenal disorders like primary adrenal insufficiency or congenital adrenal hyperplasia.
However, they are more commonly used as anti-inflammatory agents and immunosuppressants. Finally, the side effects are rare when administered for physiologic replacement therapy but the risk increases in individuals who are receiving high doses for a prolonged period of time.
The most important side effect is iatrogenic Cushing syndrome. wait there's more Here's a mind map with all the know Monix go ahead and pause the video so you can test yourself and see what you remember Stay

Mind Map16:35–16:47