Corticosteroids

Question 1

What is inflammation?

Answer 1

• Very generally speaking, inflammation is the immune response to an irritant
• The irritant might be a germ, but it could be a foreign object as a splinter in your finger

Question 2

What is the purpose of inflammation?

Answer 2

• The inflammatory response is a defence mechanism to protect from injury and infection
• To localize and eliminate the injurious agent and to remove damaged tissue components so that the body can begin to heal

Question 3

Acute vs Chronic inflammation?

Answer 3

• An inflammatory response that lasts only a few days is called acute inflammation, while a response of long duration is referred to as chronic inflammation

Question 4

What are some inflammation associated diseases? (6)

Answer 4

• Diabetes mellites
• Inflammatory breast cancer
• Pulmonary diseases, asthma
• Arthritis and autoimmune disease
• Inflammatory bowel disease
• Cardiovascular disease

Question 5

When can inflammation be bad, asthma, arthritis?

Answer 5

• Asthma, asthmatic bronchioles are much more inflamed than normal and cause restricted air flow, inhale corticosteroids
• Arthritis, inflammation of the joints, injection of corticosteroids

Question 6

What are corticosteroids?

Answer 6

Corticosteroids: class of drugs that lowers inflammation and immune system activity in the body (shut down whole immune system)

Question 7

What symptoms do corticosteroids treat?

Answer 7

corticosteroids ease swelling, itching, redness, and allergic reactions, doctors often prescribe them to help treat diseases like asthma, arthritis

Question 8

What is a steroid?

Answer 8

A steroid is a biologically active organic compound with 4 rings arranged in a specific molecular configuration

Question 9

What are steroids 2 main functions?

Answer 9

1. Important components of cell membranes which can alter membrane fluidity (made from cholesterol)
2. Are signaling molecules

Question 10

What are the two kinds of corticosteroids?

Answer 10

Corticosteroids – refers to both glucocorticoids and mineralocorticoids but is often used as a synonym for “glucocorticoid”

Question 11

What does the adrenal gland produce?

Answer 11

The adrenal gland produces cortisol, corticosteroids, aldosterone

Question 12

How does stress signal produce corticosteroids?

Answer 12

A signal (stress, illness, hypoglycemia, hemorrhage) tells the brain to produce the hormone (CRH) in the hypothalamus
CRH acts on the pituitary gland to produce ACTH
ACTH acts on the adrenal gland to produce corticosteroids

Corticotropin-releasing hormone (CRH)

Arginine vasopressin (AVP)

Adrenocorticotropic Hormone (ACTH)

Question 13

What does ACTH do?

Answer 13

ACTH: goes into the adrenal gland and regulates glucocorticoid synthesis

ACTH increases the delivery of cholesterol to the inner mitochondrial membrane (of cells in the adrenal gland)
Increases transcription of steroidogenic enzymes
(need cholesterol to produce glucocorticoids)
ACTH regulates glucocorticoid synthesis in the zonae fasciculata/reticularis

Question 14

Cortisol synthesis?

Answer 14

Starting with cholesterol, the 2 main enzymes used are CYP17 and CYP11B1

Question 15

Negative feedback of glucocorticoids?

Answer 15

Too much glucocorticoids – negative feedback
Signals to hypothalamus to stop producing CRH
Turns off pathway

Question 16

Steroid hormone receptors?

Answer 16

• Are generally intracellular receptors (cytoplasmic or nuclear) and initiate signal transduction for steroid hormones which lead to changes in gene expression over a time period of hours to days
  glucocorticoid signaling:
  chaperones bind to it and bring It into the cell – nucleus

Question 17

Anti-inflammatory Effects of Glucocorticoids?

Answer 17

• Changes in cell proliferation, survival, differentiation, migration
• Decrease pro-inflammatory cytokines, interleukins, prostaglandins
• Can affect cell growth, adverse effect in kids, need to make sure its localized affect, asthma

Question 18

Effects of glucocorticoid on inflammatory cells?

Answer 18

• Stops degradation of mast cells, stops recruitment of other cells to stop proliferation of other immune cells
• Corticosteroids inhibit immune “signals”

Question 19

Metabolic effects of glucocorticoids?

Answer 19

Generally transcriptional activation
- Metabolic – increase glucose to protect the brain and heart (fight or flight)
- Increase blood glucose by:
o Increasing glycogen breakdown (glycogenolysis)
o Increasing glucose synthesis (gluconeogenesis)
o Decreasing fat deposits (increased lipolysis)
o Increased protein catabolism and decreased synthesis

Question 20

(CBG) corticosteroid-Binding globulin?

Answer 20

• Transports glucocorticoids in the blood and thereby modulates the tissue availability of these hormones
• Basically, binding to CBG helps transport the hormone but inflammation, stress, induced release of molecules like elastase releases the steroid from the complex
• When giving someone a glucocorticoid the CBG binding, and loss of bioavailability needs to be considered
• Absence of CBG – less availability

Question 21

Pharmacokinetics of glucocorticoids?

Answer 21

• Glucocorticoids are administered through most routes, but local administration is preferred to minimize adverse effects associated with systematic actions
• Circulating cortisol is 80%-90% bound to plasma proteins with high affinity to corticosteroid-binding globulin (CBG, transcortin), 5%-10% loosely bound to albumin, and 3%-10% as the free, active fraction
• (lipid base transported in blood, CBG binding protein, CBG in blood, glucocorticoids release by adrenal gland, can bind to CBG, can move anywhere)
• CBG can also bind synthetic glucocorticoids such as prednisone and prednisolone, but not dexamethasone, resulting in almost `00% of plasma dexamethasone bioactive

Question 22

glucocorticoids absorption in the GI tract, the skin?

Answer 22

• Most glucocorticoids are absorbed rapidly and readily from the GI tract and from synovial and conjunctival spaces because of their lipophilic character, but they are absorbed very slowly through the skin

Question 23

Increased estrogen effect on cortisol and CBG?

Answer 23

• Elevated concentrations of estrogen, such as occurs in pregnancy, contraceptive use, or hormone replacement therapy, increase the biosynthesis of CBG in the liver, requiring increased plasma cortisol concentrations to maintain an appropriate bioactive fraction

Question 24

What is the circadian rhythm?

Answer 24

Circadian rhythm is the name given to your body’s 24-hour internal clock
Glucocorticoids are regulated by circadian rhythm
At different times of the day, you can have more or less glucocorticoids
If you give more corticosteroids when levels are already elevated, this has a different effect on the body

Question 25

Glucocorticoids as drugs, can modify their structure to be longer lasting?

Answer 25

- The addition of a fluorine atom at position 9 enhances glucocorticoid and mineralocorticoid activity - However, the addition of a methyl group at position 16, as presented in betamethasone and dexamethasone increase GR activation and virtually eliminates MR activation, yet does increase the duration of action of these compounds - Prednisone, prednisolone, and methylprednisolone have intermediate plasma half-lives, whereas betamethasone and dexamethasone are long-acting analogues

Question 26

Glucocorticoids are used as drugs for what? (3)

Answer 26

1. Anti-inflammatory and immunosuppressive action: asthma, EVALI, eczema 2. Replacement therapy in adrenal insufficiencies: for patients with corticosteroids deficiencies 3. Myeloproliferative diseases

Question 27

What is E-cigarette, or Vaping, Product Use-Associated Lung Injury (EVALI)?

Answer 27

- Vitamin E acetate is strongly linked to the EVALI outbreak - Evidence is not sufficient to rule out the contribution of other chemicals of concern, including chemicals in either THC or non-THC products, in some of the reported EVALI cases - (glucocorticoids able to save people’s lives, shut down inflammation in lungs allowed them to breath again) - (teens between 14–18-year-olds got EVALI)

Question 28

Glucocorticoids for Replacement Therapy: Addison’s Disease?

Answer 28

- Adrenal insufficiency occurs when the adrenal gland doesn’t make enough of the hormone cortisol. The primary kind is known as Addison’s disease - It is rare - It is when the adrenal glands don’t make enough cortisol and aldosterone Treatment for Addison’s disease involve hormone replacement therapy to correct the levels of steroid hormones the body isn’t producing. Some options for treatment include oral corticosteroids such as: - Hydrocortisone (cortef), prednisone or methylprednisolone to replace cortisol. These hormones are given on a schedule to mimic the normal 24-hour fluctuation of cortisol levels - Fludrocortisone acetate to replace aldosterone - Will have to deal with this for the rest of your life, therefore, creating many possible side effects of such a long use

Question 29

Types of glucocorticoids?

Answer 29

cortisol, hydrocortisone (cortef), prednisone, methylprednisolone, etc.

Question 30

What are Myeloproliferative disorders, how to treat them?

Answer 30

- Although myeloproliferative neoplasms usually cannot be cured - Types of blood cancer that begin with an abnormal mutation in a stem cell in the bone marrow, the change leads to an overproduction of any combination of white cells, red cells and platelets - Treatment aims to correct the abnormal blood counts - Hormones may be used in certain instances to treat side effects of MPN. In patients with angiogenic myeloid metaplasia, glucocorticoids may be given to increase the life span of red blood cells.

Question 31

Adverse effects of prolonged Glucocorticoids therapy?

Answer 31

- Osteoporosis and fracture - Glucose intolerance and diabetes, doubled in

Question 32

Long term high dose exogenous steroid leads to shut down of HPA axis and adrenal atrophy Adverse effects of glucocorticoids?

Answer 32

- Oral candidiasis (thrush) o Rinse mouth after inhalation - HPA axis suppression o Uncommon with low or medium doses - Growth inhibition o Pre-puberty patients - Decreased bone density - Oral corticosteroids (ex. Prednisone) o Extreme cases o Short duration

Question 33

What is Cushing's disease

Answer 33

Cushing’s disease can be caused by issues with the body’s hormone signaling or from the overuse of steroids At risk of getting Cushing’s disease because of excess corticosteroids due to Hormone Replacement Therapy, it does not have to do with the adrenal gland (have Addison’s disease before, then develop this disease, adds up all the side effects) (interrupt natural signaling, adrenal gland not producing any more because getting it somewhere else, externally)