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PHAR 300 > L12: Corticosteroids > Flashcards

L12: Corticosteroids Flashcards

1
Q

What is inflammation?

A

The body’s immune response to an irritant which can be a germ (infection like bacteria or viruses), but also a foreign object like a splinter, injuries like bruises also cause inflammation.

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2
Q

What is the purpose of inflammation?

A
  1. Defence mechanism in higher organisms to prevent infection and injury
  2. In case of injury: Localize and eliminate injurious agent and remove damaged tissue components so that the body can begin to heal and so that it doesn’t interfere with normal body function.
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3
Q

What changes occur during inflammation?

A

Change in blood flow, increase in blood vessel permeability, migration of fluid, change of proteins in the body. White blood cells (leukocytes): mast cells, macrophages, and neutrophils from the circulation travel to the site of injury. They’re all recruited to work together to heal the injured part

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4
Q

What do corticosteroid drugs do?

A

Corticosteroids are a class of drugs that lower inflammation in the body, reduce immune system activity (immunosuppressants), ease swelling, itching, redness, and allergic reactions. Doctors often prescribe them to help treat diseases like asthma or arthritis.

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5
Q

What is a steroid?

A

A biologically active organic compound with four rings (can be different in different steroids) arranged in a specific molecular configuration.

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6
Q

What are the two principle functions of steroids?

A
  1. Important component of cell membranes which can alter membrane fluidity.
  2. Signalling molecules.
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7
Q

What are corticosteroids? What are the 2 groups?

A

Any of a group of steroid hormones produced in the adrenal cortex or made synthetically. There are two kinds: glucocorticoids and mineralocorticoids.

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8
Q

What is a mineralocorticoid? Give an example.

A

Class of corticosteroids produced in the adrenal cortex that influences salt and water balance (electrolyte in fluid balance). A primary example is aldosterone.

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9
Q

What is the immune response to stress?

A

Stress in the body causes pain which induces the hypothalamus to release hormones that stimulate the adrenal gland. The adrenal gland releases corticosteroids which can reduce inflammation and pain.

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10
Q

What is the endocrine system?

A

The endocrine system is the circuit board of the body through which cells communicate. It’s a complex network of glands and organs. It uses hormones to control and coordinate your body’s metabolism, energy level, reproduction, growth and development, and response to injury, stress, inflammation (reduce inflammation), and mood.

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11
Q

What is autocrine signalling?

A

cell produces a ligand which interacts with a receptor on the same cell.

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12
Q

What is paracrine signalling?

A

Cell’s ligand interacts with a receptor on a nearby cell.

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13
Q

What is endocrine signalling?

A

Cell’s chemical messenger (hormone) circulates in the body and has an effect on specific receptors on distant cells via the circulation.

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14
Q

What are the major components of the endocrine system?

A
  1. Brain
  2. Hypothalamus and pituitary (make hormones)
  3. Target organs (thyroid and parathyroid, pancreas, adrenal glands, ovaries, testes, etc)
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15
Q

What is the pathway for the release of cortisol?

A
  1. stress, illness, hypoglycemia, or hemmorhage on hypothalamus
  2. release of CRH (corticotropin releasing hormone) from hypothalamus
  3. CRH stimulates release of ACTH (adrenocorticotropic hormone) from pituitary.
  4. ACTH stimulates release of cortisol from adrenals
  5. Cortisol inhibits the hypothalamus and the pituitary from releasing their hormones. Therefore, a decrease in cortisol. Negative feedback loop.
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16
Q

How is the hypothalamus stimulated? What does it release?

A

The hypothalamus gets a signal from higher neural centres in response to altered plasma levels of the hormones or other substances. It releases corticotropin-releasing hormone (CRH).

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17
Q

What is CRH? How is it activated?

A

CRH is a pro-hormone produced in the hypothalamus (a 41 amino acid peptide). To activate it, amino acids are cleaved. This is a way to control regulation.

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18
Q

Describe the stimulation of the anterior pituitary. What are the levels of control?

A

Corticotropin-releasing hormone acts on G protein-coupled receptors in the anterior pituitary to stimulate POMC synthesis, which is processed to release adrenocorticotropic hormone (ACTH), and beta-LPH. ACTH is released from corticotropin-releasing cells in the anterior pituitary

The levels of control are:

  1. Turning on the synthesis of a protein (increasing expression)
  2. Post-translational processing so you can tightly control how much of the active messenger / protein is produced.
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19
Q

What is the role of ACTH?

A
  1. Increases the delivery of cholesterol to the inner mitochondrial membrane.
  2. Increases the transcription of steroidogenic enzymes.
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20
Q

Where are the adrenal glands? What are the different sections?

A

The adrenal glands are sitting on top of the kidneys.

The adrenal glands are composed of the cortex (outer layer) and the medulla (inner layer).

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21
Q

How does ACTH affect the adrenal glands?

A

ACTH binds to its receptors in the adrenal cortex. ACTH regulates glucocorticoid synthesis in the adrenal cortex (in zona fasciculata and zona reticularis).

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22
Q

What part of the adrenal cortex makes glucocorticoids? mineralocorticoids?

A

Zona fasciculata/reticularis make glucocorticoids, zona glomerulosa makes mineralocorticoids.

23
Q

How do you synthesize aldosterone and cortisol? (steroidogenesis)

A

All steroids are made by first cleaving cholesterol side chain via CYP11A. Next, the steps can vary for different steroid synthesis. To make aldosterone (mineralocorticoid): you use CYP11β2. To make cortisol (glucocorticoid), you use CYP17, then CYP11β1.

24
Q

What can affect the negative feedback loop of cortisol production? What can happen when this loop is perturbed?

A

Treatment with external corticosteroids can affect the feedback loop.
Issues with the feedback mechanism can cause diseases.

25
Q

What is the mechanism of action of glucocorticoids?

A
  1. Glucocorticoids bind ligand binding domain of steroid hormone receptors which are found in the nucleus, cytosol, and also on the plasma membrane of target cells.
  2. The ligand-bound receptor moves from the cytoplasm into the nucleus.
  3. The DNA-binding domain of the receptor binds to specific areas of the genome (GRE: glucocorticoid response element).
  4. The transcription activating domain of the receptor turns on the transcription of very specific genes that are related to the effects of the hormone.
  5. This leads to changes in gene expression over a time period of hours to days.
26
Q

What are the 2 effects a glucocorticoid can have on gene expression? How do they occur?

A

Glucocorticoids can activate gene expression, which is referred to as transactivation. They can also repress gene expression, which is referred to as transreppression. Glucocorticoids bind GR- Alpha, which is a glucocorticoid receptor Alpha (protein). When 2 GR-Alphas (bound to glucocorticoids) come together they can bind the GRE sequence in DNA to cause either trans activation or transreppression depending on the glucocorticoid bound.

27
Q

Explain what happens when GR-Beta interacts with GR-alpha.

A

When GR-beta interacts with a GR- alpha and glucocorticoid it can cause trans repression. It is said that this is the mechanism of Tolerance. When one becomes tolerant to glucocorticoids, more GR-beta is produced (in normal situations GR-beta is less Expressed than GR-Alpha). GR-Beta then inhibits GR-alpha which causes a decreased effect of the glucocorticoids.

28
Q

What are the effects of endogenous glucocorticoids?

A

metabolic, anti-inflamatory, immunosuppressant.

29
Q

What are the anti-inflammatory effects of endogenous glucocorticoids?

A
  • Changes in cell proliferation, survival, differentiation, migration.
  • Decreased pro-inflammatory cytokines, interleukins, prostaglandins. This is because glucocorticoids can block transcription of inflammatory proteins.
30
Q

What are the metabolic effects of endogenous glucocorticoids?

A

Glucocorticoids increase glucose to protect the brain and heart (“fight or flight”) in response to a stress by transcriptional activation.

Increase blood glucose by:
- increasing glycogen breakdown (glycogenolysis)
- increasing glucose synthesis (gluconeogenesis)
- decreasing fat deposits (increased lipolysis)
- increased protein catabolism and decreased
synthesis

31
Q

How are glucocorticoids administered?

A

Glucocorticoids are administered through most routes, but local administration is preferred to minimize adverse effects associated with systemic actions.

32
Q

What is cortisol bound to in the circulation?

A

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.

33
Q

How does CBG affect bioavailability of glucocorticoids?

A

Corticosteroid-binding globulin (CBG) transports
glucocorticoids in the blood (because glucocorticoids are lipid soluble) and thereby modulates the tissue availability of these hormones. Thus the hormones are transported but there must be another reaction to make it available.

34
Q

What glucocorticoids can CBGs bind and not bind?

A

Prednisone and prednisolone can be bound. Dexamethosone cannot be bound. This results in 100% bioavailability of plasma dexamethosone.

35
Q

What causes the glucocorticoid bound to CBG to be released?

A

Inflammation, stress, and release of molecules like elastase releases the steroid from the complex.

36
Q

Describe the absorption of glucocorticoids?

A

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.

37
Q

What happens to bioavailability of glucocorticoids when estrogen concentrations are elevated? When can estrogen levels be elevated?

A

Elevated concentrations of estrogen, which occurs in pregnancy, contraceptive use, or hormone replacement therapy, increases the biosynthesis of CBG in the liver. This requires increased plasma cortisol concentrations to maintain an appropriate bioactive fraction.

38
Q

How does the circadian rhythm affect corticosteroid administration?

A

The time of day is important in administering a corticosteroid drug, if natural levels of corticoids are down, we will be more sensitive to the drug. If natural levels of corticoids are up, we will be more resistant to the drug.

39
Q

What does modifying the side chains of a glucocorticoid change?

A

It can minimize the unwanted response, allow the desired response, change the bioavailability, and change the half-life of the drug.

40
Q

What are different modifications of glucocorticoid side chains and explain their effects?

A
  1. The addition of a fluorine atom at position 9 enhances glucocorticoid and mineralocorticoid activity.
  2. The addition of a methyl group at position 16, as present in betamethasone and dexamethasone increases GR activation and virtually eliminates MR activation, yet does increase the duration of action of these compounds.
  3. Prednisone, prednisolone, and methylprednisolone have intermediate plasma half-lives, whereas betamethasone and dexamethasone are long acting analogues.
41
Q

What are the different administration methods of glucocorticoids?

A

Oral, lotions/creams, inhalers.

42
Q

What are the main therapeutic uses of glucocorticoids?

A

(1) replacement therapy for patients exhibiting inadequate endogenous cortisol production.
(2) anti-inflammatory or immunosuppressant agents
(3) adjuvants in the treatment of myeloproliferative diseases and other malignant conditions.

43
Q

What conditions do glucocorticoids with anti-iflammatory and immunosuppresive action treat?

A
  1. Asthma: treatment via inhalers bc asthma is a lung disease so it helps target inflammation directly in the lungs.
  2. Eczema: treatment via cream to prevent inflammation on the skin or treatment via pill for it to be systemic.
  3. EVALI (E-cigarette, or vaping, product use-associated lung injury): glucocorticoids helps patients breathe but its better if they’re put on a ventilator.
  4. Allergic reactions
  5. GI diseases
  6. Acute respiratory distress
  7. Infections
  8. Neurologic disorders
  9. Organ transplants
  10. Skin diseases
  11. Rheumatoid arthritis
44
Q

What is EVALI?

A

E-cigarette, or vaping, product use-associated lung injury.
Initially, they thought the inflammation in the lungs that led to fluid retention and injuries to lung tissue was due to Vitamin E acetate. When they removed Vitamin E acetate from E -cigarettes Evali still occurred. It is a fast and rapid inflammation (vs cigarettes or COPD which takes long).

45
Q

What conditions does replacement therapies in adrenal insufficiencies treat?

A

Addison’s disease: adrenal glands don’t make enough aldosterone and cortisol. Treatment: systemic glucocorticoid therapy over a period of time. Replacement drugs (glucocorticoids and mineralocorticoids) are given on a schedule to mimic the 24 hour fluctuation of cortisol that is normally occurring.

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.

46
Q

What are myeloproliferative diseases? How can glucocorticoids help?

A

Myeloproliferative neoplasms usually cannot be cured.
• types of blood cancer that begin with an abnormal mutation (change) in a stem cell in
the bone marrow. The change leads to an overproduction of any combination of white cells, red cells and platelets.
• Glucocorticoid 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.

47
Q

What are the adverse effects of cortisol replacement therapy?

A
  1. If the treatment is too low: hairiness, acne, greasy skin, irregular periods, reduced fertility, fatigue.
  2. If treatment too high: increased appetite, weight gain, muscle weakness, thin skin, easy bruising, high BP, osteoperosis (weak bones), diabetes.
48
Q

What are the consequences of prolonged glucocorticoid therapy?

A
  1. Osteoporosis and fracture (≥ 3 months - increase in fracture risk)
  2. Glucose intolerance and diabetes doubled in rheumatoid arthritis patients taking ≥7.5 mg prednisone
  3. Central obesity
  4. Muscle wasting
  5. Increased risk of infections
  6. Depression
  7. Cataracts
49
Q

What are adverse affects of glucocorticoids? Explain.

A
  1. Oral candidiasis (thrush): often in the case of people using inhalers. Can be avoided by Rinsing mouth after inhalation to remove glucocorticoids to prevent shutting down the immune responses in the mouth.
  2. HPA axis suppression
    - Uncommon with low or medium doses
    - Long term high dose exogenous steroid leads to shut down of HPA (hypothalamus, pituitary, adrenal) axis and adrenal atrophy.
    - No more ACTH to keep the adrenal glands functioning so they can atrophy. you need to slowly decrease the amount of glucocorticoid being taken to avoid this.
  3. Growth inhibition
    - Pre-pubertal patients at risk, so it is important in having the right dose of glucocorticoids administered or it can stunt their growth.
  4. Decreased bone density
50
Q

What causes Cushing’s syndrome?

A

It’s caused by excess cortisol:

1) overuse of exogenous glucocorticoids (ex: someone who has arthritis).
2) Cancers: ectopic production of ACTH can affect pituitary and produce over-expression of ACTH or it can affect the adrenal glands directly and cause excess glucocorticoid release.
3) Inhibition of the feedback loop (such as from prolonged use of corticosteroids) can cause overproduction of cortisol.

51
Q

What are the observable traits of Cushing’s syndrome?

A
  1. Obesity
  2. Hump between shoulder blades
  3. Moon face
  4. Muscle wasting and weakness
  5. Psychiatric issues
52
Q

What affect does glucocorticoids have on SARS-CoV-2?

A
  1. People using corticosteroids, especially those using inhaled corticosteroids, are more susceptible to developing severe covid-19 due to the immunosuppressant nature of glucocorticoids.
  2. Healthy people who develop covid and big lung inflammation can be helped by glucocorticoids.
53
Q

How should the dosage of glucocorticoids be affected for obese people?

A

Increase dose because the fat can act as a sink since glucocorticoids are lipid soluble.

PHAR 300 (20 decks)

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