Lecture 10 - therapeutics of corticosteroids Flashcards
what are the three steroid classes?
glucorticoids; regulate carbohydrate, lipid and protein metabolism
Mineralocorticoids; Salt balance and water retention
Sex hormones; Hormones that interact with the androgen or oestrogen receptors
Starting point for the biosynthesis ofall steroids is cholesterol
what is the process of steroid synthesis ?
Cholesterol is the starting point for steroid hormone synthesis.
In the Zona Glomerulosa, cholesterol is converted into aldosterone, a mineralocorticoid hormone that helps regulate blood pressure and electrolyte balance.
In the Zona Fasciculata, cholesterol is transformed into cortisol, a glucocorticoid hormone that plays a role in stress response, metabolism, and immune response.
In the Zona Reticularis, cholesterol is used to produce androgens like dehydroepiandrosterone (DHEA) and androstenedione, which can be further processed into sex hormones
describe cortisol control
cortisol is regulated by negative feedback loop
The hypothalamus releases CRH (corticotropin-releasing hormone).
CRH stimulates the pituitary gland to release ACTH (adrenocorticotropic hormone).
ACTH prompts the adrenal cortex to produce cortisol.
Increased levels of cortisol then signal back to the hypothalamus and pituitary to reduce CRH and ACTH production (negative feedback loop).
The slide also notes that the production of CRH can be influenced by physiological and episodic events. The production of ACTH is affected by various factors, including ADH (antidiuretic hormone), Angiotensin II, cytokines, opiates, and catecholamines.
It mentions that cortisol levels fluctuate throughout the day, typically peaking in the early morning (6–8 am) and reaching the lowest in the late afternoon or early evening (4–6 pm). This natural rhythm is known as the circadian rhythm of cortisol secretion.
describe the diurnal variation of cortisol
highest levels around 6am just when people are waking up.
as day progresses cortisol levels decline
significant drop in late afternoon
lowest level of cortisol around midnight
The cycle repeats, with cortisol levels starting to rise again towards the early morning, completing the 24-hour cycle.
what are the primary functional roles of cortisol ?
corticosteroid bin to glucorticoid receptor - cytosolic receptor and regulates transcription
metabolism of glucose: Cortisol stimulatesgluconeogenesisprimarily in liver. it Increases the concentration of glucose in the blood, Decreases sensitivity of peripheral tissue toinsulin and Impacts glucagon and adrenaline
metabolism f proteins and lips; proteolysis is to provide the relevant tissues with amino acids. introduces protein stores in essentially all body cells except those of the liver and decreases protein synthesis and increases catabolism of protein already in the cells.
the effects of cortisol on lipid metabolism complex are promotes lipolysis and works in fine balance with insulin.
immune response;
Prevents the release of inflammatory substances
Can treat conditions as a result of over-activity of the B-cell-mediated antibody response.
Inhibits production ofinterleukin (IL)-1,2,6 interferon (IFN)-gamma,IFN-alpha, andtumor-necrosis-factor (TNF)-alphaby antigen-presenting cells (APCs) andT helper (TH)1 cells
Inhibits neutrophil apoptosis
Inhibits phospholipase A2, which decreases the formation of arachidonic acid derivatives
Glucocorticoids
Exert broad anti-inflammatory effects by inhibiting the transcription and action of many of the pro-inflammatory cytokines including IL-1Beta, IL-6, TNF-Alpha, and others
Inhibit TNF-Kappa B and other inflammatory transcription factors; they promote anti-inflammatory genes like IL-10.
UpregulatesIL-4,IL-10, andIL-13by TH2 cells – enhances immune response which results in a shift toward a TH2 immune response rather than general immunosuppression.
what are the other effects of cortisol?
Low doses of corticosteroids are anti-inflammatory
- High doses are immunosuppressive
Stress response
Stimulates CNS
Reduces appetite and slows digestion
Increases bone reabsorption
Increases sensitivity to vasoactive agents
High doses of glucocorticoids for an extended period bind to the mineralocorticoid receptor
- Raising sodium levels and decreasing potassium levels
describe the steroid classes.
Glucocorticoids include:
Natural
Cortisone Hydrocortisone
Synthetic
Prednisolone Fluticasone
Dexamethasone Beclomet[h]asone
Prednisone Betamethasone
Budenoside Fluocilonone
what is the coop man classification of steroids?
Based on structure
Group A – Hydrocortisone type
Hydrocortisone, prednisolone, methylprednisolone, prednisone
Group B – Acetonides (and related substances)
Budesonide, fluocinonide, triamcinolone acetonide.
Group C – Betamethasone type
Beclometasone, betamethasone, dexamethasone, mometasone.
Group D – Esters
Group D1 – Halogenated (less labile) betamethasone dipropionate, betamethasone valerate, clobetasol propionate and mometasone furoate.
Group D2 – Labile prodrug esters ciclesonide, Various hydrocortisone salts
what is the ADME of oral steroid like?
Absorption
rapid absorption and high bioavailability
Distribution
high protein binding to albumin
Metabolism
Significant metabolism in liver eg by hydroxylation
Excretion
Very high excretion in urine (>90 %)
describe mineralocorticoid activity
mineralcoritocids are involved in the salt balance and water retention. They modulate ion transport in the epithelial cells of the renal tubules of the kidney and produce an icnrease in fluid laod and blood pressure. naturally occurign minealcortiocid is aldosterone, synthetic mineralcorticoid is fludrocortisoen adn mineralocrticoids antagonsit is spironolactone.
what are adverse effects of corticosteroids
Steroid Euphoria: Therapeutic doses of steroids can cause artificial sense of well-being, partially due to increased sensitivity to adrenaline.
Dosing Time: It’s recommended to take corticosteroids in the morning to mimic body’s natural rhythm. Taking them at night could disrupt sleep due to increased energy.
Neuropsychiatric Effects: Steroids can lead to psychiatric effects, including psychosis, anxiety, and depression.
Fat Redistribution: Long-term use can cause fat to redistribute to the face and torso, leading to a “moon face” or “buffalo hump”, a condition known as corticosteroid-induced lipodystrophy.
Hypertension
Osteoporosis: Long-term corticosteroid use can lead to osteoporosis
Due to the diversion of amino-acids to glucose
Considered anti-anabolic and can cause muscle wasting
Blood Sugar Imbalances: They can cause hyperglycemia, insulin resistance, and contribute to the development of type 2 diabetes mellitus
There’s an increased risk of peptic ulceration
Chronic use of corticosteroids may increase the risk of developing cataracts and glaucoma.
Corticosteroids have a low but significantteratogeniceffect
Use of inhaled corticosteroids among children associated with growth retardation
what are main counselling points of steroid use?
Single dose usually
Oral hydrocortisone or dexamethasone may be exceptions
Timing of dose – morning dosing
Oral hydrocortisone may be an exception
Duration of treatment
May be short or long term
Long term leads to hypothalamic-pituitary-adrenal axis suppression and increased susceptibility to infections
Withdraw by tapering does to avoid steroid-insufficiency crisis
Local side-effects – GI disturbances
Formulation – normal, soluble or enteric coated
