Corticosteroids

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Hypothalamic Pituitary-Adrenal Axis

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Regulation of cortisol synthesis and secretion is a function of the Hypothalamic-Pituitary-Adrenal axis

Hypothalamus governs emotional responses, autonomic functions, and hormone synthesis
Hypothalamus releases CRH (corticotrophin-releasing hormone) that causes the anterior pituitary to synthesize and release ACTH, which in turn causes the adrenal gland to synthesize and release cortisol.
ACTH (adrenocorticotropic hormone) is a hormone released by the anterior pituitary gland

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Hypothalamic-Pituitary-Adrenal Axis

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Hypothalamic-Pituitary-Adrenal Axis

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ACTH release is governed by hypothalamus & negative feedback
Hypothalamus
Hypothalamus releases the peptide CRH (corticotrophin-releasing hormone) (a.k.a. CRF – corticotrophin-releasing factor)
CRH acts on the pituitary to stimulate the release of ACTH
Negative Feedback by cortisol
Anterior Pituitary
decrease ACTH secretion
decrease response of pituitary to CRH
Stress (due to hypoglycemia, trauma, hemorrhage, cold, etc.) can overcome feedback inhibition by cortisol to increase the levels of secreted cortisol

Hypothalamus
dec release of CRH

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Hormones Secreted by the
Adrenal Gland: Glucocorticoids - CORTISOL

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Glucocorticoids - CORTISOL
Synthesized in the Zona Fasciculata of the Adrenal Cortex
Impacts regulation and function of the following:
- Metabolism
- Stress Response
- CNS functions
- Immunity

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Hormones Secreted by the
Adrenal Gland: Mineralocorticoids - ALDOSTERONE

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Mineralocorticoids - ALDOSTERONE
- Synthesized in the Zona Glomerulosa of the Adrenal Cortex
-- Mineralocorticoid secretion is regulated primarily by activation of angiotensin II receptors
-- Less responsive to ACTH
Impacts regulation of:
- Na+ and K+ concentrations in extracellular fluids (↓K+, ↑Na+)

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Hormones Secreted by the
Adrenal Gland: Androgens – dehydroepiandrosterone (DHEA)

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Androgens – dehydroepiandrosterone (DHEA)
- Produced in the adrenal cortex

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Metabolism/Pharmacokinetics of Cortisol

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- Most cortisol is metabolized in the liver - reduction of double bonds between C4,5 and conversion of ketone at C3 to a hydroxyl, conjugation with sulfate, glucuronate, excretion by kidneys. Similar mechanisms for related drugs.

- Only 5-10% of cortisol is freely circulating, 90-95% is bound to corticosteroid-binding globulin (CBG) – only free drug is active

- Some synthetic glucocorticoids (like dexamethasone) are primarily bound to both albumin and CBG. Other synthetic glucocorticoids do not bind to serum proteins.

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Structure Activity Relationships

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Physiological Effects 
of Corticosteroids: Metabolism

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Metabolism
Carbohydrate / Protein (sometimes referred to as the anti-insulin)
- Increase Hepatic Gluconeogenesis (formation of glucose from amino acids and glycerol in the liver)
- Increase Formation of glycogen in the liver
- Increase Protein breakdown into amino acids
(~ may lead to skeletal muscle weakness and wasting)
- decrease Glucose utilization
-- Overall - increase blood glucose

Lipid
net increase lipolysis - increase free fatty acids
- increase deposition of fat in back of neck and face (moonface)
- decrease deposition of fat in extremities
Overall – Redistribution of body fat from extremities to central regions (lateral to medial)

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Physiological Effects 
of Corticosteroids: Electrolyte and water balance

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Electrolyte and Water Balance
- Acts on distal tubules and collecting ducts of kidney to enhance reabsorption of Na+ from tubular fluids
-- Urinary retention of Na+ and  extracellular fluid volume
-- Urinary excretion of K+ and H+
- Predominantly function of mineralocorticoid activity
- Regulated by Renin-Angiotensin system

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Physiological Effects 
of Corticosteroids: Cardiovascular

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Most effects are secondary to mineralocorticoid induced changes in renal Na+ excretion
- Excess of CS - hypertension, arteriosclerosis, cardiomyopathy, and enhanced vascular responsiveness to vasoconstrictors such as norepinephrine and angiotensin
- Deficiency in CS – hypotension, unresponsiveness to vasoconstrictors

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Physiological Effects 
of Corticosteroids: CNS

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Central Nervous System
-- Indirect effects due to changes in blood pressure and electrolytes (thus, mineralocorticoid activity)
- Excess CS– mood elevation, euphoria, insomnia, motor activity
- Deficiency in CS– apathy, depression, irritability, psychosis

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Physiological Effects 
of Corticosteroids: Bone

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Bone
- Decrease osteoblast formation and activity (osteoblasts make bone)
- Increase osteoclast formation (osteoclasts break down bone ~ resorption)
-- Alters Ca++ homeostasis (decrease intestinal absorption, increase renal excretion)
-- Alters Vitamin D (increase active formation, but blocks vitamin D activity)
Overall - Osteoporosis

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Physiological Effects 
of Corticosteroids: Immune System

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Anti-inflammatory and immunosuppressive effects on the immune system are chiefly due to glucocorticoid (not mineralocorticoid) activity and are the principal therapeutic benefits of glucocorticoids.

- Decrease Transcription / translation of pro-inflammatory mediators, including IL-1, IL-2, IL-3, IL-6, GM-CSF, IFNγ, and TNFα

- Increase Transcription / translation of anti-inflammatory factors – IL-10, IκBα

incidentally Decrease Production of prostaglandins and leukotrienes (a spoiler for respiratory disorders)


Overall effects – The proliferation, activation, and chemotaxis of multiple leukocytes are impaired by glucocorticoids.

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Mechanism of Action: Corticoid receptors

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Corticoid receptors
Members of super family of nuclear receptors
Regulates the transcription of target genes – effect may be stimulatory or inhibitory
Two corticoid genes have been found
GC-glucocorticoid receptor (GCR)
Widely distributed throughout the body

MC-mineralocorticoid receptor (MCR)
Tissue distribution limited to the kidney (distal tubule, collecting ducts), colon, sweat glands
Cortisol has equal affinity for GC receptor and MC receptor. Actions of Cortisol in MCR-expressing tissues minimized by 11β-hydroxylase – converts cortisol  cortisone (no effects)

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Direct, Type I Mechanism

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PIc

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Direct, Type I Mechanism

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- Glucocorticoid (S) crosses the cellular membrane easily due to its lipophilic cholesterol-like backbone
- Glucocorticoid (S) binds to the Glucocorticoid receptor (GR)
- GR then dissociates from the complex of heat shock proteins (HSPs) to which it is normally bound
- GR/S complex crosses the nuclear membrane, entering the nucleus of the cell
- GR/S homodimers (i.e. a set of two GR/S complexes linked and operating together) bind directly to DNA in specialized regions referred to as Glucocorticoid Response Elements (GRE)
- GR/S homodimer binding alters transcription rates of DNA into mRNA
-- Alters mRNA translation into protein
-- Alters levels of mediators of inflammation

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Direct, Type I Mechanism

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Indirect, Type II
Mechanism of Action

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NF-κB signaling

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1 – Indirect (previous slide)- S/GR complex binds to the transcription factor NF-κB and acts as an antagonist
2 – Direct – S/GR complex binds directly to DNA, increases transcription rates for IκBα, increased levels of IκBα prevent NF-κB activity (shown below)

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Glucocorticoids cause the following:

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Decrease NF-κB activity (by both direct & indirect mechanisms)

Decrease transcription COX-2 (inducible cyclooxygenase) enzyme
*Decrease Prostaglandin synthesis
Decrease transcription PLA2 enzyme
*Decrease release of arachidonic acid from cellular membranes

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Glucocorticoids cause the following:cont

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*TNFα signaling is also impaired since NF-κB is an intracellular 2nd messenger for TNF (see diagram above)
*DecreaseChemotaxis of all leukocytes

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Glucocorticoids cause the following: cont

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*Decrease IL-1 transcription (by direct mechanisms)
**Decrease IL-2 (T cell growth factor) transcription (by direct mechanisms)
*Decrease T lymphocyte synthesis and activation
*also Decrease B cell, monocyte, and natural killer cell activity
IL-2 is released primarily by T cells themselves

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Glucocorticoids cause the following: cont

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Glucocorticoids cause the following: cont

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*Decrease GM-CSF transcription (direct mech.)
Decrease Leukocyte synthesis in the bone marrow

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Glucocorticoids cause the following: cont

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*Decrease TNFα transcription (direct mech.)
*Increase IL-10 Transcription Rates (direct mech.)
Decrease AP-1 activity (indirect mechanism involving S/GRec. binding to transcription factor and not DNA)

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Glucocorticoids: Adverse Effects (Cushing Syndrome)

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Cushing’s Syndrome
Hypercortisolism – various causes
- Weight gain (↑ appetite)
- Muscle weakness
- Excess hair growth*
- Hair loss*
- Fat redistribution
- High blood pressure*
- Osteoporosis
- Gonadal Dysfunction*
*Due to MC or androgen effects

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Glucocorticoids: Hypercortisolism Adverse Effects

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Hypercortisolism results from the effects of
- supraphysiologic levels of glucocorticoids from
- exogenous administration of glucocorticoids (iatrogenic Cushing’s) or
 
- endogenous overproduction of ACTH

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Glucocorticoids: Adverse Effects (Addison's disease)

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- Primary adrenal insufficiency (Addison’s disease) – due to defective adrenal function
- Secondary adrenal insufficiency – due to defective anterior pituitary or hypothalamic function
- Often caused by exogenous corticosteroid administration
May result in atrophy of the anterior pituitary and hypothalamus, impairing recovery
-- Sudden withdrawal of steroids after prolonged therapy may result in acute adrenal insufficiency
-- Longer the duration of therapy, slower the withdrawal

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Glucocorticoids: Adverse Effects Withdrawal

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- Recovery of full adrenal function may take 2-18 months
- Less than 1 week GC use: withdrawal in few steps
Rapid withdrawal: 50% reduction of dose every day
Slow withdrawal: 2.5 – 5 mg prednisolone reduced at an interval of 2-3 days
- Longer period & high dose GC use:
Halve the dose weekly until 25 mg prednisolone or equivalent is reached
Thereafter reduce dose by about 1mg every 3-7 days.

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Adverse Effects: Acute adrenal insufficiency

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Due to abrupt withdrawal of glucocorticoids or with stress in adrenally compromised patient
- life-threatening
- GI symptoms (N/V, pain), dehydration, hyponatremia, hyperkalemia, weakness, and hypotension.

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Therapeutic Uses: Replacement

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Replacement therapy for secondary or tertiary adrenocortical insufficiency
- Disease caused by dysfunction of the hypothalamus or the pituitary
- Treated with hydrocortisone, dosed as described

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Therapeutic Uses: Addison's disease

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Replacement therapy for primary adrenocortical insufficiency (Addison’s disease)
- Disease caused by adrenal cortex dysfunction
- Treated with hydrocortisone – identical to natural cortisol
- Dosed two-thirds in the morning, one-third in the afternoon to approximate the normal release of cortisol from the adrenal cortex

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Therapeutic Uses: Cushing Syndrome

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Diagnosis of Cushing’s Syndrome
- Dexamethasone is administered
If due to over production of hypothalamic or pituitary hormone the cortisol levels are decreased
- If due to a cortisol-secreting tumor, circulating cortisol levels will be unchanged

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Therapeutic Uses: Inflammation

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Inflammation
- Glucocorticoids rapidly decrease symptoms associated with inflammation: redness, swelling, heat and tenderness.
- Cause the redistribution of immune cells to lymphatic tissue
- Decreased activity of immune cells: decreased ability to respond to mitogens and antigens
- Conditions
-- Inflammatory bowel disease (IBD)
-- Asthma
-- Eczema

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Therapeutic Uses: Specific Drugs

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Specific drugs
- Prednisolone is drug of choice for systemic/oral treatment of inflammation (IBD, severe asthma)
- Beclomethasone, and budesonide for inhalation therapy (asthma)
- Triamcinolone, hydrocortisone for topical therapy (Eczema)

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Therapeutic Uses: Allergies

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Treatment of allergies
- Beneficial for the treatment of symptoms or bronchial asthma, and allergic rhinitis.
- Utility for the treatment of allergies is largely due to anti-inflammatory effects
- Drugs used are ideally administered topically to minimize the systemic effects
-- Beclomethasone dipropionate
-- Budesonide

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Therapeutic Uses: Developing Fetus

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Developing Fetus
- Stimulation of lung maturation in the fetus
- Glucocorticoid administration to mother when delivery is expected prematurely (before 34 weeks) decreases the incidence of respiratory distress syndrome
- Treated with beclomethasone 48 hours prior to birth and then 24 hours prior to birth