Corticosteroids

Haftom G. (MSc)

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Fig: The Hypothalamic-Pituitary-Adrenal Axis
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 Introduction
 Adrenal medulla: medulla and cortex

 Medulla: secretes catecholamines

 Cortex: secretes two types of corticosteroids (glucocorticoids and mineralocorticoids)

and the adrenal androgens.

• Mineralocorticoids (aldosterone): regulate salt and water metabolism

• Glucocorticoids (for example, cortisol): that are involved with metabolism and
response to stress

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 Glucocorticoids
 The glucocorticoids get their name from their effect of raising the level of
blood sugar (glucose).
• by stimulating gluconeogenesis in the liver.

 The principal human glucocorticoid is cortisol (also called hydrocortisone).

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Mechanism of Action of corticosteroids

Fig: Intracellular
mechanism of action
of the GR

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Fig: Mechanism of action of glucocorticoids
 Physiologic and pharmacologic effects of glucocorticoids

 Carbohydrate & Protein Metabolism

• Increased gluconeogenesis

• Reduce glucose uptake & utilization by peripheral tissues

• Cortisol antagonizes the effect of insulin on peripheral tissues in order to increase blood glucose

• Cortisol stimulates the translocation of glucose transporters away from the plasma membrane into

the cell interior

• Increase protein breakdown (to provide amino acids for gluconeogenesis)

• Protein breakdown affects multiple tissues including muscle & skin
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 Physiologic and pharmacologic effects of glucocorticoids

 Carbohydrate & Protein Metabolism…….

• Activate lipolysis (to provide fatty acids for gluconeogenesis)
• The effects of growth hormone on hormone-sensitive lipase in adipocytes are stimulated, resulting in the
release of free fatty acids.
• Increased free fatty acids further increase insulin resistance.

• Clinical outcomes:
• Atrophy of lymphoid tissue
• Decreased muscle mass
• Thinning of the skin (cigarette-paper-like consistency, fragile, easy to bruise)
• Hyperglycemia, worsening of diabetes
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Physiologic and pharmacologic effects of glucocorticoids

 Lipid Metabolism

• Chronically elevated glucocorticoids: redistribution of body fat.

• The redistribution of fat is believed to result from different sensitivities of peripheral vs truncal fat
cells to:
• The lipolytic effects of glucocorticoids themselves
• Lipolytic effects of insulin that is released in response to glucocorticoid-induced hyperglycemia

• Clinical outcomes:
• Increased fat in the back of the neck (buffalo hump)
• Increased facial fat (moon face)
• Loss of fat in body extremities

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 Physiologic and pharmacologic effects of glucocorticoids

 Formed Elements of Blood:

• Corticosteroids also affect circulating white blood cells.

• Addison disease is associated with an increased mass of lymphoid tissue and lymphocytosis

• Cushing syndrome is characterized by lymphocytopenia and a decreased mass of lymphoid tissue.

• The administration of glucocorticoids leads to a decreased number of circulating lymphocytes,

eosinophils, monocytes, and basophils.

• Certain lymphoid malignancies are also destroyed, most likely due to activation of programmed
cell death

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 Physiologic and pharmacologic effects of glucocorticoids cont’d….
 Catabolic and Antianabolic Effects
• They have catabolic and antianabolic effects in lymphoid and connective tissue,
muscle, peripheral fat, and skin.

• Supraphysiologic amounts of glucocorticoids lead to decreased muscle mass and

weakness and thinning of the skin.

• Catabolic and antianabolic effects on bone are the cause of osteoporosis in Cushing’s
syndrome

• In children, glucocorticoids reduce growth.

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 Physiologic and pharmacologic effects of glucocorticoids cont’d….

 Increase resistance to stress:

 ↑plasma glucose levels: provide the body with energy to combat stress caused
by trauma, fright, infection, bleeding, or debilitating disease.

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Physiologic and pharmacologic effects of glucocorticoids cont’d….

Have anti-inflammatory action:

o Have potent anti-inflammatory and immunosuppressive activities
• Lower circulating lymphocytes

• Inhibit the ability of leukocytes and macrophages to respond to mitogens and antigens.

• Decrease production and release of proinflammatory cytokines

• Inhibit phospholipase A2

• Stabilize mast cell and basophil membranes: decrease histamine release

• Reduce expression of cyclooxygenase-2

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Table: Inhibitory effects of glucocorticoids on inflammatory/immune responses 14
Physiologic and pharmacologic effects of glucocorticoids cont’d….

 Other effects include

• Adrenal insufficiency is associated with depression (CNS)

• Increased amounts of glucocorticoids often produce behavioral disturbances

in humans: initially insomnia and euphoria and subsequently depression.

• Glucocorticoids given chronically suppress the pituitary release of ACTH, GH,

TSH, and LH.

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 Other effects cont’d….
 Large doses of glucocorticoids: peptic ulcer
 Suppressing the local immune response against H. pylori

 Promote fat redistribution in the body

 Increase of visceral, facial, nuchal, and supraclavicular fat

 Antagonize the effect of vitamin D on calcium absorption.

 Cortisol deficiency: impaired renal function (particularly GF), ↑ADH secretion

 Development of the fetal lungs: structural and functional changes in the lungs near
term, including the production of pulmonary surface-active material required for air
breathing (surfactant), are stimulated by glucocorticoids.
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 Cortisol (Hydrocortisone)
 Naturally occurring glucocorticosteroid

 Pharmacokinetics
• Daily secretion, in the absence of stress,10-20 mg of cortisol.

• Cortisol bound to circulating proteins like Corticosteroid-binding globulin (CBG)

• Synthetic corticosteroids such as dexamethasone bound to albumin rather than CBG.

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 Synthetic corticosteroids
 They are administered parenterally, orally, topically or inhalation.

 Obviously the oral route is preferred for prolonged therapy (asthma ??)

 However, parenteral administration is required in certain circumstances.

• IM and IV injections are useful in emergencies.

• Some injections as suspensions are slowly absorbed, which prolongs effectiveness to ~8 h.

 Cortisol, Cortisone, Prednisone, Prednisolone, Fludrocortisone, Betamethasone and

Dexamethasone, Methylprednisolone, bechlomethasone, clobetasol, mometasone,…..

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Fig: Regulation of steroid activity by 11β-hydroxysteroid dehydrogenase (11β-HSD).
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 Glucocorticosteroids

Relative Anti-Inflammatory Relative Salt-Retaining

Agent Forms Available Activity Activity
Oral, parenteral,
Cortisol (hydro-cortisone) 1 1
topical

Cortisone Oral 0.8 0.8

Prednisone Oral 4 0.3

Oral, injectable,
Triamcinolone 5 0
topical, inhaled

Oral, injectable,
Dexamethasone 30 0
topical

Fludrocortisone
Oral 0 250
(mineralocorticoid) 20
Table: relative potencies and equivalent doses of representative corticosteroids 21
Table: Properties of Adrenocortical Steroids
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Nonproprietary name Type of preparation
Alclometasone dipropionate Topical
Amcinonide Topical
Beclomethasone dipropionate Inhaled, Nasal
Betamethasone acetate Injectable
Betamethasone sodium phosphate Oral, injectable
Betamethasone valerate Topical
Budesonide Oral, inhaled, nasal, rectal
Ciclesonide Inhaled, nasal
Clobetasol propionate Topical, shampoo
Clocortolone pivalate Topical
Desonide Topical
Desoximetasone Topical
Dexamethasone Oralophthalmic, ocular implant
Dexamethasone sodium phosphate Ophthalmic, injectable
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Nonproprietary name Type of preparation
Diflorasone diacetate Topical
Fludrocortisone acetate??? Oral
Flunisolide Inhaled, Nasal
Fluocinolone acetonide Topical, shampoo, otic, intravitreal implant
Fluocinonide Topical
Fluorometholone Ophthalmic
Fluorometholone acetate Ophthalmic
Flurandrenolide Impregnated dressing, topical
Halcinonide Topical
Hydrocortisone Topical, oral, rectal

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Nonproprietary name Type of preparation
Hydroxycortisone acetate Topical, rectal
Hydroxycortisone butyrate Topical
Hydrocortisone probutate Topical
Hydrocortisone sodium succinate Injectable
Hydrocortisone valerate Topical
Methylprednisolone Oral
Methylprednisolone acetate Injectable
Methylprednisolone sodium succinate Injectable
Mometasone furoate Inhaled, nasal, topical
Prednisolone Oral
Prednisolone acetate Oral, ophthalmic
Prednisolone sodium phosphate Oral, ophthalmic
Prednisone Oral
Triamcinolone acetonide Nasal, topical, injectable, dental
Triamcinolone hexacetonide Injectable
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 Therapeutic Uses
 Replacement therapy for primary adrenocortical insufficiency (Addison disease):

Caused by adrenal cortex dysfunction (Dx: lack of response to exogenous ACTH)

Hydrocortisone is given to correct the deficiency (Failure to do so results in death)

Administration of fludrocortisone may also be necessary to supplement

mineralocorticoid deficiency

 Replacement therapy for secondary or tertiary adrenocortical insufficiency:

Defect in CRH production by the hypothalamus or in ACTH production by the pituitary.

Hydrocortisone is used for treatment of these deficiencies.

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 Therapeutic Uses cont’d…

 Relief of inflammatory symptoms

• Rheumatoid arthritis and inflammatory skin conditions

• Persistent asthma (inhalational)

• Osteoarthritis (intra-articular corticosteroids)

• Corticosteroids are not curative in these disorders.

 Treatment of allergies:

• Rx of allergic rhinitis, as well as drug, serum, and transfusion allergic reactions.

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Therapeutic Uses cont’d…

 Acceleration of lung maturation:

• Respiratory distress syndrome is a problem in premature infants.

o Fetal cortisol is a regulator of lung maturation.

• Consequently, a regimen of betamethasone or dexamethasone administered

intramuscularly to the mother within the 48 hours proceeding premature
delivery can accelerate lung maturation in the fetus.

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 Therapeutic Uses cont’d…

Other Uses…
 Glucocorticoids frequently are used to suppress inflammation in the eye and can
preserve sight when used properly.

 Glucocorticoids are valuable in the prevention and treatment of organ transplant

rejection

 Glucocorticoids also exert a facilitatory action on neuromuscular transmission that may

contribute to their efficacy in certain neuromuscular disorders (myasthenia gravis).

 Cerebral edema????

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Table: Common Clinical Indications for Systemic Glucocorticoids
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 Adverse effects
 Adverse effects are often dose and duration of treatment related.
 Osteoporosis (↓ed intestinal Ca2+ absorption, reduced bone formation, and ↓ed sex
hormone synthesis).
 Patients are advised to take calcium and vitamin D supplements; Bisphosphonates may also be
useful in the treatment of glucocorticoid-induced osteoporosis.

 Redistribution of body fat, puffy face, hirsutism, and increased appetite

 Cataracts may also occur with long-term corticosteroid therapy

 Hyperglycemia may develop and lead to diabetes mellitus.

 Topical therapy can also cause skin atrophy, ecchymosis, and purple striae.
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High-dose, long-term glucocorticoid therapy can produce a constellation of severe
toxicities

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Fig: Symptoms of Cushing's Syndrome, or chronic systemic effects of elevated glucocorticoids 37
 Discontinuation of glucocorticoids
 Sudden discontinuation of these drugs can be a serious problem if the patient has
suppression of the HPA axis.

 In this case, abrupt removal of corticosteroids causes acute adrenal insufficiency

that can be fatal.

This risk, coupled with the possibility that withdrawal might cause an
exacerbation of the disease, means that the dose must be tapered slowly
according to individual tolerance. The patient must be monitored carefully.

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 Secondary Adrenal Insufficiency

• Several weeks of exogenous glucocorticoid therapy are typically required for

development of adrenal insufficiency

• Longer-acting glucocorticoids, and higher doses of systemic glucocorticoids (vs topical

or inhaled formulations) have been associated with a higher risk of developing adrenal
suppression.

• There are no current evidence-based guidelines regarding the optimal method for
discontinuing glucocorticoid therapy, although gradual tapering of dosages over a
period of weeks to months, prior to complete discontinuation, is recommended to
allow time for recovery of the hypothalamic-pituitary-adrenal axis

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 Secondary Adrenal Insufficiency

• Signs and symptoms of secondary adrenal insufficiency that result from a

sudden withdrawal of glucocorticoids in the presence of HPA axis
suppression are typically similar to those seen with Addison's disease, but
don't include changes in skin pigmentation (because ACTH secretion is not
increased), or significant electrolyte disturbances (because aldosterone is
regulated by the renin angiotensin system rather than ACTH).

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Figure 5. Secondary adrenal insufficiency caused by chronic glucocorticoid (GC) therapy 41
 Inhibitors of ACTH Secretion

• Pasireotide: somatostatin analogue (used in the treatment of acromegaly)

• It inhibits ACTH secretion and reduces the circulating levels of cortisol in patients with ACTH-

producing pituitary tumors

• Used in those patients with Cushing disease who are not candidates for surgery or who have

recurrent disease.

• Rx improves signs and symptoms of hypercortisolism, including blood pressure, low-density

lipoprotein cholesterol, and body mass index.

• Adverse effects include hyperglycemia, gallstones, and transient GI discomfort

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 Inhibitors of ACTH Secretion

• Cabergoline: long-acting dopamine D2 receptor agonist (Used primarily

to treat hyperprolactinemia).
• It also inhibits ACTH secretion from corticotroph tumors, which are often D2 receptor

positive.

• Several small studies have shown that 37% of patients with recurrent Cushing disease

achieve normal levels of free urinary cortisol when treated with cabergoline.

• FDA has not yet approved cabergoline for this use.

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 Inhibitors of Steroidogenesis
• Ketoconazole: an antifungal agent

• MOA: inhibits the activity of CYP17 (17α-hydroxylase) (In doses higher)

• At even higher doses, ketoconazole also inhibits CYP11A1

• An effective inhibitor of steroid hormone biosynthesis in patients with

hypercortisolism (although the FDA has not approved use for this indication, 2018).

• Side effects: hepatic dysfunction with the possibility of severe hepatic injury.

• Inhibit P-glycoprotein and CYP3A4 can lead to serious drug interactions

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 Inhibitors of Steroidogenesis

 Metyrapone
Metyrapone is a relatively selective inhibitor of CYP11B1 and thus inhibits the
conversion of 11-deoxycortisol to cortisol, thereby reducing cortisol
production

Metyrapone has been used off label to treat the hypercortisolism resulting

from either adrenal neoplasms or tumors ectopically producing ACTH.

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 Inhibitors of Steroidogenesis
 Etomidate: used primarily as an anesthetic agent and sedative, inhibits cortisol secretion at
subhypnotic doses primarily by inhibiting CYP11B1 activity.
• Etomidate has been used off label to treat hypercortisolism when rapid control is required in a patient who
cannot take medication by the oral route.

 Mitotane: is an adrenocorticolytic agent used to treat inoperable adrenocortical carcinoma.

• Its cytolytic action is due to its metabolic conversion to a reactive acyl chloride by adrenal mitochondrial
CYPs and subsequent reactivity with cellular proteins.

• It also inhibits CYP11A1: reducing steroid synthesis

• Its onset of action takes weeks to months, and GI disturbances and ataxia are its major toxicities.

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 Glucocorticoid Antagonist
• Mechanism of Action:
• A potent progesterone receptor antagonist.
• It also acts as a glucocorticoid receptor antagonist, and has occasionally been used in
refractory Cushing's syndrome

• Indications:
• Termination of Pregnancy (used in combination with misoprostol).
• Approved for the control of hyperglycemia associated with Cushing's (in patients who
have failed surgical treatment, or cannot have surgery).

• Side Effects: vaginal bleeding & infections

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 Mineralocorticoid antagonists

 Spironolactone: aldosterone antagonist (diuretic)

It is used in the treatment of primary aldosteronism

Spironolactone is also an androgen antagonist and as such is sometimes used

in the treatment of hirsutism and acne in women.

Eplerenone, another aldosterone antagonist, is approved for the treatment of

hypertension and heart failure

Drospirenone, a progestin, is an oral contraceptive, and also antagonizes the

effects of aldosterone

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Thank you
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