Corticosteroids Flashcards
Cortex of the adrenal glands secretes
glucocorticoids, mineralcorticoids, and androgens
Medulla of the adrenal gland secretes
Epinephrine and Norepinephrine
Glucocorticoids
stress hormones; increase circulating glucose concentrations; potent anti-inflammatory effects
Mineralocorticoids
Na+ retention; increase blood volume; increase blood pressure
What controls the synthesis of mineralocorticoids
Renin-angiotensin-aldosterone system
Transport of steroids
transported in plasma by plasma transport proteins
Corticoid-binding globulin (transcortin) transports
glucocorticoids and progesterone
Sex hormone binding globulin (SHBG) transports
testosterone and estradiol
Metabolism of steroids
metabolized in the liver (oxidation, sulfation, and glucuronidation)
Excretion of steroids
excreted in bile (estrogen) or in the urine (progesterone, androge, and glucocorticoids)
Glucocorticoids up-regulate enzymes for
gluconeogenesis and anti-inflammatory proteins
Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes
the rate-limiting step in gluconeogenesis
Lipocortin I suppresses
phospholipase A2, which has a critical role in eicosanoid synthesis
Mechanism of immunosuppression by glucocorticoids
activated glucocorticoid receptor (GR) binds to NFkB and prevents binding of NFkB to its response element; transcription of cytokine genes are repressed
Physiologic effects of glucocorticoids on the liver
Increase gluconeogenesis and glycogen storage
Physiologic effects of glucocorticoids on the muscle
Promote protein degradation; decrease protein synthesis and decrease sensitivity to insulin
Physiologic effects of glucocorticoids on adipose tissue
promote lipolysis and decrease sensitivity to insulin
Physiologic effects of glucocorticoids on the immune system
Block the synthesis of cytokines and inhibits the production of eicosanoids
Addison’s disease
hypoadrenalism; decreased secretion of steroid hormones by the adrenal cortex
Causes of Addison’s disease
- destruction of the cortex by TB or atropy
2. decreased secretion of ACTH due to disease of anterior pituitary
Symptoms of Addison’s disease
Extreme weakness, anorexia, anemia, nausea, vomiting, low blood pressure, hyperpigmentation, mental depression
Cushing’s disease
Hyperadrenalism
Causes of Cushing’s disease
- tumors in the adrenal cortex
- increased production of ACTH due to pituitary carcinoma
- ectopic production of ACTH due to non-pituitary carcinoma
Symptoms of Cushing’s disease
Increased protein catabolism (easy bruising, delayed wound healing, muscle wasting), increased glucose levels, osteoporosis and opportunistic infections
What is Ketoconazole?
antifungal at lower concentration (block the synthesis of ergosterol)
Ketoconazole inhibits
P450scc; 17alpha-hydroxylase, and 11beta-hydroxylase
Ketoconazole can treat
hyperglucocorticoid states (Cushing’s syndrome)
Therapeutic uses of corticosteroids
- Primary adrenal insufficiency caused by atrophy of adrenal cortex
- Allergic reactions
- Inflammation and autoimmune diseases
- Asthma
- Immunosuppressive
- Anti-cancer
What is required for GC activity in glucocorticoids?
4,5-double bond
C3 ketone
11-beta hydroxyl
C17 hydroxyl
What is required for MC activity in mineralcorticoids?
4,5-double bond
C3 ketone
Cortisol versus cortisone
Oxidation of 11 hydroxyl to ketone inactivates glucocorticoids
Cortisone should not be used to treat patients with
impaired liver functions
Short-acting systemic corticosteroids
Hydrocortisone and Cortisone
Intermediate-acting systemic corticosteroids
Prednisone;
Prednisolone;
Methylprednisolone;
Triamcinolone
Long-acting systemic corticosteroids
Dexamethasone and Betamethasone
Fludrocortisone
synthetic glucocorticoid; 9alphaF; greater glucocorticoid activity; strong mineralocorticoid activity; intense Na+ retention/edema; used in mineralocorticoid replacement therapy
Prednisone/prednisolone
extra double bond between C1 and C2; more potent glucocorticoid activity; reduced mineralocorticoid activity; interconvertible by 11beta-hydroxysteroid dehydrogenase
Methylprednisolone
synthetic glucocorticoid; 6alpha-methyl group
Triamcinolone
synthetic glucocorticoid; 9alphaF and 16alphaOH; similar to prednisone; increased hydrophilicity; low oral bioavailability
Dexamethasone
16alpha-methyl group; increased lipophilicity; stronger effect; increased stability; reduced mineralocorticoid activity
Betamethasone
Enantiomer of dexamethasone at 16; similar to dexamethasone
What does changing the hydroxyl group at 21 to an acetate or butyrate do to glucocorticoids?
increased lipophilicity; prolonged action upon IM or intra-articular injection?
What does changing the hydroxyl group at 21 to an succinate do to glucocorticoids?
makes it more soluble; slows hydrolysis
What does changing the hydroxyl group at 21 to a phosphate group do to glucocorticoids?
increased solubility; rapid hydrolysis by phosphatases; IV or IM injection for emergencies
Desired properties of topical glucocorticoids
high lipophilicity for fast absorption; minimal systeic effect; prolonged action
Acetonide or ester glucocorticoids have better potency for topical applications due to
high lipophilicity
Topical glucocorticoids
Tramcinolone acetonide
Betamethasone valerate
Fluticasone propionate
Mometasone furoate
21-chlorocorticoids
Clobetasol propionate
Halobetasol propionate
Halcinonide
Substitution of a chlorine atome for the 21-hydroxyl group does what?
greatly enhances topical anti-inflammatory activity
Desired properties for inhaled glucocorticoids
high potency; minimal systemic effects; prolonged action
Inhaled glucocorticoids
Triamcinolone acetonide Beclomethasone dipropionate Flunisolide Budesonide Mometasone furoate Fluticasone propionate
Adverse effects of corticoids
Crossover mineralocorticoid activity Steroid myopathy Reduced long bone growth in children Osteoporosis Cushing's like effects Impaired glucose tolerance Suppression of immune system GI/CNS Cataracts
What can happen upon withdrawal of corticoids?
Adrenal insufficiency - Addisonian crisis; due to negative feedback on hypothalamus and pituitary from prolonged doses
