ADRENAL STEROIDS Introduction

Loretta Walker, PhDADRENAL STEROIDSReading:Rang & Dale’s Pharmacology, 6 th Edition, Chapter 28. (ignore ADH)Objectives:1. To understand the physiological role of corticotropin (ACTH)2. To know the actions and uses of the natural and syntheticcorticosteroids3. To know the physiological action of the mineralocorticoidsDRUGSCortisol Cortisone Fludrocortisone FluticasoneCorticosterone Prednisone Triamcinolone SpironolactoneDexamethasone BetamethasoneIntroductionThe corticosteroids are cholesterol-derived endocrine hormonessynthesized and secreted from the adrenal cortex. There are two major classesof corticosteroids:GlucocorticoidsMineralocorticoids[Weak androgens are also secreted from the adrenals, but will not beconsidered here]The range of physiological effects of the glucocorticoids is remarkably diverse andwidespread. Among others, they include effects on carbohydrate, protein and lipidmetabolism, the stress response, aspects of nervous system and cardiovascularfunction, skeletal muscle and, notably, the immune system. Mineralocorticoids, onthe other hand, have strictly defined functions, namely to regulate plasma (andhence extracellular) sodium and potassium levels. In either case, thecorticosteroids are essential to life-sustaining biological systems and,consequently, their synthesis and secretion are tightly regulated via thehypothalamic-pituitary-adrenal axis (see below).

Parenteral introduction of exogenous corticosteroids for therapeutic purposeswill, within days, alter the delicate balance of this axis, leading to generalizedadrenal suppression. Chronic systemic treatment with corticosteroids musttherefore be performed under carefully controlled conditions while simultaneouslymonitoring individuals for appearance of deleterious side effects. Cessation oftreatment must be done gradually, as recovery of the hypothalamic-pituitaryadrenalbalance may take more than a year. [Abrupt cessation of chronic therapycan actually be fatal.]ACTHAdrenocorticotropic hormone (ACTH; corticotropin) is a 39 amino acidpeptide secreted from the anterior pituitary in response to corticotropin-releasinghormone (CRH) released from the endocrine hypothalamus. ACTH stimulates theadrenal cortex to synthesize and secrete glucocorticoids and mineralocorticoids.Glucocorticoids inhibit in a dose-dependent manner (negative feedback) thesecretion of both CRH and ACTH, thus tightly regulating their systemic levels (seefigure). These hormonal interactions constitute what is referred to as thehypothalamic-pituitary-adrenal axis (HPA)ACTH is also essential for maintaining the structural integrity of theadrenal cortex. Excess ACTH will cause adrenal hyperplasia and hypertrophy,leading to overproduction of corticosteroids, whereas with abnormally low ACTH,the opposite occurs.Because treatment with selective natural or synthetic corticosteroids willachieve any and all therapeutic effects (eg. treat adrenal insufficiency in Addison’sdisease) without the added problem of excessive aldosterone secretion, use ofACTH in the clinical setting is limited to a diagnostic test of corticosteroidinsufficiency under stress conditions (actually using a synthetic analog:cosyntropin).The GlucocorticoidsThe glucocorticoids are synthesized from cholesterol in a series ofreactions carried out in the zona fasciculata of the adrenal cortex via distinctP450 enzymes.

Endogenous:- In humans, the resultant major glucocorticoid is cortisol (hydrocortisone)- In many other mammals (eg. rodents) corticosterone is usually the majorglucocorticoid.Both are extensively bound to plasma proteins (corticosterone less so) andhave fairly short durations of action (8-12 h).Synthetic: (examples)Short-acting (8-12h) Intermediate (12-36h) Long-acting (36-72h)Cortisone Prednisone DexamethasoneFludrocortisone* Triamcinolone Betamethasone*significant mineralocorticoid activity in addition to glucocorticoid activity(see below)Mechanism of action: activate heteromeric receptors (see figure) residentin the cytoplasm of cells, the ligand binding component of which dimerizesand translocates to the nucleus and, in turn, activates the glucocorticoidresponse element (GRE) present on certain genes, leading to altered geneexpression (positive and negative)Physiological effects:Many ‘permissive’ effects - profound alteration in absence of glucocorticoid,but minimal change with increases over normal levels.Example: diminished responsiveness of vascular smooth muscle tocatecholamines in the absence of circulating cortisol; little effect ofsupranormal levels of cortisol (though secondary hypertension may resultfrom mineralocorticoid action of supraphysiological levels of glucocorticoids)Metabolic effects:o stimulate gluconeogenesis when fastingo increase glucose production from proteino increase lipolysis (counteracted by increased insulin secretion, whichstimulates lipogenesis)o stimulate RNA and protein synthesis in the liver

Anti-inflammatory and immunosuppressive effects:leukocyte number and prostaglandin production:- greatly reduced inflammatory responseslymphocyte (interleukin-2 production) and macrophage function:- greatly reduced immune response[antibody production is usually unaffected at low to moderate doses of glucocorticoids]Supraphysiological levels (as during chronic therapy) can leadto: dramatic fat redistribution to trunk and face; weight gain thinning of skin hyperglycemia (potentially converting to diabetes, though usuallymanageable) osteoporosis - major limitation in long-term therapy immune suppression increased susceptibility to infection hypertension (secondary to aldosteronism; usually manageable) growth retardation in children increased risk of peptic ulcers acne and hirsutismwith large doses: cataracts (children particularly at risk) myopathy; muscle wasting (more evident in Cushing’s) nervous; sometimes overt psychosis (high doses) sodium retention with concomitant fluid retention and potassium loss generalized adrenal suppression[with exemption of the last item: all of these effects are component to what is referredto as Cushing’s syndrome]

Uses:1.Treatment of altered adrenal function:Insufficiency (= Addison’s disease): treat with cortisolchronic: treatable with daily dosingacute: life-threatening immediate IV treatment a mustHyperplasia (= defective corticosteroid synthesis, resulting in excessACTH release; hence overgrowth of adrenal cortex)- if risk of congenital hyperplasia: treat mother with dexamethasoneFor all conditions of insufficiency: salt-retaining hormone must alsobe given (eg. fludrocortisone)Excess (= Cushing’s disease; usually results from pituitaryadenoma overproducing ACTH): treatment is usually surgeryduring and following surgery, cortisol must be given as abovefor replacement therapy2. Treatment of non-endocrine diseasesAnti-inflammatory systemic or organ:• systemic lupus erythrematosus (autoimmune collagendisease characterized by inflammation of the skin)• vasculitis (inflamed blood vessels)• GI inflammation (eg. Crohn’s disease)• kidney inflammation (glomerular nephritis)• severe rheumatoid arthritis (short-term treatment only)• as a rule, use intermediate-acting glucocorticoids:typically prednisone under ‘alternate-day’ therapylocal:o variety of inflammatory skin conditions (eg. rashes,etc.) readily treated topically using hydrocortisoneo nasopharygeal inflammation treated using topicalssuch as fluticasoneAllergies:o Only for non-life-threatening allergic reactions of limitedduration (eg. edema)

Asthma:Inhaled glucocorticoids (eg. triamcinolone; fluticasone) arepreferred to limit systemic effectsTransplantation:Effective immune suppression achieved in conjunction withother immunosuppressive agents prednisone usually usedbefore, during and, at lower doses, afterSpinal cord injury:Recent use in high doses just following the injury, likely toprotect against free-radical damageCerebral edema:Dexamethasone used following brain surgery to reduce edemaEye diseases:o Uveitis (inflamed iris) is treated with topicaladminstration of dexamethasoneo Optic neuritis (inflamed optic nerve) treated systemicallywith prednisoneFetal lung maturation:With risk of premature delivery, mothers may be givenbetamethasone (lower protein binding allows for betterplacental transfer) to stimulate lung maturation

MineralocorticoidsAldosterone is also synthesized from cholesterol in the adrenal cortex , butin different cells (zona glomerulosa) than those that produce glucocorticoids and,consequently, it is not controlled by ACTH. Its synthesis and release from theadrenal cortex are largely regulated by extracellular K + levels and, most notably,angiotensin II.Mechanism of action: act on distinct mineralocorticoid receptors residentin cytoplasm of distal tubule cells in the kidney, resulting in signaling similarto that found for the glucocorticoid receptorPhysiological effects:promotes reabsorption of sodium in the distal tubule (and ‘collecting’ ducts)of the kidney, leading to increase water retention (osmotic effect) andhence in an increased internal volumepromotes potassium and hydrogen secretion in the distal tubulesUses:1. Treatment of aldosterone insufficiency: fludrocortisone2. Treatment of aldosterone excess: primary hyperaldosteronism(Conn’s syndrome: rare; usually the result of an adrenal adenoma, butalso ACTH excess = pituitary tumor) or secondary hyperaldosteronism(from congestive heart failure; nephrotic syndrome)spironolactone = mineralocorticoid receptor antagonist (ie. blocksaldosterone action in the distal tubule)Read more about it: http://www.webmd.com/a-to-z-guides/Aldosterone[Modified after notes prepared by: Robert A. Nichols, Ph.D.]

HypothalamusCRHinhibitPituitaryHPA:ACTHinhibitAdrenal CortexGlucocorticoids

SCBGSCBGSGRHSP HSPSSGR*GR*HSP HSPS SGR * GR *GREgenemRNAprotein