Download Pharm of the Adrenal Cortex

Pharm Ch. 28: Pharm of the Adrenal Cortex
Intro
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Outer adrenal cortex – mesoderm
o Steroid hormones essential for salt balance, intermediary metabolism, androgenic actions
(females)
Inner adrenal medulla – neural crest cells
o Catecholamine epinephrine
Glucocorticoid analogues – efficacious and potent anti-inflammatory agents
Overview of the Adrenal Cortex
 Synthesizes 3 classes of hormones:
o Mineralocorticoids
o Glucocorticoids
o Androgens
 Divided into 3 zones:
o Zona glomerulosa – mineralocorticoid production
 Regulated by Angiotensin II, blood [K+], ACTH –
but to a much lesser extent
o Zona fasciculata
 Regulated by ACTH, which is regulated by CRH,
vasopressin, cortisol
o Zona reticularis
 Regulated by ACTH, which is regulated by CRH,
vasopressin, cortisol
Glucocorticoids
Physiology
Synthesis
 Cortisol – endogenous glucocorticoid, synthesized from
cholesterol
 RLS: conversion of cholesterol  pregnenolone; 27-C
cholesterol converted to 21-C precursor common to al
adrenocortical hormones; steroid metabolism can proceeds
down 3 different pathways to make mineralocorticoids,
glucocorticoids, or androgens
 Oxidase enzyme catalyzes each step, they are mitochondrial
cytochromes, similar to cP450s in the liver\
 Tissue specific expression different oxidase enzymes is the
reason for differences among the hormonal end products of
the different zones of the cortex
o Ex: zona fasciculata synthesizes cortisol, but not
aldosterone or androgens bc enzymes required
uniquely for cortisol synthesis (11β-hydroxylase)
are expressed in ZF
 ZG does not express 17α-hydroxylase
required for cortisol and androgen
production, but not for aldosterone
production
Metabolism
 90% circulating cortisol bound to plasma proteins: corticotropin-binding globulin (CBG, aka transcortin)
and albumin
o CBG – high affinity for cortisol, low capacity
o Albumin – low affinity for cortisol, high capacity
 Only unbound molecules are bioavailable – aka able to diffuse through plasma membranes into cells
o Affinity/capacity regulate availability of active hormone
 Liver and kidney – primary sites of peripheral cortisol metabolism
o
Liver: reduction and conjugation to glucuronic acid, liver
inactivates cortisol in the plasma; conjugation makes
cortisol more wate soluble and enables renal excretion
o Liver and kidneys express different isoforms of the 11βhydroxysteroid dehydrogenase (regulates cortisol
activity); two isoforms catalyze opposing reactions
 Kidney: 11β-HSD 2 converts cortisol to
cortisone (inactive, can’t bind
mineralocorticoid receptor); 11β-HSD 2
protects the mineralocorticoid receptor from
activation by cortisol in many cell types
(endothelial cells, vascular smooth muscle
cells)
 Liver: 11β-HSD 1 converts cortisone back into cortisol (aka hydrocortisone)
 These opposing reactions determine overall glucocorticoid activity
Physiologic Actions
 Cortisol diffused through plasma membrane and binds to cytosolic receptor
 2 types of glucocorticoid receptors
o Type I glucocorticoid (synonymous with mineralocorticoid receptor)
 Expressed in organs of excretion (idney, colon, salivary glands, sweat glands) and other
tissues – hippocampus, vasculature, heart, adipose tissue, peripheral blood cells
o Type II glucocorticoid
 Broader tissue distribution
 Cortisol binds to cytosolic receptor and forms hormone-receptor complex, transported to nucleus
o Dimerized hormone-receptor complex binds to gene promoter elements (aka glucocorticoid
response elements – GREs), which either enhance/inhibit expression of certain genes
o Cortisol – profound effect on mRNA expression; about 10% all human genes have GRE  cortisol
has an physiologic actions in most tissues, actions are usually metabolic and anti-inflammatory
 Metabolic effects of increased cortisol increase nutrient availability by raising blood glucose, amino acid
and TG levels
o Increased blood glucose by antagonizing insulin action and promoting gluconeogenesis in fasting
state
o Increases muscle catabolism  release of amino acids that can be utilized by liver for
gluconeogenesis
o Cortisol potentiates GH action on adipocytes  increases action of hormone sensitive lipase and
subsequent release of FFAs (lipolysis); FFAs further increase insulin resistance
o Cortisol levels increase as a component of stress responses
 By elevating blood glucose, physiologic effects of glucocorticoids maintain energy
homeostasis during the stress response, ensuring critical organs (brain) continue to
receive nutrients
 Cortisol – multiple anti-inflammatory effects
o Negatively regulates cytokine release from cells of
the immune system by inhibiting nuclear factor κΒ
(NF-κΒ)
o Some cytokines (IL-1, Il-2, Il-6, TNF-α) can
stimulate hypothalamic release of CRH, which
stimulates ACTH and cortisol release
 Creates feedback loop in which
inflammatory cytokines and cortisol are
coordinately regulated to control immune
and inflammatory responses
o Glucocorticoid-mediated immune suppression
applications: organ transplantation, RA, asthma
 Asthma: thought to reduce inflammation
in airways, exact mechanism unknown
Regulation
 Hypothalamic-pituitary unit coordinates production of cortisol
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In response to central circadian rhythms and stress, paraventricular nucleus of hypothalamus synthesizes
and secretes CRH (peptide hormone)
 CRH travels through hypothalamic-pituitary portal system to bind to G protein-coupled receptors on the
surface of corticotroph cells in AP
 CRH binding stimulates corticotrophs to synthesize POMC, precursor polypeptide
 Neurons in PV nucleus that release vasopressin, released together into hypothalamic-pituitary portal
system with CRH, synergizes to increase release of ACTH by AP
 POMC cleaved to produce ACTH, MSH, lipotropin, β-endorphin
o Similarities btwn MSH and SCTH peptide sequences, high [ACTH] can also bind and activate MSH
receptors  skin pigmentation (becomes apparent in primary hypoadrenalism)
o Lipotropin  lipolysis (probably)
o Β-endorphin  endogenous opioid important in pain modulation, regulation of reproductive
physiology
 ACTH regulates cortisol production (adrenal gland does not store very much cortisol) by promoting
synthesis of hormone
 ACTH – trophic effect on zona fasciculate and zona reticularis, hypertrophy of the cortex can occur in
response to chronically elevated ACTH
 Hormone (cortisol) produced by target organ (adrenal cortex) exerte negative FB regulation at the level of
BOTH hypothalamus and AP gland
o High cortisol levels decrease both synthesis and release of CRH and ACTH
 Absent ACTH  atrophy of cortisol producing zona fasciculata and androgen producing zona reticularis
o Aldosterone producing zona glomerulosa cells continue to function w/o ACTH bc angiotensin II
and blood [K+] continue to stimulate production
Pathophysio
Adrenal Insufficiency
 Addison’s – primary adrenal insufficiency
o Adrenal cortex selectively destroyed, T-cell mediated autoimmune rxn (commonly); also
infection, infiltration, cancer, hemorrhage
o Decreased synthesis of all adrenocortical hormones (cortex destroyed)
 Secondary adrenal insufficiency – hypothalamic or pituitary disorders; or prolonged administration of
exogenous glucocorticoids
o Decreased ACTH  decreased synthesis of sex homrones and cortisol; aldosterone not altered
 Adrenal insufficiency can be life threatening in the setting of stress
 Symptoms: fatigue, loss of appetite, weight loss, dizziness on standing, nausea
 Hyperkalemia commn due to lack of aldosterone
 If result of high/prolonged therapy with exogenous glucocorticoids: must taper dose slowly to allow
hypothalamic-pituitary-adrenal (HPA) axis to regain full activity (can take up to one year)
Glucocorticoid Excess
 Cushing’s Syndrome – increased cortisol production
 Cushing’s Disease – ACTH-secreting pituitary adenoma that lead to increased cortisol production
 Other causes of syndrome: ectopic secretion of ACTH (SCLC) and ectopic CRH production; also from
cortisol-secreting tumors of the adrenal cortex
 Iatrogenic Cushing’s syndrome by far the most common cause!
 Clinical features: overstimulation of target organs – centripetal adipose redistribution, HTN, proximal limb
myopathy, osteoporosis, immunosuppression, diabetes mellitus; all reflect amplified normal physiological
actions of glucocorticoids
 Endogenous Cushing’s syndrome: cortisol-mediated activation of mineralocorticoid receptors  volume
expansion, HTN, hypokalemia
Pharm Classes and Agents
Cortisol and Glucocorticoid Analogues
 Drug therapy w/glucocorticoids indicated for 2 main reasons:
o 1. Exogenous glucocorticoids can be used as replacement therapy in adrenal insufficiency; goal is
to administer physiologic dose to ameliorate effects of adrenal insufficiency
o 2. Given at pharmacologic doses to suppress inflammation and immune responses in disorders
(asthma, RA, organ rejection) – most common
Structure and Potency
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Cortisone (carbonyl group at 11 carbon) is an inactive prodrug until converted by the liver to active drug
cortisol (-OH group at 11 carbon); liver enzyme 11β-HSD reduces cortisone to cortisol
Skin does not possess 11β-HSD
Try to give pts with liver function problems the active version of the drug bc they might not be able to
convert the prodrug into the active form
Cortisol backbone essential for glucocorticoid activity, all synthetic glucocorticoids are analogues of the
endogenous glucocorticoid cortisol
Clinically, it’s important to be aware of the potency of each agent relative to cortisol, especially when
considering a change from one analogue to another that has different relative glucocorticoid and
mineralocorticoid activity
o Prednisolone – 4-5x potent anti-inflammatory potency of cortisol
o Methylprednisolone – 5-6x anti-inflammatory potency of cortisol
o Dexamethasone – 18x glucocorticoid activity, no mineralocorticoid activity
Generally, glucocorticoids used at pharm doses should have minimal mineralocorticoid activity to
minimize effects of mineralocorticoid excess (hypokalemia, volume expansion, HTN)
Duration of Action
 Depends on:
o Fraction of drug bound to plasma proteins, only free steroid is metabolized, extend of binding
determines drug’s duration of action
o Affinity of drug fro 11β-HSD 2, lower affinity  longer plasma galf-life bc they are not turned into
active metabolites immediately
o Lipophilicity of the drug – increased lipophilicty partitions drug into adipose  decreased drug
metabolism and excretion  extended half life
o Affinity of drug for glucocorticoid receptor, increased affinity  increased duration of action bc
drug bound to receptor continually exerts its effect
 Generally, glucocorticoid agents with a higher anti-inflammatory (glucocorticoid) potency have a longer
duration of action
Replacement Therapy
 Treatment of primary adrenal insufficiency – aimed at replacing both glucocorticoids and
mineralocorticoids; oral hydrocortisone is the glucocorticoids of choice; bc therapy must continue for life,
goal: deliver the smallest amount possible of effective dose; pts with primary adrenal insufficiency may
also require mineralocorticoid replacement
 Treatment of secondary adrenal insufficiently – only need to be treated w/glucocorticoid replacement
therapy bc mineralocorticoid production is preserved by the renin-angiotensin system
Pharmacologic Dosing
 Pharmacologic levels of glucocorticoids inhibit cytokine release  decreasing IL-1, IL-2, IL-6, and TNF-α
action, local regulation of cytokine release is crucial for leukocyte recruitment/activation, disruption of
this process profoundly inhibits immune function
 Glucocorticoids also block synthesis of arachadonic acid metabolites by inhibiting action of phospholipase
A2 – arachadonic acid metabolites (thromboxanes, prostaglandins, leukotrienes) mediate early
inflammatory steps (vascular permeability, platelet aggregation, vasoconstriction0
 Insulin resistance and increased plasma glucose concentration necessitate increased pancreatic β-cell
production of insulin to normalize blood glucose  diabetes mellitus is a common complication of longterm glucocorticoid administration
 Glucocorticoid inhibition of Vit-D-mediated Ca2+ absorption  secondary hypoparathyroidism 
increased bone resorption; glucocorticoids also directly suppress osteoblast function; these 2 mechanisms
contribute to bone loss  long term glucocorticoid therapy  osteoporosis
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Steroid induced bone resorption can be prevented with bisphosphonates (inhibit osteoblasts)
Chronic administration of glucocorticoid can slow linear bone growth in children  growth
retardation
 Pharmacologic dosing of glucocorticoids can cause atrophy of fast twitch muscle fibers  catabolism and
weakness of proximal muscles
 Glucocorticoids can also cause: redistribution of fat, peripheral wasting of adipose stores, and central
obesity; buffalo hump, moon facies
 Withdrawal from glucocorticoid treatment – long term glucocorticoid therapy suppresses release of CRH
and ACTH  atrophy of adrenal cortex
o Abrupt cessation of glucocorticoid treatment  acute adrenal insufficiency
o Months are required to reactivate HPA axis and more time may be needed for atrophied adrenal
cortex to begin secreting physiologic levels of cortisol
o Underlying inflammatory disease can worsen at this time
o Chronic glucocorticoid therapy must be tapered slowly with gradually decreasing doses
Routes of administration
 Glucocorticoids can be administered locally at many times the normal plasma concentration, whilie
minimizing systemic effects; ex: inhaled, cutaneous, depot, pregnancy (placenta is selectively targeted)
 Inhaled: DOC – asthma
o Goal: maximize topical-to-system ratio of glucocorticoid concentration
o Safer for long term dosing (kids)
o Fluticasone, beclomethasone, flunisolide, triamcinolone
o If pt being treated with systemic glucocorticoids is switched to inhaled glucocorticoids, can’t stop
systemic dosing abruptly (adrenal insufficiency)
o Inhaled doses deliver 20% to the lungs, 80% swallowed, first-pass hepatic metabolism inactivates
so less than 1% swallowed glucocorticoids is available systemically
o Oropharyngeal candidiasis – potential local complication, local immunosuppression permits
opportunistic infection, can be avoided by rinsing with water after each administration of by
using antifungal mouthwash
o Intransasal administration of glucocorticoids superior to antihistamines in treatment of allergic
rhinitis
 Cutaneous Glucocorticoids – glucocorticoid given must be biologically active, skin doesn’t have 11β-HSD 1
enzyme to convert prodrugs to active compounds
o Hydrocortisone, methylprednisolone, dexamethasone
 Depot Glucocorticoids
o Commonly methylprednisolone for intra-articular administration (inflammatory joint diseases)
o Good for gout attacks unresponsive to colchicine or indomethacin
o Joints lack 11β-HSD 1
 Pregnancy – placenta metabolically separates fetus from mother, prednisone can be given w/o fetal side
effects
o Maternal liver activates prednisone to prednisolone but placental 11β-HSD 2 converts it back into
inactive prednisone, fetal liver does not function during fetal life, so it doesn’t convert the drug
into active prednisolone
o Glucocorticoids given to promote lung maturity, dexamethasone is a poor substrate for 11β-HSD
2 and can cross placenta and enter fetal circulation
Inhibitors of Adrenocortical Hormone Synthesis
 Enzymes necessary for adrenal hormone synthesis are P450s,
inhibitors associated with potential toxicity to hepatic P450
enzymes
 Early step inhibitors: mitotane, aminoglutethimide, ketoconazole
o Mitotane – structural analogue of DDT toxic to
adrenocortical mitochondria; indications: medical
adrenalectomy in severe Cushing’s disease or
adrenalcortical CA; pts develop hypercholesterolemia bc
of concomitant inhibition of cholesterol oxidase
o Aminoglutethimide – inhibits aromatase, important for
conversion of androgens to estrogens, also effect
therapy for breast cancer (not used for this purpose bc
lacks specificity of other drugs)
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Ketoconazole – antifungal that inhibits fungal P450s; high doses of ketoconazole also suppress
gonadal and adrenal steroid synthesis (P450s in same family as fungal); inhibiton of 17,20-lyase
 broad inhibition effects on adrenocortical hormone synthesis
 Metyrapone and trilostane – more selective effects, later step inhibitors
o Metyrapone – inhibits 11β hydroxylation, resulting in impaired cortisol and aldosterone
synthesis; used as a diagnostic drug to test hypothalamic and pituitary response to decreased
circulating hormone levels
o Trilostane – reversible inhibitor of 3β-hydroxysteroid dehydrogenase, reduces cortisol
production in the adrenal cortex and is used to treat Cushing’s disease in dogs, not approved to
use in humans
Glucocorticoid Receptor Antagonists
 Mifepristone (RU-486) – progesterone receptor antagonist used to induce abortion in early pregnancy
 Higher concentrations also block glucocorticoid receptor, useful for treating life-threatening elevated
glucocorticoid levels (ectopic ACTH syndrome)
Mineralocorticoids
Physio
Synthesis
 Aldosterone – 21-C steroid hormone derived form cholesterol
 Enzymes unique to aldosterone synthesis only expressed in zona glomerulosa
 Secretion stimulated by angiotensin II, blood [K+], and ACTH
Metabolism
 Circulating aldosterone binds w/low affinity to transcortin (aka corticotropin binding globulin), and a
specific mineralocorticoid binding protein
o 50-60% of circulating aldosterone is bound to transport proteins, elimination half-life: 20 minutes
o orally administered aldosterone – high first pass hepatic metabolism; 75% metabolized to
inactive form during each pass; orally administered aldosterone not effective replacement
therapy for adrenal insufficient states
Physiologic Actions
 Circulating aldosterone diffuses across plasma membrane and binds to a cytosolic mineralocorticoid
receptor (synonymous with Type I glucocorticoid receptor)
 Aldosterone:mineralocorticoid receptor complex transported across nucleus (transcriptional effects); also
effects on intracellular signaling pathways – non-genomic actions mediated by hormone binding
mineralocorticoid receptors on cell surface
 Kidney: aldosterone increases Na+/K+ ATPase in basolateral membrane of distal nephron cells 
secondarily increases Na+ reabsorption and K+ secretion
o Na+ retention, K+ excretion, and H+ excretion all enhanced by aldosterone
o Increased Na+ retention – accompanied by increased H20 retention  extracellular volume
expansion
 Excess aldosterone: hypokalemic alkalosis and HTN
 Hypoaldosteronism: hyperkalemic acidosis and hypotension
 Mineralcorticoid receptor expressed in cells not involved in Na+ reabsorption: endothelial cells, vascular
smooth m. cells, cardiomyocytes, adipocytes, neurons, inflammatory cells
 Activation of mineralocorticoid receptor increases oxidative stress, promotes inflammation, regulates
adipocyte differentiation, and reduces insulin sensitivity
o Antagonists of aldosterone action at mineralocorticoid receptor (spironolactone, eplerenone)
reduce morbidity and mortality in HF, improve vascular function, reduce cardiac hypertrophy,
and reduce albuminuria
 Beneficial effects of mineralocorticoid blockade independent of changes in BP
Regulation
 3 systems regulate aldosterone synthesis:
o renin-angiotensin-aldosterone system – central regulator of ECF volume; decreases in ECF
volume decreased perfusion pressure at afferent arteriole of glomerulus  stimulates JG cells to
secrete renin  Angiotensin I  Angiotensin II  aldosterone synthesis by binding of
angiotensin II to GPCR in ZG cells
o Potassium loading increases aldosterone synthesis independent of renin activity
o
ACTH acutely stimulates aldosterone synthesis in the zona glomerulosa, aldosterone does not
negatively regulate ACTH secretion
Pathophysio
Aldosterone Hypofunction
 Result from a primary decrease in aldosterone synthesis or action, or secondary decrease (ex angiotensin
II), most result from decrease in aldosterone synthesis
 Defects in gene coding for 21-hydroxylase  CAH and salt wasting
 Addison’s disease (primary adrenal insufficiency)  hypoaldosteronism secondary to destruction of ZG
(usually form autoimmune adrenalitis)
 Aldosterone hypofunction  salt wastin, hyperkalemia, acidosis volume depletion; also decreased renin
production (hyporeninemic hypoaldosteronism – common in diabetic renal insufficiency)
 Both resistance to action of aldosterone at the level of the mineralcorticoid receptor and inactivating
mutations of ENaC in the cortical collecting duct of the nephron result in clinical hypoaldosteronism,
despite normal aldosterone levels in the blood
Aldosterone Hyperfunction
 Primary hyperaldosteronism from excess production by the adrenal cortex
 Bilateral zona glomerulosa adrenal hyperplasia and an aldosterone-producing adenoma are the 2 most
common causes
 Increased aldosterone synthesis  positive Na+ balance w/extracellular volume expansion, suppression
of plasma renin activity, K+ wasting and hypokalemia, and HTN
 Independent of its effects on BP, hyperaldosteronism also has adverse CV effects: endothelial dysfxn,
increased intima-media thickness, vascular stiffness, and left ventricular hypertrophy; also a cause of
insulin resistance
Pharm Classes and Agents
Mineralocorticoid Receptor Agonists
 Hypoaldosteronism requires replacement of physiologic dose of mineralocorticoid, can’t give aldosterone
– liver converts +75% to inactive metabolite on first-pass
o Cortisol analogue fludrocortisone is used, minimal first-pass hepatic metabolism
o Adverse effects from drug’s inability to mimic a state of mineralocorticoid excess (HTN,
hypokalemia, cardiac failure), must monitor pt serum K+ and BP
Mineralocorticoid Receptor Antagonists
 Spironolactone – competitive mineralocorticoid receptor antagonist, but also binds to progesterone and
androgen receptors (resulting in gynecomastia – limits pt compliance)
 Eplerenone – mineralocorticoid receptor antagonist that binds selectively to mineralocorticoid receptor
 Both spironolactone and eplerenone used as antihypertensive agents, both approved for pts with HF
 Antagonism of mineralocorticoid receptor can cause significant hypokalemia and most pts with HF are
also on ACE inhibitors (which also raise blood K+), must monitor serum K+ in pts taking these drugs
Adrenal Androgens
Physio
 Sex steroids produced by adrenal cortex (DHEA)
uncertain role in physio
 DHEA – probably a prohormone that is converted into
more potent androgens (primarily testosterone) in the
periphery
 Adrenocortical androgens – important source of
testosterone in females ; necessary for development of
axillary and pubic hair @ puberty when adrenal androgen
secretion is activated (adrenarche)
Pathophysio
 Congenital adrenal hyperplasia (CAH) and polycystic
ovarian syndrome both related to adrenal androgen
production
o CAH – clinical term denoting multiple inherited
enzyme deficiencies in adrenal cortex; enzyme
defects  increased adrenocortical androgen
production (hirsutism and virilization – females)
o PCOS – may be caused by CAH in a subset of pts
Most common from of CAH – steroid 21-hydroxylase deficiency  inability of adrenocortical cells to
synthesize both aldosterone and cortisol
o Cortisol – main negative FB regulator of ACTH release, increased ACTH  shunting  increased
production of DHEA and androstenedione
o Liver converts these compounds to testosterone
 Infants w/severe 21-hydroxylase deficiency commonly diagnosed in infancy during an acute salt wasting
crisis (results form the inability to synthesize aldosterone and cortisol)
 Mild 21-hydroxylase deficiency  hirsutism, acne, oligomenorrhea (young women)
 Treatment of CAH due to severe enzyme defects: physiologic replacement of glucocorticoids and
mineralocorticoids
 Treatment of CAH from mild enzyme defects: exogenous glucocorticoid to suppress excessive
hypothalamic and pituitary release of CRH and ACTH
Pharm Classes and Agents
 Anddrogens synthesized by adrenal glands can be views as prohormones
 No specific recepotors for DHEA or androstenedione, so activity of these hormones depends on their
conversion to testosterone (and then to dihydrotestosterone) in peripheral target tissues
 DHEA – commonly OTC; may be indicated in cases of Addison’s disease where there is a bona fide DHEA
deficiency; also abused for anabolic effects
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