Adrenal Corticosteroids
M. Nabeel Ghayur
Assistant Professor of Pharmacology
Learning Objectives
• Describe the role of the hypothalamus, pituitary and adrenal gland in the synthesis of
corticosteroids (CS)
• Recall the physiological effects of CS
• Describe the anti-inflammatory & immunosuppressive effects of glucocorticoids (GC)
• Compare the relative potency, GC/mineralocorticoid (MC) activity, and duration of
action of CS
• List clinical uses and adverse effects of GC & MC and their antagonists
• Describe cautions that can be taken to minimize the adverse effects of long-term
steroid therapy
Mineralocorticoid (MC)
Glucocorticoid (GC)
Hypothalamic-pituitary-adrenal axis (HPA)
Tropic Hormones
Stimulated by ACTH
Pathways in
Adrenocortical
Hormone
Biosynthesis
Corticosteroid
Mechanism of
Action
MSE
ARE
Gene regulation ¯:
• COX-2
• Inflammatory cytokines
----------------------------------------------------------Regulation ­ for Annexin A1 (Lipocortin):
• Inhibits PLA2 (¯ PG, LT)
• Inhibits COX-2
• ­ neutrophil detachment & ¯ penetration
Alter expression of numerous
genes in many tissues!
• Corticosteroids from adrenal cortex
• Glucocorticoids:
o Carbohydrate, fat and protein metabolism
o Immune responses
o Inflammation
• Mineralocorticoids
o Na and K reabsorption from kidneys
Glucocorticoids:
Metabolic Effects
• Glucose:
• Impact on carbohydrate and fat metabolism
leading to increased availability of glucose to
the brain
• Increased gluconeogenesis and reduced
peripheral use of glucose
• Fat:
• Increase in free fatty acids via increased
lipolysis & lipogenesis; appetite stimulation
(CNS)
• Redistribution of fat from the extremities to
the trunk and face (buffalo hump, moon face)
• Loss of fat in extremities
(anta of insulin)
(from aa, fa)
Clinically: hyperglycemia, worsening of DM, dyslipidemia, obesity
Glucocorticoids:
Catabolic Effects
• Protein:
• Protein catabolism results in amino acids
delivery to the liver for gluconeogenesis
• ¯ protein synthesis and ­ degradation
• Muscle wasting affecting muscle and skin
• Wasting: Lymphoid, connective tissue (striae)
• Effect on bones (osteoporosis)
• Inhibition of growth in children
• GC also ¯ absorption & ­ excretion of Ca2+
Clinically: atrophy of lymphoid
tissue, ¯ muscle mass, thin easy-tobruise skin, osteoporosis
Glucocorticoids: Immunosuppressive
& Anti-inflammatory
• Decreases levels of lymphocytes, à ¯ cellmediated immunologic functions (¯ delayed
hypersensitivity reactions)
• Lymphotoxic à use in hematologic cancers
• Glucocorticoids act as anti-inflammatory
• ¯ levels of lymphocytes, eosinophils, basophils,
monocytes; ­ neutrophils (low migration, low
apoptosis, high synthesis à WBCs appear high)
• Due to:
• PLA2 inhibitor Annexin A1
• Low COX2 & cytokines (IL, PAF)
• ¯ fibroblast activity à wound healing
Clinically: Used for immunosuppression,
inflammatory, allergies
• GI:
Glucocorticoids: Other Effects
• ­ gastric acid secretion & ¯ protection from
ulcers, GI bleeds
• ¯ mucous production
• CNS:
• In larger doses: depression, psychosis, mania (?)
(physiologic levels-balances mood)
• ­ Intraocular pressure à glaucoma; cataract
formation (irreversible)
• CV:
• Mineralocorticoid activity à Na+/water ­,
edema, HT, ­ K+ alkalosis, ¯ Ca2+
• Activation of RAS
• ­ vasoactive substances & ¯ vasodilation
Clinically: Ulcers, mood changes, HT, glaucoma
NSAIDs
Glucocorticoids: Therapeutic & Side Effects
Nonadrenal:
Anti-inflammatory: Pain, asthma,
dermatitis, IBD, ocular, RA, lupus, GI
Immunosuppressive: Hematologic
cancers, organ transplantation
Adrenal:
Replacement therapy: Adrenal
insufficiency (Addison’s); insufficiency
in shock, infection, trauma
(Na/water retention,
edema
(Oral thrush)
¯ Wound
healing
¯ Growth)
By: Craig W Clarkson
v Short-term, <2wks, ok
v Avoid long-term (>2wàadrenal
suppression may occur) & ¯ side
effects by:
§ Give short-term & ¯ dose
§ Local use (inj, inhale, topical)
§ Alternate day dosing to ¯
pituitary suppression
§ Stress doses
§ Taper dose as relief achieved
§ Taper slowly (months) for
adrenal function to normalize
Special nasal/inhaled/local GC designed for airway mucosa penetration
with short half-life so as to reduce systemic side effects
Secondary
adrenal
insufficiency by
Glucocorticoids
Use of this axis: Congenital
adrenal hyperplasia - ACTH is
stimulating abnormal steroids
from adrenal, so giving a potent
synthetic GC exogenously would
suppress ACTH secretion and thus
¯ stimulation of adrenal gland
Longer acting or
By: Craig W Clarkson
MONITORING:
• Hyperglycemia
• Sodium retention with edema or hypertension Hypokalemia
• Peptic ulcer (with NSAIDs)
• Osteoporosis
• Infections
CONTRAINDICATIONS:
• Peptic ulcer
• Heart disease or hypertension with heart failure
• Certain infectious illnesses: varicella (warn to avoid exposure)
• Psychoses, diabetes, osteoporosis, or glaucoma
Drug Interactions:
• With other immunomodulators
• Vaccines
• Antacids, space both
• Corticosteroids are CYP substrates, caution with CYP inducers and Inhibitors
Cushing's Syndrome, or chronic
systemic effects of elevated
glucocorticoids
by Mikael Häggström
Tx: reduce dose of GC, use alternate
immunosuppressant, Surgery (if inoperable,
then use antagonists & synthesis inhibitors)
Cushing Syndrome
Metabolic disorder (hyperglycemia, fat
redistribution) of ­ levels/secretion of
adrenal cortex steroids via increased
stimulation by ACTH
•Cataracts in eye
•Ulcers (stomach)
•Skin: thinning, bruising
•Hypertension/hyperglycemia
•Infections
•Necrosis, avascular necrosis of
the femoral head
•Glycosuria
•Osteoporosis, obesity
•Immunosuppression
•Diabetes
Addison’s
Disease
Low Aldosterone:
Low Na+, postural ¯BP
High K+
Dehydration
Wt loss
High plasma renin
Low Cortisol:
Hypoglycemia
Hypercalcemia
High ACTH/MSHpigmentation
Addison’s Disease
¯ (partial or complete) adrenal
cortex function - loss of GC, MC,
androgen function (weakness,
fatigue, hypotension, inability to
maintain normal glucose &
electrolyte levels, etc)
Tx: Hydrocortisone,
fludrocortisone, testosterone
Low Androgens:
Loss of body hair
Loss of libido/amenorrhea
(Cortisol)
(Aldosterone)
Metyrapone
Etomidate
Aminoglutethimide
(Eplerenone)
Fluticasone
nasal spray &
Prednisone
tablets
Corticosteroid Agonist
Glucocorticoid: Cortisol (Hydrocortisone)
• Also called the ‘stress hormone’
• The main natural GC
• Release under control of ACTH, secretion
varies as per time of day (circadian rhythm)
• In plasma, 95% bound to corticosteroidbinding globulin (CBG)
• Some salt-retaining activity à HT in
cortisol-secreting adrenal tumors or ACTHsecreting tumors (Cushing syndrome)
• Absorbed form GI, short duration of action
• Most corticosteroids require 6-8 hours
before their therapeutic onset of effect is
detected
Regulation of Steroid Activity
Licorice can block
11β-HSD2 à ­
levels of cortisol
à ­ BP
By: Craig W Clarkson
Duration of Action
Corticosteroid
Properties
Agent
Anti-Inflammatory
Activity (GC)
Salt-Retaining Activity
(MC)
1
1
0.8
0.8
Prednisone
4
0.3
Prednisolone
5
0.3
Triamcinolone
5
0
Dexamethasone
30
0
0.3
10
3000
250
Primarily GC
Cortisol
(hydrocortisone)
Cortisone (inactive)
*
Primarily MC
Aldosterone
Fludrocortisone
*Synthetic GC: ­ half-life, duration of action, penetration of lipid
barrier for topical use; ¯ salt-retention
(Cortisol)
(Aldosterone)
(Metyrapone)
(Eplerenone)
Glucocorticoid Antagonist: Mifepristone
• Progesterone receptor antagonist:
• Blocking the effects of progesterone, prevents/terminates pregnancy
• Glucocorticoid receptor antagonist:
• Used for endogenous Cushing's syndrome
• For hyperglycemia associated with Cushing's (in patients with failed surgery or
cannot have surgery)
• Side effects:
• Fatigue, headache, dizziness
• Contraindications:
• Pregnancy
• Drug Interactions:
• It is a strong CYP inhibitor
(Cortisol)
(Aldosterone)
(Metyrapone)
(Eplerenone)
Mineralocorticoid (MC)
Glucocorticoid (GC)
Pathways in
Adrenocortical
Hormone
Biosynthesis
Stimulated by Ang II
Corticosteroid Agonist - Mineralocorticoid: Aldosterone
Situation: ¯ BP and blood volume
Aldosterone
release
stimulated by
Ang II (& to
some degree:
­K+ and ACTH
Aldosterone:
Target tissue Kidney
Mineralocorticoid
(Aldosterone)
Mechanism of Action
(different genes affected
compared to GC)
MSE
Aldosterone:
Inside Renal
Tubular Cell
(does this in
epithelial cells in
colon, seat and
salivary glands)
Aldosterone + Receptor, forms a complex à Enhancement of transcription of specific DNA segments
in nucleus à forms 2 protein transporters: Na+/K+ ATPase pump & Na+ channel called ENaC.
This ­ Na+ and water (passive) reabsorption and K+ excretion à ­ BP
Duration of Action
Mineralocorticoid (MC) Agonist:
Aldosterone/Fludrocortisone
Agent
Anti-Inflammatory
Activity (GC)
Salt-Retaining Activity
(MC)
0.3
3000
Primarily MC
Aldosterone
Fludrocortisone
10
• Aldosterone accounts for 90% of mineralocorticoid activity
250
• It has a short half-life
• Other MC, the natural precursor of aldosterone, deoxycorticosterone (3%
activity)
• Fludrocortisone: Synthetic, longer duration of action
• Fludrocortisone Indications:
• Replacement therapy (adrenalectomy), mineralocorticoid deficiency
Mineralocorticoid (MC) Agonist: Fludrocortisone
Pharmacokinetics: Oral administration
Side Effects:
• Retention of Na+ and water. If uncontrolled, can lead to:
o Edema, worsen CHF
o Hypertension
o Hypokalemic alkalosis
Contraindications:
• Heart disease or hypertension
Drug Interactions:
• Antacids, space both
• Corticosteroids are CYP substrates, caution with CYP inducers and Inhibitors
(Cortisol)
(Aldosterone)
(Metyrapone)
(Eplerenone, less effect on androgens)
Mineralocorticoid Antagonist: Spironolactone, Eplerenone
• Spironolactone:
• Blocks androgen receptors; use in hirsutism, acne
• Blocks aldosterone receptor (collecting tubule):
• Protects the heart by inhibiting the cardiac contractility
impairing effects of aldosterone
• Excretes Na+ and water (so acts as diuretic and antiHT),
preserves potassium
• Indications:
• Edematous conditions (CHF, cirrhosis, nephrotic syndrome)
• Resistant HT
• hypokalemia
• Primary hyperaldosteronism (adrenal hyperplasia)
Spironolactone
Side effects:
• Gynecomastia (¯ testosterone & ­ peripheral conversion of testosterone to
estradiol), better option eplerenone
Contraindications:
• Renal impairment
• Hyperkalemia
• Pregnancy (because of antiandrogen effect)
Drug Interactions:
• With other hyperkalemic drugs (ACE inhibitors, Sulfatrim)
(Cortisol)
(Aldosterone)
Metyrapone
Etomidate
Aminoglutethimide
(Eplerenone)
AntagonistsSynthesis
Inhibitors:
K (­), A
X
K
X
Ketoconazole (K)
Aminoglutethimide (A)
Metyrapone (M)
Etomidate (E)
M, E
X
Indications:
• Cushing's syndrome
• Adrenal carcinoma
• Hirsutism
• Breast/prostate
cancer
M, E
X
Androgens and Antiandrogens
• M. Nabeel Ghayur
• Assistant Professor of Pharmacology
Learning Objectives
• Describe the role of the hypothalamus, pituitary, adrenal gland and
gonads in the synthesis of androgens
• Recall the physiological effects and regulation of androgens
• Describe the mechanism of action, clinical uses and side effects of
androgens and antiandrogens
Gonadal
Hormones
Estrogens
Progestins
Androgens
Agonist
Antagonist
Adrenal
Androgens
Adrenal cortex:
Weak androgens
Adrenal
Androgens
In the Periphery
Hair loss,
prostate growth
Androgens: Synthesis
and Influence
• Androgens are steroids, have anabolic
and masculinizing effects (men and
women):
• Gonadal:
• Testosterone (main androgen)
from Leydig cells in testes &
• Smaller quantities from thecal
cells in ovaries
• Adrenal Cortex:
• Weak androgens:
Androstenedione &
dehyroepiandrosterone (DHEA)
• 5α-dihydrotestosterone (DHT,
active metabolite)
Androgens: Regulation
• Secretion stimulated by GnRH & ACTH
• Little influence of adrenal androgens on secondary sex characteristics in
men
• In women, adrenal androgens responsible for pubic and axillary hair
• Most actions of adrenal androgens due to conversion to testosterone in
peripheral tissues
• In Cushing’s disease, when excessive androgens secreted, leads to
masculinization in both men and women
Androgens needed for:
• Androgenic:
• Spermatogenesis
• Normal maturation in the male fetus
and during puberty (male organs,
bones, hair growth, muscle mass)
• Later, maintenance of 2° sex
characteristics, fertility, libido, and
male pattern baldness
• Anabolic:
• Muscle protein and hemoglobin
synthesis
• Decreased bone resorption
Androgens: Mechanism of Action
• Testosterone itself is an active entity to interact with its
receptors in some tissues like liver
• In others (like prostate [BPH], skin[hair loss]) enters the cells,
converts to DHT (the active form in these tissues) by 5αreductase and then binds to receptors
Testosterone:
Uses
• Activation and division of
satellite cells (SC)
• Inhibition of apoptosis pf SC
• Formation of new myotubes
• Enhancement of protein
synthesis
• Replacement in hypogonadism (pituitary-hypothalamic injury from tumors), Addison
• Stimulate RBC production in certain anemias
• Promote weight gain in wasting syndromes (AIDS)
• Illicit use by athletes to increase muscle size and strength and increase aerobic performance
US FDA: They are NOT dietary
supplements, but instead are
unapproved and misbranded
drugs.
Pharmacokinetics:
• In plasma, partly bound to Sex Hormone Binding Globulin
• Oral form metabolized by liver rapidly, so given as
methyltestosterone (oral) or injectable & transdermal patch
in longer-acting format
• So-called anabolic steroids (still have androgenic effects):
oxandrolone, nandrolone, stanozolol
Toxicity (dose-dependent):
• In women, use of Testosterone leads to virilization (hirsutism,
deepened voice, acne)
• In pregnant women, exogenous use can result in virilization of
fetus external genitalia
• In men, high doses can lead to feminization (gynecomastia,
testes shrinkage, infertility) due to feedback and conversion
of externally taken testosterone to estrogen.
• Liver failure, ­ LDL
• Aggression and dependence (controlled substance)
Testosterone
Antiandrogens
Clinical use:
• Benign prostatic hyperplasia (BPH)
- Normal part of aging. With age,
testosterone levels ¯ but levels of
the 5α-reductase enzyme ­
• Malignant prostate disease
• Precocious puberty
• Hair loss in men due to ­ DHT
(androgenic thinning of hair) – use
5α-reductase Inhibitors
• Hirsutism (excessive hair growth in
women in a male type pattern; due
to hyperandrogenism) – use
Spironolactone
, BPH
• Testosterone converts to DHT in prostate under
the influence of 5 alpha-reductase enzyme
• DHT is 10 times more potent than testosterone
in binding to receptors.
• Responsible for hair loss and prostate
enlargement
• Inhibits apoptosis and lets luminal and basal
cells in prostate to grow and multiply
uninterrupted
• No risk of developing cell mutations or cancer
• Prostate gland enlarges and nodules can form,
leading to compression of urethra and
disruption in urine flow
• Also leads to bladder hypertrophy and
stagnation of urine in the bladder
• Dribbling, dysuria, hesitancy, nocturia
GnRH Agonist
1. Leuprolide: Synthetic analog
Continuous administration
suppresses LH and FSH secretion via
downregulation of GnRH receptors.
Takes 2-4weeks; initial 1-2 weeks, ­ in
testosterone (use flutamide)
Pulsatile administration stimulates LH
and FSH secretion
Use: Continuously, for prostate
cancer, precocious puberty
Side Effect: DM
GnRH Antagonist
1. Degarelix:
Receptor blocker of GnRH
Use: Advanced prostate cancer
Side Effects: Injection site reactions
and hot flashes.
Inhibitor of Steroid Synthesis
1. Ketoconazole: Gonadal and
adrenal synthesis blocker
Use: Prostate cancer
(Next slide for details)
Androgen Receptor Blockers
1. Flutamide: Nonsteroidal
Use: Prostate cancer
2. Spironolactone: Steroid-like
Use: Hirsutism
5α-reductase Inhibitors: Dutasteride, Finasteride
• Mechanism of Action: Inhibits the enzyme (5α-reductase)
• Indications:
• BPH: Long term therapy reduces prostate size by up to 30% and reduce the risk
for acute urinary retention & surgery
• Male patterned baldness
• Contraindications:
• Do not donate blood for 6 months after taking last dose prevent administration to
pregnant females.
• Pregnant women should not handle because can be absorbed through the skin
• Pharmacokinetics:
• Requires several months to produce a therapeutic effect. Up to 1 year of
continuous therapy is needed to achieve a maximal effect.
• Side Effects:
• Decreased libido (due to medication or progressing disease ?)