CORTICOSTEROIDS

Corticosteroids are a class of steroid

hormones that are produced in the adrenal
cortex.
Corticosteroids are involved in a wide range
of physiologic systems such as
stress response,
immune response and regulation of
inflammation,
carbohydrate metabolism,
protein catabolism,
blood electrolyte levels, and
behavior.

Glucocorticoids such as cortisol control

carbohydrate, fat and protein metabolism
and are anti-inflammatory by preventing
phospholipid release, decreasing eosinophil
action and a number of other mechanisms.

Mineralocorticoids such as aldosterone

control electrolyte and water levels, mainly
by promoting sodium retention in the
kidney.

common natural hormones

corticosterone (C21H30O4),

cortisone (C21H28O5, 17-hydroxy-11dehydrocorticosterone)

aldosterone

Biosynthesis

The corticosteroids are synthesized from

cholesterol within the adrenal cortex.
Most steroidogenic reactions are catalysed by
enzymes of the cytochrome P450 family. They
are located within the mitochondria and require
adrenodoxin as a cofactor
Aldosterone and corticosterone share the first
part of their biosynthetic pathway.
The last part is either mediated by the
aldosterone synthase (for aldosterone) or by
the 11-hydroxylase (for corticosterone). These
enzymes are nearly identical (they share 11hydroxylation and 18-hydroxylation functions).

Moreover, aldosterone synthase is

found within the zona glomerulosa at
the outer edge of the adrenal cortex;
11-hydroxylase is found in the zona
fasciculata and reticularis.

Classes of corticosteroids

Corticosteroids are generally grouped into

four classes, based on chemical structure.
Allergic reactions to one member of a class
typically indicate an intolerance of all
members of the class.
"Coopman classification"

The highlighted steroids are often used in the

screening of allergies to topical steroids

Group A
(short to medium acting glucocorticoids)
Hydrocortisone, Hydrocortisone acetate,
Cortisone acetate, Tixocortol pivalate,
Prednisolone, Methylprednisolone, and
Prednisone.
Group B
Triamcinolone acetonide, , Mometasone,
Amcinonide, Budesonide, Desonide,
Fluocinonide, Fluocinolone acetonide, and
Halcinonide.

Group C
Betamethasone, Betamethasone sodium
phosphate, Dexamethasone,
Dexamethasone sodium phosphate, and
Fluocortolone.
Group D
Hydrocortisone-17butyrate,Betamethasone valerate,
Betamethasone dipropionate, Prednicarbate
, , , , , and Fluprednidene acetate

Glucocorticoids

Knowledge Objectives
1. Synthesis, regulation and
mechanisms of action
2. Physiological effects
3. Pharmacological effects
4. Glucocorticoid drugs
5. Clinical uses
6. Side effects

Sites of Steroid Synthesis Adrenal gland

Adrenal Medulla
Adrenal Cortex

Zona Glomerulosa
Zona Faciculata
Cortex Zona Reticularis
Medulla

Sites of corticosteroid Synthesis

Cortex of Adrenal gland

Mineralocorticoid

Glucocorticoid
Sex steroids

Diurnal Variation of Glucocorticoids

% Change
+100

8-10 am

Note: Related to sleep-Wake Cycle

-100

LKS

2
am

12
Midnight

12
Noon

12
Midnight

Hypothalamic-Pituitary-Adrenal (HPA) Axis

Feedback
Cortico-centers
- Amygdala anterior brain
- circadian rhythm
- Reticular Formation
- Stressful stimuli
Glucocorticoid

CRH Corticotropin releasing hormone

ACTH Adreno-corticotropic hormone
ACTH binds receptors on surface
of cells in zona fasciculata of
adrenal cortex cAMP second
messenger increases
production of glucocorticoid from
cholesterol

Regulation of synthesis and secretion

of adrenal corticosteroids
CRH

The long negative feedback loop is

more important than the short loop.
Exogenous glucocorticoid negatively
regulates synthesis and secretion of
endogenous glucocorticoid

ACTH

Daily administration of corticosteroid

at physiological concentrations for at
least 2 weeks suppresses the HPA
resulting in decreased production of
endogenous hormones. Recovery may
take up to 9-12 months.
ACTH has only a minimal effect on
mineralocorticoid production.
ADH, antidiuretic hormone (vasopressin)

Biosynthesis of corticosteroids
and adrenal androgens

Cholesterol

Mineralocorticoid

Metyrapone inhibits both glucocorticoid and mineralocorticoid synthesis. Aminoglutethimide

and trilostane blocks synthesis of all three types of adrenal steroid.

Mechanism of Action

Enters target cells by simple diffusion

Binds to cytosolic receptors
The steroid receptor complex translocates
into the nucleus

Regulates the synthesis of specific

proteins

Steroid Receptor Activation

S: steroid
CBG: corticosteroidbinding globulin
HSP: heat shock protein
GRE: glucocorticoid
response element

Glucocorticoid Receptor (GR)

Expressed in a almost every cell (cytosol) in the

body and regulates genes controlling the
development, metabolism, and immune
response.
Associated with HSPs (e.g. HSP90)
Upon activation by cortisol, GR translocates as a dimer
(w/o HSPs) to nucleus
Can also activate rapid signaling events in cytosol
(non-genomic)

Target Tissues of Glucocorticoids

Liver
Skeletal Muscle
Adipose Tissue
Bone
Brain
Skin
Retina
Kidneys

Heart
Lymphoids
Smooth Muscle
Lung
Stomach
Intestines
Fibroblast
Testes

= Most Important

Physiological Effects

Direct receptor - mediated effects

Indirect effects homeostatic

responses to other endogenous
signals
e.g. increase blood glucose
increase in insulin

Physiological Effects
1. Metabolic Effects: Catabolic, glucose
2. Antiinflammatory and
Immunosuppressive Effects
3. Other Effects

Metabolic effects

Glucose
Influence carbohydrate and fat metabolism to
ensure adequate delivery of glucose to the brain
Increase gluconeogenesis, decrease peripheral
use of glucose
Fat
Increase in free fatty acids (increased lipolysis)
Redistribution of fat from the extremities to the
trunk and face (buffalo hump)
Protein
Favors protein breakdown and helps mobilize
amino acids to the liver for gluconeogenesis

Anti-inflammatory and immunosuppressant

activity

Increase in circulating levels of neutrophils by

interfering with adhesion
Decrease in eosinophils, lymphocytes, and
monocytes
Decrease leukocyte migration, and phagocytic
activity
Decrease production of phospholipase A2,
prostaglandins, thromboxanes and leukotrienes

Other Effects
1. Electolytes: Decrease absorption of Ca2+ from
the intestine and increase renal excretion of Ca2+
Increased Na+ and H2O reabsorption, increased
K+ excretion.
2. Cardiovascular effects: Facilitates the effects
of catecholamine, Maintenance of BP
3. Respiratory: Facilitates action of
catecholamines (relax airway smooth muscle)
Fetal lung maturation, increased surfactant
secretion
4. Muscle: Maintain normal skeletal muscle
5. CNS Effects: mood, sleep patterns, and EEG

Pharmacokinetic Features

Well absorbed orally

Highly bound to plasma proteins (90%) - CBG
Metabolized by liver (P450 3A4 enzymes);
excreted by kidney (75%)
Plasma half-life shorter than biological halflife
Substantial lag time before onset of action
Persistence of effect after disappearance
from plasma

Pharmacological Effects (1)

Osteoporosis of Bone
Skin Thinning and Wasting
Connective Tissue Breakdown
Blood Changes

CNS Effects: Mood Stability, Psychoses,

Neutrophils & Thrombocytes & RBCs

Lymphocytes & Eosinophils & Basophils
Excitability

H2O Retention

Pharmacological Effects (2)

Suppressed Immune Response-Antiinflammatory Reaction

Destruction of Eosinophils
Stabilization of Lysosomal Membranes
Inhibition of Arachidonic Metabolism

Lipocortin (annexin) production

Phospholipase A2

Prostaglandins & Prostacyclins & Leucotrienes

Vasoconstriction and loss of Edema

Molecular mechanism of
Anti-inflammatory effect

A. Transactivation mechanism: up-regulate the expression

of anti-inflammatory proteins (lipocortin I).
B. Transrepression mechanism: down-regulate the
expression of
proinflammatory proteins (NF-B, Fos, IL-1, TNF)
Transcriptional machinery (TM)

transcription factors (TF).

Mechanism of Anti-Inflammatory Effect

Suppress T-cell activation and cytokine production

Suppress mast cell degranulation

Decrease capillary permeability indirectly by

inhibiting mast cells and basophils

Reduce the expression of cyclooxygenase II and

prostaglandin synthesis

Reduce prostaglandin, leukotriene and platelet

activating factor levels by altering phospholipase
A2 activity

Mechanism of Action of
Anti-Inflammatory Steroids

Effects on cytokines and

Inflammatory Mediators
of

Glucocorticoid Drugs

Endogenous Glucocorticoids

Synthetic Glucocorticoids

Comparison of Corticosteroids

Differences between glucocorticoid drugs are potency, duration of

action of the base, and pharmacokinetic behavior of the salts.

Synthetic

1. Stronger potency
Drugs2. Lower dose
3. Longer duration

Clinical Uses of Glucocorticoids

Replacement Therapy
Anti-Inflammatory
Immuno-suppression
Treatment of Allergic Disorders

Glucocorticoid Insufficiency
(Addisons Disease)

Low adrenal activity

Hypoglycemia, hypotension,
weakness, anorexia, irritability

Hyperpigmentation,
hyperkalemia, hyponatremia

Anti-inflammatory and anti-allergic effects

Immuno-suppression

Glucocorticoids Uses for diseases

Arthritis
Allergic reactions
Asthma
Autoimmune diseases
Collagen disease
Collagen vascular
diseases polymyalgia
rheumatica, temporal
arteritis

Nephrotic syndrome

Prevention of graft
rejection (transplant)
Dermatological disorders
Respiratory distress
syndrome

Side Effects

Adrenocortical insufficiency: Suppression of HPA

Adrenocortical excess (Cushings disease): Moon face,

buffalo hump
Diabetes Mellitus

CNS effects: psychological and behavioral changes;

aggravation of pre-existing psychiatric disorders

Impaired wound healing

Musculoskeletal effects: osteoporosis (brittle bones),

muscle weakness and atrophy

Cardiovascular effects: fluid retention, edema,

hypertension

Cushings Syndrome

Cushings
Syndrome

HyperAdrenalism
Primarily the
Glucocorticoids

Side effects

impaired release of GH and decreased activity of insulin-like

growth factor-1 (IGF-1) in growing bone

Side effects

Withdrawal
1. Cold turkey if glucocorticoid therapy of less than 2 weeks duration
2. Taper off if Glucocorticoid therapy of greater than 2 weeks duration.
3. Rate of taper should be proportional to duration of prior therapy.
4. The longer the original therapy, the slower the rate of dose reduction.
.

Withdrawal syndrome: hypotension, hypoglycemia,

myalgia and fatigue, joint pain,
muscle stiffness, muscle tenderness,
or fever.