Pharmacology of Corticosteroids

adrenal cortex
Divided into 3 Functionally Distinct Zones Based on Steroid Biosynthesis

adrenal cortex
adrenal cortex
zona glomerulosa secretes aldosterone

zona fasciculata secretes cortisol

zona reticularis secretes DHEA and andostenedione

regulation of the HPA axis
stress in the form of
hypoglycemia
hypotension
surgery
fevery
injury

has an impact on the hypothalamus

hypothalamus secretes CRH
affects anterior and posterior pituitary
pituitary releases vasopressin, pro-inflamm cytokines, ACTH

affects the adrenals
adrenals secrete aldosterone, cortisol, DHEA, andostenedione, epi, NE

zona glomerulosa
affected mostly by renin/angiotension and potassium concentration

zona fasciculata
zona fasciculata
affected mostly by ACTH

circadian patterns
ACTH and cortisol secretion

corticosteroid biosynthetic pathways
mineralocorticoids –> aldosterone

glucocorticoids –> cortisol

androgens –> DHEA, andostenedione, testosterone, estrogen

medulla – EPI, NE

metabolism – plasma protein interactions
cortisol bound to plasma proteins

80% to transcortin or CBG
10% albumin
10% free

aldosterone is not firmly bound to serum proteins

synthetic steroids are generally NOT protein bound

mechanism of action – nuclear receptor acting
affects gene transcription

steroid bound to CBG or albumin
steroid diffuses into cell
bind to nuclear receptors
affects gene transcription

GRs – distributed widely

MRs restricted to kidney, colon, salivary, and sweat glands, hippocampus

physiological affects of glucocorticoids
Wide ranging effects on nearly every organ
Dose dependant effects: anti-inflammatory, metabolic
Permissive effects: vascular/bronchial

Glucocorticoid and mineralocorticoid cross-talk
– both bind MR and GR
Androgens act through AR

metabolic effects of glucocorticoids
Carbohydrate metabolism (catabolic)
Stimulates gluconeogenesis in liver
Mobilizes amino acids from extrahepatic tissues (muscle)
Decreases extrahepatic glucose utilization
Counteracts hypoglycemia

Protein metabolism
Mobilizes amino acids from non-hepatic tissues to liver

Fat metabolism
Mobilizes fatty acids from adipose tissue
Promotes use of fatty acids as main fuel source

physiologic effects of aldosterone
1. Increases Na+ reabsorption in: Renal distal tubule & collecting duct Sweat Saliva Gastrointestinal tract
2. H2O reabsorption occurs due to Na+ conservation
3. Promotes K+ excretion in exchange for Na+ in distal tubule
4. Promotes tubular H+ excretion

pharm uses of corticosteroids
Hormone replacement in deficiency states (rare)
Diagnostics
3. Pharmacologic (very, very common)
Anti-inflammatory
Immunosuppressive
Control of edema / blood volume

pathology of adrenal steroid deficiency
Cortisol
– Release of negative feedback inhibition of ACTH, CRH, ADH: Pigmentation, hyponatremia, ? effects on mentation, appetite
– Defective insulin counterregulation: hypoglycemia
– Impaired vascular reactivity to catechols, angiotensin: low SVR
– Decreased myocardial function: stroke volume and cardiac output
Aldosterone
– salt wasting: dehydration, decreased kidney perfusion (prerenal RF)
– impaired K+ / H+ excretion: hyperkalemia and metabolic acidosis
Androgens
– ? effects: body hair, weakness, anemia, libido, bone mass

therapeutic indications -adrenal specific
Replacement therapy
– Primary adrenal insufficiency (Addison’s disease, surgery, hemorrhage, infection)
– Secondary adrenal insufficiency due to Hypthalamo-Pituitary disorders
– Congenital adrenal hyperplasia

Diagnostic testing
Dexamethasone Suppression Test
CRF and ACTH stimulation
Metyrapone test

therapeutic indications – non-adrenal
Anti-Inflammatory
Autoimmune and allergic diseases: bronchial asthma, hemolytic anemia, thrombocytopenia, inflammatory bowel disease, dermatitis, glomerulonephritis, hepatitis, Rheumatoid arthritis, vasculitis, lupus
Cancer treatment: leukemia/lymhoma, tumor related edema
Transplantation: tolerance/rejection

Prevention of infant respiratory distress syndrome
Stimulation of fetal lung maturation in premature births

Off-label: acute mountain sickness; high altitude pulmonary or cerebral edema

Mineralocorticoid treatment for ANS insufficiency
– postural hypotension

Androgens: ? Libido, bone health in women with Addision’s

anti-inflammation
anti-inflammation
signature action of GCs

affects C-fos and C-jun as well as 1KB in the nucleus and cytoplasm, respectively

MC action
MC action
ion transport

aldosterone binds to MR
complex translocates to nucleus

upregulates structural proteins – such as sodium ion channels and sodium/potassium ATPases

MR localized
protected from GC

cortisol enters cell
cannot interact with MR
turned into cortisone
leaves cell

hydrocortisone
essentially cortisol in pill form
Preferred drug for replacement therapy

less useful as a systemic anti-inflammatory agent because of equal anti-inflammatory and salt-retaining actions

short half life (1-2 hr – stress and high doses may increase half-life)

prednisone, prednisolone, methylprednisolone
increased anti-inflammatory potency and decreased mineralocorticoid activity

good choice for chronic anti-inflammatory therapy because of intermediate half-life (12-36 hr) and relatively low salt-retaining actions

dexamethasone and betamethasone
C(16) methyl- and C(9) fluro-derivatives of prednisolone)

high anti-inflammatory potency with essentially no mineralocorticoid activity

long half life (36-54 hr)

good choices for acute anti-inflammatory therapy in which maximum effects is required e.g. septic shock, cerebral edema

not a first choice for chronic treatment as a result of their growth suppressive and bone demineralization actions

fludrocortisone
mineralocorticoid actions 25 times greater than anti-inflammatory actions

the most widely used mineralocorticoid for Na+ and fluid retention

Replacement therapy for individuals with MC deficiency

relative biologic potencies of synthetic steroids
prednisolone has high ant-inflamm and HPA suppression

methylprednisolone has high anti-inflamm and HPA suppression

fludrocortisone has very high salt retention

dexamethasone has very high anti-inflamm effects

routes of GC administration
oral

injectable – IV, IM, intra-articular

topical – creams, gels, opthalmic solutions

inhaled

suppositories

dexamethasone suppression test
Used to diagnose cushings –

Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs that has anti-inflammatory and immunosuppressant effects. It is 25 times more potent than cortisol in its glucocorticoid effect, while having minimal mineralocorticoid effect.

Give high dose of synthetic steroid
to try to suppress the normal HPA
axis.

Persons with normal HPA function
Will have suppression of cortisol to
low levels due to negative feedback.

Patients with excessive cortisol
production will not suppress, and you will want to consider primary or secondary causes of high cortisol –
— primary cause – Adenoma
— secondary cause – ACTH related

ACTH and CRH stimulation tests
usu. used in terms of finding deficiencies, not excesses

metryapone test
blocks 11-deoxycortisol transformation to cortisol — This stimulates ACTH secretion, which in turn increases plasma 11-deoxycortisol levels, so you know the problem is primary, not secondary

cushings syndrome
Signs /symptoms of glucocorticoid excess caused by:
a) ACTH secreting pituitary tumors (10/million/yr)
b) Cortisol secreting adrenal tumors (2/million/yr)
c) Exogenous glucocorticoids (15-20 million /yr)

deleterious actions of GCs
deleterious actions of GCs
decreases LH, FSH, TSH, GH secretion

depression/psychosis

carb lipid metabolism
promotes visceral obesity

bone and calcium metabolism – decreases bone formation and osteoporosis

skin/muscle/connective tissue – protein catabolism, collagen breakdown, skin thinning, muscular atrophy

glaucoma
peptic ulcers

salt and water retention, hypertension

decreases in linear growth
anti-inflamm action and immunosuppression

adverse effects of high dose GCs
Redistribution of body fat : Trunk/abdominal fat deposition, Moon facies
– Immunosuppression: cutaneous, fungal and other opportunistic infection
– Bone disease: Fractures (hip and vertebral), loss of height
– Myopathy: Proximal muscle weakness
– Dermopathy: easy bruising and violaceous striae
– Diabetes / glucose intolerance: enhanced gluconeogenesis and decreased glucose utilization
– Hypertension: sodium retention from the mineralocorticoid effects of cortisol

bone disease
a serious complication of GC excess

violaceous striae and bruising
dermal atrophy is a sign of GC exess

tertiary insufficiency
promoted by exogenous GC

stops hypothalamus and anterior pituitary from the HPA axis

hypothalamus
pituitary
adrenal cortex
go to sleep…

recovery of HPA axis after suppression with GCs
takes a while for things to wake up

initially CRH increases over several months
then ACTH

then cortisol from the adrenal glands

symptoms of steroid withdrawal syndrome
fatigue
anorexia
GI symptoms
dizziness – postural
arthralgias/myalgias
desquamation of skin

GC withdrawal
1. Exogenous steroids suppress the HPA axis in
proportion to the dose.

2. The degree of HPA suppression is a function of
the length of time steroids are given.

3. Patients with HPA suppression from exogenous
steroids are at risk for Addisonian crises.

suppression of HPA axis after steroid tx
hard to predict

pituitary-adrenal function during corticosteroid therapy
learning to live with uncertainty

GC withdrawal
1. Pharmacologic Physiologic
– monitor disease activity
2. Physiologic change to HC BID
– monitor symptoms
3. Taper evening dose first
– monitor AM cortisol
4. ACTH stim test (or metyrapone test) to verify stress response.

steroid blocking drugs
Inhibition of cortisol synthesis:
Ketoconozole, aminoglutethamide

Antagonism of the GR:
Mifepristone (RU486)

steroid blocking drugs
Spironolactone / Eplerenone

a mineralocorticoid receptor antagonist

very useful in treating conditions of aldosterone excess

potassium-sparing diuretic

Na+ and water are lost when it is administered
action requires the presence of aldosterone

summary of corticosteroids
1. Steroid hormones produced in the adrenal cortex with a broad range of physiologic effects.
2. In adrenal deficiency states synthetic corticosteroids are essential.
3. Glucocorticoids are very useful as drugs because of their potent anti-inflammatory effects.
4. Glucocorticoid drugs are nearly as toxic as they are beneficial and need to be used judiciously and with care.
5. Long-term use of corticosteroid drugs causes suppression of the H-P-A axis and requires careful tapering.

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