CORTICOTROPIN AND ADRENAL CORTICOSTEROIDS

Dwi Indria Anggraini

Introduction ADRENAL PHYSIOLOGY :

Adrenal Cortex : Homeostatic organ, regulating reactions to stress

Release : Controlled by CNS

Stimuli : Trauma, chemicals, diurnal rhythms, emotion

Corticotropin-releasing

factors (CRF)

Corticotropin (adrenocorticotropic hormone (ACTH)

Glucocorticoids

GLUCORTICOID- Metabolic effect

- Antiinflamatorry/ Immunosupresive

MINERALOCORTICOID

Retension of Na-H2O

BP, Edema

Emotional stress Trauma Diurnal

rhythms

Hypothalamus CRF

Anterior pituitary glands

Negative ACTH inhibition Adrenal cortex

Adrenal steroids

The pathway of adrenocorticotropic hormone (ACTH) and adrenal steroid secretion.

INTRODUCTION

Inflammation ? Causative trauma , MO, Cold, Organ transplants Symptomatic Cell NSAID

CS Inflammation : color,

dolor, flame Masking effect

Introduction 1. CS hormone That effects almost every organ/systems SE … (1) 2. Therapeutic Uses - Endocrine substitution therapy - Non endocrine AI & Immunosuppresive

Obat dewa …(2) Masking effect

3. (1) & (2) Pedang bermata dua

Adrenal cortex releases a number of endogenous CS GLUCOCORTICOID

▪ Zona fasciculata▪ Chiefly affect carbohydrate, protein

metabolism and resistance to stress▪ Feedback inhibitor of corticotropin and

corticotropin-releasing factor (CRF) secretion

▪ Endogenous glucocorticoids : ▪ Cortisol (hydrocortisone) major endog.glucocort, secreted : 10-25 mg/daily

▪ Cortisone▪ Corticosterone 0,5-2 mg /daily

▪ Diurnal rhythm : ▪ 4 AM & 8 AM, 4 PM

Mineralocorticoids

▪ Zona glomerulosa▪ Chiefly affect electrolyte and water

metabolism▪ Sodium & water retention edema

BP▪ Endogenous mineralocorticoids :

▪ Aldosterone 30-150 g/daily

▪ Desoxycorticosterone

REGULATION

Synthesis & secretion Regulation FBM CS level FBM (-) CS level FBM (-) What happens to the patient who

chronically consume CS exogenous in large dosage ?

CS level FBM (-) Adrenal gland suppression ATROPHY

ADRENOCORTICOTROPIC HORMONE (ACTH)

Mechanism of action

To stimulate specific protein receptor sites on the adrenal cortical cell membrane

ACTH is required for the synthesis of mineralocorticoids & glucocorticoids

(stimulate the synthesis of gluco > mineralo.)

Therapeutic uses

Diagnostic tool : Primary adrenal insufficiency (Addison’s

disease)▪ The adm. of ACTH no effect▪ Adrenal cortex dysfunction

Secondary adrenal insufficiency▪ The adm. of ACTH effect (+)▪ Anterior pituitary dysfunction

Administration :

• Parenterally (IM)• T ½ : 15 minutes

Untoward effects :

• Rare• Hypersensitivity reactions • Toxicity is dose-related (corticosteroid excess)

ADRENAL CS ACTIONS Glucocorticoids

▪ Promote normal intermediary metabolism▪ Gluconeogenesis Amino acid uptake by the liver and kidney

Elevating activities of gluconeogenic enzymes

▪ Stimulate protein catabolism (except in the the liver) and lipolysis

▪ Glucocorticoid insuff. hypoglycemia

Increase resistance to stress Plasma glucose levels energy >< stress (trauma, fright,

infection, bleeding, debilitating disease) Blood pressure (vasoconstrictor action)

Alter blood cell levels in plasma Eosinophils, basophils, monocytes,

lymphocytes Hb,erythrocytes, platelets ,

polymorphonuclear leukocytes

Anti-inflammatory action- Reduce the inflammatory response

- To suppress immunity

Inhibition of phospholipase A2 block the release of arachidonic acid (precursor of PG & leukotriens)Affects other components of the endocrine

system - Feedback inhibition - Growth hormone production Effects on other systems

- Stimulate gastric acid & pepsin production (high doses)

exacerbate ulcers - Severe bone loss (chronic glucocorticoid therapy) - Myopathy weakness

Mineralocorticoids Aldosterone - reabsorption of

sodium, bicarbonate and

water

- decreases reabsorption of

potassium

Alkalosis & hypokalemia Blood volume & Blood

Pressure

Hyperaldosteronism >< spironolactone

THERAPEUTIC USES

Replacement therapy for primary adrenocortical insufficiency

(Addison’s disease) :

Hydrocortisone natural cortisol•Dosage : 2/3 morning + 1/3 afternoon

Fludrocortisone (synthetic mineralocorticoid with some

glucocr. activity)

• An enzymes defect in the synthesis of one or more adrenal steroid hormone

Replacement therapy for congenital

adrenal hyperplasia

(CAH)

• Inflammation : (redness, swelling,heat, tenderness)• rheumatoid• osteoarthritic inflammations• inflammatory skin

Relief of inflammatory

symptoms

• Treatment of the symptoms of drug, serum, transfusion allergic reactions, bronchial asthma, allergic rhinitis

• Beclomethasone dipropionate, triamcinolone , etc topical/inhalation (SE )

Treatment of allergies

ADRENAL CORTICOSTEROIDS

Hydrocortisone (Cortisol)

• Pharmacokinetics :• Synthesized from cholesterol • Adrenal corticosteroids & their derivates are readily absorbed from GIT• Secretion in adult ( stress) : 10-25 mg/daily• 90 % bound to plasma proteins (CBG= corticosteroid-binding globulin),

5-10 % free or bound to albumin.

If conc. > 20-30 µg/dL, CBG is saturated free cortisol

CBG is increased in :PregnancyAdministration of estrogen Synthesis by the liver Hyperthyroidism

CBG is decreased in :HypothyroidismGenetic defects in synthesisProtein deficiency states

Synthetic corticosteroid (dexamethason) bound to albumin

T1/2 : 60-90 minutes

Increase if : - Large amounts

adm. - Stress - Hypothyroidism - Liver disease

Metabolized by the liver microsomal oxidizing

enzymes conjugated to glucoronic acid or

sulfate excreted by the kidney

Classification of Glucocorticoids and Mineralocorticoids

Group Drugs Anti-inflammatory effect

Salt-retaining effect

-Short-acting (8-12 hours) -Intermediate- acting (18-36 hours)

-Long-acting (1-3 days)

-Mineralocorticoids

-Hydrocortisone-Cortisone

-Prednison-Prednisolone-Methylprednisolone-Triamcinolone

-Betamethasone-Dexamethasone-Paramethasone

-Fludrocortisone-Deoxycorticosterone

10,8

4555

353010

100

10,8

0,30,80,50

000

12520

DOSAGE

•Glucocorticoids vs mineralocorticoids activity•Duration of action•Type of preparation •The time of day that steroid is administered

Consideration :

•Suppresion of HPA axis •To prevent : regimen of alternate-day administration

Long Time Period &

large doses (> 2 weeks):

Adverse Effects of Corticosteroids

EFFECT-SIDE EFFECT OF CORTICOSTEROIDTruncal

obesity

Moon face

Buffalo hump

Atrophi

Inhibitors of adrenocorticoid biosynthesis

Metyrapone

Aminoglutethimide

KetoconazoleMifepristone

Spironolactone

Glucocorticoids: principal and adverse effect