Kortikosteroid

Edy Junaidi

Three Distinct Anatomically and Functionally CompartmentThree Distinct Anatomically and Functionally Compartment

Physiologic regulator of steroid synthesis

2 Class of steroid produced by Adrenal CortexCorticosteroid*

GlucocorticoidCortisol/Hydrocortisone

MineralocorticoidAldosterone

(*based on relative potency of Na+ retention & carbohydrate metabolism)

Androgen

Physiological Function & Pharmacological Effects

Alterations of lipid, protein, & carbohydrate metabolism

Maintenance of fluid & electrolites balance

Preservation of normal function of:

Nervous system

Cardiovascular system

Immune system

Endocrine system

The kidney

Skeletal muscle

General Mechanisms of Corticosteroid

Ligand-receptor gene expression regulation

GR – MRMR receptor distribution principally in the kidney, colon, salivary glands, sweat glands, & hippocampus

Receptor – independent for Corticosteroid specificity

Cortisol & aldosterone showed equal affinity to MR

Type 2 isozyme of 11β-hydroxysteroid dehydrogenase play key role in the specificity of corticosteroid, particularly in the kidney, colon, & salivary glands

Carbohydrate & Protein metabolismCarbohydrate & Protein metabolism

Corticosteroid profoundly affect carbohydrate & protein metabolism → protecting protecting glucose-dependent tissueglucose-dependent tissue (heart & brain) from starvation

Glycogenesis

Gluconeogenesis

Diminish glucose utilization

Protein breakdown

Activate lipolysis

Increase blood glucose levels

Lipid metabolismLipid metabolism

Two established effects of steroid:

Dramatic redistribution of body fat result from hypercorticism

Endogenously

Pharmacologically-induced

Permissive facilitation of lipolytic effects of other agents,e.g., Growth hormone, beta-agonists

Electrolites & Water BalanceElectrolites & Water Balance

Aldosterone is the most potent corticosteroid in respect of electrolites & water balance

Features of hyperaldosteronism:

Positive Na+ balance + water expansion

Increase plasma Na+ concentration

Hypokalemia

Alkalosis

Interfere Ca2+ uptake in the gut & increase excretion from kidney

Chronic hyperaldosteronism can cause hypertension

Hypoaldosteronism → hypotension and vascular collapse

Glucocorticoid: Principal & adverse effects

Cardiovascular systemCardiovascular system

Aldosterone induced cardiac fibrosis unrelated to its effect on raising blood pressure

Spironolactone, MR antagonist, block fibrosis without altering blood pressure

Enhance vasoreactivity to other vasoactive substances

NE, AngII, endothelin-1,etc

Skeletal muscleSkeletal muscleNormal function of skeletal muscle require permissive concentration of corticosteroid → diminished work capacity is prominent sign of adrenocortical insufficiency

Muscle weakness,in primary aldosteronism primarily result from hypokalemia rather than direct effect of mineralocorticoid on skeletal muscle

Chronic glucocorticoid excess (endogenously/pharmacologically) → skeletal muscle wasting ⇒ steroid myopathysteroid myopathy

Central nervous systemCentral nervous system

Indirect effects :Maintenance of blood pressure

Maintenance of blood glucose

Maintenance of electrolites

Direct effects :Steroids affecting on mood, behaviour, & brain excitability

Adrenal steroids secreted in the diurnal cycle are reponsible for reversibly activating exploratory activity, food-seeking behavior, carbohydrate appetite and synaptic efficacy

paradox in the actions of adrenal steroids

They exert protection in the short run and have the potential to cause damage in the long run if the allostatic, that is, the adaptation-promoting, responses are not managed efficiently

Allostasis ≈ achieve stability through changes/adaptation

The result of the inefficiency or overactivity of allostatic systems

repeated activation by many stressful events

failing to shut off after the challenge is over

inability to be activated adequately, allowing other systems that are normally counter-regulated to become overactive,e.g., inflammatory cytokines

Repeated psychosocial stress in primates and rodents causes pathological changes in various body organs, including neuronal loss

corticosterone causes atrophy of neurons in the hippocampus

Antiinflammatory & Antiinflammatory & Immunosuppresive effectsImmunosuppresive effects

Decrease release of vasoactive & chemoattractive factors

Diminished secretion of lipolytic & proteolytic enzymes

Decrease extravasation of leucocytes to area of injury

Decrease expression of proinflammatory enzymes (e.g., COX-2 & NOS)

Glucocorticoid Toxicity

1.Withdrawal of steroid therapy

Flare-up underlying treated disease

Acute adrenal insufficiency (most severe)

1.Continued use of supraphysiological doses

Exaggeration of its physiological effects:

Fluid & electrolites disturbances, hypertension, infection susceptibility, osteoporosis, behavioral changes, myopathy, etc

Cortisol Release and Its Modification by GlucocorticoidCortisol Release and Its Modification by Glucocorticoid

Therapeutic UsesReplacement therapy

Acute & chronic adrenal insufficiency

Congenital adrenal hyperplasia (CAH)

Rheumatic disorders

Renal disease

Allergic disease

Bronchial asthma

Preterm infants

Ocular disease

GI diseases (chronic ulcerative colitis, Crohn's disease)

Malignancies, organ transplants,

Spinal cord injuries