Steroidal HormonesSteroidal Hormones(Adrenocorticosteroids, (Adrenocorticosteroids,

Adrenocorticoids, Corticosteroids, Adrenocorticoids, Corticosteroids, Corticoids)Corticoids) Secretion:Secretion:

Adrenal cortex of the adrenal gland.Adrenal cortex of the adrenal gland.

Regulation:Regulation: Stimulation:Stimulation: ACTH. ACTH. Inhibition:Inhibition: Feed back Mechanism. Feed back Mechanism.

Classification of Classification of corticosteroidscorticosteroids

They are all C21 hormones.They are all C21 hormones.

Corticosteroids

GlucocorticoidsRegulate carbohydrates, lipids

and proteins metabolism

e.g. Hydrocortisone

MineralocorticoisControl electrolytes and water

balance

e.g. Aldosterone.

Numbering System of Numbering System of Steroidal ring:Steroidal ring:

HO

1

2

34

56

7

8910

1112

13

1415

16

17

18

19

2021

22 23 2425

26

27

O

Progesterone

O

O

O

17-Hydroxyprogesterone

OH

HO

O

Pregnenolone

HO

Cholestrol

Biosynthesis of Adrenocorticosteroids

O

O

11-Deoxycortisol

OH

HO

O

O

CortisolHydrocortisone

OH

HO

HO

O

O

21-Hydroxyprogesterone

HO

O

O

Corticosterone

HO

HO

O

CHOO

Aldosterone

HO

HO

Physiological Functions and Physiological Functions and Pharmacological Effects:Pharmacological Effects:

Carbohydrates and Proteins Metabolism:Carbohydrates and Proteins Metabolism: Stimulate glucose formation in the brain.Stimulate glucose formation in the brain. Decrease peripheral utilization of glucose.Decrease peripheral utilization of glucose. Promote storage of glucose in the liver.Promote storage of glucose in the liver. Promote gluconeogenesis.Promote gluconeogenesis.

Lipids Metabolism:Lipids Metabolism: Redistribution of body fat (Buffalo hump, Redistribution of body fat (Buffalo hump,

Moon face).Moon face). Enhance lipolyses of Triglycerides.Enhance lipolyses of Triglycerides.

Electrolyte and Water balance:Electrolyte and Water balance: Enhance reabsorption of sodium and water Enhance reabsorption of sodium and water

into plasma.into plasma. Increase urinary excretion of potassium.Increase urinary excretion of potassium.

Blood Picture:Blood Picture: Increase hemoglobin and Red blood cells.Increase hemoglobin and Red blood cells. Decrease white blood cells.Decrease white blood cells.

Anti-inflammatory effects:Anti-inflammatory effects: Suppress inflammations regardless to their Suppress inflammations regardless to their

cause.cause.

Immunosuppressive Effects:Immunosuppressive Effects: Decrease immunity as a result of decrease Decrease immunity as a result of decrease

the WBC’s.the WBC’s.

Cell Growth:Cell Growth: Retardation of cell division and cell Retardation of cell division and cell

growth.growth.

Disease Disease States:States:

Addison’s disease:Addison’s disease: Rare syndrome 1/100,000 due to Hypoadrenalism.Rare syndrome 1/100,000 due to Hypoadrenalism. Causes:Causes:

Atrophy of adrenal gland.Atrophy of adrenal gland. Tuberculoses.Tuberculoses. Low level of ACTH.Low level of ACTH.

Symptoms:Symptoms: Weakness, fatigue, apathy, depression and irritability.Weakness, fatigue, apathy, depression and irritability. Anemia and low blood pressure.Anemia and low blood pressure. Loss of sodium and dehydration.Loss of sodium and dehydration. Hypersensitivity to Insulin.Hypersensitivity to Insulin. Hyper pigmentation.Hyper pigmentation. Nausea and vomiting.Nausea and vomiting.

Cushing’s disease:Cushing’s disease: Rare syndrome 2- 5/Million due to Hyperadrenalism.Rare syndrome 2- 5/Million due to Hyperadrenalism. Causes:Causes:

Tumor of the Adrenal Cortex.Tumor of the Adrenal Cortex. Tumor of the Pituitary gland.Tumor of the Pituitary gland.

Symptoms:Symptoms: Alteration of fat distribution.Alteration of fat distribution. Hypertension.Hypertension. Osteoporosis.Osteoporosis. Growth retardation.Growth retardation. Decrease Immunity.Decrease Immunity.

Conn’s syndrom:Conn’s syndrom: Causes:Causes:

Inability of adrenal cortex to carry out 17Inability of adrenal cortex to carry out 17-hydroxylation of -hydroxylation of pregnenolone. That leads to low level of Cortisol and high level pregnenolone. That leads to low level of Cortisol and high level of Aldosterone.of Aldosterone.

Symptoms:Symptoms: Hypertension.Hypertension. Alkalosis.Alkalosis. Polyuria.Polyuria. Edema.Edema.

PharmacokinetiPharmacokinetics:cs: Absorption:Absorption:

Well absorbed from all sites of administration.Well absorbed from all sites of administration.

Plasma Protein binding:Plasma Protein binding: 90% to albumin or globulin.90% to albumin or globulin.

Half life (tHalf life (t1/21/2):): 1- 1.5 hr.1- 1.5 hr.

Metabolism and Excretion:Metabolism and Excretion: Excreted in urine after glycosylation with Excreted in urine after glycosylation with

glucuronic acid.glucuronic acid.

O

O

OH

HO

HO

A B

C D

Structure-Activity Relationship

Essential for activity

1

2

3

4

5

9

10

19

18

11 13

14

16

17

1, 2 Double bond improve carbohydrate

metabolism to Na+ retention

-CH3 increaseglucocorticoid activity

6

-CH3 in Cortisol increase all activities

-CH3 in Prednisolone increase antiinflammatory activity

&Decrease Na+ retaining activity

9-Fluoro increase all activitiesF Br Cl

Essential for antiinflammatory activity& carbohydrate regulatory activity

12

-F increase all activities if no OH at C-17-F with 16dihydroxy--inactive compounds

CH3 or OH eleminate

Na+ retention activity

Essential for activity

Essential for antiinflammatory activity

Ether & esters increase antiinflammatory &

glucocorticoid activities

21

Halogen & halomethylene greatly increase Topical antiinflammatory activity

Adrenocorticoid DrugsAdrenocorticoid Drugs Systemic Corticosteroids:Systemic Corticosteroids:

They can be administered by IV, IM injections, oral, topical or by They can be administered by IV, IM injections, oral, topical or by inhalation.inhalation.

They can be short, intermediate or long-acting. Unlike natural They can be short, intermediate or long-acting. Unlike natural corticoids they do not undergo first pass metabolism.corticoids they do not undergo first pass metabolism. Cortisone and Cortisone acetate:Cortisone and Cortisone acetate:

Can be given orally or by IM injection.Can be given orally or by IM injection. Acetate has longer duration of action.Acetate has longer duration of action. Drug of choice in replacement therapy.Drug of choice in replacement therapy.

O

O

OH

HO

O

O

O

OH

HO

HO

Cortisone CortisolHydrocortisone

Fludrocortison:Fludrocortison: 99-fluorocortisone. -fluorocortisone. 10 times more active than cortisone as antiinflammatory.10 times more active than cortisone as antiinflammatory. 300- 800 times more active as mineralocorticoids.300- 800 times more active as mineralocorticoids.

Prednisone and Prednisolone:Prednisone and Prednisolone: They are They are ΔΔ1 1 corticoids. corticoids. 3, 4 times more active than cortisone and hydrocortisone.3, 4 times more active than cortisone and hydrocortisone. Prepared by microbial dehydrogenation (Prepared by microbial dehydrogenation (Corynebacterium Corynebacterium

simplexsimplex) or chemically using SeO) or chemically using SeO22..

O

O

OH

HO

O

O

O

OH

HO

HO

Prednisone Prednisolone

Triamcinolone:Triamcinolone: 99-fluoro, 16-fluoro, 16-hydroxyprednisolone.-hydroxyprednisolone. Activity equal to prednidolone but with less Activity equal to prednidolone but with less

mineralocorticoid activity.mineralocorticoid activity.

Dexamethasone:Dexamethasone: 99-fluoro, 16-fluoro, 16-methylprednisolone.-methylprednisolone. 5- 7 times more active than prednidolone.5- 7 times more active than prednidolone.

Betamethasone:Betamethasone: 99-fluoro, 16-fluoro, 16-methylprednisolone.-methylprednisolone. Slightly more active than Dexamethasone.Slightly more active than Dexamethasone.

O

O

OH

HO

Dexamethasone

F

CH3

O

O

OH

HO

Betamethasone

F

CH3

HOHO

Topical Corticosteroid:Topical Corticosteroid: Beclomethasone:Beclomethasone:

99-fluoro, 16-fluoro, 16-methylprednisolone.-methylprednisolone. 99-chloro analog of Betamethasone.-chloro analog of Betamethasone. Topical activity 500 times more than Topical activity 500 times more than

Betamethasone.Betamethasone.

O

O

OH

HO

Cl

CH3

HO

Inhaled Corticosteroids:Inhaled Corticosteroids: Beclomethasone 17, 21-dipropionate Beclomethasone 17, 21-dipropionate

(BDP):(BDP): Prodrug metabolized to more active 17-Prodrug metabolized to more active 17-

BMP.BMP. 17-BMP is 30 times more active than BDP.17-BMP is 30 times more active than BDP. Topical activity 500 times more than Topical activity 500 times more than

Betamethasone.Betamethasone.

Triamcinolone Acetonide:Triamcinolone Acetonide:

Clinical uses:Clinical uses: Hypoadrenalism.Hypoadrenalism. Rumatic diseases.Rumatic diseases. Renal diseases.Renal diseases. Collagen diseases.Collagen diseases. Ocular diseases.Ocular diseases. Skin diseases.Skin diseases. GIT inflammation.GIT inflammation. Liver diseases.Liver diseases.

Diagnostic uses:Diagnostic uses: Cause of Hyperadrenalism:Cause of Hyperadrenalism:

Non specific due to obesity or stress.Non specific due to obesity or stress. Cushing’s syndrome.Cushing’s syndrome.

2 mg Dexamethasone every 6 hr for 8 doses 2 mg Dexamethasone every 6 hr for 8 doses to diagnose the cause.to diagnose the cause.

Side effects:Side effects: Due to Prolonged use:Due to Prolonged use:

Fluid and electrolyte disturbances, edema and Fluid and electrolyte disturbances, edema and hypertension.hypertension.

Hyperglycemia and glucosuria.Hyperglycemia and glucosuria. Peptic ulcer.Peptic ulcer. OsteoporosesOsteoporoses MyopathyMyopathy Growth arrestGrowth arrest Increase susceptibility to infections.Increase susceptibility to infections.

Withdrawal Symptoms:Withdrawal Symptoms: Rapid withdrawal after prolonged use leads to Rapid withdrawal after prolonged use leads to

sever hypoadrenalism.sever hypoadrenalism.