Corticosteroids (2 of 2)

Corticosteroids
History Synthesis Pharmacological Actions Pharmacokinetics Preparations Therapeutic principles Uses: Therapeutic Diagnostic Adverse reactions Contraindications Precautions during therapy Glucocorticoid antagonists

Dosage schedule & Steroid withdrawal

Pharmacokinetics
Absorption: all are rapidly & completely absorbed
(Except DOCA)

Transport:
Transcortin 75% Albumin 5% Free form 20%

Metabolism:
by liver enzymes, conjugation & excretion by urine partly excreted as 17-ketosteroids. t1/2 of cortisol 1.5 hours

Preparations
Glucocorticoids
Short acting Intermediate acting Long acting

Mineralocorticoids Inhalant steroids Topical steroids

Short Acting Preparations (t1/2 < 12 h) Drug Cortisol Anti-inflam. Salt retaining 1 1.0
Preapartions & dose

5 mg tablet 100 mg/vial (i.m., i.v) Topical; enema 5 mg tablet 25 mg/vial (i.m)

Cortisone

0.8

0.8

Intermediate Acting Preparations (t1/2 = 12 -36 h)

Prednisone
Prednisolone Methyl prednisolone Triamcinolone

4
5 5 5

0.8
0.3 0 0

5, 10 mg tablet 20 mg/vial (i.m, intrarti) 0.5, 1.0 gm inj. for i.m. or slow i.v. 4 mg Tab., 10, 40 mg/ml for i.m. & intrarticular inj.

Drug

AntiSalt retaining inflam.

Preapartions & dose

Long Acting Preparations (t1/2 > 36 h) Dexamethasone Betamethasone Paramethasone 25 25 10 0 0 0 0.5 mg tab. 4mg/ml inj (i.m., i.v.) 0.5, 1 mg tab. 4mg/ml inj (i.m., i.v.) 2- 20 mg/day (oral)

Mineralocorticoids - Preparations
Drug Fludrocortisone DOCA Antiinflammatory 10 0 Salt retaining 150 100
Preapartions & dose

100 mcg tab. 2.5 mg sublingual Not used clinically

Aldosterone

0.3

3000

Inhalant Steroids: Bronchial Asthma

Beclomethasone dipropionate Fluticasone propionate 50,100,200 mcg/md inhaler 100, 200, 400 mcg Rotacaps 25, 50 mcg/md inhaler 25,50,125/md MDI 50, 100, 250 mcg Rotacaps 100,200 mcg/md inhaler 0.25, 0.5 mg/ml respules

Budesonide

Topical steroids
Drug
Beclomethasone dipropionate

Topical preparation
0.025 % cream

Potency
Potent Potent Potent

Betamethasone benzoate 0.025 % cream, ointment & B. valerate 0.12 % cream, ointment Clobetasol propionate 0.05 % cream

Halcinonide
Triamcinolone actonide Fluocinolone actonide Mometasone Fluticasone Hydrocortisone acetate

0.1 cream
0.1 % ointment 0.025% ointment 0.1 % cream, ointment 0.05 % cream 2.5 % ointment

Potent
Potent Moderate Moderate Moderate Moderate

Hydrocortisone acetate

0.1 1.0% ointment

Mild

Topical Steroids
Benefits due to anti-inflammatory, immunosuppressive, vasoconstrictor and anti-proliferative actions

Good response
Atopic eczema,

Slow response
Cystic acne

Allergic contact dermatitis, Alopecia areata Lichen simplex, Discoid LE Primary irritant dermatitis, Hypertrophied scars Seborrheic dermatitis, Keloids Psoriasis of face, Lichen planus Varicose eczema Psoriasis of palm, sole, elbow & knee

Topical steroids are combined with antimicrobial agents for

Impetigo Furunculosis Secondary infected dermatoses Napkin rash Otitis externa Intertriginous eruptions

Guidelines for topical steroids

Penetration differs at different sites:
High: axilla, groin, face, scalp, scrotum Medium: limbs, trunk Low: palm, sole, elbow, knee

Occlusive dressing enhance absorption (10 fold) Absorption is greater in infants & Children Absorption depends on nature of lesion:
High: atopic & exfoliative dermatitis Low: hyperkeratinized & plaque forming lesions

More than 3 applications a day is not needed Choice of vehicle is important

Lotions & creams: for exudative lesions Sprays & gels: for hairy regions Ointments: for chronic scaly lesions

Therapeutic principles

Dose selection by trial & error; Needs frequent

evaluation Single dose: No harm Few days therapy unlikely to be harmful Incidence of side effects related to duration of therapy Use is only palliative (except replacement therapy) Inter-current illness: Dose is doubled Abrupt cessation of prolonged high dose leads to adrenal insufficiency (contraindicated)

Dosage schedule
Goal of therapy:
To relieve pain or distressing symptom (e.g.,
rheumatoid arthritis): start with low dose To treat life threatening condition (e.g., pemphigus): initial dose must be high

Prevention of HPA axis suppression:

Single dose (morning) Alternate dose therapy (short lived glucocorticoids) Pulse therapy (higher glucocorticoid therapy)

Steroid withdrawal
Longer the duration of therapy, slower the withdrawal

Less than 1 week: withdrawal in few steps

Rapid withdrawal: 50% reduction of dose every day Slow withdrawal: 2.5 5 mg prednisolone reduced at an interval of 2-3 days

Longer period & high dose:

Halve the dose weekly until 25 mg prednisolone or equivalent is reached Later reduce by about 1mg every 3-7 days.

HPA axis recovery may take months or up to 2 years

Therapeutic uses: Endocrine & Non-endocrine

Endocrine Disorders
Acute adrenal insufficiency Primary adrenocortical insufficiency Ad. Insufficiency second. to Ant. Pituitary Congenital adrenal hyperplasia
Isotonic saline Glucose Hydrocortisone inj. i.v. Gradullay substitue with i.m or oral Addisons disease Oral cortisol (20 +10 mg) Fludrocortisone (0.1 or 0.2 mg daily, p.o.)

Congenital adrenal hyperplasia

Familial disorder Signs of cortisol deficiency Increased ACTH Excessive androgens

Deficiency of 21- hydroxylase and 11 - hydroxylase enzymes

Cholesterol 17-- Hydroxy pregnenolone Oestriol Dehydro-epi androsterone

Pregnenolone

Progesterone

17- Hydroxy progesterone

21, hydroxylase

Androstenedione

Oestrone

11-Desoxycorticosterone

11- Desoxycortisol Corticosterone

11, hydroxylase

18-Hydroxycorticosterone
ALDOSTERONE CORTISOL TESTOSTERONE OESTRADIOL

Non-endocrine diseases (1/7)

1. Arthritis
Not the drug of first choice Prednisolone 5 or 7.5 mg Intra-articular injection

2. Rheumatic carditis Not responding to salicylates Severely ill pts. Prednisolone 40mg in divided doses Salicylates given concurrently to prevent reactivation

Non-endocrine diseases (2/7)

3. Renal diseases (Nephrotic syndrome)
Prednisolone 60 mg in divided doses for 3 4 weeks If remission occurs continue for 1 year Do not modify the course of disease; Some may benefit 4. Collagen diseases DLE, pemphigus vulgaris, polyarteritis nodosa Defect in connective tissue proteins in joints, various organs and deeper layer of skin Prednisolone 1mg/Kg start; gradually reduce the dose

Non-endocrine diseases (3/7)

5. Allergic diseases
Anaphylactic shock, blood transfusion reaction, hay fever Prednisolone (short course) 6. Bronchial asthma Not routinely used except in Status asthmaticus Methyl prednisolone sodium i.v. given followed by oral prednisolone Inhaled steroids (Minimal HPA axis suppression)

Non-endocrine diseases (4/7)

7. Ocular diseases
Outer eye & anterior segment: local application Posterior segment: systemic use Caution: bacterial, viral & fungal conjunctivitis 8. Dermatological conditions Pempigus: Life saving therapy is steroids Eczema, dermatitis & psoriasis: respond well

Non-endocrine diseases (5/7)

9. Diseases of intestinal Tract Ulcerative colitis: cortisol retention enema 10. Cerebral oedema Questionable value in cerebral oedema following trauma, cerebrovascular oedema Valuable in oedema associated with neoplasm and parasites 11. Malignancy Part of multi drug regimens for acute lymphatic leukaemia (children), chronic lymphatic leukaemia (adult)

Non-endocrine diseases (6/7)

12. Liver diseases
Subacute hepatic necrosis & chronic active hepatitis: Improves survival rates Alcoholic hepatitis: reserved for pts. with severe illness Non-alcoholic cirrhosis: helpful if no ascites

13. Shock
Often helpful but no convincing evidence

14. Acute infectious diseases

Helpful due to its anti-stress & anti-toxic effects Used in gram ve septicemia, endotoxic shock, TB meningitis, miliary T.B., encephalitis Appropriate anti-microbial agent is a MUST

Non-endocrine diseases (7/7)

- Miscellaneous

Organ transplantation Bells palsy Thrombocytopenia Myasthenia gravis Spinal cord injury Sarcoidosis

Diagnostic Uses Cushings syndrome:

ACTH dependent (pituitary tumor, ectopic
ACTH secreting tumors) Non-ACTH dependent (obesity, tumor of adrenal cortex) (Dexamethsone suppression test is done)

To locate the source of androgen production in hirusitism

(Dexamethasone suppress androgen secretion from ad.cortex)

Adverse reactions (1/2) Metabolic toxicity:

Iatrogenic Cushings syndrome Hyperglycaemia, glycosuria, diabetes Myopathy (negative nitrogen balance)
Osteoporosis (vertebral compression fracture) Retardation of growth (children) Hypertension, oedema,CCF Avascular necrosis of femur

Adverse reactions (2/2) HPA axis suppression Behavioral toxicity: Euphoria, psychomotor
reactions, suicidal tendency Ocular toxicity: steroid induced glaucoma, posterior subcapsular cataract.

Others:
Superinfections Delayed wound healing Steroid arthropathy Peptic ulcer Live vaccines are dangerous

Contraindications
Infections Hypertension with CCF Psychosis Peptic ulcer Diabetes mellitus Osteoporosis Glaucoma Pregnancy : (prednisolone preferred)

Precautions during therapy

Following examinations of the patient to be done before, during and after steroid therapy

Body weight X-ray of spine Blood glucose Examination of the eye B.P.

Glucocorticoids antagonists
Mitotane: structure similar to DDT, used in
inoperable adrenal cancer

Metyrapone: inhibit 11 -hydroxylase Aminoglutethamide: inhibit conversion of

cholesterol to pregnolone, medical adrenelectomy

Trilostane: inhibit conversion of pregnolone to

progesterone; used in Cushings syndrome

Ketoconazole: anti-fungal, inhibit CYP450

enzymes, inhibit steroid synthesis in ad.cortex and testis; used in Cushings syndrome & Ca.prostate

Mifepristone: glucocorticoid receptor antagonist;

anti-progesterone, used in Cushings syndrome

Cholesterol 17-- Hydroxy pregnenolone Oestriol Dehydro-epi androsterone

Pregnenolone

Progesterone

17- Hydroxy progesterone

21, hydroxylase

Androstenedione

Oestrone

11-Desoxycorticosterone

11- Desoxycortisol Corticosterone

11, hydroxylase

18-Hydroxycorticosterone
ALDOSTERONE CORTISOL TESTOSTERONE OESTRADIOL

Thanks for your patience