CORTICOSTEROIDS ROLE IN RESPIRATORY MEDICINE

Dr. Bindu Goyal JR, Pulmonary Medicine GMC Patiala.

1

INTRODUCTION
Corticosteroids or corticoids refers to natural gluco and mineralocorticoids and their synthetic analogues. Natural : Adrenal cortex produces mineralocorticoids i.e. aldosterone & glucocorticoids i.e. hydrocortisone (cortisol) Synthetic steroids : include Prednisolone, Methylprednisolone, dexamethasone, Betamethasone, Deflazacort and Triamcinolone
2

Cholesterol Oestriol Dehydro-epi androsterone Androstenedione

Pregnenolone

17- - Hydroxy pregnenolone 17- Hydroxy progesterone

21, hydroxylase

Progesterone

Oestrone

11-Desoxycorticosterone

11- Desoxycortisol Corticosterone

11, hydroxylase

18-Hydroxycorticosterone ALDOSTERONE CORTISOL TESTOSTERONE OESTRADIOL

4

Basal secretions
Group Glucocorticoids Hormone Cortisol Corticosterone Daily secretions 5 30 mg 2 5 mg

Mineralocorticoids Aldosterone 5 150 mcg 11- deoxycorticosterone Trace Sex Hormones Androgen Progestogen Oestrogen DHEA Progesterone Oestradiol 15 30 mg 0.4 0.8 mg
Trace

From Essential of Pharmacotherapeutics, ed. FSK Barar. P.351

Circadian Rhythm

Mechanism of action
Corticosteroids act via receptors which are present in almost all the cells of the body. Corticosteroids diffuse in to target cells where they combine with steroid receptors in the cytoplasm. The activated drug receptor complex enters nucleus and binds to an element on RNA molecule mRNA protein synthesis steroid response.
8

Physiological effects
Alteration in carbohydrate, protein and fat metabolism. Maintenance of fluid and electrolyte balance. Normal functioning of CVS, immune system, kidney, skeletal muscles and nervous system. Provides resistance to stress and noxious stimuli and environment changes. Permits and facilitates action of other hormones permissive action.
9

Anti-inflammatory effect
Recruitment of WBC & monocyte- macrophage into affected area & elaboration of chemotactic substances. Lipocortin ELAM1 & ICAM-1 in endothelial cells TNF from phagocytic cells IL1 from monocyte-macrophage Formation of Plasminogen Activator Action of MIF & fibroblastic activity
10

Expression of cyclooxygenase II

Anti-inflammatory actions of corticosteroids

Corticosteroid inhibitory effect

11

Immunosuppressive & anti-allergic actions

Suppresses all types of hypersensitivity & allergic phenomenon At High dose: Interfere with all steps of immunological response Causes greater suppression of CMI (graft rejection & delayed hypersensitivity) Transplant rejection: antigen expression from grafted tissues, delay revascularization, sensitization of T lymphocytes etc.

12

13

Pharmacokinetics
Absorption: all are rapidly & completely absorbed.
oral bioavailability of synthetic steroids is high. (Except DOCA)

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

Metabolism:
by liver enzymes, conjugation & excretion by urine Hydrocortisone undergoes high 1st pass metabolism. Synthetic steroids undergo reduction in liver to active metabolites. partly excreted as 17-ketosteroids. t1/2 of cortisol 1.5 hours
14

PREPARATIONS

15

CLASSIFICATION
By chemical structure : 4 gps.
Group A Group B Group C Group D

By Route of administration By duration of action.

16

ROUTES OF ADMINISTRATION
Oral forms Prednisone Prednisolone / Methylprednisolone Betamethasone /dexamethasone Fludrocortisone Hydrocortisone /cortisone Triamcinolone Deflezacort Injectable forms Hydrocortisone Betamethasone dexamethasone Prednisolone Methylprednisolone Triamcinolone

Topical steroids Betamethasone Dexamethasone Triamcinolone Clobetasol Mometasone flucinolone

Inhaled steroids Flunisolide Fluticasone propionate Triamcinolone acetonide Beclomethasone dipropionate Budesonide Mometasone Ciceclosonide

17

Short Acting Preparations (t1/2 < 12 h) (8-12 hrs) Drug Cortisol (8-12 hrs) Antiinflam. 1 Salt retaining 1 Topical 1
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) (18-36 hrs)

Prednisone
Prednisolone

4 5

0.8 0.3

0 4

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 18 i.m. &intrarticular inj.

Methyl prednisolone
Triamcinolone

5 5

0 0

5 5

Drug

AntiSalt inflam. Retaining

Topical

Preapartions & dose

Long Acting Preparations (t1/2 > 36 h) (36-54 hrs) Dexamethasone 25 0 10 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)

Betamethasone

25

10

Paramethasone

10

MINERALOCORTICOIDS

Fludrocortisone

10

150

10

100 mcg tab.

DOCA Aldosterone

0 0.3

100 3000

0 -

2.5 mg sublingual Not used clinically 19

Equivalent glucocorticoid oral doses

Prednisolone 5mg Hydrocortisone 20mg Betamethasone 750mcg Dexamethasone 750mcg Methylprednisolone 4mg Deflazacort 6mg Triamcinolone 4mg
20

Inhaled Steroids
Beclomethasone dipropionate Fluticasone propionate Budesonide 50,100,200 mcg/md MDI 100, 200, 400 mcg Rota caps 50,125 , 250 mcg/md MDI 100, 250, 500 mcg Rotacaps 0.5, 2.0 mg/ml respules 100,200 mcg/md MDI 100, 200, 400 mcg Rotacaps 0.5, 1.0 mg/ml respules

21

Inhaled steroids
Budesonide :
Low dose
Adult: 200-400 mcg Child: 100-200mcg

Medium dose
Adult: 400-800 mcg Child : >200-400mcg

High dose
Adult: >800-1600 mcg Child: >400mcg

Fluticasone :
Low dose
Adult: 100-250mcg) Child: 100-200mcg

Medium dose
Adult: >250-500 mcg Child: >200-500 mcg

High dose
Adult: >500-1000mcg Child: >500 mcg
22

Inhaled steroids
Beclomethasone Dipropionate
Low dose
Adult: 200-500 mcg/day Child: 100-200 mcg/day

Medium dose
Adult: >500-1000 mcg/day Child: >200-400 mcg/day

High dose
Adult: >1000-2000 mcg/day Child: >400 mcg/day

Triamcinolone
Dose per puff: 100 mcg/puff Low dose
Adult: 400-1000 mcg/day Child: 400-800 mcg/day

Medium dose
Adult: >1000-2000 mcg/day Child: >800-1200 mcg/day

High dose
Adult: >2000 mcg/day Child: >1200 mcg/day
23

Inhaled steroids
Mometasone
Low dose
Adult: 200-400 mcg/day Child: 100-200 mcg/day

Medium dose
Adult: >400-800 mcg/day Child: >200-400 mcg/day

High dose
Adult: >800-1200 mcg/day Child: >400 mcg/day

Cicelosonide
Low dose
Adult: 80-160 mcg/day Child: 80-160 mcg/day

Medium dose
Adult: >160-320 mcg/day Child: >160-320 mcg/day

High dose
Adult: >320-1280 mcg/day Child: >320 mcg/day
24

Clinical application
Therapeutic Replacement therapy Non endocrine uses Diagnostic

Physiological doses are used for replacement therapy in endocrine diseases. Supra physiological doses are used for their anti inflammatory effects in arthritis, asthma, inflammatory bowel diseases etc. In organ transplant and autoimmune disorders, steroids are used for their immunosuppressive effect.
25

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) To establish steroid resistant asthma- <15% increase in
FEV1 after 20 mg/day oral prednisolone for 7 days.
26

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)
27

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.)

28

RESPIRATORY DISEASES

29

Bronchial Asthma
Indications : Status asthmatic
methyl prednisolone 120 mg / day iv in divided doses for 24 to 72 h, oral prednisone at 60 mg daily, (when the FEV1 reaches a threshold of 50 percent of predicted normal) 2 7 days ; gradual tapering of the dose over 1 to 3wk.

Systemic steroids not preffered in chronic stable asthma. Inhaled steroids preferably in combination with LABA are prescribed in moderate to severe asthma.

30

COPD
Indications : Stage 3 & 4 ; FEV1<50% ; frequent exacerbations- inhaled corticosteroids are given in combination with LABA. In case of acute exacerbation, a short course of medium dose i.e. 40 mg/day is given for short course, 7-14 days. Long course therapy with corticosteroids is avoided as it leads to steroid induced myopathy which further worsens the respiratory functioning.
31

Tuberculosis
Indications : TB of adrenal gland or associated addisons disease ; absolute indication. Seriously ill patient/ miliary TB/ severe pulmonary TB (2030mg/day) Disseminated TB with hypoxemia; higher dose given (6080mg/day) AIDS patient with severe manifestations Hypersensitivity reactions to drugs Tubercular meningitis (60-80mg/day iv in divided doses; converted to oral and tapered gradually over 8-12 wks) Genitourinary TB / Tubercular pericarditis / pleural effusion/tubercular lymphadenitis. Endobronchial tuberculosis esp. children Local steroid therapy for BCG related keloid reaction. C/I Intestinal TB ( coz of risk of silent perforation) Dose usually 20mg/day ; 40 mg if rifampicin is used ; higher in severe conditions. 32 Caution never use without adequate chemotherapy cover.

ARDS
Steroids may have a role in chronic ARDS in patients, without infection, with high O2 requirements days to weeks into the disease process. The patient must have no demonstrable infection Steroids should not be started less than 7 days, or more than 28 days, from admission. The patient should not have a history of gastric ulceration of active gastrointestinal bleeding. The patient should have evidence of ALI and require an FiO2 >/= 50% The steroid regimen: Loading dose 2mg/kg Then 2mg/kg/day from day 1 to 14 Then 1mg/kg/day from day 15 to 21 Then 0.5mg/kg/day from day 22 to 28 Then 0.25mg/kg/day on days 29 and 30 Finally 0.125mg/kg on days 31 and 32.
33

Others
IPF & other ILDs
1st line therapy as per ATS guidelines is combination of corticosteroids and immunosuppressive agents Dose - 0.5 mg/kg/day orally 4wks ; 0.25mg/kg/day orally 8wks ; 0.25mg/kg every other day.

Hypersensitivity pneumonitis
indicated in severely symptomatic patient. Dose - 40-60 mg/day 2wks ; tapered over 2-4wks.
34

Contd
Sarcoidosis
Mainstay of treatment Dose - 20-40mg/day 2 wks ; tapered by 5mg every 2 wks ; maintenance dose of 10-15mg/day 8-12mths.

ABPA
Mainstay of treatment Dose- 0.5-1.0mg/kg/day orally 1-2 wks; 0.5mg/kg alternate day 6-12wks / maintenance dose of 7.5 mg/day.
35

Contd
Antenatal
used frequently in premature labour. Decrease incidence of RDS, IVH and death. Dose Betamethasone 12 mg im every 24 hrs 2doses or Dexamethasone 6 mg im every 12 hrs 4 doses administered to women with premature labour between 27 34 wks.

Pneumocysttis carnii pneumonia

In AIDS patients with moderate to severe hypoxia. may prevent intubation by reducing pulmonary inflammation. 40 - 60 mg / day in divided doses orally / iv in 1st 72 hrs; then tapered over 2 wks. 36

Contd
Bronchiectasis
controversial may reduce sputum volume & purulence and decrease exacerbations.

Cystic fibrosis
to decrease airway inflammation.

Community acquired pneumonia

in patients with adrenal insufficiency in severally ill patients.
37

Contd
Lung transplantation
pre-operatively Methyl prednisolone 500mg iv; postop methyl prednisolone 125 mg iv 8 hrly prednisolone 20mg/day for 7-14 days.

Pulmonary vasculitidis
Wagener's granulomatosis, churg strauss syndrome, poly arteritis nodosa.

Pulmonary eosinophillic diseases Systemic diseases

38

Non-endocrine diseases
1. Arthritis
Prednisolone 5 or 7.5 mg (5-10 mg/day) Intra-articular injection (prednisolone 10-40mg; triamcinolone 5-20 mg) 2. Rheumatic carditis Severely ill pts. Prednisolone 40mg in divided doses or 1-2 mg/kg 3 days; followed by reduction of 5 mg / wk. 3. Allergic diseases Anaphylactic shock, blood transfusion reaction, hay fever Prednisolone (short course)
39

Non-endocrine diseases
4. Renal diseases (Nephrotic syndrome)
Prednisolone 60 mg (2mg/kg) in divided doses for 3 4 weeks followed by gradual tapering over 6 8 wks. If remission occurs continue for 1 year Do not modify the course of disease; Some may benefit 5. 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
40

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

41

Non-endocrine diseases
8. Diseases of intestinal Tract Ulcerative colitis: cortisol retention enema 9. Cerebral oedema Questionable value in cerebral oedema following trauma, cerebrovascular oedema Valuable in oedema associated with neoplasm and parasites 10. Malignancy Part of multi drug regimens for acute lymphatic leukaemia (children), chronic lymphatic leukaemia (adult)
42

Non-endocrine diseases
11. 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

12. Shock
Often helpful but no convincing evidence

13. 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
43

Non-endocrine diseases
- Miscellaneous

Organ transplantation Bells palsy Thrombocytopenia Myasthenia gravis Spinal cord injury

44

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)  Low dose prednisolone upto 7.5mg/day even for
long term
45

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.

46

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

47

Adverse effects
Two types :
From abrupt withdrawal Chronic therapeutic use of high doses.

1. Abrupt Withdrawal Flare up of underlying disease Suppression of HPA axis and acute adrenal insufficiency. Increase in ICT and papilledema.
48

Cushingoid habitus

High blood sugar High blood pressure Vertigo Blurred vision Female baldness Menstrual irregularities Hirsutism Severe depression Cognitive impairment Emotional instability Easy fatigability

49

Cautions and contraindications

Infections (flare up)
HIV/AIDS previous TB wound infection Herpes simplex viral & fungal infections

Conditions which will be exacerbated

Hypertension, diabetes, heart failure, osteoporosis, glaucoma, epilepsy, mood disorders, pressure sores.

Conditions where potassium loss will prove dangerous Situations where muscle weakening could be problematic

Liver failure

Recent myocardial infarction, muscle wasting, elderly, bedridden.

50

Cautions and contra-indications

Masking of serious symptoms: peptic ulcer, inflammatory bowel disease, pneumonia Corticosteroids worsen cardiovascular risk factors. Their long-term use should be carefully evaluated in patients already at high risk of stroke or heart attack. Lower doses are needed in patients unable to eliminate drugs at the normal rate:
hypothyroidism, liver failure, renal failure, elderly.
51

Cautions and contra-indications

Pregnancy. The risks of intrauterine growth retardation with repeated courses of intra-muscular corticosteroids are administered to prevent respiratory distress of the new-born are currently under investigation. When cortIcosteroids are administered for severe maternal disease, the benefits are likely to outweigh any risks. Most prednisolone (unlike dexamethasone) is inactivated by the placenta. Breastfeeding: avoid if >40mg prednisolone /day (or equivalent) administered. Doses below those causing systemic side effects are considered safe.
52

Interactions
1. Some drugs intensify the adverse reactions of corticosteroids:
Increased risk of gastro-intestinal bleeding: alcohol, anticoagulants, aspirin, NSAIDs Increased fluid retention and hypertension: beta2 agonists, NSAIDs, sodium-containing preparations, oestrogens, liquorice, ginseng, some Asian herbal mixtures Increased potassium depletion: beta2 agonists, diuretics, digoxin, laxatives
53

Interactions
2. The effects of some drugs and appliances are antagonised:
anti-epileptics, anti-diabetics, anti-hypertensives, growth hormone, intra-uterine contraceptive devices.

3.

The dose of corticosteroids is effectively reduced by:

co-administration with antacids, within 2 hours carbamazepine, phenytoin, rifampicin, theophylline

4.

The dose of corticosteroids is effectively increased by:

erythromycin, ketoconazole, itraconazole, ciclosporin, some antivirals
54

Misuses
Illogical use by unqualified practitioners/faith healers
Excessive Dose Prolonged Duration No clinical Indication

Irrational/Over use in medical practice Misuse of anabolic steroids e.g

Sick debilitated patients Athletes, body builders
55

56

THANK YOU

57