Pharma - 4th Asessment - Mineralo-glucocorticoids - 2007

Adrenal Cortex  Zona Glomerulosa – Mineralocorticoids  Zona Fasiculata –Glucocorticoids  Zona Reticularis – Sex hormones

HYPOTHALAMUS CRH + ADRENOHYPOPHYSIS ACTH

_ _ CORTISOL

+ ADRENAL CORTEX

Glucocorticoid-Binding Proteins  80% Transcortin  10% Albumin  10% Free

Aldosterone-Binding Proteins  10% Transcortin  50% Albumin  40% Free

Cell membrane

R St

R

+ St

Nucleus

Cytoplasm

St

DNA R St mRNA mRNA Specific Proteins )e.g. enzymes( Glucocorticoid response

21 CH2OH 20 C 18 11

12

19 1 3 O

4

10 5

13 14

9 6

17 16 15

O OH

8 7

DEOXYCORTICOSTERONE CORTICOSTERONE – 11-OH CORTISOL - 17 – OH PREDNISOLONE – 1,2 - Double Bond FLUROCORTISOL – 9 - F TRIAMCINOLONE – 16 – OH DEXAMETHASONE – 16 – CH3

Glucocorticoids-Physiological Actions   Plasma glucose and FFA   Protein synthesis and  degradation   Myocardial contractility   Sensitivity of myocardium to CA   Muscle work capacity   Adrenal CA synthesis

Glucocorticoids-Pharmacological Actions   Vascular permeability   Neutrophil migration and phagocytosis   Mast cell histamine release   Antibody formation   Thymocytes and lymphocytes mass

STEROID

ANTI-INFLAMMATORY ACTIVITY

Short-Acting 1. Cortisol 2. Cortisone

1 0.8

Intermediate-Acting )12-36 hr( 1. Prednisolone 5 2. Prednisone 4 3. α1-methyl prednisone 4 4. Triamcinolone 5 5. 9-flurocortisol 10 Long-Acting )36-54 hr( 1. Betamethasone 2. Dexamethasone

40 30

SALT RETAINING EQUIVALENT ACTIVITY ORAL DOSE )mg( 1 0.8

20 25

0.3 0.3

5 5

0.3 0 125

5 4 0.1

0 0

0.6 0.75

Glucocorticoids-Replacement Therapy  Addison disease - primary  Adrenocortical insufficiency - secondary  Congenital adrenal hyperplasia  Cushing’s syndrome

Addison’s Disease Clinical Features  Hyperpigmentation  Weakness and weight loss  Postural hypotension   Glucose level

Congenital Adrenal Hyperplasia  ZG-21-Hydroxylase – salt looser  ZF-21-Hydroxylase – short statur   11ß-Hydroxylase – hypertension, hypokalemia   17α-Hydoxylase - hypogonadism

CHOLESTEROL )1( Pregnenolone

3

)2( Deoxycorticosterone

4



)5(

Progesterone

Corticosterone

)3(

)8(

17-Hydroxyprogesterone



)4(

18-Hydroxycorticosterone

11-Deoxycortisol

)9(

)5(





ALDOSTERONE

CORTISOL

1. 20,22-Desmolase 2. 3-ß-dehydrogenase 3. 17-α-hydroxylase

4. 21-Hydroxylase 5. 11-ß-Hydroxylase 6. 17,20-Desmolase

17-Hydroxypregnenolone )6( Dehydroepiandrosterone )2( Androstenedione )7( TESTOSTERONE  ESTRADIOL 7. 17-ß-dehydrogenase 8. 18-Hydroxylase 9. 18-Dehydrogenase

ZG-21-Hydroxylase Deoxycorticosterone )5( Corticosterone )8(  18-Hydroxycorticosterone )9(  ALDOSTERONE

4 Progesterone

ZF-21-Hydroxylase 17-Hydroxyprogesterone )4( 11-Deoxycortisol

TESTOSTERONE

)5(





ESTRADIOL

CORTISOL

 11ß-Hydroxylase – hypertension,hypokalemia CHOLESTEROL )1( Pregnenolone )2(  Progesterone )3( 17-Hydroxyprogesterone )4( 11-Deoxycortisol )5(  CORTISOL

 17α-Hydoxylase - hypogonadism CHOLESTEROL )1( Pregnenolone

3 17-Hydroxypregnenolone )6( Dehydroepiandrosterone )2( Androstenedione )7( TESTOSTERONE  ESTRADIOL

Cushing’s Syndrome-Pathogenesis  Adrenal tumor  Excessive pituitary ACTH secretion  Ectopic ACTH release

Cushing’s Syndrome-Clinical Features  Muscle wasting  Poor wound healing  Rounded face and trunk obesity  Hypertension and Diabetes  Osteoporosis and Thinning of the skin

Glucocorticoids-Pharmacological Use  Rheumatoid arthritis  Lupus erythematosis  Asthma  Polymiositis  Chronic lymphocytic leukemia  Organ transplant rejection  Septic shock

Side Effects A. Hematological and Immunological 1. Leukemia 2. Lymphopenia 3. Eosinopenia 4. Decrease resistance to infections B. Gastrointestinal 1. Peptic ulceration 2. Fatty liver 3. Nausea & vomiting

C. Metabolic 1. Hyperglycemia 2. Protein wasting 3. Hyperlipidemia 4. Obesity D. Muscoskeletal 1. Myopathy 2. Growth failure 3. Osteopenia E. Ocular 1. Cataracts 2. Increased intraocular pressure

F. CNS 1. Insomnia 2. Depression 3. Psychosis G. Fluid and Electrolyte 1. Na+ H2O retention 2. K + Hypokalemia 3. Hypertension 4. Negative calcium balance

H. Dermatological 1. Skin Atrophy 2. Perioral dermatitis 3. Impaired wound healing 4. Fungal infections

Glucocorticoids-Contraindications  Peptic Ulcer  Heart disease and Hypertension  Psychoses  Diabetes  Osteoporosis  Glucoma and Herpes complex

Glucocorticoids-Diagnosis  Dexamethasone suppression test  Metyrapone stimulation test  ACTH and cosyntropin test

Glucocorticoids-Inhibitors  Aminogluthemid  Metyrapone  Ketoconazole