1
TREATMENT OF ADRENAL COETEX DISEASE :-
Adrenal cortex secrete a steroid molecules hormones that used in diagnosis & treatment of
adrenal function disorder . these hormone classified as 1- having as important effects on
intermediary metabolism(glucocoetecoids )cortisol . 2- having salt retaining activityies
(mineralocortecoids) aldosterone . 3-having androgenic or estrogenic activities .
A-naturally occurring glucocortecoids (cortisol ) , it synthesized from cholesterol , in absence
of stress about 10-20 mg daily secreted , rate of secretion is of circadian rhythm(more in
morning hours & after meals) , 90% binding to circulating cortisol binding globulin , 90
minutes their half-life , increase in case of given a large doses , under stress, hypothyroidism
& liver disease . 1% secreted as unchanged in urine , 20% of cortisol converted in kidney into
cortisone . their mechanism of action mediated via gluycocorticoids receptors .
Classification of corticosteroid drugs :-
1-short to medium acting glucocorticoid : like hydrocortisone(as topical ,IV, IM) ,
cortisone(as topical ,IV, IM) , prednisone orally only , prednisolone as orally , IM, IV &
topically , methyl- prednisolone & meprednisone both as oral , IV,IM .
2-inter-mediate acting glucocorticoids like : triamcinolone (as oral , topical , IM,IV ),
paramethasone(as oral ,IV ,IM) & fluprednisolone (orally only ) .
3-long acting glucocorticoids like : betamethasone & dexamethasone as orally , topically
, IM,IV .
4-mineralocorticoids like : fludrocortisone (as oral , topical IM,IV ) &
desoxycorticosterone acetate as IM, IV .
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CLINICAL PHARMACOLOGY
:-
A- diagnosis & treatment of disturbed adrenal function
;
1-Adrenocortical insufficiency including [a-chronic Addison’s disease by using 20-30
mg hydrocortisone /day the dose increase during the stress , need to give the patient salt
retaining hormone like fludrocortisone since hydrocortisone has some mineralocorticoid
activity .
b-acute state of disease that need correction of fluid & electrolytes , treatment of
underlying causes , hydrocortisone sodium succinate or phosphate in dose of 100 mg IV x
3/day till the patients become stable] .
2-adrenocortical hypo-hyper- function : including [a- congenital adrenal hyperplasia due
to a defect in cortisol synthesis( in high risky pregnant woman we can save the fetus by give
him dexamethasone) , in acute state treat the infant as above till the patient become stable
then oral hydrocortisone 12-18 mg/m
2
/day in two unequal doses that two-third at morning &
one-third at later afternoon . + fludrocortisone in dose 0.05-0.2 mg/day orally only .
b-Cushing’s syndrome (excessive glucocorticoid ) treated as follow : surgical removal of
tumor & irradiation , cortisol in large dose up to 300 mg during & follows surgical procedure
with a continuous IV infusion then gradually reduce the dose to normal level .
c-Aldosteronism(primary one) : treated by deoxycorticosteroid acetate 20 mg /day for 3
days or fludrocortisone 0.2 mg x 2 /day orally for 3 days . ]
3-using of glucocorticoid for diagnostic purpose : the dexamethasone suppressive test for
diagnosis of Cushing’s syndrome & differential diagnosis of psychiatric state by 1 mg of
dexamethasone at 11p.m orally & blood sample taken in the morning , in normal person
cortisol conc. less than 3 microgram/dL while in Cushing’s syndrome more than 5
2
microgram/dL .
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B- corticosteroid & stimulation of lung maturation in the fetus
:
treating of the
mother with large dose of glucocorticoid will reduce the incidence of respiratory distress
syndrome in the infants delivered prematurely , when deliver anticipated before 34 weeks of
gestation IM dexamethasone in dose of 12 mg follow by additional dose at 12 , 18 , 24 hours
later is commonly used .
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C- corticosteroid & non- adrenal disorders :
by their ability to suppress the
inflammatory & immune responses , by suing medium to intermediate acting glucocorticoids
(like prednisolone & prdnisone ) , on prolong uses we must do the following [1-chest-x ray &
tuberculin test since the steroid activate the disease ./2-take in consider osteoporosis , peptic
ulcer , diabetes . / 3-diet rich in potassium & low with sodium to prevent electrolyte
disturbance & hypertension . / 4-calories measurement to prevent obesity . /5-increase protein
intake to compensate the loss due to breakdown of protein for gluconeogenesis . /
6-approperiate antacid in patient prone to gastric distress . / 7-physical therapy + androgen to
limited glucocorticoids inducing osteoporosis .]. so such condition to be treated include :-
1-allergic reaction like angioneurotic edema , asthma , bee sting , contact dermatitis , drug
reaction , , allergic rhinitis , serum sickness , urticaria .
2-collagen vascular disorders like giant cell arteritis , lupus erythromatous , mixed connective
tissues syndrome , polymeylitis , ruhmatoid arthritis .
3-eye disease like acute uveitis , allergic conjunctivitis , optic neuritis .
4-infection like gram-ve septicemia .
5-bone & joints inflammatory disease like arthritis , bursitis , tenosynovitis .
6-hematological disorder like acquired hemolytic anemia , acute allergic purpura , leukemia ,
autoimmune hemolytic anemia , idiopathic thromobocytopenic purpera
7-neurological disorder like cerebral edema(post-operatively ) , multiple sclerosis .
8-organ transplantation to prevent rejection .
9-pulmonary disorder like asthma , aspiration pneumonia .
10-renal disorder like nephritic syndrome .
11-skin disorder like atopic dermatitis , dermatosis
12-thyroid disorder like sub-acute thyroidis .
13- miscellaneous like hypercalcemia & mountain sickness .
The toxicity :-
In patient receiving the medication for more than14 days of 100 mg hydrocortisone include ;[
moon face , over growth of hair on thigh - face – trunk , punctuate acne , increase appetite ,
insomnia , weight gain( due to breakdown of protein & glucose production that need increase
insulin) , visceral fat deposition , wasting to much , skin thinning , striae , brusing ,
osteoporosis , aseptic necrosis of the hip , diabetes , impair wound healing , peptic ulcer ,
infection , hypomania or psychosis , sub acute cataracts , depression , increasing intraocular
pressure & glaucoma , benign intracranial hypertension , growth retardation in dose 45
mg/m2/day or more of hydrocortisone ] .
Their contraindication & precaution include : [especial precaution like peptic ulcer , heart
disease , hypertension with congestive heart failure , infection , osteoporosis , glaucoma ,
diabetes . ] .
3
To reduce the systemic effects some preparation used as nasal spray for nasal rhinitis ,
intra-articular for joint disease , topical for skin disease , inhalation for asthma , ophthalmic
form foe eye disease , as enema for ulcerative colitis .
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mineralocorticoids :
include aldosterone , deoxycorticosterone & fludrocortisone .
the most common are aldosterone & fludrocortisone is synthetic corticosteroid agents .
ALDOSTERONE
;
synthesized in zona glomerula of adrenal cortex .
Their effects include [1- promote the re-absorption of sodium from the distal convoluted &
proximal collecting tubules , loosely coupled to excrete potassium & hydrogen ions . /2-
increase sodium absorption from GIT , sweet gland , salivary gland , /3- on excessive level
cause hyper-Na , hypo-K , metabolic alkalosis , increase plasma volume & hypertension .] .
Their mode of action mediated by Mineralocorticoid receptors in the cytoplasm of target cells
, , their metabolite to excrete at rate of 100-200 microgram/day , their half-life 15-20 minutes
.
Deoxycorticosterone
,
it is the precursor of aldosterone , excreted at rate of 200
microgram /day , their half-life 70 minutes .
Fludrocortisone
,
it is a potent steroid of both mineralocorticoids & glucocorticoids in
activity , most common uses , used in dose of 0.1 mg 2-7 times /week , use in treatment of
adrenal insufficiency , its dose very small to get anti-inflammatory effects .
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ADRENOCORTICOID ANTAGONIST
:-
A- glucocorticoids
antagonist agents like :-
1-metyrapone , it is selected steroid inhibitors , interfere with cortisol & corticosterone
synthesis , its toxic effects include [ dizziness , GIT disturbance, salt & water retention ] , its
dose 0.25 g x 2 -1 g x4 /day , useful in treatment of excessive cortisol syndrome , use in
testing of adrenal function
.
2-Aminoglutethimide
:- block conversion of cholesterol into pregnenolone & cause a
reduction in synthesis of all active steroid agents , use in case of [1- breast cancer its dose 1
g/day well tolerated , 2- in case of cushings syndrome due to adrenocortical causes , in
combination with metyrapone or ketoconazole in patients not response to mitotane , 3- it
enhance metabolism of dexamethasone . ] .
3-ketoconazole it is anti-fungal agent of imidazole derivatives , a potent non-selective
inhibiting agent of adrenal & gonadal steroid synthesis , use in treatment of Cushing’s
syndrome due to several cause in dose of 200-1200 mg /day
.
4-Mifepristone
, it block glucorticoids receptors , their half –life 20 hours , 1% of daily
dose excreted in urine , give orally to several patients with Cushing’s syndrome due to
ectopic ACTH production or adrenal carcinoma
.
5- Mitotane
give orally in divided dose up to 12 g/day , use in case of adrenal carcinoma ,
not widely use due to their toxic effects
.
6-Trilostane
it interfere with adrenal & gonadal hormones synthesis
.
B- mineralocorticoid antagonist
:-
include
4
1-progestrone
is mildly active by compete with aldosterone for binding site & decrease
effectiveness peripherally
.
2-Eplerenone
it is a newer androgen antagonist , it is in advance clinical trial .
3-Drospirenone
,
it is oral contraceptive agents , also androgen antagonist , it is a progestin
.
4-Spironolactone
;
used in treatment of [1-primary aldosteronism in a dose of 50-100 mg
/day to reverse the manifestation of aldosteronism . /2- for diagnosis purpose for detection of
aldosteronism in hypo-kalemic patient with hypertension in a dose of 400-500 mg/day for 4-8
days with adequate sodium , potassium will restore potassium level toward normal ./ 3- for
preparation of patient for surgery in a dose of 300-400 mg/day for 2 weeks for this purpose &
also reduce incidence of cardiac arrhythmias . /4- it al;so androgen antagonist to us in
treatment of hirsutism in woman in dose of 50-200 mg/day (decrease density , diameter &
rate of hair growth in face) , in case of androgen excess or idiopathic hirsutism ./ 5- also use
as diuretic & use in congestive heart failure .
their adverse effects include hyperkalemia , cardiac arrhythmias , menstrual abnormality ,
gyeneomastia , sedation , headache , GIT disturbance & skin rashes .