Pemicu 4 Blok

Metabolisme

Dept. Pharmacology &

Therapeutic

Anamnesis
Laki-laki, 48 tahun, BB >>, lemah, sejak
6 bulan yang lalu. Ia menderita sakit
persendian (OA) dan mengkonsumsi berbagai
obat penghilang rasa sakit yang dibelinya
sendiri.
Ia diperkirakan mengkonsumsi kortikosteroid.

Pertanyaan
1. Bagaimana mekanisme kerja
kortikosteroid dalam menghilangkan nyeri
sendi?
2. Bagaimana hubungan pemakaian obat
tersebut dengan terjadinya kelainan
fungsi hormon supraadrenal?
3. Bagaimana tatalaksana awal
supraadrenal failure?

Adrenocorticosteroids

Control of Aldosterone Secretion

Circadian Rhythm of Cortisol Secretion

2.

GLUCOCORTICOID
(CORTISOL : HYDROCORTISONE)

MECHANISM OF ACTION
Nuclear
membr
ane

Cell
membra
ne

Ster
oid

Steroi
d+
recep
tor
compl
ex

recep
tor

Steroi
d+
recep
tor
compl
ex
chrom
atin

accce
ptor

Physiological Actions of Glucocorticoids

Metabolic
Anti-inflammatory
Immunosuppression

GLUCOCORTICOID

1.

(CORTISOL : HYDROCORTISONE)

IMMUNOSUPPRESSIVE AND ANTI-INFLAMMATION EFFECT

ANTIGENANTIBODY
COMPLEX
PHOSP
OLIPID
ARACHIDO
NIC ACID

ASE A2

CYCLOOXYG
ENASE

LIPOXYGE
NASE

LEUKOT
RIENE

INHIBITED
BY
GLUCOCOR
TICOID
PHOSPOLIP

THROMB
OXANES

PROSTAC
YCLIN
PROSTAGL
ANDINS

HypothalamicPituitaryAdrenal
(HPA)
Axis

Side Effects of Glucocorticoid Therapy

Antagonists of
Adrenocortical Agents
A. Synthetic inhibitors and glucocorticoid
antagonists
1. Metyrapone inhibits 11-hydroxylation,
interfering with cortisol and corticosterone
synthesis (0.25g BID to 1g QID)
- used in tests of adrenal function (300500mg q 4hrs. X 6doses, ffed by urine
collection
- treat hypercorticotism: 4 g/day

2. Aminoglutethimide blocks the

conversion of cholesterol to
pregnanelolone and causes a
reduction in the synthesis of all
hormonally active steroids; breast Ca
and Cushings syndrome due to
adrenocortical Ca: 250 mg every 6hrs.
- enhances metabolism of
dexamethasone

3. Ketoconazole an antifungal
imidazole derivative; potent, nonselective inhibitor of adrenal and
gonadal steroid synthesis; tx of
Cushings syndrome (200-1200mg/d)

4. Mifepristone (RU 486)

11-aminophenyl-substituted 19norsteroid;
has strong anti-progestin activity;
blocks
glucocorticoid receptor

5. Mitotane adrenal Ca; 12

g/daily results in reduction in tumor
mass; caution: adverse effects
(80%)
6. Trilostane - 3-17
hydroxysteroid dehydrogenase
inhibitor that interferes
with the synthesis of adrenal and
gonadal hormones
- comparable to aminogluthemide

B. Mineralocorticoid Antagonists
Spirinolactone diagnosis of
aldosteronism (400-500mg/day fro 4-8
days); preparing for surgery (30040mg/day x 2 wks to reduce the
incidence of arrhythmias); hirsutism in
women (androgen antagonist 50200mg/d x 2-6 mos); diuretic
Eplerenone in clinical trials
Drospirenone progestin in a new oral
contraceptive, antagonizes the effect of
aldosterone

Classification of
Adrenocorticosteroids
I. Short to medium-acting
glucocorticoids:
a. Hydrocortisone (cortisol)
b. Cortisone
c. Prednisone
d. Prednisolone
e. Methylprednisolone
f. Meprednisone

II. Intermediate-acting glucocorticoids

a. Triamcinolone
b. Paramethasone
c. Fluprednisolone

III. Long-acting glucocorticoids

a. Betamethasone
b. Dexamathasone

IV. Mineralocorticoids
a. Fludrocortisone
b. desoxycorticosterone acetate

Therapeutic Uses:
A. Replacement Therapy
1. Adrenal Insufficiency
a. Acute adrenal insufficiency
ssx: GIT symptoms, dhn, hypoNa, hyperK, weakness,
lethargy,
hypotension
cause: disorder of the adrenal
abrupt withdrawal of glucocorticoids at high doses
or
prolonged use
mgt: IV : D5 0.3%NaCl solution
Monitor for fluid overload
Hydrocortisone (cortisol) 100mg bolus, ffed by
100mg every 8 hrs. ; once stable, may give 25mg IM
hydrocortisone every 6-8hrs.; thereafter, same mgt with
chronic adrenal insufficiency

1. Adrenal Insufficiency (cont.)

b. Chronic Adrenal Insufficiency (Addisons disease)
ssx:hyperpigmentation, wt. loss, inability to
maintain fasting blood sugar, weakness,
fatigue,
hypotension
cause: primary adrenal insufficiency, tuberculosis
mgt: Hydrocortisone 20-30mg/day BID
Fludrocortisone acetate 0.05 0.2mg/day
(valuable indicator of adequate replacement:
disappearance of hyperpigmentation and
resolution of electrolyte abnormalities)
-monitor plasma ACTH levels or measure
urinary free cortisol; dosage adjustments for
stress

Therapeutic Uses (cont.)

2. Adrenocortical hypo- and
hyperfunctioning
a. Congenital Adrenal Hyperplasia
ssx: after puberty with infertility, hirsutism, amenorrhea and
acne; female pseudohermaphroditism; accelerated
linear growth but height at maturity is reduced; salt
wasters CV collapse (volume depletion)
cause: Genetic disorder; activity of enzymes required for
the biosynthesis of corticosteroid is deficient (21
hydroxylase)
mgt: 1st seen as acute adrenal crisis
oral hydrocortisone 0.6mg/kg/day BID or TID
fludrocortisone acetate 0.05-0.2mg/day
treatment in-utero: mothers at risk glucocorticoid
therapy is initiated before 10 weeks gestation ffed by
genotyping and sex determination

b. Cushings syndrome
cause: pituitary adenoma, tumors of the
adrenalgland
ssx: round, phletoric face, truncal obesity,
muscle wasting, thinning, purple striae and
easy
bruising of the skin, poor wound
healing,osteoporosis
mgt: surgery
hydrocortisone 300 mg IV on the day of the
surgery, then maintenance oral dose

B. Stimulation of fetal lung maturation

betamethasone 12mg ffed by 12mg
18-24 hrs. later
C.Nonendocrine Diseases
1. Rheumatic disorders suppress the
disease and minimize
resultant tissue damage
mgt: prednisone 10 mg/kg/day (taper
thereafter by decreasing 1mg/kg/day every 23 wks)
intraarticular injection: triamcinolone
acetonide
osteoarthritis : intraarticular injections with
interval of 2-3
mos. to minimize complications

C. Non-Endocrine Diseases (cont.)

2. Renal Disorders nephrotic syndrome
mgt: prednisone: 1-2 mg/kg x 6 wks, ffed.
by gradual tapering over 6-8 wks or
alternate-day therapy (diminished
proteinuria in 85% pts in 2-3 wks and 95%
pts will have remission in 3 mos.
- membranous glomerulonephritis
mgt: alternate-day prednisone 8-10 wks
ffed
by 1-2 month period of tapering

C. Non-Endocrine Diseases (cont.)

3. Allergic Disease epinephrine 0.5ml

of a 1:1000 solution IM or SQ,
repeated every 15 mins up to 3
doses is needed (anaphylaxis)
- onset of action of glucocorticoid is
delayed

C. Non-Endocrine Diseases (cont.)

4. Bronchial Asthma role of inflammation in
the immunopathogenesis
- onset of action is delayed for 6 12 hrs.
mgt: IV methylprednisolone 60-120mg
initially ffed. by oral prednisone 40-60mg
daily as the attack resolves
inhaled steroids reduces bronchial
hyperreactivity with les suppression of
adrenal function (dysphonia or
oropharyngeal candidiasis)

C. Non-Endocrine Diseases (cont.)

5. Infectious Disease P. carinii pneumonia
increases oxygenation and decreases the
incidence of respiratory failure and
mortality
H. influenzae type b meningitis decrease
the long-term neurological impairment
6. Ocular disease 0.1% dexamethasone
- C/I: herpes simplex keratitis (clouding of
the cornea) , glaucoma

C. Non-Endocrine Diseases (cont.)

7. Skin diseases inflammatory dermatoses
8. GIT diseases inflammatory bowel disease
9. Hepatic diseases prednisolone 80%
histologic remission in pts. with chronic, active
hepatitis
10. Malignancies ALL, lymphomas
11. Cerebral edema
12. Miscellaneous dis Sarcoidosis (induce
remission), thrombocytopenia (decrease bleeding
tendency), organ transplantation, spinal cod injury

D. Diagnostic Application
Dexamethasone suppression test
differentiates Cushings syndrome vs.
stress and if Cushings syndrome,
whether its an adrenal or a pituitary
tumor
Baseline cortisol levels are determined
Dexamethasone 0.5mg every 6hrs x 48
hrs.
Dexamethasone 2 mg every 6 hrs. x 48
hrs.

Toxicity:
Withdrawal of therapy:
ssx: fever, myalgias, arthralgias, malaise,
pseudomotor cerebri ( ICP, papilledema)
Continued use at supraphysiologic doses
ssx: fluid and electrolyte abnormalities,
hypertension, hyperglycemia, increased
susceptibility to infection, myopathy, behavioral
disturbances, cataracts, growth arrest and fat
redistribution, acne, hirsutism, striae, ecchymoses,
osteonecrosis, peptic ulcer
Adrenal suppression - >2 wks.
Contraindications: peptic ulcer, heart disease or
Hpn with CHF, infections, psychoses, diabetes,
osteoporosis, glaucoma or herpes simplex
infection

Supplemental measures:
Diet rich in potassium and low in
sodium
Caloric mgt to prevent obesity
High protein intake
Appropriate antacid therapy
Calcium and vit D, physical therapy
Alendronate biphosphonate