FARMAKOLOGI

KLINIK

OBAT GOLONGAN
KORTIKOSTEROID
Definisi
 Kortikosteroid: senyawa kimia
termasuk hormon steroid yang
secara alami diproduksi oleh korteks
adrenal dan analognya dapat
disintesis dapat digunakan baik
sebagai penegakan diagnosis dan
pengobatan gangguan fungsi adrenal
Review Kelenjar Endokrin Utama Manusia
Anatomi-Fisiologi Kelenjar Adrenal
Regulasi Sekresi Hormon Adrenal
Fungsi Kortikosteroid
 Kortikosteroids mempengaruhi
sebagian besar proses fisiologi,
termasuk respon terhadap stress,
immune dan regulasi peradangan,
matabolisme KH, katabolisme
protein, kadar elektrolit, dan prilaku
Contoh Regulasi Sekresi terhadap stress
Klasifikasi berdasarkan
Aktivitas / Fungsi
 Glucocorticoids seperti kortisol, berfungsi
untuk mengendalikan metabolisme KH,
protein, dan lemak dan memiliki efek anti
inflamasi mll penghambatan pelepasan
fosfolipase, menurunkan aksi eosinophil
dan beberapa mekanisme lainnya
 Mineralcorticoids seperti aldosterone
berperan dalam mengatur kadar air dan
elektrolit terutama melalui proses retensi
Na di ginjal
Biosintesis
Biosintesis
 The corticosteroids are synthesized
from cholesterol within the adrenal
cortex. Most steroidogenic reactions
are catalysed by enzymes of the
cytochrome P450 family. They are
located within the mitochondria and
require adrenodoxin as a cofactor
(except 21-hydroxylase and 17α-
hydroxylase).
 Biosintesis
 Aldosterone and corticosterone share the first part of
their biosynthetic pathway. The last part is mediated
either by the aldosterone synthase (for aldosterone) or
by the 11β-hydroxylase (for corticosterone). These
enzymes are nearly identical (they share 11β-
hydroxylation and 18-hydroxylation functions), but
aldosterone synthase is also able to perform an 18-
oxidation. Moreover, aldosterone synthase is found
within the zona glomerulosa at the outer edge of the
adrenal cortex; 11β-hydroxylase is found in the zona
fasciculata and zona glomerulosa.
Klasifikasi berdasarkan Struktur Kimia

 In general, corticosteroids are

grouped into four classes, based on
chemical structure. Allergic reactions
to one member of a class typically
indicate an intolerance of all
members of the class. This is known
as the "Coopman classification", after
S. Coopman, who defined this
classification in 1989.
Group A — Hydrocortisone Type

 Hydrocortisone, hydrocortisone
acetate, cortisone acetate, tixocortol
pivalate, prednisolone,
methylprednisolone, and prednisone
(Short- to medium-acting
glucocorticoids).
Group B — Acetonides
(and related substances)
 Triamcinolone acetonide,
triamcinolone alcohol, mometasone,
amcinonide, budesonide, desonide,
fluocinonide, fluocinolone acetonide,
and halcinonide
Group C — Betamethasone Type

 Betamethasone, betamethasone
sodium phosphate, dexamethasone,
dexamethasone sodium phosphate,
and fluocortolone.
Group D — Esters

Group D1 — Halogenated (Less Labile)

 hydrocortisone-17-valerate, aclometasone
dipropionate, betamethasone valerate,
betamethasone dipropionate, prednicarbate,
clobetasone-17-butyrate, clobetasol-17-
propionate, fluocortolone caproate,
fluocortolone pivalate, and fluprednidene
acetate.
Group D2 — Labile Prodrug Esters
 Hydrocortisone-17-butyrate, 17-aceponate,
17-buteprate, and Prednicarbate.
Kortikosteroid Sintetis
Pendahuluan
 Glucocorticoids are distinguished from
mineralocorticoids and sex steroids by
their specific receptors, target cells, and
effects. In technical terms, "corticosteroid"
refers to both glucocorticoids and
mineralocorticoids (as both are mimics of
hormones produced by the adrenal
cortex), but is often used as a synonym for
"glucocorticoid".
Potensi Kortikosteroid
 Indikasi Terapeutik
Kortikosteroid
 Glucocorticoids may be used in low doses in
adrenal insufficiency.
 In much higher doses, oral or inhaled
glucocorticoids are used to suppress various
allergic, inflammatory, and autoimmune disorders.
 Inhaled glucocorticoids are the first-line treatment
for preventing asthma.
 They are also administered as post-transplantory
immunosuppressants to prevent the acute
transplant rejection and the graft-versus-host
disease. Nevertheless, they do not prevent an
infection and also inhibit later reparative processes
Physiological replacement

 Any glucocorticoid can be given in a dose

that provides approximately the same
glucocorticoid effects as normal cortisol
production; this is referred to as
physiologic, replacement, or maintenance
dosing. This is approximately 6–12
mg/m²/day (m² refers to body surface area
(BSA), and is a measure of body size; an
average man's BSA is 1.7 m²).
Therapeutic immunosuppression

 Glucocorticoids cause immunosuppression, and the

therapeutic component of this effect is mainly the decreases
in the function and numbers of lymphocytes, including both
B cells and T cells.
 The major mechanism for this immunosuppression through
inhibition of nuclear factor kappa-light-chain-enhancer of
activated B cells(NF-κB). NF-κB is a critical transcription
factor involved in the synthesis of many mediators (i.e.,
cytokines) and proteins (i.e., adhesion proteins) that
promote the immune response. Inhibition of this
transcription factor, therefore, blunts the capacity of the
immune system to mount a response.
Anti-inflammatory
 Glucocorticoids are potent anti-inflammatories, regardless
of the inflammation's cause; their primary anti-inflammatory
mechanism is lipocortin-1 (annexin-1) synthesis. Lipocortin-
1 both suppresses phospholipase A2, thereby blocking
eicosanoid production, and inhibits various leukocyte
inflammatory events (epithelial adhesion, emigration,
chemotaxis, phagocytosis, respiratory burst, etc.).
 In other words, glucocorticoids not only suppress immune
response, but also inhibit the two main products of
inflammation, prostaglandins and leukotrienes. They inhibit
prostaglandin synthesis at the level of phospholipase A2 as
well as at the level of cyclooxygenase/PGE isomerase
(COX-1 and COX-2),the latter effect being much like that of
NSAIDs, potentiating the anti-inflammatory effect.
 In addition, glucocorticoids also suppress cyclooxygenase
expression.
 Glucocorticoids marketed as anti-inflammatories are often
topical formulations, such as nasal sprays for rhinitis or
inhalers for asthma. These preparations have the
advantage of only affecting the targeted area, thereby
reducing side effects or potential interactions. In this case,
the main compounds used are beclometasone, budesonide,
fluticasone, mometasone and ciclesonide. In rhinitis, sprays
are used. For asthma, glucocorticoids are administered as
inhalants with a metered-dose or dry powder inhaler.
Hyperaldosteronism
 Glucocorticoids can be used in the
management of familial
hyperaldosteronism type 1. They are
not effective, however, for use in the
type 2 condition.
 Hyperaldosteronism
Resistance
 Resistance to the therapeutic uses of
glucocorticoids can present difficulty; for
instance, 25% of cases of severe asthma
may be unresponsive to steroids. This may
be the result of genetic predisposition,
ongoing exposure to the cause of the
inflammation (such as allergens),
immunological phenomena that bypass
glucocorticoids, and pharmacokinetic
disturbances (incomplete absorption or
accelerated excretion or metabolism).
Withdrawal
 In addition to the effects listed above, use of
high-dose steroids for more than a week
begins to produce suppression of the patient's
adrenal glands because the exogenous
glucocorticoids suppress hypothalamic
corticotropin-releasing hormone and pituitary
adrenocorticotropic hormone. With prolonged
suppression, the adrenal glands atrophy
(physically shrink), and can take months to
recover full function after discontinuation of the
exogenous glucocorticoid.
Strategi Tappering Off
 If patients have been receiving daily high doses for five
days or less, they can be abruptly stopped (or reduced to
physiologic replacement if patients are adrenal-deficient).
Full adrenal recovery can be assumed to occur by a week
afterward.
 If high doses were used for six to 10 days, reduce to
replacement dose immediately and taper over four more
days. Adrenal recovery can be assumed to occur within
two to four weeks of completion of steroids.
 If high doses were used for 11–30 days, cut immediately
to twice replacement, and then by 25% every four days.
Stop entirely when dose is less than half of replacement.
Full adrenal recovery should occur within one to three
months of completion of withdrawal.

Strategi Tappering Off
 If high doses were used more than 30 days, cut dose
immediately to twice replacement, and reduce by 25% each
week until replacement is reached. Then change to oral
hydrocortisone or cortisone as a single morning dose, and
gradually decrease by 2.5 mg each week. When the
morning dose is less than replacement, the return of normal
basal adrenal function may be documented by checking
0800 cortisol levels prior to the morning dose; stop drugs
when 0800 cortisol is 10 μg/dl. Predicting the time to full
adrenal recovery after prolonged suppressive exogenous
steroids is difficult; some people may take nearly a year.
 Flare-up of the underlying condition for which steroids are
given may require a more gradual taper than outlined
above.
Efek Samping Kortikosteroid

 Corticosteroid withdrawal syndrome

(rebound effect) is a frequently seen
occurrence, also called "Red Skin
Syndrome". Total cessation of the steroid is
mandatory and, while reversible, it can be a
prolonged and difficult process to overcome.
 Side effects such as cutaneous addiction
with the development of uncomfortable and
unsightly dermatoses, can occur with just
one 15gm tube of moderate steroid over a
period of one year
 Use of corticosteroids has several severe side-
effects as for example: hyperglycemia,insulin
resistance, diabetes mellitus,osteoporosis,
cataract, anxiety,depression, colitis, hypertension,
ictus, erectile dysfunction, hypogonadism,
hypothyroidism, amenorrhoea, and retinopathy.
 While the evidence for corticosteroids causing
peptic ulceration is relatively poor except for high
doses taken for over a month,the majority of
doctors as of 2010 still believe this is the case,
and would consider protective prophylaxis
measures.
Jenis ESO penggunaan KS

 Immunodeficiency
Glucocorticoids cause immunosuppression,
decreasing the function and/or numbers of
neutrophils, lymphocytes (including both B
cells and T cells), monocytes, macrophages,
and the anatomical barrier function of the
skin.[28] This suppression, if large enough,
can cause manifestations of
immunodeficiency, including T cell deficiency,
humoral immune deficiency and neutropenia
 Hyperglycemia due to increased gluconeogenesis,
insulin resistance, and impaired glucose tolerance
("steroid diabetes"); caution in those with diabetes
mellitus
 Increased skin fragility, easy bruising
 negative calcium balance due to reduced intestinal
calcium absorption
 Steroid-induced osteoporosis: reduced bone density
(osteoporosis, osteonecrosis, higher fracture risk,
slower fracture repair)
 weight gain due to increased visceral and truncal fat
deposition (central obesity) and appetite stimulation
 adrenal insufficiency (if used for long time
and stopped suddenly without a taper)
 muscle breakdown (proteolysis),
weakness, reduced muscle mass and
repair
 expansion of malar fat pads and dilation of
small blood vessels in skin
 anovulation, irregularity of menstrual
periods
 growth failure, delayed puberty
 increased plasma amino acids,
increased urea formation, negative
nitrogen balance
 excitatory effect on central nervous
system (euphoria, psychosis)
 glaucoma due to increased cranial
pressure
 cataracts
Mineralkortikoid Sintetis
 An example of a synthetic
mineralocorticoid is fludrocortisone.
 Important mineralocorticoid inhibitors
are spironolactone and eplerenone
Abnormalitas Kadar Mineralkortikoid

 Hyperaldosteronism (the syndrome caused by

elevated aldosterone) generally results from
adrenal cancers. The two main resulting problems:
1. Hypertension and edema due to excessive Na+
and water retention.
2. Accelerated excretion of potassium ions (K+). With
extreme K+ loss there is muscle weakness and
eventually paralysis.
 Underproduction, or hypoaldosteronism, leads to
the salt-wasting state associated with Addison's
disease, although classical congenital adrenal
hyperplasia and other disease states may also
cause this situation.
 Video tutorial

http://www.youtube.com/watch?v=
eGJRH48-UV4
 Peran Farmasis

Penggunaan Kortikosteroid ?
Asuhan Kefarmasian pada Penggunaan
Kortikosteroid

1.Memastikan bahwa penggunaan KS

sesuai dgn indikasi pasien
2. Memastikan bentuk sediaan, dosis KS
yang diberikan sesuai
3. Merekomendasikan pengelolaan efek
samping yang tidak diharapkan pada
penggunaan KS
4. Merekomendasikan pengelolaan IO yang
diperlukan pada penggunaan KS
5. Memastikan pasien dapat menggunakan
sediaan KS sesuai petunjuk (misal: bentuk
sediaan salep, tetes / salep mata, tetes
telinga, inhaler)
6. Memastikan pasien akan menjalani terapi
tappering off pada penggunaan KS (bila
diperlukan)
7. Memonitoring efektivitas, ESO, IO,
kepatuhan penggunaan KS
8. Mem follow up kondisi pasien dan
data obyektif terkait selama
penggunaan KS