Kuliah

Farmakodinamik &
Farmakokinetik Kortikosteroid

ASRAWATI SOFYAN

Bagian Ilmu Kesehatan Kulit dan Kelamin

 Kompetensi yang diharap

Farmakodinamik KS
Farmakokinetik KS
 Farmakodinamik

Kortikosteroid mempengaruhi metabolisme :

Karbohidarat, protein dan lemak
Mempengaruhi fungsi sistem kardiovaskuler,
ginjal, otot lurik, sistem saraf & organ lain.

Korteks adrenal berfungsi homeostatik

(mempertahankan diri dlm menghadapi
perubahan lingkungan)  Fungsi kortikosteroid
untk kelangsungan hidup
Farmakodinamik
Efek kortikosteroid kebanyakn berhubungan dgn besarnya
dosis.
<<<< dosis = <<<<efek

Permissive effects = kortikosteroid diperlukan supaya

terjadi suatu efek hormon lain (diduga mekanismenya a/
melalui pengaruh steroid terhadap pembentukan protein
yg mengubah respons jar. terhadap hormon lain.

Kortikosteroid  berbagai macam aktivitas biologik,

potensi sediaan alamiah maupun sintetik di tentukan oleh
besarnya efek retensi natrium & penyimpanan glikogen di
hepar/ besarx khasiat anti inflamasinya.
Farmakodinamik
Klinik, kortikosteroid dibedakan menjadi 2 golongan besar :
a. Glukokortikoid
b. mineralokortikoid

Glukokortikoid :
Penyimpanan glikogen hepar dan ef. Anti inflamasi
Kesimbangan air & elektrolit kecil.
Prototip: kortisol

Mineralokortikoid :
Keseimbangan air & elektrolit >>
Penyimpanan glikogen hepar <<
Prototip : desoksikortikosteron
 Basal secretions
Group Hormone Daily
secretions
Glucocorticoids • Cortisol 5 – 30 mg
• Corticosterone 2 – 5 mg
Mineralocorticoids • Aldosterone 5 – 150 mcg
• 11- deoxycorticosterone Trace

Sex Hormones
•Androgen • DHEA 15 – 30 mg
•Progestogen • Progesterone 0.4 – 0.8 mg
•Oestrogen • Oestradiol Trace

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

Farmakodinamik
Pengaruh kortikosteroid terhadap fungsi dan organ
tubuh :
a. Metabolisme
b. Keseimbangan air dan elektrolit
c. Sistem Kardiovaskuler
d. Otot rangka
e. Susunan Saraf pesat
f. Elemen pembentuk Darah
g. Efek anti inflamasi
h. Jaringan Limfois dan sistem imunologi
i. Pertumbuhan
a. Metabolisme
Metabolisme karbohidrat & protein

Kortikosteroid dosis besar dalam waktu yg lama dpt

menimbulkan gejala seperti DM. Dimana glukosa darah
cenderung meninggi, resistensi terhadap insulin meninggi
,toleransi terhadap glukosa menurun & mungkin terjadi
glukosuria

Di perifer steroid  efek katabolik : atrofi jar.

Limfoid, pengurangan massa jar. Otot, terjadinya
osteoporosis tulang (p- matriks protein t
a. Metabolisme
Metabolisme lemak

Penggunaan glukokortikoid dosis besar jangka panjang/ pd

sindrom Cushing  ggn distribusi lemak yg khas. Lemak
terkumpul berlebihan pd depot lemak  buffalo hump,
daerah supraklavikula & moon face, sebalikx lemak di
ekstemitas menghilang.

Kadar insulin meningkat akb hiperglikemi yg ditimbulkn olh

glukokortikoid, insulin ini mempunyai ef. Lipogenik &
antilipolitik pd jar. Lemak di btg tubuh, sdgkn sel lemak di
ekstremitas kurang sensitif terhdp insulin & lebih sensitif
trhdp ef. Lipolitik hormon lain (epinefrin, noreepinefrin,
hormon pertumbuhan) yg di induksi ol glukokortikoid.
b. Keseimbangan air dn elektrolit
Mineralkortikoid dpt meningkatkan reabsorpsi Na+ serta
ekskresi K+ dan H+ di tubuli distal.
Dengan dasar mekanisme inilah, pd hiperkotisisme
terjadi retensi Na yg disertai ekspansi volume cairan
ekstrasel, hipokalemia, dan alkalosis. Pada
hipokortisisme terjadi keadaan sebaliknya :
hiponatremia, hiperkalemia, volume ekstrasel berkurang
dan hidrasi sel.

Aldosteron : mineralokortikoid alam plg kuat

c. Sistem kardiovaskular
Kortikosteroid mempengaruhi sistem kardiovaskular scr
langsung & tdk langsung.

Tdk langsung : terhadap keseimbangan air & elektrolit

mis : hipokortisisme, terjadi pengurangan volume yg
diikuti peningkatan viskositas darah. Jk di diamkan 
hipotensi  kolaps kardiovaskuler.

Langsung : kapiler, arterial & miokard.

d. Otot rangka
Otot rangka dpt berfungsi dgn baik  KS yg cukup, apabila
berlebih, timbul ggn fx otot rangka tsbt.

pasien sindrom cushing/ pemberian glukokortikoid dosis

besar u/ waktu lama dpt timbul wasting otot rangka
(pengurangan massa otot).

Mekanisme miopati  efek katabolik & antianaboliknya

pd protein otot yg disertai hilangnya massa otot,
penghambatan aktivitas fosforilase & adanya akumulasi
kalsium otot  penekanan fx mitokandria.
e. Susunan saraf Pusat
Secara tdk langsung  ef. Metabolisme karbohidrat,
sistem sirkulasi & keseimbangan elektrolit. Efek steroid pd
SSP : perubahan mood, timgkah laku, EEG & kepekaan otak
pd mereka yg sedang menggunakan KS waktu lama (penyakit
addison : gej. Apatis, depresi & cepat tersinggung bahkan
psikosis)

Sind. Cushing  neurosis & psikosis.

f. Elemen pembentuk darah
Meningkatkan kadar hemoglobin & sel darah merah.
leukosit polimorfonuklear (mempercepat masuknya sel2
ke dalam darah dri sumsum tulang & m(-) kec. Berpindahnya
sel dri sirkulasi.

jumlah sel limfosit, eosinofil, monosit, & basofil dlm

darah

Sind. Cushing  polisitemia.

Peny. Addison  anemia normokromik, normositik yg
ringan.
 g. Efek Anti-Inflamasi
Kortisol & analog sintetikx dpt mencegah atau menekan
timbul gejala inflamasi akb radiasi, infeksi, zat kimia,
mekanik atau alergen (kemerahan, rasa sakit & panas,
pembengkakan di tempat radang)

Hambat inflamasi dini : edema, deposit fibrin, dilatasi

kapiler, migrasi leukosit ke tempat radang & aktivitas
fagositosis.

Inflamasi lanjut : proliferasi kapiler dn fibroblas,

pengumpulan kolagen & pembentukan sikatriks.

Terapi paliatif  gejala di hambat

Hambat migrasi leukosit ke daerah inflamasi.
h. jar. Limfoid & sistem imunologi.
M(-) jumlah sel pd leukemia limfoblastik akut & bbrp
keganasan sel limfosit. Serta mengurangi respon imun.

Glukokortikoid & ACTH  mengatasi gej. Klinik rx

hipersensitivitas tipe lambat (cell-mediated).
Pembentukan antibodi dhambat jk glukokortikoid sangat
tinggi. Dosis sedang (prednison 20mg/hr) tdk
menghambat.
 i. Pertumbuhan
Pada anak  hambat pertumbuhan  ef. Antagonisnya
terhadap kerja hormon pertumbuhan di perifer.
Kombinasi bbg faktor : hambatan somatomedin & hormon
pertumbuhan, hambatan sekresi hormon pertumbuhan,
berkurangnya proliferasi sel di kartilago epifisis &
hambatan akt. Osteoblas tulang.

BBrp jaringan (otot & tulang)  menghambat sintesis &

menambah degradasi protein & RNA.
Tulang  menghambat maturasi & proses pertumbuhan
memanjang.
 Farmakokinetik

• Absorption
• Distribution
• Metabolism
• Elimination
 Pharmacokinetic of glucocorticoid
• Approximately 10 to 12mg of cortisol per m2 surface
area is produced by the adrenal cortex in a normal
adult each day
• Cortisol is secreted in a pulsatile or episodic fashion,
the mean plasma concentration of cortisol varies
predictably over a 24 hour period, with highest
concentrations in the early morning & lowest levels
at midnight (circadian rhythm) (the normal plasma
concentration at 8am is 10 to 15ug/100ml)
Farmakokinetik
Kadar tinggi & cepat dlm cairan tubuh  ester kortisol
& derivat sintetiknya diberikn scr IV.
Ef. Lama  scr IM.
Dpt di absorpsi di kulit, sakus konjungtiva & rg.
Sinovial. Penggunaan jngka panjang & daerah luas  ef.
Sistemik : supresi korteks adrenal.

Setelah penyuntikn IV steroid radioaktif sebagian besar

dlm waktu 72 jam di eksresi dlm urin, sdgkn feses &
empedu hampir tdk ada. ± 70% di metabolisme di
hepar.
Masa paruh eliminase kortisol sktr 1,5jam.
Table 2. Comparison of Glucocorticoid Bases.

Relative K/Na Equivalnt Duration Structural

Base
Potency1 Effect Dose2 (HPA)3 Difference

Short Acting
Hydrocortiso
1 ++ 20 12
ne
Cortisone4 0.8 ++ 25 12 11 ketol
Intermediate Acting

Prednisone4 3.5 + 6 12 - 36 1 ketol; 1=2

Prednisolone 4.0 + 5 12 - 36 1=2

Methylpredniso
5.0 0 4 12 - 36 6-me; 1=2
lone
9-F;16-
Triamcinolone 5.0 0 4 12 - 36
OH;1=2
Long Acting

Paramethasone 10 0 2 > 48 6-F;16-me;1=2

Betamethasone 25 0 0.8 >48 9-F;16-bme;1=2
Dexamethasone 30 0 0.7 >48 9-F;16-me;1=2
1. Glucocorticoid potency
2. Dose suggested is replacement therapy for a 20 kg. dog
3. Durations for other effects are likely to be different (see mechanism of action notes)
4. pro-drug, activated by conversion to hydrocortisone or prednisolone.
 Half-life & Duration of Action
• The plasma half-life of cortisol is approximately 90
minutes
• In general, the plasma half-life of prednisone is
slightly longer (3.4 to 3.8h) than that of prednisolone
(2.1 to 3.5h)
• Cortisone & hydrocortisone are extensively
metabolized (t1/2=30 min & 1.5h respectively)
• Dexamethasone t1/2 4h
 INDIKASI
6 prinsip terapi
1. Tiap penyakit pd tiap pasien, dosis efektif hrs ditetapkn
dgn trial and error, hrs di evaluasi dri waktu ke waktu
sesuai dgn perubahan penyakit
2. dosis tunggal besar KS umumx tdk berbahaya.
3. Penggunaan KS u/ bbrp hari tanpa KI spesifik, tdk
membahayakn kcli dgn dosis sgt besar.
4. Pengobatan di perpanjang > 2 mgg/ >  ef. Samping &
ef.letal akan bertambah. Hidrokortisol 100mg/hr . 2mgg :
iatrogening cushing syndrome.
5. Terapi paliatif : ef.antiinflamasi
6. Penghentian tiba@ pd terapi jangka panjang dgn dosis
besar  resiko insufisiensi adrenal yg hebat & dpt
mengancam jiwa.
 INDIKASI

1.TERAPI SUBSTITUSI
Insufisiensi adrenal akut
Insufisiensi adrenal kronik
hiperplasia adrenal kongenital
insufisiensi adrenal sekunder akibat insufisiensi
adenohipofisis
 INDIKASI
2. TERAPI NON-ENDOKRIN
•Fungsi paru pada fetus
•Artritis
•Karditis reumatik
•Penyakit ginjal
•Penyakit kolagen
•Asma bronkial & peny. Sal. Napas
•Peny. Alergi
•Peny. Mata
•Peny. Kulit.
•peny. Hepar
•Keganasan
•Ggn hematologik lain
•Syok
•Edema serebral trauma sumsum tulang belakang
 KONTAINDIKASI
Kontraindikasi absolut

Kontraindikasi relatif:
Diabetes mellitus, tukak peptik/ duodenum, infeksi berat,
hipertensi / ggn kardiovaskular.
Efek samping
Efek dpt timbul
•Penghentian pemberian scr tiba-tiba
•Pemberian terus menerus (dosis besar)

Pemberian jangka lama : insufisiensi adrenal akut

(demam, mialgia, atralgia dan malaise)
Komplikasi : ggn cairan & elektrolit, hiperglikemi &
glikosuria, mudah mendapat infeksi (TB,), pasien tukak
peptik (perdarahan/ perforasi), osteoporosis, miopati yg
karakteristik, psikosis, habitus pasien cushing.
 Inhalation therapy
• Local irritation of the oropharynx & fungal
infections of the upper respiratory tract occurs.
• Long-term use may cause a reversible
dysphonia, due to weakening of the adductors
of the vocal cords
 Local aplication to the skin
• May cause atrophy with scarring &
telangiectasia.
• Systemic effect from local treatment are
uncommon, but may occur if large areas are
treated under occlusive dressings
 Local application to the eyes
• Infections may be exacerbated, with resultant
corneal damage. This is particularly important
in herpetic infections
• Glaucoma may occur & is unpredictable; it is
due to a genetic susceptibility & is usually
reversible
• Cataract occur occasionally
 There two ways of reducing the
risk of adverse effects
• By appropriate timing of the doses during the
day
• By alternate-day therapy
 Appropriate timing
• The inhibitory effects of exogenous corticosteroids on
endogenous steroid secretion are much less marked when
the steroid are taken in the morning than at night
• The risk of adrenal suppression may be reduced by giving all
of the dose in the morning or splitting it between the morning
and early afternoon
• This does not apply to corticosteroid replacement therapy
(taken two-thirds in the morning & one-third at night to mimic
the normal pattern of endogenous steroid secretion)
 Alternate-day therapy
• May reduce the unwanted catabolic effects of the corticosteroids &
lessen the degree of suppression of the hypothalamic-pituitary-
adrenal axis
• However, since the anti-inflammatory & immunosuppressive effects
continue over 48h these are not necessarily lost
• In some patients it may therefore be possible to reduce a dosage of
prednisolone of, for example, 60 mg daily to 80 mg on alternate
days, a reduction in total daily dosage of 20 mg (tapering doses)
• However, in some patients, notably those with asthma and
rheumatoid arthritis, alternate day therapy is not suitable, because
for some reason the therapeutic effect is also lost
Systemic Effects of
Glucocorticoids
Central Nervous Euphoria and behavioral changes
System Maintenance of alpha rhythm
Lower Seizure Threshold
Autonomic
Required for normal sensitivity of adrenergic
Nervous
receptors
System
Gastrointestinal Decreased calcium and iron absorption
Tract Facilitation of fat absorption
Increased acid, pepsin, and trypsin
Structural alteration of mucin
Skeletal Muscle Weakness (excess and deficiency)
Muscle atrophy (chronic excess)
Skin Atrophy and thinning (chronic excess)
Calcinosis Cutis
Hematopeoietic Involution of lymphoid tissue (species
system dependent)
Decrease in peripheral lymphocytes, monocytes,
eosinophils
Increase in peripheral neutrophils, platelets,
RBCs
Decreased Clotting Time
Decreased phagocyte competence
Cardiovascular Positive inotropic effect
system Increased blood pressure (increased blood
volume)
Kidneys Increased reabsorption of water, sodium,
chloride
Increased excretion of potassium, calcium
Increased extracellular fluid
Bone Inhibition of collagen synthesis by fibroblasts
Acceleration of Bone resorption
Antagonism of Vitamin D
Cells "Stabilization" of liposomal membranes
Inhibition of macrophage response to
migration inhibition factor
Lymphocyte sensitization blocked
Cellular response to inflammatory mediators
blocked
Inhibition of fibroblast proliferation
Reproductive Tract Parturition induced during the latter part of
pregnancy in ruminants and horses
Less reliable in dogs and cats
Teratogenesis during early pregnancy.
Kortikosteroid & Infeksi
Kepekaan terhadap infeksi pd pasien yg mendapat KS
tdk bersifat spesifik untk bakteri/ fungus patogen
tertentu.

Bila terjadi infeksi, dosis KS harus tetap di pertahankn

/ ditambah, dan harus dilakukan pengobatan Antibiotik/
antifungal yg terbaik terhadap infeksi scr bersamaan
Sediaan KS
Sediaan dpt diberikan:
Oral
Parental (IV, IM, intrasinovial & intralesi)
Topikal pd kulit & mata (salep, krim, lotion)
Aerosol mll jalan napas.
Sangat Kuat: Kuat:

Sedang: Lemah:
TERIMA KASIH
 tugas
• Sediaan KS dan pengobatannya ?