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ACTH &

Corticosteroids
Department of Pharmacology & Therapeutics
Faculty of Medicine Diponegoro University
2018
Adrenal glands

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lations/hear/adrenal.html
http://www.biology.ucr.edu/people/faculty/Garland/HPA_axis.jpg

Notes: while glucocorticoid (GC) is ACTH-driven, mineralocorticoids (MC) is regulated


mainly by the renin-angiotensin (RA) system & blood potassium level
Endogenous
steroidogenesis
Physiological actions of
Corticosteroids
• Glucocorticoids:
- Carbohydrate metabolism
- Protein metabolism
- Fat deposition
- Maintenance of BP
- Anti-vitamin D
- Fluid & electrolytes balance
- Anti-inflammatory & immunosuppresive
• Mineralocorticoids:
- Maintenance of electrolytes balance by stimulating
reabsorption of sodium & excretion of potassium
• Adrenal androgens: virilisation of genitals
Farmakokinetik
• Glukokortikoid utama adalah kortisol yang dilepas di
sirkulasi di bawah pengaruh ACTH.
• Kortisol disekresikan 10-20 mg/hari. Kecepatan
sekresi berubah oleh irama sirkadian pulsasi ireguler
ACTH yang puncaknya pada dini hari dan sesudah
makan serta dipengaruhi oleh cahaya.
• Di plasma kortisol terikat oleh Corticosteroid Binding
globulin (CBG).
• 75% terikat globulin, 20% bentuk bebas, 5% terikat
lemah pada albumin.
Farmakodinamik
1. Mekanisme Kerja
 Kortikosteroid bekerja dengan mempengaruhi kecepatan
sintesis protein. Molekul hormon memasuki sel
melewati membran plasma secara difusi pasif.
 Hormon ini hanya bereaksi dengan reseptor protein
spesifik di jaringan target dengan membentuk kompleks
reseptor steroid dan menghasilkan sintesis protein
spesifik.
 Induksi sintesis protein ini yang akan menghasilkan efek
fisiologi steroid.
Farmakodinamik
2. Efek Fisiologi
 Konsekuensi metabolisme utama dari sekresi/pemberian
glukortikoid disebabkan oleh kerja langsung hormon ini di
dalam sel.
 Efek permisif : kortikosteroid diperlukan supaya terjadi efek
dari hormon lain misalnya respon otot vaskular dan otot
bronkus terhadap katekolamin akan berkurang pada
keadaaan tanpa adanya kortisol.
 Respon lipolitik sel lemak terhadap katekolamin, ACTH dan
hormon pertumbuhan melemah tanpa adanya
glukokortikoid.
Farmakodinamik
3. Efek Metabolisme
 Glukokortikoid mempunyai efek penting yang
berhubungan dengan dosis terhadap metabolisme KH,
protein, dan lemak.
 Glukokortikoid meningkatkan penimbunan glikogen dan
produksi glukosa dari protein. Peningkatan kadar glukosa
serum merangsang produksi insulin.
 Glukokortikoid menghambat ambilan glukosa oleh sel
lemak yang menyebabkan ↑ lipolisis.
 Peningkatan insulin akan merangsang lipogenesis 
meningkatkan penimbunan lemak.
Farmakodinamik
4. Efek Katabolik
 Glukokortikoid mempunyai efek katabolik pada jaringan
limfoid, jaringan ikat, otot, lemak, dan kulit.
 Dalam jumlah suprafisiologik menyebabkan
pengurangan massa otot dan kelelahan.
 Efek katabolik pada tulang menyebabkan osteoporosis
pada sindrom cushing.
 Pada anak-anak dalam jumlah berlebih dapat
menghambat pertumbuhan
Farmakodinamik
5. Efek Anti-inflamasi dan Immunosupresi
 Glukokortikoid mempunyai kapasitas mengurangi
peradangan dengan cepat yang disebabkan oleh efek
hebat terhadap konsentrasi, distribusi, dan fungsi leukosit
perifer serta penghambatan aktifitas fosfolipase A2.
 Menghambat fungsi makrofag dan jaringan makrofag
sehingga respon terhadap Ag dan mitogen ↓
 Mengurangi sintesis prostaglandin dan leukotrien.
 Menyebabkan vasokontriksi dengan manghambat
aktivitas kinin, endotoksin bakteri, dan histamin.
Farmakodinamik
5. Efek Lainnya
 Pada sistem saraf, insufisiensi adrenal menyebabkan perlambatan
irama alfa EEG.
 Dalam dosis besar glukokortikoid meningkatkan produksi asam dan
pepsin dalam lambung shg menyebabkan ulkus peptikum.
 Memudahkan absorpsi lemak dan antagonis efek vitamin D
terhadap absorpsi kalsium.
 Meningkatkan jumlah trombosit dan eritrosit.
 Tanpa kortisol dalam jumlah fisiologi, ginjal tidak bisa
mengekskresikan air
 Efek perkembangan janin  Glukokortikoid merangsang produksi
bahan aktif pada permukaan paru yang dibutuhkan untuk respirasi.
In what cases do we need glucocorticoid
therapy?
Autoimmune diseases: Cancer:
• multiple sclerosis • acute lymphoblastic
• rheumatoid arthritis leukemia
• inflammatory bowel disease • chronic lymphoblastic
• ulcerative colitis leukemia
• psoriasis • Hodgkin lymphoma
• Eczema
• Non-Hodgkin lymphoma
Allergies & asthma
• multiple myeloma
Adrenal insufficiency
Surgery
Classification of GC Based on Duration
of Action
Short acting Intermediate acting Long acting
(biological T1/2 8-12 h (biological T1/2 12-36 h) (biological T1/2 36-72)
Cortisol (Hydrocortisone) Prednisone Betamethasone
Cortisone Prednisolone Dexamethasone
Methylprednisolone
Triamcinolone

Table adapted from NICE, 2012 [1]; Furst et al., 2012


Relative Potency of Commonly-used
Corticosteroids
Preparation Potency relative to Hydrocortisone
Glucorticoid Mineralocorticoid Growth Inhibitory

Hydrocortisone 1 1 1
Cortisone 0.8 0.8 0.8
Prednisolone 4 0.8 5
Prednisone 4 0.8 5
Methylprednisolone 5 0.5 7.5
Dexamethasone 25 0 80
Fludrocortisone 10 125 -
Short Acting Glucocorticoid (t1/2 < 12 h)
Drug Anti-inflam. Salt retaining Preapartions & dose

Cortisol 1 1.0  5 mg tablet


 100 mg/vial (i.m., i.v)
 Topical; enema
Cortisone 0.8 0.8  5 mg tablet
 25 mg/vial (i.m)
Intermediate Acting Glucocorticoid (t1/2 = 12 -36 h)
Prednisone 4 0.8 5, 10 mg tablet

Prednisolone 5 0.3  5, 10 mg tablet


 20 mg/vial (i.m, intrarti)
Methyl 5 0  0.5, 1.0 gm inj. for i.m.
prednisolone or slow i.v.
Triamcinolone 5 0  4 mg Tab.,
 10, 40 mg/ml for i.m. &
intrarticular inj.
Drug Anti- Salt Preapartions & dose
inflam retaining

Long Acting Glucocorticoid (t1/2 > 36 h)

Dexamethasone 25 0 0.5 mg tab.


4mg/ml inj (i.m., i.v.)
Betamethasone 25 0 0.5, 1 mg tab.
4mg/ml inj (i.m., i.v.)
Paramethasone 10 0 2- 20 mg/day (oral)
Therapeutic
principles

 Dose selection by trial & error; Needs frequent


evaluation
 Single dose: No harm
 Few days therapy unlikely to be harmful
 Incidence of side effects related to duration of therapy
 Use is only palliative (except replacement therapy)
Abrupt cessation of prolonged high dose leads to
adrenal insufficiency (contraindicated)
Application of GC therapy
- Physiological secretory rate of cortisol ~ 6 mg/m2/day  maintenance dose is
adjusted above this conc., with consideration of reduction by gastric acid & first-pass
metabolism.
- Dosing is based on the degree of severity of the diseases, with extra doses in the
presence of “stress”.
- The schedule of GC treatment is designed to mimic the normal diurnal rhytm.
Application of GC therapy

• Monitoring of BP, weight, height and other laboratoric


parameters (what are they?) during GC treatment
• Prolonged GC therapy suppresses HPA axis  tapering
dose is needed.
• Tapered until physiological dose is reached, change to
once daily short-acting preparations until HPA axis is
recovered
• Withdrawal symptoms & signs: weaknesses, fatigue,
decreased appetite, nausea, vomiting, diarrhea,
weight-loss, abdominal pain, myalgia, arthralgia, etc.
Toxicity / overdose /
Prolonged-use of GC
Mineralocorticoids (MC)
• Aldosterone  exerts 90% of overall MC activity
• Regulating Na+ reabsorption in the distal tubule
and cortical collecting tubule
• Maintain extracellular fluids volume
• Regulation system of MC: serum K+, Angiotensin II,
ACTH
• Aldosterone level fluctuates in parallel to cortisol
rhythm
• Preparations: Fludrocortisone
Mineralocorticoids - Preparations
Drug Anti- Salt retaining Preapartions &
inflammatory dose

Fludrocortisone 10 150 100 mcg tab.

DOCA 0 100 2.5 mg


(deoxycortico- sublingual
sterone acetate)
Aldosterone 0.3 3000 Not used
clinically
Steroid withdrawal
Withdrawal symptoms & signs: weaknesses, fatigue, decreased appetite,
nausea, vomiting, diarrhea, weight-loss, abdominal pain, myalgia,
arthralgia, etc

Longer the duration of therapy, slower the withdrawal

• Less than 1 week: withdrawal in few steps


• Rapid withdrawal: 50% reduction of dose every day
• Slow withdrawal: 2.5 – 5 mg prednisolone reduced at an interval of 2-
3 days
• Longer period & high dose:
• Halve the dose weekly until 25 mg prednisolone or equivalent is
reached
• Later reduce by about 1mg every 3-7 days.
HPA axis recovery may take months or up to 2 years
Adverse
reactions
• Metabolic toxicity:
• Iatrogenic Cushing’s syndrome
• Hyperglycaemia, glycosuria, diabetes
• Myopathy (negative nitrogen balance)
• Osteoporosis (vertebral compression
fracture)
• Retardation of growth (children)
• Hypertension, oedema, CCF
• Avascular necrosis of femur
Adverse reactions (2)

 HPA axis suppression


 Behavioral toxicity: Euphoria, psychomotor
reactions, suicidal tendency
 Ocular toxicity: steroid induced glaucoma,
posterior subcapsular cataract.
 Others:
– Superinfections
– Delayed wound healing
– Steroid arthropathy
– Peptic ulcer
– Live vaccines are dangerous
Contraindications

• Infections
• Hypertension with CCF
• Psychosis
• Peptic ulcer
• Diabetes mellitus
• Osteoporosis
• Glaucoma
• Pregnancy : (prednisolone
preferred)
Glucocorticoids
antagonists
• Mitotane: structure similar to DDT, used in inoperable adrenal cancer
• Metyrapone: inhibit 11 -hydroxylase
• Aminoglutethamide: inhibit conversion of cholesterol to pregnolone,
medical adrenelectomy
• Trilostane: inhibit conversion of pregnolone to progesterone; used in
Cushing’s syndrome
• Ketoconazole: anti-fungal, inhibit CYP450 enzymes, inhibit steroid
synthesis in ad.cortex and testis; used in Cushing’s syndrome & Ca.prostate
• Mifepristone: glucocorticoid receptor antagonist; anti-progesterone,
used in Cushing’s syndrome
Further readings:
• Liu, et al. A practical guide to the monitoring and
management of the complications of systemic
corticosteroid therapy. Allergy, Asthma & Clinical
Immunology 2013, 9:30
• Gupta P, Bathia V. Corticosteroid physiology and
principle of therapy. Indian Journal of Pediatrics
October 2008;75.