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OBAT-OBAT SISTEM IMMUN

Fathiyah Safithri
Laboratorium Farmakologi
Fakultas Kedokteran UMM
2009
DEFINITION

The immune system protect individuals


against pathogenic viruses, microorganism and
parasites. Immune responses depend on the
ability of the system to recognize foreign
molecules (antigens) then to amount an
appropriate reaction to eliminate the source of
the antigen.
IMMUNE SYSTEM

Innate immunity Adaptive immunity


(immune system nonspesific) (spesific system)
The defenses against pathogenic Respond specifically to substances
microorganism that are present in and organisms
host who has not been previously
exposed to the pathogen

Complement Immunoglobulins
Natural Killer Cells T Lymphocytes
Phagocytic cells
Immunofarmakologi : ilmu yang mempelajri
tentang bagaimana mengontrol (menekan /
meningkatkan ) respon imun dengan
mediator biologis ataupun khemis
Obat Immunosupressan : mempelajari obat
yg digunakan pd keadaan overaktivasi sistem
imun (penyakit autoimun, post transplantasi)
Obat Immunostimulan : mempelajari obat
yang dapat meningkatkan status imun pada
keadaan immunodefisiensi, HIV-AIDS, kanker
Obat Sistem Imun

Obat utk Penyakit Allergi


Obat utk Penyakit Autoimmun &
Keganasan (Immunosupressan)
Immunostimulan
OBAT UNTUK PENYAKIT
ALLERGI
H1 reseptor antagonis
Glukokortikoid (Kortikosteroid)
Cystenyl-Leukotrien Recept Antagonis
5-Lipoxygenase inhibitors
Kromolin sodium
Epinefrin
Mekanisme
Mekanisme
Allergi
Allergi
Target Terapi Anti Allergi
Target Terapi Anti Allergi

1. Me IgE berikatan dg sel mast (anti-IgE antibody)


2. Mencegah degranulasi sel mast
(kromolin, simpatomimetik)
3. Menghambat kerja mediator yg dilepaskan sel mast
(anti H1, antagonis leukotrien reseptor)
4. Me respon inflamasi (glukokortikosteroid)
ANTI-Ig
ANTI-Ig E
E MONOCLONAL
MONOCLONAL
ANTIBODY
ANTIBODY (Omalizumab)
(Omalizumab)
merup immunoglobulin G yang
bekerja sebagai antihuman Ig dg cara
menghambat ikatan IgE dengan mast
sel
Dapat menurunkan frekuensi dan
eksaserbasi berulang penyakit allergi
Half life sangat panjang diberikan
1X / bulan
Diberikan melalui injeksi subkutaneus
KROMOLIN
KROMOLIN &
&
NEDOKROMIL
NEDOKROMIL
Per inhalasi
Absorbsi per oral <<< (tdk ada sediaan oral)
Mek kerja :
Hambat degranulasi sel mast (mast cell
stabilization) mencegah release histamin &
mediator inflamasi lain
Mempengaruhi aktivasi sel inflamatori lain, mis
alveolar makrofag
Mencegah rekruitmen sel inflamatori di jaringan
Menekan reflek neuronal yg berlebihan yang
ditimbulkan reseptor irritan di jalan nafas
Penggunaan : profilaksis (slow onset), efektif utk
asma yg diinduksi oleh allergen / aktivitas
NH2

HISTAMIN
5 4

1 3
N N
H
2

Histamine

dibentuk dr asam amino histidin & disimpan dlm


konsentrasi tinggi di sel mast jaringan dan basofil darah.
Lokasi paru, kulit, GIT
Histamin diproduksi & disekresi oleh granula mast sel.
Me pd reaksi allergi yg diperantarai Ig-E (immediate),
mis : seasonal rhinitis (hay fever), urticaria, and
angioneurotic edema.
SUB TIPE RESEPTOR HISTAMIN
Rec. Distribusi Mek Kerja Prototype
subtype Antihistamin

H1 Jaringan saraf, Otot IP3, DAG Diphenhidramine


polos (resp, GIT, UG, Ca 2+intake Chlorpheniramine
kardiovask, med adr,
endothel, limfosit)
H2 Lambung, jantung, mast cAMP Cimetidine
cell Ranitidin
Famotidin
H3 Ujung saraf, SSP cAMP -

H4 Jar intestinal, lien cAMP -


thymus, Sel immune
Ca 2+
aktif (netrofil, T-cell,
eosinofil
Pathophysiology Histamine Release
Efek Aktivasi Reseptor
Histamin-1
Manifestasi pd allergic reactions H1 receptor
Mekanisme kerja : release IP3 & DAG Ca2+
intake

Kontraksi otot polos (bronkhokonstriksi, peristaltik )


Arteri vasodilatasi (H1 & H2), akibat dr pe release
endothelium-derived relaxing factor (EDRF) & PGI2.,
Permeabilitas vaskuler edema, angioedema
Kontraksi jantung , aliran koroner
Sekresi kelenj eksokrin hidung & bronkus
Headache, kewaspadaan
Release katekolamin oleh adrenal
Gatal, eritema eczema, urtica
Mekanisme Kerja AH1

Mek kerja AH1 : kompetitif inhibitor pd reseptor H1

Struktur sgt mirip dg muscarinic blockers & alpha


adrenoceptor blockers (anti H1 sedatif) efek
antikolinergik & antagonis adrenergik
Bbrp bisa memblok resept serotonin (cetirizine).
efek pd resept H2 (-)
Antihistamin
Antihistamin -- H
H11

Sedative (1st Generation) Non sedative (2nd Generation)


difenhydramin terfenadine
chlorpheniramine astemizol
embramin cetirizin
prometazin loratadin
cyproheptadin
bisulepin
dimetinden
azatadin
klemastin
Anti-H1
Anti-H1 sedatif
sedatif &
& non
non sedatif
sedatif

Pembeda Anti H1 sedatif Anti H1 non sedatif

Generasi I ( 1st generation) II (2nd generation)


Prototipe Diphenhydramine & Terfenadine
chlorpheniramine
Durasi 4-6 jam (short acting) > 12 jam (long acting)
Lipid Tinggi penetrasi ke SSP Rendah penetrasi ke SSP
solubulity (+) sedatif (-) nonsedatif
Efek >> : mulut kering, takikardi, <<
antikolinergik midriasis, retensi urine, dll
Pemakaian Efek (ok induksi enzim Risk of VT (Torsade de Pointes)
kronis mikrosom) with Terfenadine and
Astemizole**
EFEK AH1

1. Antiallergi (Blok pd H1 4. Antikolinergik (retensi


urine, pand kabur,
receptors perifer) u/
konstipasi,mulut
reaksi allergi ringan (insect kering)
bite, urtica, dll)
2. Sedasi (blok resep H1 & M
di SSP)
3. Anti emetik u/ motion
sickness (Dimenhidrinate)
Toksisitas:
Sedasi (t.u AH1 sedatif)
Antimuscarinic effects (dry mouth, blurred vision etc.)

Interaksi :
Obat dg efek sedatif (benzodiazepin, alcohol).
Obat yg menghambat metab di hepar (ketakonazol)
kdr AH 1 lethal arrhythmia (terfenadin).
ANTI
ANTI LEUKOTRIEN
LEUKOTRIEN

1. LT-1 reseptor antagonis (Zafirlukast,


montelukast, pranlukast)
efektif hamb Ag / exercise-induced asthma
p.o 1-2 x sehari
2. 5-lipoxygenase inhibitor (Zileuton)
Hamb produksi leukotrien
Interaksi obat : me konsentr teofilin &
walfarin di serum
GLUKOKORTIKOSTEROID

Newton, Thorax
2000;55:603-613
Hypothalamic-Pituitary Adrenal (HPA) Axis

Negative Feedback control


of ACTH Production.
Suppression of HPA

STRESS: Overrides the


neg. feedback mechanism.

Adrenal cortex

Produces 30 steroid hormones

Major divisions include:


Glucocorticoids
Mineralocorticoids
Adrenal Sex steroids
Biosynthesis of Glucocorticoids
(GCs)

Glucocorticoids

Cortisol (95%)
Corticostrone
Cortisone

90% bound to
plasma proteins

Circadian release
Of GCs; highest in
the early morning
and lowest in the
evening.
Disorders of the Adrenal Cortex
Primary Adrenocortical Insufficiency (Addisons Disease)
Destruction of the adrenal cortex leads to inadequate production of
cortisol and aldosterone.
Tuberculosis, cancer, hemorrhage
Atrophy of the adrenal cortex
Autoimmune disease
Prolonged corticosteroid treatment (Long-term admin)
Surgical excision of the adrenal glands

Secondary Adrenocortical Insufficiency; inadequate secretion of corticosteroid.


Mainly a GC deficiency
Prolonged treatment with cortocosteroids (early effects)
Mineralocorticoid secretion is not altered.

Congenital Adrenogenital Syndromes and Adrenal Hyperplasia


Synthetic enzyme deficiency
Abnormally low cortisol levels results in excessive ACTH secretion,
excessive adrenal secretion of androgens and hyperplasia.

Adrenocortical Hyperfunction (Cushings Disease: Moonface)


Excessive ACTH secretion
Adrenal tumor (benign or malignant)
Abnormally high corticosteroid levels
Aktivasi Reseptor Steroid
Aktivasi Reseptor Steroid
S mengikat resept S(R) di sitoplasma, R sec normal berhub
dg 2 molekul hsp90. kompleks S-R translokasi ke nukleus
dan berinteraksi dg GRE (glucocorticosteroid response
element) pd rantai promotor sel target mempengaruhi
proses transkripsi & sintesa protein

Antara lain menyebabkan :


Induksi sintesa polipeptida (lipocortin-1) yg menghambat enzim
fosfolipase A2 menurunkan produksi mediator inflamasi (PG,
leukotrien, platelet-activating factor /PAF)
Netralisasi peran transcription factor (mis. AP1) dlm sintesa sitokin
(IL5, TNF) sintesa sitokin me inflamasi
Penggunaan Glukokortikoid
Insufisiensi Adrenal
Supresi HPA-axis overaktif
Supresi penyakit autoimmun
Mencegah rejeksi organ transplantasi
Terapi limfosit-derived tumor
Terapi penyakit allergi (asma, penyakit kulit
allergi)
KortiKosteroids
KortiKosteroids

Anti-inflammatory effect
Antiproliferative effect
Immunosuppressive effect
Penggunaan Kortikosteroid
Mechanism of Action for
Anti-Inflammatory Steroids
Mekanisme Kerja
Steroid sbg Anti-Inflammasi
Menghambat aktivasi T-cell dan produksi sitokin.

Menghambat degranulasi mast cell.

Menurunkan permeabilitas kapiler secara tidak langsung akibat hambatan


pada mast cells dan basophils.

Menurunkan ekspresi cyclooxygenase II (COX2) dan sintesa prostaglandin.

Induksi sintesa lipocortin1 hamb enz fosfolipase A2 me kadar


prostaglandin, leukotriene and platelet activating factor(PAF)
Routes of Administration for GC

Local (Preferred)
Intra-articular, IA
Intrabursal, IB
Intralesional, IL
Intrasynovial, IS
Soft tissue, ST
Intrarectal, IR
Topical
Nasal
Inhaled

Systemic
Oral, PO
Intramuscular, IM
Intravenous, IV
Farmakokinetik GC
Pemberian corticosteroids pd konsentrasi fisiologis
selama minimal 2 minggu akan menekan HPA axis,
shg terjadi penurunan endogenous hormones.
Recovery setelah 9-12 bulan.

Metabolisme Hepar :
Hepar : tempat inaktivasi / metabolisme utama GC. GC
dimetabolisme oleh enzim cytochrome P450 3A4
25% GC diekskresi bersama empedu & feces .

Renal Clearance
75 % metabolit GC diekskresi bersama urine .
Dampak Pemberian Kortikosteroid pada
Cortisol Release
Mineralocorticoid actvity

Corticosteroids control symptoms and DO NOT stop progression (cure) of the disease
Anti-inflammatory Drugs
Glucocorticoids
Inhaled
Beclomethasone
Budesonide
Flunisolide
Fluticasone propionate
Triamcinolone acetonide

Metered Dose
Inhaler
Also, Dry-powder inhalers
Oral (Quick relief of asthmatic symptoms) and Nebulizers
Prednisone
Prednisolone
* Unresponsive to 2 agonists
Inhaled Glucocorticoids:
Long-term control of Chronic Asthmatic Symptoms

Beclomethasone Taken Daily, over a long period of


Budesonide time
Flunisolide
Fluticasone propionate SE: oropharyngeal candidiasis
Triamcinolone acetonide (Thrush), dysphonia (hoarseness),
adrenal suppression, bone loss, in
children, retarded growth
Reduced risk of toxicity with inhaled
preparations
Mechanisms of Action:
Reduce bronchial hyperreactivity
Decreased synthesis and release of inflammatory mediators,
e.g, leukotrienes, prostaglandins and histamine
Decreased infiltration and activity of inflammatory cells, e.g.
eosinophils, leukocytes)
Decreased edema of the airway mucosa and mucus production
Increase responsiveness to 2 agonists
Kortikosteroid Sistemik

Triamcinolone 5 0 18-36 3,0


Betamethasone 25 0 18-36 4,0
Kortikosteroid Topikal
Level of Potency Corticosteroid Commercial Products

Ultra-high Halobetasol propionate Ultravate crm/oint


Clobetasol propionate Temovate crm/oint
Betamethasone dipropionate Diprolene oint
Diflorasone diacetate Psorcon oint

High Halcinonide Halog crm


Amcinonide Cylocort oint
Betamethasone dipropionate Diprolene AF crm
Mometasone furoate Elocon oint
Diflorasone diacetate Florone oint
Fluocinonide Lidex crm,gel,oint
Desoximetasone Topicort crm,oint,gel

Mild to high Halcinonide Halog oint,crm,soln


Triamcinolone acetonide Aristocort A oint
Betamethasone dipropionate Diprosone crm
Fluocinonide Lidex-E crm
Kortikosteroid Topikal
Level of Potency Corticosteroid Commercial Products

Mild Hydrocortisone valerate Westcort


Triamcinolone acetonide Kenalog crm and oint
Flurandrenolide Cordran oint
Mometasone furoate Elocon crm
Fluocinolone acetonide Synalar oint

Low to mild Hydrocortisone valerate Westcort crm


Triamcinolone acetonide Kenalog crm and oint
Flurandrenolide Cordran crm
Betamethasone dipropionate Diprosone lotion
Hydrocortisone butyrate Locoid crm
Flucolone acetonide Synalar crm

Low Alclometasone dipropionate Aclovate crm and oint


Betamethasone valerate Valisone lotion
Fluocinolone acetonide Synalar soln and crm
Hydrocortisone, dexamethasone,
prednisolone, methylprednisolone
Efek Samping Pemakaian KortikoSteroid
jangka panjang
Efek Samping

Glucocorticoid Withdrawal: Should be


performed slowly
Withdrawal syndrome: hypotension, hypoglycemia, myalgia
and fatigue
Strategi Mencegah ES Jangka Panjang
Kortikosteroid

Pemberian dengan dosis intermitten


(alternate-day), mis. setiap 2hari sekali
Pemberian yg berefek lokal : topikal atau
inhalasi
Drug Interactions
Drugs that Enhance Corticosteroid Effects
Estrogens
Oral contraceptives
Antifungal agents
Antibiotics
*all of these agents inhibit cytochrome P450 enyzymes

Drugs that Reduce Corticosteroid Effects


Antacids
Cholestyramine
*these drugs decrease the absorption of
corticosteroids
Phenytoin: activate cytochrome P450 enyzymes
SYOK ANAFILAKTIK
Clinical Features of Anaphylaxis

- Is there a predisposition? Latex and food allergies usually


Urticarial Rash
occur against a background of atopy and other allergic
disorders e.g. asthma and eczema.

- Onset is rapid (5-10 minutes of exposure) peaking in 30


minutes. Duration can be long especially if allergen persists
(e.g. swallowed) or the response is biphasic (classical late-
phase allergic response in the airways)

- May be heralded by impending sense of doom.


Subsequent features reflect to some extent route of allergen
exposure:

Systemic (IV drugs) - cardiovascular


(hypotension/syncope)
Ingested (food allergens) - respiratory (laryngeal
oedema/bronchoconstriction)
Percutaneous (insect stings) - respiratory or
cardiovascular problems equally likely

All may be accompanied by cutaneous features


e.g. urticarial rash.
Features Suggesting Severe Anaphylactic Reaction

Wheeze
Stridor
Cyanosis
Skin Pallor*
Prominent Tachycardia**

* 80% of fatal food-related anaphylactic reactions have no skin signs


** Compared to bradycardia in vasovagal attack
2005
Guidelines
of the UK
Resuscitati
on Council
EPINEFRIN /ADRENALIN
Bukan anti allergi, tp sering dipakai pd kasus
allergi 1st line drug syok anafilaktik
Mek kerja : agonis kuat resept &
adrenergik
Berfungsi :
memberi efek antagonis thd efek mediator
inflamasi pada otot polos
Menghambat Ag-induced release mediator
inflamasi dari sel mast akibat aktivasi resept -2
The Use of Adrenaline in Anaphylaxis

The problems with its use:

Variable Absorption - give IM AVOID SC


Arrhythmogenic in high dose - NEVER give 1:1000 ADRENALINE IV

If using ADRENALINE as an IVI, it must be diluted and do not delay


administration of ADRENALINE to set up IVI and gain IV access.

Therefore:

1. Give ADRENALINE IM promptly (can repeat at 5-10 min intervals)


2. Gain IV access
3. If patient remains shocked resort to IVI thus .
Dilute 0.5ml of 1:1000 ADRENALINE in 50ml of N/saline (1:100,000)
4. Infuse at 0.1-2ml/min (1-20ug/min) until haemodynamically stable
Other drugs used in Anaphylaxis

Nebulised or IV 2 agonist (e.g. salbutamol) - useful where


bronchospasm is the major sign and fails to respond promptly to IM
adrenaline.

IV Glucocorticoid (e.g. hydrocortisone 200-500mg) - probably of


limited efficacy (onset of action delayed 3-6 hrs) except where the
response is biphasic or asthmatic features predominate.

IV Glucagon (1mg in 1L, infused at 5-15ml/min) - anecdotal reports of efficacy in


refractory hypotension. Releases catecholamines and +ve inotrope (raising cAMP
independent of cardiac -adrenoceptors).
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