Farmakologi Obat Untuk

Penyakit Imun

 Immunofarmakologi adalah bidang

biologi yang terdapat overlap
antara immunologi, patologi dan
farmakologi

Imunomodulator
Immunostimulator
Imunosupressan

 Concept and Definition:

Immunomodulators are Biological
Response Modifiers (BRM), used to
treat cancer, exert their anti-tumor
effects by improving host defense
mechanisms against tumor
(Encyclopedia Britannica).

 Immunostimulation in drug-induced
immunosuppression and
immunosuppression in experimental
hyper-reactivity model by the same
preparation can be said to be true
immunomodulation.

The Immune Response - why

and how ?
Discriminate: Self / Non self
Destroy:
Infectious invaders
Dysregulated self (cancers)

Immunity:
Innate, Natural
Adaptive, Learned

Who are involved ?

Innate
Complement
Granulocytes
Monocytes/macropha Adaptive:
B and T
ges
lymphocytes
NK cells
B: antibodies
Mast cells
T : helper, cytolytic,
Basophils
suppressor.

Tahapan utama respon imun

1- Pengenalan antigen
2- Produksi IL-1
3- Ekspresi IL-2 dan cytokine
lain
4- Proliferasi dan diferensiasi
lymphocyte

MAJOR STEPS IN IMMUNE RESPONSES

Antigen

IL-2

CD8 cell

antigen
presenting
cell

4
2

IL-1

IL-2
CD4
helper
cell

cytotoxic
T cells

primed
CD4
helper
cell

4
IL-2

plasma
cells

Gangguan Imunitas &

Intervensinya
Kondisi gangguan
imun:
Respon/status imun
rendah atau kurang
Respon imun
berlebihan /
hiperaktif

Intervensi
Meningkatkan
respon / status imun
Menekan respon
imun

IMMUNE
MODIFIERS

Immunosuppressants

Immunostimulants

? Immune tolerance

Meningkatkan respon / status imun

Imunoterapi aktif:

Terapi vaksin (BCG, DPT, Polio, Campak,

Hepatitis, dll)
Vaccines

Administration of antigen as a whole, killed

organism, or a specific protein or peptide
constituent of an organism
Booster doses
Anticancer vaccines immunizing patients
with APCs expressing tumor antigen.

Agen Sintetik
Levamizole Aksi utama: meningkatkan
jumlah dan aktivitas sel T; Penggunaan utama:
kanker kolorektal; Efek Samping:
agranulositosis
Thymic Hormones
Improve primary immune deficiency in children

Imunisasi adoptif
Infus: limfosit donor, limfosit T cytotoxic
(diaktivasi ex vivo), limfosit terinfiltrasi
tumor
Imunisasi Toleransi perifer buatan
(Desensitisasi)
Imunoterapi peny gg. Autoimmun
autoantigen
Imunoterapi pd hipersensitifits /
penolakan cangkok organ

Immunostimulatory Cytokines
Interleukins
IL-2

(enhance antitumor actions of cytotoxic T cells

and NK cells)

Colony

Stimulating Factors

G-CSF (neutropenia)

and GM-CSF (bone marrow

transplant patients)
Interferons
alpha

(uses)

(anticancer uses)
beta (relapsing type multiple sclerosis)
gamma (chronic granulomatous disease)

Interferon Uses
Interferon Alpha

(prod. by leukocytes)

(antiviral,

antiproliferative)
malignant melanoma, renal cell carcinoma,
hairy cell leukemia, Kaposis sarcoma
Interferon

Beta (prod. by fibroblasts)

(antiviral,

antiproliferative)
relapsing type MS
Interferon

Gamma (prod. by
lymphocytes)
(stimulates

NK cells and macrophages)

chronic granulomatous disease

Imunostimulator Herbal

Echinacea

Phylantus niruri immunostimulator

fitofarmaka - Indonesia

Imunoterapi pasif
Seroterapi

/ terapi serum
Serum heterolog hiperimun
serum imunosupresif
serum agen antiinfeksi
serum antibisa
Serum homolog
serum homolog imun (human
tetanus Ig)
serum homolog hiperimun

 Antibodi

monoklonal (mAbs)
mAbs antiinfeksi organisme
mAbs antitoksik
mAbs antiplatelet
mAbs antikanker (keganasan
hematologik, tumor solid)
mAbs antihipersensitifitas tipe I
mAbs imunosupresif
mAbs imunostimulan

 Ligan

imunosit
Ligan imunosupresif
Ligan imunostimulan
Sistem haptofor-toksofor
Radioimmunotherapy (RIT)
imunotoksin
TAP (Tumor Activated Prodrug)
ADEP (Antibody-directed enzyme prodrug)
delivery of scMHC class peptide
complexes
Immuno-gene therapy

Obat penekan respon imun

Obat-obat imunosupresif menghambat
fungsi dan / atau aktivasi limfosit
terutama dengan menghambat sintesis
DNA (antiproliferatif) atau produk gen
spesifik (melalui interfensi dalam
signaling)

SITES OF ACTION OF
IMMUNOSUPPRESSIVE DRUGS
CD8 cell 4
Antigen
IL-2

1
X
A

BIL-1
antigen
presenting
cell

X
D

IL-2

CD4
helper
cell

primed
CD4
helper
cell

X
cytokines

cytotoxic
T cells

plasma
cells

Inhibitors of Immune Response

(site of action)
_
_
_
_

ABCD-

Immune Globulin (antigen recognition)

Corticosteroids (IL-1 production, cell proliferation)
OKT3 (CD3 receptor on T cell), ALG
Cyclosporine, Tacrolimus, (1L-2 gene expression
and production), Sirolimus (IL-2 signal
transduction in T cells)
E- Methotrexate, Cyclophosphamide, rapamycin,
mycophenolate

t
a
n
In

l
a
r
atu
N
e,

e
v
i
t
ap
d
A

Obat-obat Imunosupressan
Cyclosporine
Tacrolimus
Sirolimus
Mycophenolate
Kortikosteroid

(Prednisone,
Methylprednisolone)

Cyclosporine
Strukture
lipophilic

cyclic peptide

Mekanisme
Menghambat

trasnkripsi gen IL-2 dan ekspresi

cytokine lain (IL-3, gamma interferon)
Tempat aksi: ikatan protein yang menghambat
calcineurin (suatu phosphatase) yang melibatkan
signal transduction pada stimulasi antigen terhadap
reseptor sel T yang sedang berlangsung
MA

Cyclosporine

(R) [Sandimmune]

Pharmacokinetics
Absorpsi

peroral tidak lengkap

Metabolisme di hati, diekskresi dalam empedu
Pengunaan single / kombinasi dg prednisone dan
azathioprine (atau obat anti kanker lain)
Adverse

Effects

nephrotoxicity, hepatotoxicity, hirsutism,

neurotoxicity
Interaksi obat: induksi dan inhibisi enzim
cytochrome P450

Cyclosporine (R)[Neoral]
Pharmacokinetics
microemulsion

of cyclosporine

(capsules and oral solution)

improved

oral absorption
60% oral availability vs 30% for
Sandimmune
terminal half-life approx. 8.4 hours vs 19
hours for Sandimmune

Tacrolimus
Strukture
macrolide

(structure like erythromycin)

Mekanisme
Sama

dg cyclosporine kecuali ikatan pada protein

yang berbeda dalam menghambat calcineurin (suatu
enzim phosphatase dalam transkripsi gen IL-2,
gamma interferon and other cytokines)

MA

Tacrolimus
Bioavailability
Pemberian

infus IV atau peroral

Digunakan bersamaan dg kortikosteroids
Adverse

Effects

nephrotoxicity, meningkatkan

resiko
lymphoma, hypersensitivity, hyperglycemia,
tremor, headache

Sirolimus
Sirolimus (Rapamune)

Struktur
Structure

macrolide similiar to tacrolimus

macrolide similiar to tacrolimus
Mekanisme

Mechanism

Berikatan dg protein imunofilin yg berikatan pada

binds
immunophilin
protein
that binds pada
to a key
kunci to
pengaturan
kinase
dan diperlukan
regulatory
required for T cell activation
aktivasi selkinase
T

(new
(new unique
unique mechanism
mechanism to
to inhibit
inhibit T
T lymphocyte
lymphocyte
activation
activation by
by IL-2)
IL-2)

different
site yang
of action
than dengan
cyclosporine
and
Tempat aksi
berbeda
cyclosporine
dan
tacrolimus
tacrolimus
MA

Sirolimus ~ TOR
Target

of rapamycin (TOR) berperan penting pd

jalur pengenalan antigen untuk memperkuat
respon immune mengikuti (urutan) pengenalan
anitgen, aktivasi T cells synthesize dan pelepasan
IL-2 serta proinflammatory cytokines IL-2 lain
yang berikatan pada sel T dan menunjuk aktivasi
TOR yang mengawali kejadian cascade

Consequences
of
TOR
Action
Konsekuensi aksi TOR
Proliferasi
Lymphocyte
dan
celldiferensiasi
proliferation

&

Sel T
differentiation
Sel
T cells
B
B cells Antibodi
Produksi

Antibody
Proliferasiproduction
sel mesenkimal
Mesenchymal
Sel otot polos cell
proliferation
pembuluh
darah
Sel
Vascular
smooth
Endothelial
Fibroblasts
Endothelial
Fibroblasts

cells

muscle cells

Properties of TOR Inhibitors

such as Sirolimus
(Rapamune)
Sirolimus:
Inhibitor
TOR
Selective

blockade of cytokine signal

transduction
Selective menghambat transduksi signal
Inhibition
cytokine, of cell division and proliferation
Potent
and effective
immunosuppression
Menghambat
proliferasi
dan pembagian sel,
Imunosupresi potensial dan efektif,
Mempunyai sinergi yang kuat dengan
immunosuppressants lain.

 other

theoretical actions of sirolimus include:

blockade

of B cell Ig synthesis
inhibition of antibody-dependent cellular toxicity
inhibition of lymphocyte activated killer cells
inhibition of natural killer cells
inhibition of immune and nonimmune cell
proliferation (via inhibition of growth factor
signalling)

Mycophenolate Mofetil
Adverse

Effects

diarrhea,

leukopenia and CMV infections

increased incidence of lymphomas and other
malignancies

MA

New Immunosuppressants
_

Mizoribine (investigational)
_

Brequinar (investigational)
_

Inhibitor of de nove pyrimidine synthesis

15-Deoxyspergualin (investigational)
_

Inhibitor of purine nucleotide synthesis

Antimonocytic that decreases MHC antigen

expression

Pimecrolimus (Elidel)
_
_

Calcineurin inhibitor like cyclosporine

Approved for topical treatment of eczema

Antibodies Used for Acute Rejection

of Organ Transplants
OKT3

(Muromonab-CD3)

MA

monoclonal

antibody to CD3 on T cell

inhibits cytotoxic T killer cell function
opsonizes circulating T lymphocytes and enhances
their removal
used to prevent or reverse acute graft rejection
Antilymphocyte
polyclonal

antibody similiar to OKT3

Antithymocyte
used

Globulin

Globulin-Rabbit

to treat acute renal transplant rejection

Azathioprine

Tacrolimus
Sirolimus

Baxiliximab
Daclizumab

Cyclosporin
Corticosteroid

OKT3

Mycophenolate

Antithymocyte Globulin-Rabbit
(Thymoglobulin)
Rabbit

gamma immune globulin

preparation
Composed of antibodies to variety of T
cell markers
Mechanisms
removal

of T cells from circulation

modulation of T cell activation, homing and
cytotoxicity
decreases cytokine induced reactions

Adverse Effects of Antibody Preps

_

Reaksi hipersensitif meliputi kedinginan, febris,

thrombocytopenia, erythema, pruritis. Untuk
membatasi efek tersebut pemberian antibodi AntiOKT3, hanya diberikan melalui infus IV selama 714 hari

Sediaan antibodi yang lain

Rh

(D) Immune Globulin

Untuk

ibu Rh (neg.) setelah melahirkan bayi

Rh(pos.)

Abciximab
Untuk

reseptor permukaan pada aktivasi platelet

untuk mencegah restenosis setelah coronary
angioplasty

Rituximab
Untuk

CD20 pada sel pre-B dan sel B mature pada

terapi non-hodgkins lymphoma

Antibodi reseptor IL-2

Basiliximab

(Simulect)

Chimeric

murine monoclonal antibody against

human IL-2 receptor alpha subunit of activated T to
block T cell
Blocks activation and inhibits clonal expansion of T
cells
Used to induce immunosuppression and to prolong
organ transplants in combination with
immunosuppressants
MA

Other IL-2 Receptor Antibodies

Daclizumab (Zenapax)
a

humanized immunoglobulin similar to Basiliximab

which blocks IL-2 receptor
Formed by splicing complementary portions of light
and heavy chain variable regions of murine antibody
into human-derived Fab framework and fusing the
Fab to the Fc portion of human IgG

MA

Azathioprine

Tacrolimus
Sirolimus

Baxiliximab
Daclizumab

Cyclosporin
Corticosteroid

OKT3

Mycophenolate

Corticosteroids
Prednisone

used most often orally

Methylprednisolone used parenterally
Numerous available preparations

Corticosteroid Actions
Inhibition

of IL-1 and TNF gene expression and

synthesis
Decreased activation of T lymphocytes by
decreasing IL-1 release
Decreased activation of T lymphocytes by
decreasing IL-1 release
Decreased neutrophil functions esp chemotaxis
Decreased antibody production (high doses)
Decreased release of kinins and
proinflammatory eicosanoids (prostaglandins
and leukotrienes)

Corticosteroid
Immunosuppression
_

Decreased cell-mediated immune

reactions that mediate rejection of organ
transplants
_

Mechanism involves decreased activation of

T lymphocytes by inhibition of IL-1 synthesis
by macrophages and decresed lymphocyte
mobilization out of lymphoid organs

MA

Azathioprine

Tacrolimus
Sirolimus

Baxiliximab
Daclizumab

Corticosteroid
Cyclosporin
Corticosteroid

OKT3

Mycophenolate

Corticosteroid Adverse Reactions

_
_
_
_
_
_

All commonly occur because high doses used for

immunosuppression
Suppression of HPA function
Hypertension
Weight gain, hyperglycemia
Euphoric personality changes
Cataracts

Antimetabolites
Immunosuppresion

by inhibition of
lymphocyte proliferation and cause bone
marrow suppression
Azathioprine
Cyclophosphamide

MA

Cytokine Inhibitors
_

TNF inhibitors (disease modifiers to treat

rheumatoid arthritis)
_
_

Etanercept (Enbrel)
_ Recombinant version of TNF receptor
Infliximab (Remicade)
_

Chimeric human/murine anti-TNF monoclonal

antibody

Anakinra (Kineret)
_
_

Human IL-1 receptor antagonist

Disease modifier agent for Rheumatoid
arthritis

 Reference:
Textbook

of Immunopharmacology
Website: Immunotherapy

Dan apabila aku sakit, Dialah Yang

menyembuhkan aku, (QS. Syu'ara':
80).

Dari Usamat bin Syarik, seorang laki-laki dari

kaumnya berkata, datang seorang dusun kepada
Rasulillah saw dan bertanya: ...,Ya Rasulallah
apakah kami mesti berobat? Nabi menjawab:
Berobatlah, sebab, Allah tidak menurunkan
penyakit kecuali juga menurunkan obatnya,
diketahui oleh orang yang mengetahuinya dan
tidak diketahui oleh orang yang tidak
mengetahuinya," (HR Ahmad)

Thank's a lot
Terima kasih
Matur nuwun
Syukran katsira

Wassalamualaikum Wr. Wb.