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FARMAKOLOGI
ANTIINFLAMASI &
IMUNOSUPRESAN
Dr. Nanang Munif Yasin, M.Pharm,Apt
nanangy@yahoo.com
Fakultas Farmasi
Universitas Gadjah Mada
Yogyakarta
03/03/2017
TUJUAN PEMBELAJARAN
03/03/2017
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COX = enzim siklooksigenase
L PGG2 = hidroperoksi endoperoksida
A prostaglandin G2
N PGH2 = prostaglandin H2
PGD2 = prostaglandin D
D PGE2 = prostaglandin E
I PGF2 = prostaglandin F
PGI2 = prostasiklin
N TxA2= tromboksan
EFEK PROSTAGLANDIN
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OBAT GOLONGAN NSAID
Activation of the arachidonic acid pathway causes:
pain
headache
fever
inflammation
Analgesia—treatment of headaches and pain
Block the undesirable effects of prostaglandins, which
cause headaches
Antipyretic: reduce fever
Inhibit prostaglandin E2 within the area of the brain that
controls temperature
Relief of inflammation
Inhibit the leukotriene pathway, the prostaglandin
pathway, or both
AKSI NSAID : EFEK ANALGETIK
NSAIDs
Prostaglandins
factors
pGE2 pGF2
+ Bradikinin
histamine
Nerve ending of
pain
• block prostaglandins
production
Pain •Sites of action:
peripheral tissue
AKSI NSAID : EFEK ANTIPIRETIK
Prostaglandins Pyrogen
pGE2
NSAIDs
thermoregulatory
center
•Antipyretic Mechanism
Block prostaglandins
set point ↑
production
heat production ↑
•Sites of action: Central
Heat dissipation ↓
Nervous System
Fever
AKSI NSAID : EFEK ANTIINFLMASI
NSAIDs
Prostaglandins
Inflammatory
pGE2 pGF2 factors
Bradikinin
+
Histamine
Symptoms of 5-HT
inflammation
•block prostaglandins
production
Red, swelling,
Heating, Pain •Sites of action:
peripheral tissue
KLASIFIKASI NSAIDs
As a group, with the exception of aspirin, these drugs may have the
potential to increase myocardial infarctions and strokes
4. PERBANDINGAN ANGGOTA NSAID
4.PERBANDINGAN ANGGOTA NSAID
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5. NSAIDs: Side Effects
Gastrointestinal
dyspepsia, heartburn, epigastric distress,nausea
**GI bleeding
**mucosal lesions (erosions or ulcerations)
Misoprostol (Cytotec) can be used to reduce these
dangerous effects.
Renal
reductions in creatinine clearance
acute tubular necrosis with renal failure
Cardiovascular
noncardiogenic pulmonary edema
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EFEK NSAID PADA GINJAL
ADVERSE EFFECTS
Mainly on liver due to its active metabolite (
N-acetyl-p-benzoquinone).
At therapeutic doses increases hepatic
enzymes.
At high doses causes hepatic necrosis & renal
necrosis.
Treatment of paracetamol toxicity with N-
acetylcystine (SH donor ) as life saving
C. OBAT UNTUK ARTHRITIS
Slow acting anti-inflammatory drugs (Disease modifying drugs)
1. Used as a second line in treating arthritis.
2. When the disease is progressing & causing deformties.
3. Can not repair existing damage,but prevent further injury.
4. Have no analgesic effects
5. Need weeks or months to act.
C. OBAT UNTUK ARTHRITIS: Hydroxychloroquine
Mechanism of action Adverse effects
1. Suppress Tlymphocytes 1. Nausea & vomiting
2. Decrease leukocytes action 2. Cinchonism ( tinnitus.vertigo )
3. Stabilize lysosomal activity 3. Irreversible retinal damage
4. Inhibits DNA& RNA synthesis 4. Ototoxicity
5. Traps free radicals 5. Corneal deposits
6. Allergic skin reaction
Clinical uses
7. Hepatitis
Arthritis used in a large doses & long
duration
C. OBAT UNTUK ARTHRITIS: Methotrexate
Mechanism of action
1. Dihydrofolate reductase
inhibitor
2. Immunosuppressive agent
Adverse effects
1. Nausea
2. Mucosal ulcers
3. Bone marrow depression which
can be reversed by leucovorin.
4. Hepatotoxicity is dose related.
C. OBAT UNTUK ARTHRITIS: Anti- TNF-alpha drugs
Infliximab
Is a chimeric(25%mouse &75%human).
Binds with high affinity to humanTNF-alpha.
Given as I.V.infusion
Half-life 8-12 days.
Given at 0,2,6 weeks followed by intervals of rest 4-6 weeks.
Improvement reaches up to 60%
Can be used in combination with methotrexate reduce the prevalence
of human antichimeric antibodies.
Clinical Uses Adverse effects
Rheumatoid arthritis 1. Upper respiratory tract infections.
Ulcerative colitis 2. Cough.
Psoriasis 3. Nausea.
Psoriatic arthritis 4. Headache.
Giant cell arteritis 5. Rash.
Sarcoidosis. 6- Activate latent tuberculosis
7- Infusion site reaction
C. OBAT UNTUK ARTHRITIS: LEFLUNOMIDE
1. Immunosuppressive drug used in the
treatment of R.A.
2. Undergoes rapid conversion in intestinal
mucosa & plasma to active metabolities.
Mechanism of action
Inhibits dihydroorotate dehydrogenase
which lead to inhibition of
ribonucleotide synthesis & arrest the
stimulated cells in G1 phase.
Inhibits T cell proliferation &production
of autoantibodies by β cells
Increase interleukin 10 receptor
mRNA.
Decrease interleukin 8 receptor typeA
m RNA.
Decrease TNF-α- dependentNFkB
C. OBAT UNTUK ARTHRITIS: LEFLUNOMIDE
Clinical Uses Adverse effects
Rheumatoid arthritis 1. Diarrhea
Can be given with methtrxate 2. Elevated liver enzymes
3. Mild alopecia
Pharmacokinetics
4. Weight gain
Orally effective
5. Increased blood pressure
Half-life 15 days
6. Leukopenia & thrombocytopenia
Highly bound to plasma proteins
7. Contraindicated in pregnancy
Cholestyramine increases its
clearance
C. OBAT UNTUK ARTHRITIS:SulfASALAZINE
MECHANISM OF ACTION
Through its active metabolite sulfapyridine &the parent drug
itself.
Suppression of T cell.
Inhibition of B cell proliferation
PHARMACOKINETICS
Only 10-20% of orally administered sulfa is absorbed.
Fraction undergoes enterohepatic circulation into the bowel.
Reduced by intestinal bacteria to liberate 5-aminosalicylic acid
And sulfapyridine which is well absorbed while 5-aminosalicylic
remains unabsorbed.
Excreted partly unchanged as sulfasalazine in urine
Sulfapyridine metabolized in liver by acetylation &hydroxylation
Half-life 6-17 hours.
C. OBAT UNTUK ARTHRITIS:SulfASALAZINE
CLINICAL USES ADVERSE EFFECTS
Rheumatoid arthritis Nausea, vomiting
reduce the rate of Headache
appearance of new joint Skin rash
damage. Hemolytic anemia
Juvenile chronic Methemoglobinemia
arthritis Reversible infertility in men
Ankylosing spondylitis. Neutropenia &
thrombocytopenia (rare)
D. OBAT UNTUK GOUT
ADR Kolkisin
PENDAHULUAN: IMUNOSUPRESAN
Immune system
Is designed to protect the host from harmful foreign molecules. This system can result into serious problem. Allograft introduction can elicit a
damaging immune response. Immune system include two main arms:1) Cell –mediated immunity.; 2)Humoral (antibody –mediated immunity).
PENDAHULUAN: IMUNOSUPRESAN
Cytokines
Cytokines are soluble , antigen-nonspecific
signaling proteins that bind to cell surface
receptors on a variety of cells.
Cytokines include
Interleukins,
Interferons (IFNs),
Tumor Necrosis Factors (TNFs),
Transforming Growth Factors (TGFs)
Colony-stimulating factors (CSFs).
TH1 interferon-γ:
inhibits TH2 cell proliferation TH2 cells
TH2 IL-10:
inhibits TH1 cytokine production
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1. IMUNOSUPRESAN:
Inhibitors of cytokines (IL-2) production or action
Mechanism of action:
SRL blocks the progression of activatedT
cells from G1 to S phase of cell cycle
(Antiproliferative action).
It Does not block the IL-2 production but
blocks T cell response to cytokines.
Inhibits B cell proliferation &
immunoglobulin production.
1c. IMUNOSUPRESAN: Sirolimus (Rapamycin)
Pharmakinetics Toxic effects
Given orally and topically, Hyperlipidaemia (cholesterol,
reduced by fat meal. triglycerides).
Thrombocytopenia
Extensively bound to plasma
Leukopenia
proteins
Hepatotoxicity
metabolized by CYP3A4 in liver. Hypertension
Excreted in feces. GIT dysfunction
Pharmacodynamics
USES
Immunosuppressive effects Solid organ allograft
Anti- proliferative action.
Renal transplantation alone or combined
with (CSA, tacrolimus, steroids,
Equipotent to CsA. mycophenolate).
Heart allografts
In halting graft vascular disease.
Hematopoietic stem cell transplant
recipients.
Topically with cyclosporine in
uveoretinitis.
Synergistic action with CsA
2.IMUNOSUPRESAN: Inhibitors of cytokine gene expression
Corticosteroids
Prednisone
Prednisolone
Methylprednisolone
Dexamethasone
They have both anti-inflammatory action and immunosuppressant effects.
Mechanism of action
Bind to glucocorticoid receptors and the complex interacts with DNAto
inhibit gene transcription of inflammatory genes.
Decrease production of inflammatory mediators as prostaglandins,
leukotrienes, histamine, PAF, bradykinin.
Decrease production of cytokines IL-1, IL-2, interferon, TNF.
Indications
are first line therapy for solid organ allografts & haematopoietic stem
cell transplantation.
Autoimmune diseases as refractory rheumatoid arthritis, systemic lupus
erythematosus, asthma
Acute or chronic rejection of solid organ allografts.
3. IMUNOSUPRESAN: Cytotoxic drugs
Inhibitors of purine or pyrimidine synthesis
(Antimetabolites):
Azathioprine
Myclophenolate Mofetil
Leflunomide
Methotrexate
Alkylating agents
Cyclophosphamide
3a. IMUNOSUPRESAN: AZATHIOPRINE
CHEMISTRY:
Derivative of mercaptopurine.
Prodrug.
Cleaved to 6-mercaptopurine
then to 6-
mercaptopurine nucleotide,
thioinosinic acid (nucleotide
analog).
MOA
Inhibits de novo synthesis of
purines required for
lymphocytes proliferation.
Prevents clonal expansion of
Adverse effects
1. Elevation of liver enzymes
2. Renal impairment
3. Teratogenicity
4. Cardiovascular effects (tachycardia).
3d. IMUNOSUPRESAN: Methotrexate
A folic acid antagonist
Orally, parenterally (I.V., I.M).
Excreted in urine.
Inhibits dihydrofolate reductase
required for folic acid activation
(tetrahydrofolic)
Inhibition of DNA, RNA
&protein synthesis
Interferes with T cell replication.
Rheumatoid arthritis &
psoriasis and Crohn disease
Graft versus host disease
Adverse effects
Nausea-vomiting-diarrhea
Alopecia
Bone marrow depression
Pulmonary fibrosis
Renal & hepatic disorders
3e. IMUNOSUPRESAN: Cyclophosphamide
Alkylating agent to DNA. Side Effects
Prodrug, activated into Alopecia
phosphamide. Hemorraghic cystitis.
Is given orally& intravenously Bone marrow suppression
GIT disorders (Nausea -
Destroy proliferating lymphoid
vomiting-diarrhea)
cells.
Sterility (testicular atrophy &
Anticancer & amenorrhea)
immunosuppressant Cardiac toxicity
Effective in autoimmune
diseases e.g rheumatoid arthritis
& systemic lupus
erythrematosus.
Autoimmune hemolytic anemia
4. IMUNOSUPRESAN: Antibodies
block T cell surface
molecules involved in
signaling
immunoglobulins
antilymphocyte
globulins (ALG).
antithymocyte
globulins (ATG).
Rho (D)
immunoglobulin.
Basiliximab
Daclizumab
Infliximab
4. IMUNOSUPRESAN: Antibodies
Preparation
1. by immunization of either horses or rabbits with human lymphoid cells
producing mixtures of polyclonal antibodies directed against a number of
lymphocyte antigens (variable, less specific).
2. Hybridoma technology
produce antigen-specific, monoclonal antibody (homogenous, specific).
produced by fusing mouse antibody-producing cells with immortal,
malignant plasma cells.
Hybrid cells are selected, cloned and selectivity of the clone can be
determined.
Omalizumab
a humanized monoclonal IgE
Directed against Fc receptor on mast &basophils
Is approved for asthma in steroid-refractory patient
4e. IMUNOSUPRESAN: INTERFERONS
Three families: Interferon Effects:
Type I IFNs ( IFN-α, β ): IFN- γ : Immune Enhancing
acid-stable proteins; act on increased antigen presentations
same target cell receptor with macrophage, natural killer
induced by viral infections cell, cytotoxic T lymphocyte
leukocyte produces IFN-α
activation
Fibroblasts & endothelial cells
IFN- α, β :
produce IFN-β
effective in inhibiting cellular
Type II IFN (IFN-γ): proliferation
acid-labile; acts on separate (more effective than IFN- γ in this
target cell receptors regard)
Produced by ActivatedT
lymphocytes.
Open for
Discussion
03/03/2017