REVIEW :

FARMAKOLOGI
ANTIINFLAMASI &
IMUNOSUPRESAN
Dr. Nanang Munif Yasin, M.Pharm,Apt
nanangy@yahoo.com
Fakultas Farmasi
Universitas Gadjah Mada
Yogyakarta

03/03/2017
 TUJUAN PEMBELAJARAN

1. Mampu menjelaskan penggolongan

antiinflamasi dan imunosupresan
2. Mampu menjelaskan mekanisme kerja
antiinflamasi dan imunosupresan
3. Mampu menjelaskan indikasi terapeutik
utama antiinflamasi dan imunosupresan
4. Mampu menjelaskan profil farmakokinetik
5. Mampu menjelaskan ADR dan Interaksi obat

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

 Non-Selective COXs  Selective COX2 Inhibitor

Inhibitor
 1. KLASIFIKASI NSAIDs
Acetic acids Carboxylic Propionic Enolic Fenamic acids Nonacidic
acids acids acids compounds

• diclofenac Acetylated • fenoprofen • phenylbuta • meclofenamic • nabumetone

sodium (Nalfon) zone acid (Relafen)
• aspirin (ASA) (Butazoli (Meclomen)
(Voltaren) • choline • flurbiprofen din)
• diclofenac (Ansaid) • mefenamic
magnesium • piroxicam acid (Ponstel)
potassium salicylate • ibuprofen (Feldene)
(Cataflam) (Trilisate) (Motrin,
• etodolac others)
• diflunisal
(Lodine) • ketoprofen
(Dolobid)
• indomethacin (Orudis)
(Indocin) • ketorolac COX-2 I nhibitors
• sulindac Nonacetylated (Toradol)
(Clinoril) • salicylamide • naproxen celecox ib (Celebre x)
• tolmetin • salsalate (Naprosyn)
(Tolectin) (Disalcid) • oxaprozin rofeco ib (Vioxx)
• sodium (Daypro)
salicylate
x
2. MEKANISME AKSI NSAID
2. MEKANISME AKSI NSAID
 2. MEKANISME AKSI NSAID
Rasio COX-2/COX-1 pada NSAID
NSAID COX-2 COX-1 COX-2/COX-1
Tolmetin 7 0.04 175
Aspirin 50 0.3 166
Ibuprofen 15 1 15
Asetaminofen 20 2.7 7.4
Diklofenak 0.35 0.5 0.7
Naproksen 1.3 2.2 0.6
Celecoxib 0.34 1.2 0.3
Refecoxib 0.84 63 0.013

IC80 = drug concentration to achieve 80

percent inhibition of cyclooxygenase
3. NSAIDs: Drug Effects
 Analgesic (mild to
moderate)
 Antigout
 Antiinflammatory
 Antipyretic
 Relief of vascular headaches
 Platelet inhibition (ASA)
3. NSAIDs: Therapeutic Uses
 Relief of mild to moderate pain
 Acute gout
 Various bone, joint, and muscle
pain
 Osteoarthritis
 Rheumatoid arthritis
 Juvenile rheumatoid arthritis
 Dysmenorrhea
 Fever
 4. PERBANDINGAN ANGGOTA NSAID

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
5
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 EFEK NSAID PADA GINJAL

Cyclooxygenase inhibitors prevent the synthesis of PGE2 and PGI2 ”prostaglandins

that are responsible for maintaining renal blood flow, particularly in the presence of
circulating vasoconstrictors (Figure 41.6). Decreased synthesis of prostaglandinscan
result in retention of sodium and water and may cause edema and hyperkalemia in
some patients. Interstitial nephritis can also occur with all NSAIDs exceptaspirin.
5. NSAIDs: Salicylate Toxicity
 Adults: tinnitus and hearing
loss
 Children: hyperventilation
and CNS effects
 Effects arise when serum
levels exceed 300g/mL.
 Metabolic acidosis and
respiratory alkalosis may be
present.
 5. NSAIDs: Drug Interactions
 NSAIDs are highly bound to
albumin and will displace other
drugs from these binding sites
causing increased concentration
of active drugs in the blood such
as
 Oral anticoagulants, e.g.,warfarin
 Antibiotics,Anticonvulsants,
Methotrexate

 Increased risk of hepatotoxicity

when given with alcohol,
barbiturates, anticonvulsants,
rifampin
6. NSAIDs: Pharmaceutical Care
 Before beginning therapy, assess for conditions that may be
contraindications to therapy, especially:
 GI lesions or peptic ulcer disease
 Bleeding disorders
 Assess also for conditions that require cautious use.
 Perform lab studies as indicated (cardiac, renal, liver studies,
CDC, platelet count).
 Perform a medication history to assess for potential drug
interactions.
 Several serious drug interactions exist:
 alcohol
 heparin
 phenytoin
 oral anticoagulants
 steroids
 sulfonamides
6. NSAIDs: Pharmaceutical Care
 Salicylates are NOT to be given to children under age 12
because of the risk of Reye’s syndrome.
 Because these agents generally cause GI distress, they are
often better tolerated if taken with food, milk or an antacid
to avoid GI irritation.
 Explain to patients that therapeutic effects may not be seen
for 3 to 4 weeks.
 Educate patients about the various side effects of NSAIDs,
and to notify their physician if these effects become severe
or if bleeding or GI pain occur.
 Patients should watch closely for the occurrence of any
unusual bleeding, such as in the stool.
 Enteric-coated tablets should not be crushed or chewed.
6. NSAIDs: Pharmaceutical Care
 Monitor for therapeutic effects, which vary according to the
condition being treated:

decrease in swelling, pain,stiffness,

and tenderness of a joint or muscle area
 A1. NSAIDs: Carboxylic acids (Aspirin)
Mechanisms of action 2-Analgesic
1 Antiinflammatory  For mild & moderate dull aching pain as
A)Inhibit prostaglandines synthesis antiinflammatory
through irreversible inhibition of cyclo-  Inhibits pain stimuli at subcortical site
oxygenase enzymes ( Cox-1 & Cox-2). 3-Antpyretic
Interferes with the chemical mediators of  COX inhibition in the C.N.S.
the kallikrein system.  Inhibition of IL-1
B)Inhibits the migration of 4- Antiplatelet
polymorphonuclear leukocytes to the site  Irreversible inhibition of platelet COX
of inflammation.  Aspirin effect lasts 8-10 days ( life of
C) Anti-oxidant activity. platelets )
D) Stabilizing lysosomes
Clinical Uses
Pharmacology action A) Analgesic
A) Analgesic B) Antipyretic
B) Antipyretic C) Anti-inflammatory
D) Antithrombotic( cardioprotective)
C) Antithrombotic E) Chronic gouty arthritis
D)Anti-inflammatory F)Cancer pain in combination with opioid
E) Uricosuric ( large dos) drugs
 A1. NSAIDs: Carboxylic acids (Aspirin)
Adverse Effect High doses or Prolonged use of aspirin
At therapeutic doses A) Salicylism( tinnitus,vertigo,
A)Gastric upset ( intolerance) & gastric or decreased hearing).
duodenal ulceration B)Hyperapnea
B) Gouty arthritis C)Respiratory alkalosis
C) Asthma,rashes D) Metabolic acidoses
D)Hepatotoxicity & renal toxicity are less E) Hyperthermia
F) Gastric & doudenal ulcer & bleeding
frequent.
H) Glucose intolerance
E) Reye syndrome
Contraindication
A) Pregnancy
B) Haemophilic patients
C) Hypersensitivity reaction to aspirin
D) Viral infections mainly in children
E) Peptic ulcers
Drug interaction
Potentiates the gastric irritant effect of alcohol
Potentiates the hypoglycaemic effects of oral
hypoglycaemic drugs
 A2. NSAIDs: Propionic acids (Ibuprofen)
Pharmacokinetics Clinical Uses
1. Rapidly absorbed after oral ingestion. A) Analgesic
2. Half-life 1-2 hours B) Antipyretic
3. Highly bound to plasma proteins C) Anti-inflammatory
4. Excreted through kidney as D)Acute gouty arthritis
metabolites E) Patent ductus arteriosus
5. The same mechanism &
pharmacological actions of aspirin Preparations
Except that it is reversible inhibitor Oral preparations.
for COX enzymes Topical cream for osteoarthritis.
6. More potent as antiinflammatory A liquid gel for rapid relief of
than aspirin postsurgical dental pain.
Intravenous route as In patent
ductus arteriosus
 A2. NSAIDs: Propionic acids (Ibuprofen)
Adverse Effect Contraindications
1. Gastric upset ( less frequent than 1. Peptic ulcer
aspirin ). 2. Allergic patients to aspirin
2. Fluid retention 3. Kidney impairment
3. Hypersensetivity reactions 4. Liver diseases
4. Ocular disturbances 5. Pregnancy
5. Rare hematologic 6. Haemophilic patients
effects(agranulocytosis & aplastic 7. The concomitant
anaemia ). administration of ibuprofen
antagonizes the irrevesible
platelet inhibition of aspirin
(limit cardioprotective effect of
aspirin ).
A3. NSAIDs: Oxicam derivatives (Piroxicam)
Mechanism of actions Pharmacokinetics
A. Non-selective inhibitors to Cox1 & Well absorbed orally
Cox2 Half- Life 45 hours
B. Traps free radicals Given once daily
C. Inhibits polymorphonuclear
leukocytes migration Adverse Effect
D. Inhibits lymphocyte function Less frequent gastric upset (20%) .
Dizziness
Tinnitus
Headache
Allergy
A3. NSAIDs: Oxicam derivatives (Meloxicam)
Mechanism of actions Pharmacokinetics
Relatively selective Cox2 inhibitors. Given orally ,rectally, I.M.,I.V.
Safer than piroxicam Metabolized in liver to inactive
Clinical use metabolites.
Analgesic Excreted in urine 50% and in feces
Rheumatoid arthritis 50%.
Osteoarthritis Half-life 20 hours.
Given once daily
Adverse Effect
Gastric upset Drug interaction
Skin rash Cholestyramine increases the
Headache clearance of the drug .
A4. NSAIDs: Acetic acid derivatives (Diclofenac)
Mechanism of actions
As aspirin ,but non-selective inhibitor
to cox1 & Cox2.
More potent as anti-inflammatory than
analgesic and antipyretics
Clinical use
A) Any inflammatory conditions
B) Musculoskeletal pain
C) Dysmenorrhoea
D)Acute gouty arthritis
E) Fever
F) Locally to prevent or treat post
opthalmic inflammation
G) A topical gel for solar keratoses
Pharmacokinetics
Accumulates in synovial Fluid
Adverse Effect
Gastric upset
Renal impairment
Elevation of serum aminotransferase
Salt & water retention
Preparations
Oral mouth wash.
Intramuscular preparations
Diclofenac with misoprostol
decreases upper gastrointestinal
ulceration ,but result in diarrhea.
Diclofenac with omeprazole to
prevent recurrent bleeding.
.1% opthalmic preparation for
postoperative opthalmic
inflammation.
A topical gel 3% for solar keratoses.
Rectal suppository as analgesic or for
postoperative nausea
A5. NSAIDs: Nonacidic compounds (Nabumetone)
Pharmacokinetics Adverse Effect
Well absorbed orally. Gastric upset
Metabolized in liver to active Allergy (skin rash ).
metabolities. Headache
Half-life 26 hours. Tinnitus
Taken once daily Pseudoporphyria
Clinical use Photosensitivity
Rheumatoid arthritis
Osteoarthritis
 A6. Selective Cox2 inhibitors
Advantages :
1. Highly selective inhibitors to cox2 enzyme.
2. Potent anti-inflammatory.
3. Have analgesic& antipyretic
4. Highly bound to plasma proteins.
5. Lower incidence of gastric upset
6. No effect on platelet aggregation (cox1 )
7. Renal toxicities ( they are not recommended for patients with severe
renal insufficiency)
8. High incidence of cardiovascular thrombotic events with some of them
as rofecoxib.
9. They are recommended in postoperative patients undergoing bone
repair.
10. Also, indicated in primary familial adenomatous polyposis,
dysmenorrhea,Acute gouty arthritis, acute musculoskeletal pain ,
ankylosing spondylitis
 A6. Selective Cox2 inhib: Celecoxib
 Absorption is decreased by food.
 Half-life 11hours
 Highly bound to plasma proteins
 No effect on platelet aggregation
 Metabolized in liver by CYP2C9 to in active metabolite.
 Its clearance is decreased in liver impairment.
 Given twice daily.
Clinical uses Drug Interaction
 Rheumatoid arthritis With warfarrin potentiate its,through
 Osteoarthritis interfering with its metabolism.actions
Side Effect
 Dyspepsia & heart burn.
 edema & renal adverse effects.
 Allergy (skin rash ).
 Comparative action between COX-1/COX-2 COX-2
COX inhibitors inhibitors inhibitors
1. Analgesic action (+) (+) (+)

2. Antipyretic action (+) (+)

3. Antiinflammatory action (+) (+) (+)

4. Antiplatelet aggregatory (+) (-)

5. Gastric mucosal damage (+) (+) (+) (+)

6. Renal salt / water retention (+) (+)

7. Delay/prolongation of labor (+) (+) (+)

8. Infertility (-) (+) (+)
9. Ductus arteriosus closure (+) ?

10. Aspirin-like asthma (+) ?

11. Cardiotoxicity (-) (+) (+)
 B. ANALGESIK LAIN: PARASETAMOL
 Is effective only as analgesic & antipyretic.
 Has no antiinflammatory effect.
 Has no platelet effect.
 Can be used in patients with haemophilia or
peptic ulcer or allergic to aspirin.
 Can be used during pregnancy.
 In children with viral infections.

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

Pathophysiologic events in a gouty joint

Synoviocytes phagocytose urate crystals and then secrete inflammatory
mediators, which attract and activate polymor- phonuclear leukocytes
(PMN) and mononuclear phagocytes (MNP) (macrophages). Drugs active in
gout inhibit crystal phagocytosis and polymorphonuclear leukocyte and macro-
phage release of inflammatory mediators.
(PG – prostaglandin; IL-1 – interleukin-1; LTB4 – leukotrieneB4)
 D1. OBAT GOUT: INDIKASI KLINIK
Treatment of gout, a special Drugs in this class include
inflammatory condition in
which uric acid deposits in the Acute treatment
joint fluid of the toes, knees,or Colchicine
Aspirin, naproxen
kidneys because uric acid is
 overproduced or Prophylaxis
 not efficiently excreted Allopurinol blocks uric acid
production
Probenecid for uric acid excretion
Phagocytes digest the uric acid Sulfinpyrazone for uric acid
and set up acycle of localized excretion
inflammation
 D2. KLASIFIKASI OBAT GOUT

(1) Acute goat

Colchicine
Diclofenac, Indometacin,
Naproxen, Phenylbutazone, Piroxiam
(2) Chronic gout
Uricostatics (xantine oxidase inhibitors)
Allopurinol, Febuxostat
Uricosurics
Benzbromarone, Probenecide
Sulfinpyrazone
Uricolytics: Uricase, Rasburicase
Drug combinations
Harpagin® (allopurinol & benzbromarone)
D3. MEKANISME AKSI OBAT GOUT
D4. ADR OBAT 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).

IL-2 stimulates the proliferation of antigen-

primed (helper) T cells
 PENDAHULUAN: IMUNOSUPRESAN
Cell-mediated Immunity
 TH1 produce more IL-2, TNF-β and IFN-γ.
 Activate
 NK cells (kill tumor & virus-infected cells).
 Cytotoxic T cells (kill tumor & virus-infected cells).
 Macrophages (kill bacteria).
 PENDAHULUAN: IMUNOSUPRESAN
Humoral Immunity
B-lymphocytes TH2 produces (interleukins) IL-4 & IL-5 which in turn causes:
B cells proliferation & differentiation into
 memory B cells
 Antibody secreting plasma cells
 Mutual regulation of T helper lymphocytes

 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

Inhibitors of cytokines (IL-2) production

Calcineurin inhibitors
 Cyclosporine
 Tacrolimus (FK506) Inhibitors
of cytokines (IL-2) action
Sirolimus (rapamycin).
 1a. IMUNOSUPRESAN: CYCLOSPORINE
Chemistry
Cyclosporine is a fungal polypeptide composed of 11 amino
acids.
Mechanism of action:
 Acts by blocking activation of T cells by inhibiting
interleukin-2 production (IL-2).
 Decreases proliferation and differentiation of Tcells.

 Cyclosporine binds to cyclophilin (immunophilin)

intracellular protein receptors.
 Cyclosporine- immunophilin complex inhibits calcineurin, a
phosphatase necessary for dephosphorylation of transcription
factor (NFATc) required for interleukins synthesis (IL-2).
 NFATc (Nuclear Fcator of ActivatedTcells).
 Suppresses cell-mediated immunity.
 MEKANISME AKSI IMUNOSUPRESAN

Mechanism of action of cyclosporine and tacrolimus. Il-2 = interleukin-2; mTOR = mammalian

target of rapamycin; NFATc = cytosolic nuclear factor of activated T cells.
 1a. IMUNOSUPRESAN: CYCLOSPORINE
Pharmacokinetics:
 Can be given orally or i.v.infusion
 orally (25 or 100 mg) soft gelatin
capsules, microemulsion.
 Orally, it is slowly and incompletely
absorbed.
 Peak levels is reached after 1– 4
hours, elimination half life 24 h.
 Oral absorption is delayed by fatty
meal (gelatin capsule formulation)
 Microemulsion (has higher
bioavailability-is not affected by
food).
 50 – 60% of cyclosporine
accumulates in blood (erythrocytes
– lymphocytes).
 metabolized by CYT-P450 system
(CYP3A4).
 excreted mainly through bile into
faeces, about 6% is excreted in
urine.
Therapeutic Uses:
 Organ transplantation (kidney,
liver, heart) either alone or with
other immunosuppressive agents
(Corticosteroids).
 Autoimmune disorders (low dose
7.5 mg/kg/d). e.g. endogenous
uveitis, rheumatoid arthritis,
active Crohn’s disease, psoriasis,
psoriasis, nephrotic syndrome,
severe corticosteroid-dependent
asthma, early type I diabetes.
 Graft-versus-host disease after
stem cell transplants
 1a. IMUNOSUPRESAN: CYCLOSPORINE
Adverse Effects
Drug Interactions
(Dose-dependent)
 Clearance of cyclosporine is
Therapeutic monitoring is essential enhanced by co-administration of
Nephrotoxicity CYT p 450 inducers
(increased by NSAIDs and (Phenobarbitone, Phenytoin &
aminoglycosides). Rifampin )  rejection of
 Liver dysfunction. transplant.
Hypertension, hyperkalemia.
(K-sparing diuretics should not be
used).  Clearance of cyclosporine is
decreased when it is co-
 Hyperglycemia.
administered with erythromycin
 Viral infections (Herpes -
or Ketoconazole, Grapefruit juice
cytomegalovirus).
 cyclosporine toxicity.
 Lymphoma (Predispose
recipients to cancer).
 Hirsutism
 Neurotoxicity (tremor).
 Gum hyperplasia.
 Anaphylaxis after I.V.
 1b. IMUNOSUPRESAN: TACROLIMUS (FK506)
 A fungal macrolide antibiotic. Pharmacokinetics:
 Given orally or i.v or topically
 Chemically not related to
(ointment).
cyclosporine
 Oral absorption is variable and
 both drugs have similar incomplete, reduced by fat and
mechanism of action. carbohydrate meals.
 The internal receptor for  Half-life after I.V. form is 9-12 hours.
tacrolimus is immunophilin (  Highly bound with serum proteins
FK-binding protein, FK-BP). and concentrated in erythrocytes.
 Tacrolimus-FKBPcomplex  metabolized by P450 in liver.
inhibits calcineurin  Excreted mainly in bile and
minimally in urine.
USES as cyclosporine
 Organ and stem cell transplantation
 Prevention of rejection of liver and kidney transplants (with
glucocorticoids).
 Atopic dermatitis and psoriasis (topically).
 1b. IMUNOSUPRESAN: TACROLIMUS (FK506)
Toxic effects
 Nephrotoxicity (more than
CsA)
 Neurotoxicity (more than CsA)
 Hyperglycemia ( require
insulin).
 GIT disturbances
 Hperkalemia
 Hypertension
 Anaphylaxis
NO hirsutism or gum hyperplasia
Drug interactions
 as cyclosporine.
What are the differences between CsA
and TAC ?
 TAC is more favorable than CsA due
to:
 TAC is 10 – 100 times more potent
than CsA in inhibiting immune
responses.
 TAC has decreased episodes of
rejection.
 TAC is combined with lower doses of
glucocorticoids.
But
 TAC is more nephrotoxic and
neurotoxic.
 1c. IMUNOSUPRESAN: Sirolimus (Rapamycin)
 SRL is macrolide antibiotic.

 SRL is derived from fungus origin.

 It binds to FKBP and the formed complex
binds to mTOR (mammalian Target Of
Rapamycin).
 mTOR is serine-threonine kinase essential
for cell cycle progression, DNA repairs,
protein translation.

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.

 Stabilize lysosomal membranes .

 Decrease generation of IgG, nitric oxide and histamine.
 Inhibit antigen processing by macrophages.
 Suppress T-cell helper function
 Decrease T lymphocyte proliferation.
 2. IMUNOSUPRESAN: CORTICOSTEROIDS
Kinetics Adverse Effects
Can be given orally or parenterally. Adrenal suppression
Dynamics Osteoporosis
Hypercholesterolemia
1. Suppression of response to Hyperglycemia
infection Hypertension
2. anti-inflammatory and Cataract
immunosuppresant. Infection
3. Metabolic effects.

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

both B and T lymphocytes.

 3a. IMUNOSUPRESAN: AZATHIOPRINE
Pharmacokinetics USES
 orally or intravenously. Acute glomerulonephritis
 Widely distributed but does not Systemic lupus erythematosus
cross BBB. Rheumatoid arthritis
 Metabolized in the liver to 6- Crohn’ s disease.
mercaptopurine or to thiouric
acid (inactive metabolite) by Adverse Effects
xanthine oxidase.
Bone marrow depression:
 excreted primarily in urine.
leukopenia, thrombocytopenia.
Gastrointestinal toxicity.
Drug Interactions: Hepatotoxicity.
 Co-administration of Increased risk of infections.
allopurinol with azathioprine
may lead to toxicity due to
inhibition of xanthine oxidase
by allopurinol.
3b. IMUNOSUPRESAN: MYCOPHENOLATE MOFETIL
 Is a semisynthetic derivative of
mycophenolic acid from fungus
source.
 Prodrug; is hydrolyzed to
mycophenolic acid.
Mechanism of action:
 Inhibits de novo synthesis of
purines.
 mycophenolic acid is a potent
inhibitor of inosine
monophosphate dehydrogenase
(IMP), crucial for purine
synthesis deprivation of
proliferating T and B cells of
nucleic acids.
 3b. IMUNOSUPRESAN: MYCOPHENOLATE MOFETIL
Pharmacokinetics:
 Given orally, i.v. or i.m.
 rapidly and completely
absorbed after oral
administration.
 It undergoes first-pass
metabolism to give the active
moiety, mycophenolic acid
(MPA).
 MPA is extensively bound to
plasma protein.
 metabolized in the liver by
glucuronidation.
 Excreted in urine as
glucuronide conjugate
 Dose : 2-3 g /d
CLINICAL USE:
Solid organ transplants for
refractory rejection.
Steroid-refractory hematopoietic
stem cell transplant patients.
Combined with prednisone as
alternative to CSA or tacrolimus.
Rheumatoid arthritis, &
dermatologic disorders.
ADVERSE EFFECTS:
GIT toxicity: Nausea, Vomiting,
diarrhea, abdominal pain.
Leukopenia, neutropenia.
Lymphoma
Contraindicated during
pregnancy
 3c. IMUNOSUPRESAN: LEFLUNOMIDE
 A prodrug
 Active metabolite undergoes
enterohepatic circulation.
 Has long duration of action.
 Can be given orally
 antimetabolite immunosuppressant.
 Pyrimidine synthesis inhibitor
 Approved only for rheumatoid arthritis

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.

 Recombinant DNA technology can be used to replace part of the mouse

gene sequence with human genetic material (less antigenicity-longerhalf
life).
 Antibodies from mouse contain Muro in their names.
 Humanized antibodies contain ZU or XI in theirnames.
 4a. IMUNOSUPRESAN: Antilymphocyte globulins (ALG)
&Antithymocyte globulins (ATG)
 Polyclonal antibodies obtained
from plasma or serum of horses
hyper-immunized with human
lymphocytes.
 Binds to the surface of
circulating T lymphocytes, which
are phagocytosed in the liver and
spleen giving lymphopenia and
impaired T-cell responses &
cellular immunity.
Kinetics
Given i.m. or slowly infused
intravenously.
Half life extends from 3-9 days.
Uses
Combined with cyclosporine for bone
marrow transplantation.
To treat acute allograft rejection.
Steroid-resistant rejection.
Adverse Effects:
Antigenicity.
Leukopenia, thrombocytopenia.
Risk of viral infection.
Anaphylactic and serum sickness
reactions (Fever, Chills, Flu-like
syndrome).
 4b. IMUNOSUPRESAN: Muromonab-CD3
 Is a murine monoclonal antibody
 Prepared by hybridoma technology
 Directed against glycoprotein CD3 antigen of human T cells.
 Given I.V.
 Metabolized and excreted in the bile.
Mechanism of action Uses
The drug binds to CD3 proteins on T Used for treatment of acute renal
lymphocytes (antigen recognition site) allograft rejection & steroid-
leading to transient activation and resistant acute allograft
cytokine release followed by disruption To deplete T cells from bone
of T-lymphocyte function, their marrow donor prior to
depletion and decreased immune transplantation.
response. Adverse effects
Prednisolone, diphenhydramine are Anaphylactic reactions.
Fever
given to reduce cytokine release CNS effects (seizures)
syndrome. Infection
Cytokine release syndrome (Flu-like
illness to shock like reaction).
 4c. IMUNOSUPRESAN: Monoclonal antibodies
Basiliximab and Daclizumab
 Obtained by replacing murine amino acid sequences with human ones.
 Basiliximab is a chimeric human-mouse IgG (25% murine, 75% human
protein).
 Daclizumab is a humanized IgG (90% human protein).
 Have less antigenicity & longer half lives than murine antibodies

Mechanism of action Given I.V.

IL-2 receptor antagonists
Are Anti-CD25
Bind to CD25 (α-subunit chain of IL-2
receptor on activated lymphocytes)
Block IL-2 stimulated T cells
replication & T-cell response system
Basiliximab is more potent than
Daclizumab.
Half life Basiliximab (7 days )
Daclizumab (20 days)
are well tolerated - only GIT
disorders
USES
Given with CsA and corticosteroids
for Prophylaxis of acute rejection in
renal transplantation
 4d. IMUNOSUPRESAN: Monoclonal antibodies
Infliximab dan Omalizumab
Infliximab
 a chimeric human-mouse IgG
 Directed against TNF-α
 Is approved for ulcerative colitis, Crohn’s disease &rheumatoidarhritis

Omalizumab
 a humanized monoclonal IgE
 Directed against Fc receptor on mast &basophils
 Is approved for asthma in steroid-refractory patient
 4e. IMUNOSUPRESAN:
Three families:
Type I IFNs ( IFN-α, β ):
 acid-stable proteins; act on
same target cell receptor
 induced by viral infections
 leukocyte produces IFN-α
 Fibroblasts & endothelial cells
produce IFN-β
Type II IFN (IFN-γ):
 acid-labile; acts on separate
target cell receptors
 Produced by ActivatedT
lymphocytes.
INTERFERONS
Interferon Effects:
IFN- γ : Immune Enhancing
increased antigen presentations
with macrophage, natural killer
cell, cytotoxic T lymphocyte
activation
IFN- α, β :
effective in inhibiting cellular
proliferation
(more effective than IFN- γ in this
regard)

Recombinant DNA cloning technology.

Antiproliferative activity.
Antiviral action
Immunomodulatory effect.
 4e. IMUNOSUPRESAN:
Recombinant DNAcloning
technology.
Antiproliferative activity.
Antiviral action
Immunomodulatory effect.
INTERFERONS
USES:
 Treatment of certain
infections e.g. Hepatitis C
(IFN- α ).
 Autoimmune diseases e.g.
Rheumatoid arthritis.
 Certain forms of cancer e.g.
melanoma, renal cell
carcinoma.
 Multiple sclerosis (IFN- β):
reduced rate of exacerbation.
 Fever, chills,
myelosuppression
 4f. IMUNOSUPRESAN:
A sedative drug.
Teratogenic (Class-X).
Can be given orally.
Has immunomodulatory actions
Inhibits TNF-α
Reduces phagocytosis by
neutrophils
Increases IL-10 production
THAMLIDOMIDE
USES
 Myeloma
 Rheumatoid arthritis
 Graft versus host disease.
 Leprosy reactions
 treatment of skin manifestations
of lupus erythematosus
 SUMMARY : IMUNOSUPRESAN

Sites of action of immunosuppressants. Il-2 = interleukin-2. NFATc = cytosolic nuclear

factor of activated T cells.
 PENGGUNAAN KLINIS IMUNOSUPRESAN

DISEASE AGENT USED

Autoimmune Disease:
Acute glomerulonephritis Prednisone*,
mercaptopurine.
Cyclophosphamide.

Autoimmune haemolytic Prednisone*,

anaemia. cyclophosphamide,
mercaptopurine,
azathioprine, high dose -
globulin.
Organ transplant:
• Renal Cyclosporine, Azathioprine,
Prednisone, ALG,
Tacrolimus.
• Heart

• Liver Cyclosporine, Prednisone,

Azathioprine, Tacrolimus.

• Bone marrow Cyclosporine,

Cyclophosphamide,
Prednisone, Methotrexate,
ALG, total body radiation.
 PENGGUNAAN KLINIS IMUNOSUPRESAN

American Journal of Pharmaceutical Education 2009; 73 (8) Article 144.

 PENGGUNAAN KLINIS IMUNOSUPRESAN

American Journal of Pharmaceutical Education 2009; 73 (8) Article 144.

Thank You.

Open for
Discussion

03/03/2017