Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf
-
Upload
puteri-rara-balerna-pratiwi -
Category
Documents
-
view
7 -
download
1
description
Transcript of Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf
![Page 1: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/1.jpg)
1
Instiaty & Dewi S.R.Module Immunology and Infection
FMUI, March 2013
IMMUNOMODULATORS and ANTIPYRETICS
![Page 2: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/2.jpg)
2
IMMUNOMODULATORS
![Page 3: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/3.jpg)
Immunomodulators are drugs used to suppress or to enhance immune response
Classification:A. ImmunosuppressantsB. Immunostimulants
3
![Page 4: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/4.jpg)
4
IMMUNOSUPPRESSANTS
![Page 5: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/5.jpg)
Classification of immunospressants1. Corticosteroids (glucocorticoids) 2. Calcineurin inhibitors: cyclosporine and tacrolimus3. Cytotoxic agents:
- Azathioprine- Methotrexate- Cyclophosphamide
4. Mycophenolate mofetil5. Antibodies
- Anti CD3 (Muromonab CD3)- Rho (D) Immune Globulin- IL-2 reseptor antagonis: basiliximab anddaclizumab
5
![Page 6: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/6.jpg)
Indications of immunosuppressants
Prevention of rejection to organ transplant Autoimmune diseasesPrevention of Rhesus hemolysis in neonates
6
![Page 7: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/7.jpg)
1. CORTICOSTEROIDS
Affect various stages in the activation process of immune system
Can be used alone or in combination in preventing the rejection of organ transplant and in the treatment of autoimmune diseases.
7
![Page 8: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/8.jpg)
ACTH↓
8
‐ Inflammatory responses ↓
‐ Immunological responses ↓
‐ Liver glycogen deposition ↑‐ Gluconeogenesis ↑‐ Glucose utilization ↓‐ Glucose output from liver ↑
‐ Protein catabolism ↑
‐Bone catabolism ↑
‐Mood change
‐Gastric acid ↑
‐Na+ reabsorption ↑
‐K+/H+ excretion ↑
‐Adrenal suppression
‐Increased susceptibility to infections
‐Diabetes mellitus
‐Muscle wasting
‐Growth suppression
‐Osteoporosis
‐Psychosis
‐Peptic ulceration
‐Na+ , H2O retention
‐Hypertension,
‐Hypokalemia
Adverse effects
Ster
oid
effe
cts
Mechanism of action and adverse effects of corticosteroids
Endogenous/exogenous steroid
![Page 9: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/9.jpg)
Immune response ↓ because of:Inhibition of T lymphocyte proliferationInhibition of cytokine production (IL-1, IL-2, IL-6, IFN- α, and TNF-α) Redistribution phenomenon: circulatingneutrophil ↑, while lymphocyte, monocyte, and eosinophil ↓
9
![Page 10: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/10.jpg)
Relative potency and equivalent doses of various corticosteroids
10
AgentsAnti-
inflammatory potency
Potency of Na+
retensi Equival
ence (mg)
T1/2 (h)
Short acting :HydrocortisoneIntermediate acting:PrednisolonePrednisoneMethylprednisoloneTriamcynoloneLong acting :BetamethasoneDexamethasone
1.0
4.04.05.05.0
25.025.0
1.0
0.80.80.50
00
20
5544
0.50.75
1.5 - 2.0
2.5 – 3.62.5 – 3.5
3.32.5 – 3.3
5 – 73.4 – 4.0
![Page 11: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/11.jpg)
Contraindication: Absolute contraindication: noneRelative contra indications:
Diabetes mellitusGastric/duodenal ulcerSevere infections
11
![Page 12: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/12.jpg)
12
2. CALCINEURIN INHIBITORS
• Mechanism of action:– Cyclosporine binds to cyclophylin (an
intracellular protein) → complex → inhibits calcineurin (an enzyme responsible for the activation of T-cell specific transcription factor called NFAT) → inhibits the synthesis of IL-2 and other interleukins
– Tacrolimus binds to a receptor called FKBP →subsequently also inhibits calcineurin
![Page 13: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/13.jpg)
13
• Side effects:
- Nephrotoxicity
- Neurotoxicity- Hepatotoxicity- Gastrintestinal disturbances- Hirsutism, gingival hyperplasia (cyclosporine)- Hiperglycemia (mainly due to tacrolimus)
![Page 14: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/14.jpg)
14
• Indications:
- Given alone or combined with other immunosuppressants: to prevent rejection of organ transplant
- Autoimmune diseases: psoriasis, rheumatoid arthritis, nephrotic syndrome
![Page 15: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/15.jpg)
3. CYTOTOXIC AGENTSAzathioprineMechanism of action: inhibits purine synthesis
proliferation of lymphocyte ↓Indications: prevention of rejection to organ transplant and autoimmune diseasesSide effects:
MyelosuppressionGastro intestinal disturbanceIncreased risk to infection
15
![Page 16: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/16.jpg)
MethotrexateInhibits dihidrofolate reductase blocks thymidilate and purine synthesisActs on S phase of cell cycle T cell functions are disturbedUsed as single drug or in combination with cyclosporine for prevention of transplant rejection, rheumatoid arthriritis, and psoriasisSE: myelotoxicity, liver cirrhosis, gastro intestinal disturbance
16
![Page 17: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/17.jpg)
CyclophosphamideMech. of action: alkylates the DNAInhibits mainly B cell (humoral immunity), and less so to T cellIndications (in small dose): autoimmune diseases ( SLE, Idiopathic Thrombocytopenia Purpura , RA, nephrotic syndrome)SE: hemorrhagic cystitis, pancytopenia, cardiotoxicity
17
![Page 18: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/18.jpg)
4. MYCOPHENOLATE MOFETIL (MMF)
MA: strongly inhibits inosine monophosphate dehydrogenase (an important enzyme in purine synthesis ) → blocks the activation of B and T-cellsIndications: prevention of rejection to kidney transplant (in combination with prednisone), rheumatoid arthritis, lupus nephritisSide effect: gastrointestinal disturbance, myelosuppression
18
![Page 19: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/19.jpg)
5. IMMUNOSUPPRESSIVE ANTIBODIES
Polyclonal antibody: ATG (antithymocyte globulin) Binds to various molecules on T-cell surface (CD2, CD3, CD4 , etc.) → lymphocyte number ↓ and inhibition of lymphocyte function
Monoclonal antibody: Muromonab CD3 (anti CD3, OKT3)
Binds specifically to CD3 molecule on the surface of T-cells → failure to recognize antigen
19
![Page 20: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/20.jpg)
Rho(D) Immune GlobulinThis contains a specific antibody against Rh antigen on the surface of red blood cells
Indication: Mothers with negative Rh to prevent sensitization to antigen of positive Rh from their fetusesThe drug is given IM to the mother at 24-72 hr after delivery to clear the infant’s RBC from the mother’s circulation
20
![Page 21: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/21.jpg)
Basiliximab and daclizumab- These drugs block the binding of IL-2
to the activated lymphocyte →immunosuppressive effect
- Block the activation and proliferation of T-cells
21
![Page 22: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/22.jpg)
22
IMMUNOSTIMULANTS
![Page 23: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/23.jpg)
Immunostimulant drugs consist of:1. Isoprinosine2. Levamisole3. Cytokines:
- IL-2- Interferron- Colony Stimulating Factors
23
![Page 24: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/24.jpg)
Indication: to improve immune function in immune-compromised individuals. E.g.: AIDS, chronic infections, malignancies
Disadvantages:Weak therapeutic effects and non-specific to certain cell or antibody
24
![Page 25: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/25.jpg)
Examples of immunostimulants (1)
1. Isoprinosine• Improve the functions of NK cell, T cell, dan
monocyte• Its clinical usefulness is highly controversial
2. Levamisole• Increases the cellular immunity• Indications: colorectal cancer and Hodgkin
disease• SE: agranulocytosis
25
![Page 26: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/26.jpg)
3. Cytokines
a. IL-2 (T cell growth factor)
It binds to its receptor on the cell surface → activates proliferation and differentiation of T-helper, T-cytotoxic, B cells, and macrophage.Side effects: Severe hypotension, lung edema, nephrotoxicity, myelosuppression
26
Examples of immunostimulants (2)
![Page 27: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/27.jpg)
b. InterferronsConsisted of IFN-α, IFN-β, IFN-γ,
Indications:Melanoma, Chronic Myelocytic Leukemia, Kaposi’s sarcoma, chronic HCV infection SE: fever, chilling, myalgia, myelosuppression, depression
27
Examples of immunostimulants (3)
![Page 28: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/28.jpg)
c. Colony Stimulating Factors- Granulocyte Colony Stimulating Factor, (G-
CSF), e.g. filgrastim: prevents neutropenia caused by cancer chemotherapy
- Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF), e.g. sagramostim: to speed up recovery after autologous bone marrow transplant
28
Examples of immunostimulants (4)
![Page 29: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/29.jpg)
29
ANTIPYRETICS
![Page 30: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/30.jpg)
Antipyretics
Antipyretics are drugs capable of reducing body temperatures in patients with fever
Antipyretics do not reduce normal body temperature
![Page 31: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/31.jpg)
Induction of fever31
antipyretics
![Page 32: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/32.jpg)
Mechanism of action of NSAIDs32 Phospholipids
Arachidonic acidNSAIDs
Endoperoxides
Steroids
ProstacyclinProstaglandins• PGE2
• PGD2
Thromboxane A2
Phospholipase A2
Cyclooxygenase
Blocked by
Blocked by
![Page 33: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/33.jpg)
Commonly used antipyretics
AspirinIbuprofenMetamizol Paracetamol
33
![Page 34: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/34.jpg)
AspirinAcetyl salicylic acidMA: inhibits biosynthesis of PGE2
Well absorbed → hydrolyzed in the liver →salicylic acid → excreted through the kidneyDosage (as antipyretic):
adult: 325 – 650 mg every 4 – 6 hchildren: 10 mg/kg BW every 4 – 6 h (max. ≤
3,6 g/day)Over-the-counter (OTC) drug
![Page 35: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/35.jpg)
Side effects:GI disturbance: abdominal pain, nausea, dyspepsia, gastric/duodenal ulcer, diarrhea
Inhibition of platelet aggregation →prolonged bleeding timeReye’s syndrome: may occur (rare) if aspirin is given to children with viral infection. Symptoms: coma, seizure, cerebral edema, multi-organ failure and death
35
![Page 36: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/36.jpg)
Salicylate intoxication → “salicylism” characterized by vomiting, tinnitus, hearing loss, hyperventilation, vertigo.
Tinnitus usually occur when plasma level of salicylic acid reaches 200-450 μg/mL (antipyreic dose of aspirin → plasma level of < 60 μg/mL)
![Page 37: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/37.jpg)
IbuprofenIs a derivative or propionic acidAnalgesic and antipyretic effect: equal to aspirinAntiinflammatory effect: less than aspirinSide effect: GI disturbances (less than aspirin)OTC drug
![Page 38: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/38.jpg)
Methampyron (dipyron, metamizole)
• Is a pyrazolon derivative with weak antiinflammatory effect
• Side effect: agranulocytosis, aplastic anemia, thrombocytopenia → prohibited in many countries
• Indication:• Analgesic and antipyretic for conditions
failing to respond to the more safe agents • When parenteral administration is needed
![Page 39: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/39.jpg)
Paracetamol (acetaminophen)
Paracetamol has a very weak antiinflammatory effect, but it is used in arthralgia because of its good analgesic effect Mechanism of antipyretic: Inhibition of PGE2 production in the preoptic region of hypothalamus
![Page 40: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/40.jpg)
PharmacokineticsWell absorbed through oral route, metabolized in the liver, and excreted through the kidneyA minor but highly reactive metabolite N-acetyl-p-benzo-quinone imine (NAPQI)is hepatotoxic and nephrotoxicT½ is 2-3 hours, but may be doubled if very high dose is given
![Page 41: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/41.jpg)
Side effects
Relative safe, also in pregnancy
In therapeutic dose (3-4 x 500 mg/day):does not affect the CVS system, respiration, platelet function and blood coagulationDoes not irritate or induce bleeding of the stomach
In a very high dose (10-15 g or 150-250 mg/kg BW) → NAPQI ↑ ↑ → depletion of body GSH (glutathion) → liver necrosis. Drug of choice for this condition: N-acetylcystein (given in 24 h)
![Page 42: Lect-Mod-inf & immunol-immunomodulators+antipyretics-Insti-dewi-Mar13.pdf](https://reader030.fdocuments.us/reader030/viewer/2022032515/563db7f2550346aa9a8f7189/html5/thumbnails/42.jpg)
42
Thank You