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Instiaty & Dewi S.R.Module Immunology and Infection

FMUI, March 2013

IMMUNOMODULATORS and ANTIPYRETICS

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IMMUNOMODULATORS

Immunomodulators are drugs used to suppress or to enhance immune response

Classification:A. ImmunosuppressantsB. Immunostimulants

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IMMUNOSUPPRESSANTS

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

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Indications of immunosuppressants

Prevention of rejection to organ transplant Autoimmune diseasesPrevention of Rhesus hemolysis in neonates

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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.

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ACTH↓

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‐ 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

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 ↓

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Relative potency and equivalent doses of various corticosteroids

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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

Contraindication: Absolute contraindication: noneRelative contra indications:

Diabetes mellitusGastric/duodenal ulcerSevere infections

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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

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• Side effects:

- Nephrotoxicity

- Neurotoxicity- Hepatotoxicity- Gastrintestinal disturbances- Hirsutism, gingival hyperplasia (cyclosporine)- Hiperglycemia (mainly due to tacrolimus)

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• Indications:

- Given alone or combined with other immunosuppressants: to prevent rejection of organ transplant

- Autoimmune diseases: psoriasis, rheumatoid arthritis, nephrotic syndrome

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

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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

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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

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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

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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

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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

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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

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IMMUNOSTIMULANTS

Immunostimulant drugs consist of:1. Isoprinosine2. Levamisole3. Cytokines:

- IL-2- Interferron- Colony Stimulating Factors

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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

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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

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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

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Examples of immunostimulants (2)

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

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Examples of immunostimulants (3)

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

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Examples of immunostimulants (4)

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ANTIPYRETICS

Antipyretics

Antipyretics are drugs capable of reducing body temperatures in patients with fever

Antipyretics do not reduce normal body temperature

Induction of fever31

antipyretics

Mechanism of action of NSAIDs32 Phospholipids

Arachidonic acidNSAIDs

Endoperoxides

Steroids

ProstacyclinProstaglandins• PGE2

• PGD2

Thromboxane A2

Phospholipase A2

Cyclooxygenase

Blocked by

Blocked by

Commonly used antipyretics

AspirinIbuprofenMetamizol Paracetamol

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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

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

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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)

IbuprofenIs a derivative or propionic acidAnalgesic and antipyretic effect: equal to aspirinAntiinflammatory effect: less than aspirinSide effect: GI disturbances (less than aspirin)OTC drug

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

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

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

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)

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Thank You