Dr.B.V.VenkataramanProfessor in Pharmacology

International Medical SchoolFaculti Perubatan, New BEL Rd

Bangalore - 560054Venkataraman_bv@yahoo.com

Drugs Used in Arthritis

Immune SystemImmune SystemImmune System

Foreign bodies Foreign bodies Own cells

Eradicated Failed

No infection Infection

Auto immuneDiseases

What is rheumatoid arthritis?

It is an auto immune disease Affects the lining of the joints, causing pain, swelling, and stiffness. Left untreated, joints may be damaged badly Most common in young-adult to middle-age women.

What is osteoarthritis?Osteoarthritis results from wear and tear on the joints.

What are the drugs used in RA?

1. Anti inflammatory drugs: NSAIDs

2. Corticosteroids: Prednisolone

3. Disease modifying antirheumatic drug(DMARDS)

Non biologic Biologic

DMARDS (Non biologic)

Target immune cells usually by unknown mechanisma. Immunosuppressants:

Methotrexate, leflunomide, azathioprine, cyclosporine etc

b. Antimalarials: Hydroxy Chloroquine

c. Gold salts: aurothiomalate, aurothioglucose

d. MiscellaneousSulphasalazine

DMARDS (biologic)

Target specific parts of inflammatory cascadeSpecificExamples:Anakinra, inflixima,TNFα inhibitors and IL-1 antagonist etc.

What is the mechanism of action of NSAIDS?

MechanismInhibit the synthesis of prostaglandins and reduce cause of pain and inflammation. Main drugsDiclofenac, ibuprofen, indomethacin, piroxicam etc.Long term side effects Allergy, peptic ulcer, bleeding disorders, renal function impairment etc.

What is the mechanism of action of NSAIDs?

NSAIDs

Interactions

Bleeding tendency with oral anticoagulantsFluid retention decreases the efficacy of diuretics and antihypertensives.Protein binding increases the risk by displacement principle

COX-2 INHIBITORSLess gastric irritation No anti platelet action; no protection against heart attack or stroke

How does corticosteroid act on inflammation?

Steroids

Glucocorticoid

How does corticosteroid

act on immunity?

Corticosteroids

Prednisone, methyl prednisolone and hydrocortisoneInflammation, suppress the immunitySide effects: bone loss, weight gain, acne, high blood pressure, mood swings, and infection Topical. Intra articular administration also possible

DMARDS (Non biologic)

Heterogenous class without common propertySymptomatic improvementSlow progressMost of them were developed for other disorder – cancer, immunosuppressionToxicity and inadequate response limit the useCombined with biologic DMARDs

METHOTREXATE

Inhibition of folic metabolism – for anti cancer activityProposed Mechanism:Inhibit T-cell proliferation to inhibit transmethylation reactions required for T-cell cytotoxicityto promote the release of adenosine, an endogenous anti-inflammatory mediatorto interfere with glutathione metabolism, and alter the recruitment of monocytes to the inflamed joint

AzathioprineMethotrexate

Mechanism of immunosuppressants drugs

METHOTREXATE (Contd)

Useful in patients refractory to other drugsGiven with folic or folinic acid (Leucovorin) to decrease mouth ulcer, anaemia etcLiver function testLow dose (not anticancer dose) given weekly

LEFLUNOMIDE

Alternative to MethotrexateGiven to patients who can not tolerate methotrexateInhibits dihydro orotate dehydrogenase (dihydro folatereductase) – anticancer activity Inhibit proliferation (similar to methotrexate)Dose is daily (methotrexate weekly)Liver function test

Hydroxy chloroquine

Interfering with tumor necrosis factor (TNF) released from macrophages, or Diminishing the presentation of antigens to CD4+ T cells. Slow progress – used in mild diseaseWell toleratedRetinal toxicity – ophthalmic examination required

Sulfasalazine (Salicylazosulfapyridine)

Sulfasalazine

5-Aminosalicylic acid Sulfapyridine

Coliform bacteria

Local antiinflammatory

Immunomodulating

Systemic side effect

(Carrier)

Mechanism not clear; also used in other auto immune conditions

Not used in sulpha sensitivity

MESALAMINE

MESALAMINE

5-Aminosalicylic acid

Coliform bacteria

Local antiinflammatory

Immunomodulating

No systemic effect

(Carrier)Ethylcellulose/pH

sensitive resin

GOLD SALTS

Organic complexes: sodium aurothiomalate, auranolin.Mechanism: poorly understoodVery slow progressOral & parenteral preparations availableToxic symptoms:Proteinuria, thrombocytopenia, and neutropenia – decreased WBCs and kidney damage

ANTI-TNF AGENTS

InfliximabAdalimumabEtanercept All useful in mild to moderate RAInfliximab (iv) other two (sc)Risk of infection such as tuberculosisRisk of Malignancy

MechanismAnti-TNF monoclonal antibody

Binds to TNF- TNF- fails to bind to receptor cell surfaceSide effectsbreathlessness, hypotension, headache.

INFLIXIMAB

ADALIMUMAB

Mechanism Similar to Infliximab

ETANERCEPTMechanismfusion protein composed of 2 recombinant soluble TNF receptors binds to TNF-α, and lymphotoxin-α

ANAKINRA

Interleukin-1βDecrease WBC count, risk of infection (TB) and malignancy - similar to anti-TNF agent.Dramatic relief similar to anti-TNF agent.