NSAIDs & drugs in arthritis

Osteoarthritis (OA)

• General
• Degenerative joint disease
• No known cure
• Therapeutic objectives
• reduce pain
• improve joint mobility
• limit functional impairment
• Management
• Patient education
• lose weight
• lessen burden of weight-bearing joints
• exercise
• Non-medicinal & rebilitative
• exercises
• range-of-motion
• muscle-strengthening
• braces, orthotics, assistive devices
• appropriate footwear
• occupational therapy
• Pharmacotherapy
• Oral
• NSAIDs
• COX2 selective inhibitors
• glucosamine
• Intra-articular injection
• Glucocorticoids
• Hyaluronic acid
• Topical
• NSAIDs
• Surgery

Rheumatoid arthritis (RA)

• Therapeutic objectives
• Pain relief
• Reduce inflammation
• Control disease activity
• prevent/slow joint damage
• prevent loss of function
• improve quality of life
• correct/compensate mechanical & structural abnormalities by assistive devices
• Induce a remission (if possible)
• a state of absence of chronic disease
• Therapeutic measures
• Pharmacologic
• NSAIDs
• reduce joint pain & swelling
• pharmacologic actions
• analgesic
• antipyretic
• anti-inflammatory
• Glucocorticoids
• Drugs that suppress the rheumatoid disease process
• Disease-modifying anti rheumatic drug (DMARDs)
• Biologic response modifiers

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NSAIDs

• pharmacologic actions
• analgesic
• antipyretic
• anti-inflammatory
• pharmacology
• Inhibits COX-1 & COX-2
• reduce production of prostaglandins
• analgesic, antipyretic, anti-inflammatory
• Side effects
• Inhibition of COX-1 in gastric epithelial cells
• gastic ulcer/bleeding
• Inhibition of COX-1 & 2 in kidney
• interfere with regulation of renal blood flow
• nephrotoxicity
• Inhibit platelet TXA2 formation
• prevent platelet aggregation
• Increased cardiovascular thrombotic risk
• but can be used as anti-thrombosis
• Classification (based on potency)
• Moderate potency
• Fenamates
• mefenamic acid
• Propionic acids
• naproxen
• ibuprofen
• ketoprofen
• Paraaminophenol derivative
• acetaminophen
• paracetamol
• High potency
• Salicylates
• aspirin
• diflunisal
• Acetic acids & derivatives
• indomethacin
• sulindac
• etodolac
• diclofenac sodium
• Oxicams
• piroxicam
• meloxicam
• Pyrazolones
• phenylbutazone
• COX-2 selective inhibitor
• Celecoxib
• valdecoxib
• meloxicam
• Therapeutic uses
• Analgesic, Antipyretic, Anti-inflammatory
• Closure of patent ductus arteriosus
• in neonates
• indomethacin
• Dysmenorrhea
• COX2 inhibitors
• Systemic mastocytosis
• due to prostaglandin released from mast cells
• induce vasodilation & hypotension
• prevented by NSAIDs
• Bartter’s syndrome
• excessive productionof renal prostaglandins
• Prevention of colon cancer
• Contraindication
• Aspirin in children <16 yo
• risk of Reye’s syndrome
• Adverse effects
• Gastric/intestinal ulceration
• Increased bleeding time
• prevent formation of platelet-TXA2
• Renal dysfunction
• decrease RBF & GFR
• renal insufficiency
• hyperkalemia
• proteinuria
• Salt & water retention
• oedema
• hypertensive
• antagonize the action of anti-hypertensives
• Hypersensitivity
• rashes
• urticaria
• vasomotor rhinitis
• angioneurotic oedema
• bronchial asthma (aspirin)
• Abnormal liver function tests
• During pregnancy
• prolongation of gestation
• delay labour
• early closure of ductus arteriosus
• fetal distress
• Choice of NSAIDs
• based on side effects
• risks of upper GI side effects
• Phenylbutazone
• highest risk
• Ibuprofen
• lowest risk
• do not use more than 1 oral NSAIDs simultaneously
• COX-2 inhibitors (NSAIDs)
• as effective as older NSAIDs
• lower incidence of upper GI ulceration
• for patients with high risk of GI ulceration
• no difference in bleeding
• more expensive
• Higher rate of thrombotic events
• non-fatal myocardial infarction
• non-fatal strokes
• Acetaminophen & paracetamol
• Inhibits COX-3
• analgesic & antiypyretic effects
• metabolised in liver
• through glucoronic acid conjugation
• small % undergo cytochrome P450 mediated N-hydroxylation
• forming highly reactive intermediate
• associated with hepatotoxicity in large doses
• half life of 2 hours
• no risk of upper GI ulceration & bleeding
• effective for osteoarthritis
• less for inflammatory arthritis

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Glucocorticoids

• RA
• low-dose oral glucocorticoids
• relieve symptoms
• slows rate of joint damage
• Local injection

• Pharmacological actions

1. anti-inflammatory & immunosuppression

• suppress activation of T-cells, APC, macrophages
• by cytokines
• suppress production of cytokines
• block PLA2
• decrease release of chemical mediators of inflammation (from mast cells, eosinophils etc)
• histamine
• prostaglandins
• leukotrienes
• PAF
• stabilize lisosomal membranes of neutrophils
• prevent release of catabolic enzymes
• acid phosphatase
• increase synthesis of lipocortin
• inhibit PLA
• decrease prostacyclin
• decrease capillary permeability
• promote vasoconstriction
• reduce inflammation

Carbohydrate, Protein & Fat metabolism

• Increase serum glucose
• increase insulin secretion
• stimulate hormone sensitive lipase
• lipolysis
• increase insulin secretion stimulate lipogenesis, inhibit lipolysis
• fat deposition on trunk
• Cushing’s disease

Catabolic effect on lymphoid tissue, muscle & skin

Clinical uses

• Replacement therapy in adrenal insufficiency
• Anti-inflammatory & immunosuppressive
• Allergy
• bronchial asthma
• RA, OA
• organ transplantation
• ARDS
• malignancies
• cerebral oedema
• nephrotic syndrome
• eye, skin disease
• IBD

Special precautions

• Check & monitor for:
• hyperglycemia
• glaucoma
• cataract
• hidden infections
• BP
• hypokalemia
• peptic ulcer
• osteoporosis

Contraindications

• Patietns with
• Diabetes mellitus
• Glaucoma
• Peptic ulcer disease
• hypertension
• with heart failure
• TB
• Varicella virus infection
• Psychosis
• Osteoporosis

Adverse effect

• Cushing’s syndrome
• Adrenal suppression
• avoid sudden withdrawal
• Immunosuppression
• infection
• Others
• osteoporosis
• hypertension
• weight gain
• fluid retention
• hyperglycemia
• cataracts
• glaucome
• skin fragility
• premature atherosclerosis

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Disease Modifying Anti-rheumatic Drugs (DMARDs)

• In RA
• reduce/prevent joint injury
• early use
• preserve joint integrity & function
• Advantages
• economic
• control symptoms in the long term
• Disadvantages
• no immediate analgesic effects
• slow action: 8-12 weeks

DMARDs Agents

• Methotrexate (MTX)
• MOA
• folic acid inhibitor
• inhibits
• lymphocyte proliferation
• production of cytokines
• rheumatoid factor
• Interferes with neutrophil chemotaxis
• reduces production of cytotoxins & free radicals
• that damage synovial membrane & bone
• effective in reducing signs & symptoms of RA
• Highest efficacy
• without excess toxicity on long term use
• Taken orally/subcutaneously
• Adverse effects
• Most serious (but rare)
• hepatic cirrchosis
• interstitial pneumonitis
• severe myelosuppression
• Stomatitis, Mild alopecia, GI upset
• related to folic acid antagonism
• management: give folic acid
• Contraindication
• patients with pre-existing
• liver disease
• hepatic dysfunction
• alcohol abuse
• Leflunomide
• MOA
• block intracellular enzyme
• needed for de novo pyrimidine synthesis
• Actions
• antiproliferative
• anti-inflammatory
• immunosuppressive
• As effective as methotrexate
• decrease signs & symptoms
• decrease joint damage
• Metabolism
• converted to active metabolite in GI wall & liver
• Onset of action
• relatively fast (1-2 months)
• sustained
• Adverse effects
• diarrhea
• rashes
• alopecia
• elevation of liver enzymes
• possible liver damage
• Potent teratogen
• discontinue & undergo cholestyramine washout before attempting conception
• Monitor blood count & hepatic function
• Sulfasalazine (SSZ)
• Metabolism
• reaches the colon
• splits into 2 components by bacteria
• important for action
• Onset of action
• as early as 1 month
• Action
• reduce
  signs & symptoms of RA
• slow/halt radiolographic progression
• Adverse effects
• hypersensitivity
• sulfa allergy
• mild GI upset
• mild cytopenia
• Monitor blood every 1-3 months
• Good alternative to methotrexate
• for patients with liver disease
• less toxic to liver
• Hydroxychloroquine
• MOA
• reduces chemotaxis & phagocytosis of polymorphs
• Onset
• slow
• Use for
• milder RA
• less effective than SSZ & MTX
• but less toxic & better tolerated
• Side effects
• ocular toxicity*
• maculopathy
• scotoma
• Monitor
• baseline & annual ophthalmologic assessments
• Stop therapy
• if any impairement of vision
• severe rash
• Sodium aurothiomalate (Gold therapy)
• Given Intramuscularly
• after injection, do CBC & urine test for protein
• Side effects
• skin rash
• stomatitis
• flushing
• hypotension
• tachycardia

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Biologic response modifiers

TNF-alpha blockers

• Etanercept
• recominant fusion protein (consist of)
• soluble human TNF-receptor
• human IgG1-Fc fragment
• MOA
• binds TNF-alpha in the circulation & in joint
• prevent interaction with cell surface TNFa receptors
• reduce TNF activity
• clears TNFa from circulation
• Used in combination with MTX
• if MTX alone not enough
• Onset
• 1-4 weeks
• Given subcutaneously
• Very expensive
• Infliximab/Adalimumab
• MOA
• Monoclonal antibody that binds TNFa
• with high affinity & specificity
• same mechanism as (above)
• Used in combination with MTX (same)
• Onset
• days – weeks

Adverse effects for TNFa blockers

• Injection site
• pain
• swelling
• itching
• Serious infections
• sepsis
• death
• Disseminated tuberculosis
• reactivation of latent disease
• screening for latent TB essential before treatment
• Lymphoma
• non-hodgkin’s lymphoma
• RA itself is a risk
• Do not use in patients with
• demyelinating disease
• congestive heart failure

Other drugs

• Anakinra
• recombinant
• non-glycosylated human IL-1Ra
• MOA
• inhibits binding of cytokine to IL-1 receptor
• Used with DMARDs
• Onset
• 2-4 weeks
• Given subcutaneously
• Side effects
• injection site reactions
• serious infections
• decreased white blood cell count
• lymphoma
• Combination of biologics not recommended
• risk of infections increased if combine with TNFa inhibitors
• Advantage
• no case of TB reported
• does not reactivate latent TB
• Abatacept
• MOA
• inhibits activation of T cells
• by blocking co-stimulatory signal
• Given alone/with DMARDs
• Side effects
• risk of infection
• URTI
• Rituximab
• MOA
• targets lymphocytes
• cause depletion of B cells
• Given IV
• Side effects
• rashes
• Advantage
• does not reactivate TB
• does not cause lymphoma

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Algorithm for Rheumatoid arthritis