Rheumatoid Arthritis and NSAIDs

Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout

• The immune response activates immunologically competent cells against foreign organisms or antigenic substances causing inflammation.
• Chronic inflammation involves cytokines, chemokines, and immunoactive cells, leading to autoimmune diseases and inflammatory conditions.
• Inflammation damages cells, releasing lysosomal enzymes and arachidonic acid, which synthesizes eicosanoids and promotes inflammation.
• Neutrophil stimulation produces oxygen-derived free radicals, perpetuating the inflammatory process.

Therapeutic Strategies

• Treatment goals: relieve symptoms/maintain function and slow/arrest tissue damage.
• Reduction of inflammation with NSAIDs often relieves pain and other nonopioid analgesics.
• Glucocorticoids have anti-inflammatory effects, but their toxicity limits their use compared to other medications.
• Disease-modifying antirheumatic drugs (DMARDs), including biologics, reduce inflammation, improve symptoms, and slow bone damage.

Nonsteroidal Anti-Inflammatory Drugs

• Salicylates and similar agents suppress inflammation, including pain and fever.
• Many NSAIDs have been developed to improve aspirin's efficacy and reduce toxicity.
• NSAIDs are grouped into chemical classes, leading to diverse pharmacokinetic characteristics.
• Most NSAIDs are weak organic acids, well-absorbed, highly metabolized, and primarily eliminated through renal excretion.
• NSAIDs are highly protein-bound, found in synovial fluid, and their anti-inflammatory activity relies on prostaglandin biosynthesis inhibition.
• Additional mechanisms include inhibiting chemotaxis, down-regulating IL-1 production, decreasing free radicals, and impacting calcium-mediated intracellular events.
• Aspirin irreversibly blocks the COX enzymes, non-selective NSAIDs are reversible inhibitors.

Selectivity of COX-1 and COX-2 Inhibitors

• The selectivity for COX-1 versus COX-2 is variable for older NSAIDs, but COX-2 inhibitors have been synthesized.
• Selective COX-2 inhibitors do not affect platelet function at their usual doses.
• The efficacy of COX-2-selective drugs equals that of the older NSAIDs, while GI safety may be improved.
• Selective COX-2 inhibitors increase the incidence of edema, hypertension, and possibly, myocardial infarction.
• Celecoxib has an FDA "black box" warning concerning cardiovascular risks as of August 2011.

General Information on NSAIDs

• All NSAIDs can cause heart attacks or strokes, and all labels are revised to cardiovascular risks as of July 2015.
• NSAIDs decrease vessel sensitivity to bradykinin/histamine, affect lymphokine production, and reverse vasodilation.
• Newer NSAIDs are analgesic, anti-inflammatory, and antipyretic, and inhibit platelet aggregation (except COX-2 selective agents and nonacetylated salicylates).
• NSAIDs irritate the gastric system.
• Can cause GI ulcers and bleeds.
• New agents tend to cause less GI irritation than aspirin.
• Reported for all NSAIDs: nephrotoxicity due to renal blood flow interference
• Hepatotoxicity can occur.

Lack of Effectiveness in Specific Disorders

• These drugs effectively inhibit inflammation but do not alter the course of any arthritic disorder.
• Several NSAIDs reduce colon cancer incidence when taken chronically.
• Effective ones for RA, arthritis, OA, and Gout: aspirin, tolmetim, ibuprofen & naproxen.

Aspirin Properties

• Long use and availability without prescription diminishes its glamour.
• It is now rarely used as an anti-inflammatory medication and will be reviewed only in terms of its antiplatelet effects
• Pharmacokinetics: Salicylic acid is a simple organic acid with pK 3.0
• Aspirin (acetylsalicylic acid; ASA) has a pK of 3.5.
• Aspirin is absorbed; hydrolyzed to acetic acid and salicylate by esterases
• Salicylate is nonlinearly bound to albumin.

Aspirin Mechanisms of Action

• Aspirin irreversibly inhibits platelet COX, the antiplatelet effect lasts 8–10 days
• In other tissues inactivated enzyme is replaced
• Ordinary doses have a duration of action of 6-12 hour.
• Clinical uses: Aspirin decreases incidence of cardiac events with myocardial infarction.
• Epidemiologic studies find long-term use of aspirin at low dosage is associated with a lower incidence of colon cancer.

Aspirin Side Effects and Contraindications:

• Gastric upset and ulcer.
• Hepatotoxicity, asthma, rashes, GI bleeding, and renal toxicity rarely occur at antithrombotic doses.
• Contraindicated for those with hemophilia.
• Valuable for treating preeclampsia-eclampsia during pregnancy

Nonacetylated Salicylates

• Drugs: magnesium choline salicylate, sodium salicylate, and salicyl salicylate.
• Are effective anti-inflammatory drugs, and they do not inhibit platelet aggregation.
• Preferable when COX inhibition is undesirable like with asthma.
• The nonacetylated salicylates is administered in doses up to 3-4 g use serum salicylate measurements

COX-2 Selective Inhibitors

• Were developed in an attempt to inhibit prostaglandin synthesis.
• In usual doses have no impact on platelet aggregation.
• They do inhibit COX-2-mediated prostacyclin synthesis in the vascular endothelium.
• Recommended doses cause renal toxicities.
• Cardiovascular thrombotic events risk.

Information on Specific Nonselective Cox Inhibitors

Celecoxib:

• A selective COX-2 inhibitor (10-20x more selective for COX-2 than COX-1).
• Clinical data given in Table 36–1.
• Fewer endoscopic ulcers than most other NSAIDs.
• May cause rashes and occasionally interacts with warfarin.

Meloxicam:

• Is an enolcarboxamide related to piroxicam that preferentially inhibits COX-2 over COX-1.
• Fewer clinical Gl symptoms/complications than piroxicam, diclofenac, and naproxen.

Diclofenac:

• Is a phenylacetic acid derivative inhibitor.
• Characteristics outlined in Table 36-1.
• Gastrointestinal ulceration may occur less frequently than with some other NSAIDs.
• Diclofenac 150 mg/d, appears to impair renal blood flow and glomerular filtration rate.
• 0.1%ophthalmic preparation promoted for postoperative ophthalmic inflammation
• Topical gel containing 3% effective for solar keratoses.

Diflunisal:

• Derived from salicylic acid, it is not metabolized to salicylic acid or salicylate.
• Half-lives at various dosages approximating that of salicylates (Table 36-1).

Etodolac:

• Is a racemic acetic acid derivative with intermediate half-life (Table 36–1).

Flurbiprofen:

• Is a propionic acid derivative non selective inhibition.
• Hepatic metabolism is extensive.

Ibuprofen:

• Is a simple derivative of phenylpropionic acid (Figure 36-1).
• About 2400 mg daily is equivalent to 4 g of aspirin.

Indomethacin:

• Introduced in 1963, is an indole derivative.
• It is also may inhibit phospholipase A and C, reduce neutrophil migration.
• It’s ophthalmic preparation is efficacious for conjunctival inflammation

Ketoprofen:

• A propionic acid derivative that inhibits both COX.
• Can be antagonized the irreversible platelet inhibition induced by aspirin.

Nabumetone:

• Is the only nonacid NSAID in current use.
• It is renal impaired results in doubling of its half-life .

Naproxen:

• Is a naphthylpropionic acid derivative.
• Rare cases of allergic pneumonitis.

Oxaprozin:

• Another propionic acid derivative NSAID.
• Is mildly uricosuric.

Piroxicam:

• When piroxicam is used in dosages higher than 20 mg/d, an increased incidence of peptic ulcer and bleeding is encountered.

Sulindac:

• Is a sulfoxide prodrug.
• Prolongs action to 12-16 hours.

Tolmetin:

• Not effective in treatment of gout.

Choice of NSAID

• All NSAIDs are equally efficacious (exception: tolmetin isn't effective for gout).
• Differentiated on basis of toxicity & cost-effectiveness (GI & renal side effects and liver issues).
• May have higher cardiovascular toxicity.
• Requires balance of efficacy, cost-effectiveness, numerous personal factors.

Disease-Modifying Antirheumatic Drugs

• RA is a progressive immunological disease that shortens lift.
• Treatements are being developed to slow progression by modifying the disease itself.
• Effects of therapies mat take about 2 weeks to 6 months.
• Therapies: cs DMARDs and bDMARDs, respectively.
• bDMARDs approved for RA include a T-cell-modulating biologic (abatacept).

Abatacept Treatment

Mechanisms of Action:

• Is a biologic modulator that inhibits the activation of t cells.

Pharmacokinetics:

• Dose is determined by the patient's weight.

Indications:

• Has been tested in other rheumatic diseases like SLE, inflammatory bowel, and psoriasis vulgaris.

Adverse Effects:

• Infusion reactions and hypersensitivity reactions are reported but rare.

Azathioprine Treatment

• Acts through its major metabolite, 6-thioguanine.

Pharmacokinetics:

• Production of 6-thioguanine is dependent on TPMT.

Indications:

• Is approved for use in RA at 2 mg/kg per day .

Adverse Effects:

• Toxicity includes bone marrow suppression. Lymphomas increased with azathioprine use.

Chloroquine & Hydroxychloroquine Treatment

• Non-biologic drugs that supress T-lymphocyte responses to to mitogens and leukocyte chemotaxis.

Pharmacokinetics:

• Tissue-bound extensively.

Indications:

• Dose-loading may increase rate of response.

Adverse Effects:

• Can occur at dosages.
• Ophthalmologic monitoring recommended every 12 months .

Cyclophosphamide Treatment

• Major metabolite is phosphoramide mustard.
• T-cell and B-cell function by 30-40%.

Indications:

• Used regularly to treat SLE vasculitis.

Cyclosporine Treatment

• Mechanism: peptic antibiotic but is a DMARD and has gene transcription

Pharmacokinetics:

• Food and grapefruit juice may also effect bioavailability.

Indications:

• Is approved for use in RA.

Adverse Effects :

• Sterility, and can be cardiotoxic.

Leflunomide

Mechanism:

• Rapid conversion both in the intestine.
• Has effects on tumor necrosis.

Pharmacokinetics:

• Has a mean plasma half-life of 19 days.

Indications:

• Inhibits bony damage

Adverse Effects:

• Diarrhea

Methotrexate Treatment

• Synthetic nonbiologic antimetabolite. Principal of action and doses is probably relates to inhibition.

Pharmacokinetics:

• Drug can either be administered orally or parentally.

Dosage and Indication :

• It recommended start treatment.
• Decreases appearances of erosions.

Adverse Effects:

• Nausea and mucosal ulcers, and many other such as leukopenia.

Mycophenolate Mofetil Treatment

• Downstream, it interferes with leukocyte adhesion to endothelial cells through.
• Effective for treatment of renal disease due to SLE.
• Adverse Effects: MMF is used in the with nausea and dyspepsia.

Rituximab Treatment:

• Indication is treatement to those whose Moderate to severely active Ra treatment that is combination is with methotrexate
• About (30%) patient the develop rash within first (1000.mg), treatment: the incidence decreases.

Sulfasalazine Treatment

Mechanisms of Action:

• Metabolized to sulfapyradine AND 5-aminosalicylic acid.

Indication:

• Effective in RA and also redices radiologic diseases.

Adverse Effects:

• Common nausea vomiting and headache .
• Neutropenia

Glucocorticoids

Indications:

Used treat extra-articular from SLE or pericardities ###Dosage: Administered with 60% to 70% of their patients.

###Tocilizumab Treatment

Mechanisms of Action:

• A newer biologic human binds to soluble and then its mediated signaling ,
• Interleukins 6 is in flammatory cytokine produce type cell(bcell t cels and endothelial

Pharmacokinetics :

_ The half life tocilizumab and suppresses several (Cyp450)- Has significant effects with others drugs adjustments

Tnfa (tumornecrosis factor) blocking

Mechanisms of action - cellular unction by action.

Indications

• The combination approved treat RA PA JIA inflammatory bowel Dosage (The 40%)presence Methotrexate time,
• Treatment Adalimumab by other hand.

TNF-α-Blocking Agents Common Adverse Effects

• Increased risk of upper respiratory tract infections, lymphoma
• Screening for tuberculosis should be done prior to beginning treatment.
• Upper respiratory tract infections, headache, hypertension, increased liver enzymes.

Colchicine

• Although NSAIDs, corticosteroids, or colchicine are now first-line drugs for acute gout, colchicine was the primary treatment for many years.

• Pharmacokinetics:: Colchicine is absorbed readily after oral administration, reaches peak plasma levels within

• Pharmacodynamics Colchicine relieves the pain and inflammation of gouty arthritis in 12–24

Dosage :

the dosage of colchicine is 0.6 mg one to three times daily.

SIDE EFFECTS

Colchicine -Nausea vomiting abdominal Pain .and hepatic necrosis.and reanul failure

###NSAIDs Indometacin commonly used as replacement of cholchine All Nsaids except for asperin that is to have in cholchicine also use of other medications.

• Treatment: Reduce body pool and patient with tophaceous those frequently.
• The renal tube reabsorbed with net reabsorption of active.
• Dosages: Probenecid 0.5g, Orally in divided doses increasing 1g week

ALOL OPURINOL

• Chemistry and Pharmacokinetics
• Like acid allopurinol by xanthine oxidase with compound alloxanthine
• Safety by children and if pregnant by safety had establish Interactions and

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