• Overview: Antimalarials

  • Efficacious in management of rheumatoid arthritis and systemic lupus erythematosus

  • Wth long-term chloroquine use: 

    • Rheumatoid factor levels decreased

    • No evidence of eeffect on progressivein erosive bone lesions

• Possible Mechanisms of Action: 

  • Reduced T lymphocyte mitogen responsiveness

  • Reduced leukocyte chemotaxis

  • Stabilization of lysosomal membranes

  • Trapping free radicals

• Clinical Indications:  antimalarials

  • Used for patients not responding adequately salicylate/NSAIDs

• Gold and Rheumatoid Arthritis

  • Overview:   gold

    • Parenteral gold reduces: 

      • Symptoms

      • Slows disease progression

        • May reduce bone/articular cartilage destruction

    • Toxicities:   reduce likelihood of long-term use

  • Chemistry:    available gold preparations

    • Aurothiomalate-- parenteral (intramuscular; water-soluble gold salts (50% elemental gold)

    • Aurothioglucose--parenteral (intramuscular; water-soluble gold salts (50% elemental gold)

    • Auranofin -- substitute gold thioglucose derivative-- oral route administration

  • Pharmacokinetics:    gold

    • Highly plasma protein-bound

    • Concentrated synovial membranes

      • Also concentrates in liver, kidney, spleen, lymph nodes, bone marrow, adrenal glands

    • Body half-life:   about one-year

    • Oral administration:   25% absorption

  • Pharmacodynamics:    gold

    • Mechanism of action:   uncertain

    • Gold affects macrophage function/morphology

    • Many other effects including: 

      • Reduced lysosomal enzyme activity

      • Decreased mast cell histamine released

      • Inactivation of first component of complement

      • Suppression of phagocytosis by polymorphonuclear leukocytes

      • Reduced macrophage function

      • Inhibition of Shwarzman phenomenon

  • Clinical Use/contraindications:   gold

    • May be used for active rheumatoid arthritis

    • Gold may be used for patients showing active inflammation/erosive changes

    • Gold for rheumatoid arthritis in patients with Sjogren's syndrome or juvenile rheumatoid arthritis

    •  Major Contraindications:   gold

      • Previous history toxicity

      • Pregnancy

      • Significant liver or renal function impairment

      • Blood dyscrasia

  •  Adverse Effects:   gold

    • Frequency of adverse effects:   33%

    • Most common:   pruritus -- frequency 15%-20% and gastrointestinal disturbances (diarrhea)

    •  Hematologic:   frequency 1%-10%: 

      • Thrombocytopenia

      • Leukopenia

      • Pancytopenia

      • Aplastic anemia (rare) -- but potentially fatal

    •  Proteinuria:   frequency -- 8% -- 10%; some cases progressed to nephrotic syndrome

    •  Diverse, other adverse effects: 

      • Somatitis

      • Metallic taste

      • Skin pigmentation

      • Enterocolitis

      • Cholestatic jaundice

      • Peripheral neuropathy

      • Pulmonary infiltrates

      • Corneal gold deposition

• Penicillamine

  • Overview:    penicillamine

    • Metabolite of penicillin; analog of cysteine

    • D-form (isomer) is used clinically

  • Pharmacokinetics:   penicillamine

    • 50% absorption following oral Route of Administration

    • 60% of drug excreted in 24 hours

  • Pharmacodynamics:   penicillamine

    • Mechanism of action:   penicillamine

      • Uncertain

        • Interacts with lymphocyte membrane receptors

        • May interfere with DNA synthesis, collagen, mucopolysaccharides

      • Long latency (3-4 months)

  • Clinical Indications:    penicillamine

    • Active, progressive erosive rheumatoid disease-uncontrollable by more conservative treatment

    • Mainly prescribed for patients not responsive to gold therapy

    • Not useful for seronegative arthropathies

    • Caution:   penicillamine significantly interferes with absorption of many other drugs

  •  Adverse Effects:  penicillamine

    • Proteinuria:   frequency 20%

    • Immune complex nephritis:   frequency 4% (reversible)

    • Leukopenia and thrombocytopenia -- may occur at any time, may be preceding aplastic anemia

    • Most common adverse effects:   skin/mucous membrane reactions

    • Autoimmune Diseases associated with penicillamine use:   (requires immediate cessation of drug)

      •  Goodpasture's syndrome

      •  Lupus erythematosus

      •  Hemolytic anemia

      •  Thyroiditis

    • Diverse adverse effects: 

      • Reduced taste perception, anorexia, nausea, vomiting, mammary hyperplasia, alopecia, psychological changes

    •  Contraindications:   penicillamine

      • Pregnancy

      • Renal insufficiency

      • Concurrent treatment with: 

        • Gold, cytotoxic drugs, phenylbutazone

    •  Frequency of adverse effects requiring discontinuation of penicillamine treatment:   40%

• Sulfasalazine

  • Overview:    sulfasalazine

    • First introduced for management of ulcertive colitis

    • Effective in management of rheumatoid arthritis

  • Pharmacokinetics:  sulfasalazine

    • Main metabolites:   5-acetylsalicyclic acid (5-ASA), sulfapyridine

    • Active drug for inflammatory bowel disease:   5-ASA

    • Active drug for rheumatoid arthritis:   either sulfapyridine or sulfapyridine + sulfasalazine

  • Pharmacodynamics:   sulfasalazine

    • Mechanism of action:   probably NOT dihydrofolate inhibition

    • Sulfasalazine does have effects on B lymphocyte function

    • FDA approved for rheumatoid arthritis

  •  Adverse Effect:   sulfasalazine

    • In rheumatoid arthritis patients:   Most common side effects --

      • Gastrointestinal disturbance

      • Rashes

      • Dizziness

      • Photosensitivity

      • Neutropenia (rare)-May require drug withdrawal; hypersensitivity pneumonitis (rare); sterility (rare)

• Glucocorticoids

  • Overview:  glucocorticoids

    • Very effective in treating rheumatoid arthritis

    • Prednisone and related agents may slow development of new bone erosions

  • Pharmacodynamics:   glucocorticoids

    • Inhibition:   phospholipase A₂:   causes liberation of membrane lipid arachidonic acid

    • Glucocorticoids:   selective inhibition of COX-II expression

  •  Adverse Effects:  glucocorticoids

    •  Prolonged Use: 

      • Fractures

      • Infections

      • Cataracts

    • In certain patients, with prolonged use:   diabetes, hypertension, accelerated atherosclerotic heart disease

  • Clinical Uses:   glucocorticoids

    • Extra-articular presentations: 

      • Pericarditis

      • Eye involvement

      • Exacerbations

    • Intra-articular corticosteroids: 

      • Pain reduction

      • Preferable to increasing systemic dosage

• Diet

  • Eating unpurified eicosapentaenoic acid: 

    • Reduced platelet aggregation

    • Reduced chemotactic activity-- caused by leukotriene B4

    • Reduced polymorphonuclear adherence-- caused by leukotriene B4

    • Eicosapentaenoic acid treatment: 

      • Reduces morning stiffness

      • Decreases number of painful joints in rheumatoid arthritis patients

      • Reduces erythema associate with psoriasis

    • May be beneficial as an adjunct to traditional management

• Acetaminophen

  • Overview:  acetaminophen

    • Important drug for management of mild/moderate pain AF anti-inflammatory effect is not required

    • Phenacetin (prodrug, more toxic)® metabolized to acetaminophen

    • Weak prostaglandin inhibitor

    • No appreciable anti-inflammatory actions

  • Pharmacokinetics:   acetaminophen

    • Oral administration

    • Peak plasma levels:     30-60 minutes

    • Partial hepatic metabolism:    -- inactive metabolites

      • Acetaminophen sulfate

      • Acetaminophen glucuronide

      • < 5% excreted unchanged

    •  Toxic, minor metabolite:     N-acetyl-p-benzoquinone

      • Liver, kidney toxicity

        • A concern at high doses

  • Clinical Uses:   acetaminophen

    • Comparable to aspirin analgesia and antipyretic effect;

    • No anti-inflammatory effects

    • No effect on uric acid levels

    • No platelet inhibition

    • Effective in management of mild/moderate pain due to: 

      • Headache

      • Myalgia

      • Postpartum pain

    • For analgesia, acetaminophen preferable if: 

      •  Patient allergic to aspirin

      •  Salicylates -- poorly tolerated

      •  Patient has hemophilia

      •  Peptic ulcer disease present

      •  Aspirin induces bronchospasm

      •  No antagonism of probenecid (uricosuric drug); may be used with probenecid for management of gout

      •  In children with viral infection:   preferable to aspirin (Reye's syndrome concern)

  •  Adverse Effects:  acetaminophen

    • Small increase in hepatic enzymes (reversible) -- occurs at therapeutic doses

    • Larger doses: 

      • Dizziness, excitement, this orientation

    •  Very high doses:   (15 grams):   maybe fatal due to: 

      •  Severe hepatotoxicity --

        • Central lobular necrosis

        • Symptoms of hepatic damage:   nausea, diarrhea, abdominal pain, vomiting

      •  Acute renal tubular necrosis

        •  Renal pathology may occur or in the absence of hepatic damage

      •  Management of overdosage: 

        • Supportive

        • Sulfhydryl groups:   may neutralize toxic metabolites (acetylcysteine)

    • Cautious use in patients with liver disease

Primary Reference:   Katzung, B. G. and Furst, D. E. Nonsteroidal Anti-Inflammatory Drugs; Disease-Modifying Antirheumatic Drugs; Nonopioid Analgesics; Drugs Used in Gout, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 578-602.

Lipsky, P.E. Rheumatoid Arthritis, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 1880-1888.Agudelo, C.A.

Gout in Medicine for the Practicing Physician, Fourth edition, (Hurst, J. Willis, editor in chief) Appleton and Lange, 1996, pp 223-226.