• Overview: antimalarials

  • Efficacious in management of rheumatoid arthritis and systemic lupus erythematosus

  • with 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

• 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:

    • stomatitis

    • metallic taste

    • skin pigmentation

    • enterocolitis

    • cholestatic jaundice

    • peripheral neuropathy

    • pulmonary infiltrates

    • corneal gold deposition

• 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%

• 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)

• 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

• 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

• 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