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
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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
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
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
previous history toxicity
pregnancy
significant liver or renal function impairment
blood dyscrasia
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
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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
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%
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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
In rheumatoid arthritis patients: Most common side effects --
gastrointestinal disturbance
rashes
dizziness
photosensitivity
neutropenia (rare)-May require drug withdrawal; hypersensitivity pneumonitis (rare); sterility (rare)
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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
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
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
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)
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
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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 & Lange, 1996, pp 223-226. |