6.
Appendix E. Formulary
Manual of Rheumatology and Outpatient Orthopedic Disorders
Appendix E. Formulary
Arthur M. F. Yee and Jane E. Salmon
| Pregnancy and Medications | |
| Nonsteroidal Antiinflammatory Drugs | |
| Aspirin | |
| Celecoxib | |
| Diclofenac | |
| Diflunisal | |
| Etodolac | |
| Fenoprofen Calcium | |
| Flurbiprofen | |
| Ibuprofen | |
| Indomethacin | |
| Ketoprofen | |
| Ketorolac | |
| Meclofenamate Sodium | |
| Mefenamic Acid | |
| Nabumetone | |
| Naproxen | |
| Oxaprozin | |
| Piroxicam | |
| Rofecoxib | |
| Salicylate Salts | |
| Salsalate | |
| Sulindac | |
| Tolmetin Sodium | |
| Corticosteroids and Corticotropin | |
| Corticosteroids | |
| Corticotropin | |
| Disease-Modifying Antirheumatic Drugs | |
| Azathioprine | |
| Chlorambucil | |
| Chloroquine | |
| Co-trimoxazole | |
| Cyclophosphamide | |
| Cyclosporin A | |
| Dapsone | |
| Gamma Globulin | |
| Gold Compounds | |
| Hydroxychloroquine | |
| Leflunomide | |
| Methotrexate | |
| Minocycline | |
| Mycophenolate Mofetil | |
| D-Penicillamine | |
| Protein A Immunoadsorption Column | |
| Quinacrine Hydrochloride | |
| Sulfasalazine | |
| Biologic Agents | |
| Etanercept | |
| Medications for Crystalline Arthritides | |
| Allopurinol | |
| Colchicine | |
| Probenecid | |
| Sulfinpyrazone | |
| Analgesics | |
| Acetaminophen | |
| Amitriptyline | |
| Capsaicin | |
| Gabapentin | |
| Tramadol Hydrochloride | |
| Drugs for Osteoporosis and Metabolic Bone Diseases | |
| Alendronate | |
| Calcitonin | |
| Calcium Preparations | |
| Estrogens | |
| Etidronate Disodium | |
| Fluoride, Sodium | |
| Pamidronate | |
| Raloxifene | |
| Risedronate | |
| Tiludronate | |
| Vitamin D | |
| Anticoagulants | |
| Ardeparin | |
| Dalteparin | |
| Danaparoid | |
| Enoxeparin | |
| Heparin, Unfractionated | |
| Warfarin Sodium | |
| Vasoactive Agents | |
| Amlodipine | |
| Captopril | |
| Diltiazem | |
| Enalapril/Enalaprilat | |
| Nifedipine | |
| Prazocin | |
| Verapamil | |
| Supplements and Miscellaneous | |
| Chondroitin Sulfate/Glucosamine Sulfate | |
| Cisapride | |
| Hyaluronans | |
| Lansoprazole | |
| Lyme Disease Vaccine | |
| Metoclopramide | |
| Misoprostol | |
| Omeprazole | |
| Pilocarpine Hydrochloride | |
| Sunscreens | |
Recent progress in understanding the pathophysiology of rheumatic diseases and in the development of new therapeutic approaches has greatly expanded the pharmacologic armamentarium with which to treat these illnesses. Moreover, the spectrum of conditions that fall under the realm of rheumatology increasingly overlaps with that of other medical specialties, and so previously known medicines have frequently found new application. Thorough appreciation of the indications , contraindications, goals of therapy , and potential adverse effects of any medicine is essential for appropriate administration. Nonetheless, although the clinical situation may define the need for a given therapeutic category, the use of a specific agent is often determined by an empiric trial that considers patient response, tolerance, and compliance, as well as by drug expense. As with all medications, recognition of contraindications and careful monitoring of potentially adverse effects are of paramount importance, especially in children, the elderly, and pregnant women.
PREGNANCY AND MEDICATIONS
As many rheumatic diseases affect women of childbearing age, the clinician should be keenly aware of the many possible complications of medications and their effects on fertility and fetal development. A frank and thorough discussion with the patient is paramount even before pregnancy is attempted.
Although it is impossible to create absolute rules regarding the management of medications, the overriding principle will always be the weighing of the potential benefits of any drugs against the potential risks, to be considered on an individual case basis. Although minimizing drug intervention during pregnancy is always desired, there is very strong evidence for discontinuing the use of certain drugs, such as methotrexate (MTX) or cyclophosphamide (CTX), both before and during gestation. For other medications, such as azathioprine or hydroxychloroquine, the evidence is not as clear, although they are probably relatively safe. Warfarin should be discontinued because of its known teratogenic effects and should be substituted with heparin. Aspirin and nonsteroidal antiinflammatory agents should be discontinued in the latter part of pregnancy because of the potential for premature closure of the ductus arteriosus; nonetheless, in the anti-phospholipid syndrome, low-dose aspirin is an important treatment option in ensuring a successful pregnancy. Prednisone and methylprednisolone at low to moderate doses will not cross the placenta and are considered to be safe for fetal development. In contrast, the fluorinated corticosteroids (e.g., dexamethasone and betamethasone) will cross the placenta.
NONSTEROIDAL ANTIINFLAMMATORY DRUGS
Nonsteroidal antiinflammatory drugs (NSAIDs) exhibit antipyretic, antiinflammatory, and analgesic activity. They are used for degenerative musculoskeletal problems, systemic inflammatory illnesses, crystalline diseases, soft- tissue injuries, and hypercoagulable states, among others. All act by interrupting the arachidonic acid metabolic cascade, but therapeutic effects may involve actions other than, or in addition to, the inhibition of prostaglandin synthesis. NSAIDs are essentially equipotent, although individual responses may vary among patients . Most have similar side effects. Individual patient tolerance may vary between preparations. If an inadequate therapeutic response or intolerance occurs, a trial of an alternative agent, especially from a different chemical class, is often worthwhile. Compliance may be related to the schedule of administration (Table E-1). Concurrent use of aspirin and another NSAID or of multiple non-aspirin NSAIDs is not generally recommended. Side effects common to most NSAIDs include gastrointestinal intolerance, tinnitus, fluid retention, platelet abnormalities, and hepatic and renal dysfunction. In patients being treated on a long- term basis with NSAIDs, regular monitoring of hepatic and renal function is necessary.
 |
Table E-1. Nonsteroidal antiinflammatory drugs
All NSAIDs should be used cautiously in patients with impaired renal or hepatic function and in the elderly. They are relatively contraindicated in patients with a history of peptic ulcer disease. If NSAIDs are needed in such patients or other high-risk groups, gastroprotective agents, such as misoprostol or proton pump inhibitors , should be used concurrently to reduce the risk for gastrointestinal complications. Asthma attacks, urticaria, and angioedema may be related to enzymatic inhibition of prostaglandin synthesis in susceptible persons or to immunoglobulin E (IgE)-mediated reactions, which usually occur with pyrazolone-type drugs. Patients who have these reactions to aspirin or other NSAIDs may be sensitive to all NSAIDs. Pregnancy is another relative contraindication to NSAID use, as NSAIDs may cause hemorrhagic complications or premature closure of the ductus arteriosus. The benefits of NSAID use in pregnant women must be weighed very carefully against the risks.
The platelet-inhibiting effects of aspirin are irreversible, whereas the effects of non-aspirin NSAIDs on platelet function are variable. However, in general, discontinuation of all NSAIDs for up to 1 week should be considered before any invasive procedure is undertaken.
Major recent advances have been made in the development of a new generation of NSAIDs that preferentially inhibit the activity of cyclooxygenase-2 (COX-2). Because of their relative sparing of constitutive COX-1 activity, which is necessary for mucosal protection, COX-2 inhibitors have been shown to have fewer adverse gastrointestinal effects than do traditional NSAIDs. Moreover, COX-2 inhibitors do not affect platelet function or increase bleeding time at therapeutic concentrations. Celecoxib and rofecoxib are the first COX-2 inhibitors to be approved for use in the United States, and it is anticipated that others will soon be available.
Aspirin
Action
Inhibits prostaglandin synthesis.
Metabolism
Aspirin (acetylsalicylic acid) is metabolized in the liver and excreted by the kidney. Its half-life increases with increasing doses. It is highly bound to albumin in plasma and widely distributed to all tissues, including synovium.
Adverse Reactions
Gastrointestinal discomfort with nausea and dyspepsia is common, especially in the elderly. Increased gastrointestinal blood loss occurs. Tinnitus, decreased hearing acuity, or both are related to mild toxicity and are reversible with a decrease in dosage. Central nervous system symptoms such as headache , vertigo, and irritability can occur in the elderly. Aspirin may induce mild, reversible hepatocellular injury in patients being treated for acute rheumatic fever , juvenile rheumatoid arthritis (JRA), and active systemic lupus erythematosus (SLE). Platelet adhesiveness and aggregation and adenosine diphosphate release are inhibited by irreversible acetylation of platelet membrane protein.
Caution
Idiosyncratic reactions such as asthma occur in 0.02% of patients. Patients with asthma and nasal polyps are at higher risk for this reaction. Cross-reactivity exists with other NSAIDs but has not been reported with sodium or magnesium salicylates. Aspirin is uricosuric at high doses (>45 g/24 h), but low doses (<2 g/24 h) may lead to urate retention. Aspirin may displace other drugs bound to albumin, thereby potentiating the effects of oral hypoglycemic agents, warfarin, and other medications. Because aspirin inhibits platelet aggregation and prolongs bleeding time, it should be avoided or used with great caution in patients receiving heparin or warfarin anticoagulants. In patients receiving large doses of salicylates, salicylate toxicity may occur during tapering of corticosteroids.
Supply
Tablets, 325, 500, and 650 mg. Buffered tablets, formulated with either absorbable (bicarbonate) or nonabsorbable antacids, are not associated with reduced gastrointestinal bleeding. Enteric-coated tablets are often better tolerated, with less dyspepsia and occult gastrointestinal blood loss, but also have more variable absorption rates than either buffered or nonbuffered tablets. Rectal suppositories are incompletely absorbed. Time-release tablets have delayed absorption with possibly more sustained plasma levels. The physician should be aware of the fact that a large number of over-the-counter drug combinations containing aspirin are widely available.
Dosage
The dosage is 600 to 1,200 mg every 4 to 5 hours, preferably with meals. For optimal antiinflammatory effects, blood levels between 20 and 30 mg/dL and a total daily dose of 3 to 6 g are usually required. Dosages necessary to achieve adequate therapeutic concentrations vary with the individual patient. The maximum tolerated dose must be reached slowly, so that waiting 1 week between dosage changes is appropriate. Salicylate levels are routinely available and may be useful to determine adequacy of dosage, patient compliance, and toxicity.
Celecoxib (Celebrex)
Action
Inhibits prostaglandin synthesis via preferential inhibition of COX-2.
Metabolism
Celecoxib is a diaryl-substituted pyrazole. Celecoxib may be generally administered without regard to timing of meals and will achieve peak plasma levels within 3 hours, although high-fat meals may delay peak plasma levels. About 97% of the drug is protein-bound, primarily to albumin. Metabolism is largely mediated via cytochrome P-450 2C9, and excretion is via both feces and urine. The effective half-life is about 11 hours.
Adverse Reactions
Dyspepsia and gastrointestinal intolerance are common, and vigilance for gastrointestinal hemorrhage is necessary. The renal effects are similar to those of other NSAIDs. Other forms of intolerance include hypertension, edema, and dermatologic reactions.
Caution
Lower initial doses are recommended in the elderly and in the setting of hepatic insufficiency. Potential drug interactions have been identified with lithium and fluconazole. Celecoxib may be taken with low-dose aspirin, warfarin, and MTX and appears to have no effect on platelet function at therapeutic levels. The drug is contraindicated in patients with known allergies to other NSAIDs or to sulfonamides and should also be avoided in pregnancy.
Supply
Capsules, 100 and 200 mg.
Dosage
The dosage is 200 mg in one or several divided doses daily. The maximum daily dose is 400 mg.
Diclofenac (Cataflam, Voltaren, Arthrotec)
Action
Inhibits prostaglandin synthesis.
Metabolism
Diclofenac is a phenylacetic acid derivative. Absorption is delayed by food. Peak plasma level after administration occurs in 2 to 3 hours. Ninety-nine percent is reversibly bound to plasma albumin. Half-life is approximately 2 hours. It is eliminated through metabolism and excretion in urine (65%) and bile (35%).
Adverse Reactions
Gastrointestinal ulceration, bleeding, and perforation occur in 1% of patients. Headaches and dizziness are common. Elevation in transaminases is present in 2% of patients and is generally reversible, although severe hepatotoxicity has been reported. Fluid retention, edema, and nephrotoxicity can occur. Cross-reactivity in patients with aspirin sensitivity occurs.
Caution
Because of potential hepatotoxicity, serum liver chemistries should be followed very closely. Signs and symptoms of gastrointestinal bleeding and renal dysfunction should be monitored . Diclofenac displaces albumin-bound drugs, which may lead to interaction with other drugs. Renal prostaglandin effects may increase toxicity of MTX, digoxin, and cyclosporine. In patients taking anticoagulants, extreme caution should be used, or the drug should be avoided altogether.
Supply
Tablets, 25, 50, and 75 mg. The 50-and 75-mg preparations are also available in combination with misoprostol.
Dosage
The dosage is 50 to 75 mg twice daily, which may be increased to a maximum daily dose of 200 mg.
Diflunisal (Dolobid)
Action
Inhibits prostaglandin synthesis.
Metabolism
Diflunisal is a difluorophenyl derivative of salicylic acid that is not metabolized to salicylic acid. Peak plasma level occurs 2 to 3 hours after ingestion . Ninety percent is excreted in the urine as glucuronides. Plasma half-life is 8 to 12 hours.
Adverse Reactions
See Aspirin. Diflunisal may cause less gastrointestinal irritation than aspirin does. The dose-related effect on platelet function is reversible.
Caution
See Aspirin. More than 99% of diflunisal is protein-bound and may displace other protein-bound drugs, with resultant drug interactions. Serious interaction with indomethacin has been reported.
Supply
Tablets, 250 and 500 mg.
Dosage
The dosage is 250 to 500 mg twice daily. An initial loading dose of 1,000 mg may accelerate attainment of steady-state serum levels. The maximum daily dose is 1,500 mg.
Etodolac (Lodine)
Action
Inhibits prostaglandin synthesis.
Metabolism
Etodolac is an indole acetic acid derivative. Food or antacids do not appear to compromise gastrointestinal absorption, although peak serum concentrations and time to peak concentration may be affected.
Adverse Reactions
Dyspepsia and gastrointestinal intolerance are common. Hepatic and renal toxicities should be concerns. Other forms of intolerance include hypertension, edema, malaise, depression, and dermatologic reactions.
Caution
Hepatic and renal function should be monitored closely with long-term use.
Supply
Capsules, 200 and 300 mg; tablets, 400 mg and 500 mg.
Dosage
The dosage is 200 to 300 mg two or three times daily. The maximum daily dose is 1,200 mg.
Fenoprofen Calcium (Nalfon)
Action
Inhibits prostaglandin synthesis.
Metabolism
Fenoprofen is a propionic acid derivative. It is rapidly absorbed, with peak plasma levels attained in 90 minutes and a half-life of 160 minutes; concomitant food ingestion decreases rate and extent of absorption. Enterohepatic circulation of the drug occurs. Ninety percent is excreted in the urine as glucuronides. Aspirin decreases the peak blood levels.
Adverse Reactions
Dyspepsia and gastrointestinal bleeding occur less commonly than with aspirin. Rash, headache, sodium retention, and, rarely, interstitial nephritis and nephrotic syndrome may occur.
Caution
Fenoprofen reduces platelet aggregation and may increase the risk for bleeding in patients on warfarin or heparin. Fenoprofen is 90% protein-bound and may displace other protein-bound drugs, with resultant drug interactions. The drug is not recommended in pregnancy. Cross-reactivity in patients with aspirin sensitivity occurs.
Supply
Tablets, 600 mg; capsules, 200 and 300 mg.
Dosage
The dosage is 300 to 600 mg four times daily. The maximum daily dose is 3.2 g.
Flurbiprofen (Ansaid)
Action
Inhibits prostaglandin synthesis.
Metabolism
Flurbiprofen is a phenylalkanoic acid derivative. It is well absorbed, with peak levels in 1.5 hours and an elimination half-life of 5.7 hours. It is extensively metabolized and excreted primarily in the urine. It is 99% protein-bound.
Adverse Reactions
Dyspepsia, nausea, diarrhea, and abdominal pain are common. Gastrointestinal ulceration and bleeding may occur. Headaches and fluid retention are also common. Renal and hepatic dysfunction may occur but usually are reversible on discontinuation of the drug.
Caution
Flurbiprofen may interfere with actions of diuretics and b -adrenergic blocking effects. Because it is protein-bound, it may modify levels of other protein-bound drugs. Flurbiprofen may affect bleeding parameters and should be used with caution in patients receiving anticoagulants.
Supply
Tablets, 50 and 100 mg.
Dosage
The dosage is 200 to 300 mg daily administered in three to four divided doses.
Ibuprofen (Advil, Motrin, Nuprin, Vicoprofen)
Action
Inhibits prostaglandin synthesis.
Metabolism
Ibuprofen is a propionic acid derivative. It is 38% protein-bound, and the half-life is 2 hours. It is primarily metabolized by the liver. Roughly equivalent amounts of the metabolized drug are excreted in urine and feces.
Adverse Reactions
Dyspepsia is common. Occult gastrointestinal bleeding may be less common than with aspirin. Occasionally, headaches, rashes, and salt retention occur. Aseptic meningitis and hypersensitivity reactions in patients with lupus erythematosus have been reported.
Caution
Ibuprofen decreases platelet aggregation and prolongs bleeding time. Caution must be used in patients taking anticoagulants. Cross-reactivity in patients with aspirin sensitivity occurs. It is not recommended during pregnancy. There is no clear evidence that exceeding 2,400 mg daily increases effectiveness.
Supply
Tablets, 300, 400, 600, and 800 mg (200 mg available over the counter). Also available in combination with hydrocodone bitartrate (7.5 mg).
Dosage
The dosage is 1,200 to 2,400 mg in three to four divided doses.
Indomethacin (Indocin)
Action
Inhibits prostaglandin synthesis.
Metabolism
Indomethacin is an indole acetic acid and is 90% bound to albumin. The kidneys excrete 65% of the metabolized drug. Probenecid may increase plasma levels of indomethacin by interfering with its excretion.
Adverse Reactions
Gastrointestinal side effects (dyspepsia, bleeding, nausea, and vomiting) occur in 10% to 40% of patients. Central nervous system effects, occurring in 10% to 25%, include headaches, vertigo, dizziness, and psychiatric disturbances. Less common effects include sodium retention, exacerbation of hypertension, hepatitis, and bone marrow suppression.
Caution
Indomethacin is not recommended for pregnant women or nursing mothers. It antagonizes the natriuretic and antihypertensive effects of furosemide. Indomethacin should be used cautiously in patients with coagulation defects or receiving anticoagulants because it inhibits platelet aggregation. Cross-reactivity in patients with aspirin sensitivity occurs.
Supply
Capsules, 25 and 50 mg; sustained-release capsules, 75 mg; oral suspension, 25 mg/mL; rectal suppositories, 50 mg.
Dosage
The dosage is 25 mg three or four times daily, taken with meals. The dosage can be gradually increased by 25-mg increments to 150 to 200 mg daily. The sustained-release preparation may be taken once or twice a day to a maximum daily dose of 150 mg.
Ketoprofen (Orudis, Oruvail, Actron)
Action s
Inhibits prostaglandin synthesis.
Metabolism
Ketoprofen is a propionic acid derivative that is well absorbed after oral administration, but peak concentrations are delayed and reduced when the drug is administered with food. Peak plasma levels are reached at 0.5 to 2 hours, and the half-life is 2 to 4 hours. The drug is 99% bound to protein. The kidneys excrete 60% as glucuronide, and enterohepatic recirculation accounts for the other 40%.
Adverse Reactions
Dyspepsia, gastrointestinal ulceration, bleeding, and perforation may occur in up to 1% to 2% of patients. Central nervous system side effects such as headache, dizziness, and drowsiness are the second most common reaction. Impaired renal function (edema, increased blood urea nitrogen) and interstitial nephritis may occur. Reversible mild elevation of transaminase levels may be seen in up to 15% of patients, but marked elevations are seen in fewer than 1%. Cross-reactivity in patients with aspirin sensitivity occurs.
Caution
Ketoprofen displaces albumin-bound drugs, which may lead to interactions with MTX and other protein-bound drugs. It decreases platelet adhesion and aggregation and should be used with caution in patients on anticoagulation.
Supply
Capsules, 25, 50, and 75 mg; sustained-release capsules, 100, 150, and 200 mg (12.5 mg tablets are available without prescription).
Dosage
The starting dose is 75 mg three times daily or 50 mg four times daily. The daily dose is 150 to 300 mg in three or four divided doses.
Ketorolac (Toradol)
Action
Inhibits prostaglandin synthesis.
Metabolism
Ketorolac, a pyrrolizine carboxylic acid derivative, is available as a tromethamine salt that can be administered orally or parenterally for either IM or IV use. The bioavailability of the drug is very high regardless of the route of administration, although the rate of absorption is slowest following IM injection. When it is administered orally, the rate, but not the extent, of absorption may be diminished with food. The rate of absorption is also reduced in the geriatric patient or in the setting of hepatic or renal impairment . Peak plasma concentrations may be achieved within 3 minutes after IV administration. The drug is hydroxylated in the liver and mainly excreted in urine.
Adverse Reactions
Adverse nervous system reactions, including headache, somnolence, and dizziness, have been reported in up to 23% of patients. Gastrointestinal intolerance is reported in 13% of patients and may occur regardless of route of administration. Borderline elevations of serum liver enzymes may be detected in up to 15% of patients, although fewer than 1% have elevations more than three times greater than normal limits. Anaphylactoid reactions have been rarely reported.
Caution
Ketorolac is bound tightly to serum proteins . However, it does not displace digoxin and only slightly displaces warfarin. Gastrointestinal hemorrhage is a significant concern, and it is recommended that the use of ketorolac be limited to acute and severe pain and not exceed 5 days consecutively. Dosage adjustment is necessary with renal or hepatic impairment.
Supply
Tablets, 10 mg; injectable suspension, 15 and 30 mg/mL.
Dosage
The oral dose is 10 mg up to four times daily. The initial IV and IM doses are 15 to 30 mg and 30 to 60 mg, respectively. Up to 30 mg can then be used for maintenance parenteral administration every 6 hours.
Meclofenamate Sodium (Meclomen)
Action
Inhibits prostaglandin synthesis.
Metabolism
Meclofenamate sodium is an anthranilic acid derivative. Peak plasma levels occur in 30 to 60 minutes with a half-life of about 3 hours; concomitant antacid administration does not interfere with absorption. About two- thirds is excreted in the urine, mostly as the glucuronide conjugate, and about one-third appears in the feces.
Adverse Reactions
Gastrointestinal reactions occur more frequently than with aspirin. Diarrhea may occur in up to one-third of patients, and nausea in about 10%. Headache, dizziness, rash, and other reactions associated with NSAIDs may also occur.
Caution
Meclofenamate sodium enhances the effect of warfarin but has a smaller effect than aspirin on platelet aggregation. The drug is not recommended for use in pregnancy. Cross-reactivity in patients with aspirin sensitivity occurs.
Supply
Capsules, 50 and 100 mg.
Dosage
The dosage is 50 to 100 mg four times daily.
Mefenamic Acid (Ponstel)
Action
Inhibits prostaglandin synthesis.
Metabolism
Mefenamic acid is an anthranilic acid derivative that is rapidly absorbed after oral administration. After metabolism in the liver, about two-thirds of the drug is excreted in urine, and the remaining one-third is eliminated in the feces.
Adverse Reactions
Gastrointestinal adverse reactions are the most common and include diarrhea, nausea, dyspepsia, and peptic ulcer disease. Mild liver enzyme abnormalities are frequent (up to 15%) but rarely progress.
Caution
Mefenamic acid is highly protein-bound. It enhances the effects of warfarin and can elevate serum lithium concentrations.
Supply
Capsules, 250 mg.
Dosage
The loading dose is 500 mg, followed by 250 mg every 6 hours.
Nabumetone (Relafen)
Action
Inhibits prostaglandin synthesis.
Metabolism
Nabumetone, a naphthylkanone derivative, is a pro-drug that is activated by oxidation in the liver.
Adverse Reactions
Although it has been reported that gastrointestinal effects may be fewer than those seen with other NSAIDs, precautions should still be observed .
Caution
Because the drug is activated in the liver, it should be used cautiously in the setting of hepatic impairment.
Supply
Tablets, 500 and 750 mg.
Dosage
The dosage is 1,000 to 2,000 mg daily in single or divided doses.
Naproxen (Naprosyn, Naprelan, Aleve)
Action
An arylalkanoic derivative that inhibits prostaglandin synthesis.
Metabolism
Absorption is not significantly delayed by food. Ninety-eight percent is protein-bound. The half-life is 12 to 15 hours. The kidneys excrete 80% to 90% in conjugated form. Aspirin decreases peak plasma levels.
Adverse Reactions
Gastrointestinal bleeding, dyspepsia, headache, dizziness, and sodium retention occur less frequently than with aspirin. Interstitial nephritis rarely occurs.
Caution
Naproxen displaces albumin-bound drugs, which may lead to drug interactions. It inhibits platelet aggregation and should be used with caution in patients taking anticoagulants. Cross-reactivity in patients with aspirin sensitivity occurs.
Supply
Tablets, 250, 375, and 500 mg. Sustained-release formulations for once-daily dosing are available. Tablets are also available in nonprescription strength.
Dosage
The dosage is 250 mg twice daily, which may be increased to 500 mg twice daily. Up to 1,000 mg of the sustained-release form may be taken once daily.
Oxaprozin (Daypro)
Action
Inhibits prostaglandin synthesis.
Metabolism
Oxaprozin is a propionic acid derivative. The rate but not the extent of gastrointestinal absorption is reduced by food but not by antacids.
Adverse Reactions
Gastrointestinal precautions should be observed, as with other NSAIDs.
Caution
Geriatric patients may tolerate the drug less well because of the long half-life of the drug. Modification of the dosage is necessary in the setting of renal impairment and severe liver disease.
Supply
Tablets, 600 mg.
Dosage
The dosage is 600 to 1,800 mg daily in single doses.
Piroxicam (Feldene)
Action
Inhibits prostaglandin synthesis.
Metabolism
Piroxicam is an oxicam derivative that is well absorbed after oral administration with no effect of antacids on plasma levels. Peak levels are achieved 3 to 5 hours after administration with a long but variable half-life (range, 30 to 86 hours). The drug is excreted in urine and feces (in a ratio of about 2:1), with less than 5% unchanged by biotransformation. Piroxicam is highly protein-bound.
Adverse Reactions
Gastrointestinal bleeding, peptic ulceration, dyspepsia, tinnitus, dizziness, headache, edema, and other reactions associated with NSAIDs may occur.
Caution
Piroxicam can displace other protein-bound drugs, such as warfarin. Platelet aggregation may be affected. The drug is not recommended for use during pregnancy. Cross-reactivity in aspirin-sensitive patients may occur. As with other drugs having long half-lives, special care should be taken in the elderly.
Supply
Capsules, 10 and 20 mg.
Dosage
The dosage is 20 mg/d. Higher doses are not recommended and may be associated with increased gastrointestinal side effects.
Rofecoxib (Vioxx)
Action
Inhibits prostaglandin synthesis via preferential inhibition of COX-2.
Metabolism
Rofecoxib is a furanone derivative. Peak plasma levels are reached within 3 hours. Although high-fat foods may delay absorption after administration of the tablet form, rofecoxib may be generally administered without regard to timing of meals, and overall absorption is not affected. However, concomitant use of calcium- or magnesium-based antacids may impede absorption marginally. The effects of food and antacids on the absorption of the rofecoxib suspension have not been fully studied. About 87% of the drug is protein-bound. Elimination is largely mediated by hepatic metabolism and excretion in both urine and feces. The effective half-life is 14 hours. With continuous dosing, steady-state plasma concentrations are reached in 4 days.
Adverse Reactions
Dyspepsia and gastrointestinal intolerance are common, and vigilance for gastrointestinal hemorrhage is necessary. The renal effects are similar to those of other NSAIDs. Other forms of intolerance include elevations in liver enzymes, anemia, hypertension, edema, and fluid retention.
Caution
Lower initial doses are recommended in elderly patients and in the setting of hepatic or renal insufficiency. Rofecoxib may decrease the effectiveness of angiotensin-converting enzyme (ACE) inhibitors and may increase the risk for gastrointestinal complications when administered together with aspirin. Rofecoxib increases plasma concentrations of MTX and increases the prothrombin time in patients taking warfarin. The drug is contraindicated in patients with known allergies to other NSAIDs and in late pregnancy.
Supply
Tablets, 12.5 and 25 mg.
Suspension, 12.5 mg/5 mL and 25 mg/5 mL.
Dosage
The dosage is 12.5 to 25 mg daily. For acute pain and primary dysmenorrhea, 50 mg daily may be administered, although administration for more than 5 days has not been evaluated for safety and should be avoided.
Salicylate Salts (Trilisate)
Action
Inhibits prostaglandin synthesis.
Metabolism
See Aspirin.
Adverse Reactions
See Aspirin. Non-aspirin salicylates may cause fewer gastrointestinal disturbances and less gastrointestinal bleeding than aspirin does. They have less effect on platelet function.
Caution
Sodium salicylate may constitute a substantial sodium load for patients with heart failure or hypertension. Hypermagnesemic toxicity may develop with magnesium salicylate in patients who have renal insufficiency. See also Aspirin.
Supply
Sodium salicylate tablets, 325 and 650 mg; choline salicylate liquid, 870 mg/5 mL; magnesium salicylate tablets, 325, 500, 545, and 600 mg; choline magnesium trisalicylate tablets, 293 mg/363 mg, 440 mg/544 mg, 587 mg/725 mg; choline magnesium trisalicylate liquid, 293 mg/5 mL choline salicylate and 362 mg/5 mL magnesium salicylate; trolamine salicylate 10% cream or lotion.
Dosage
Sodium salicylate, 325 to 650 mg every 4 hours, maximum of 5,400 mg daily.
Choline salicylate, 435 to 870 mg every 4 hours, maximum of 7,200 mg daily.
Magnesium salicylate, 300 to 600 mg every 4 hours, maximum of 3,500 mg daily.
Choline magnesium trisalicylate, maximum of 4,500 mg total salicylate daily in divided doses.
Trolamine salicylate 10% cream or lotion for topical use, two to four times daily.
Salsalate (Disalcid, Argesic, Salflex, Salsitab)
Action
Inhibits prostaglandin synthesis.
Metabolism
Salsalate is the salicylate ester of salicylic acid and is activated after hydrolysis to salicylate. It is completely absorbed by the gastrointestinal tract , mostly in the small intestine. However, because up to 13% of the drug is conjugated with glucuronic acid in the liver and not hydrolyzed to active metabolites, the bioavailability of salsalate is less than that of a theoretically equivalent intake of salicylate. The drug is almost exclusively excreted in urine.
Adverse Reactions
See Salicylate Salts.
Caution
See Salicylate Salts.
Supply
Capsules, 500 mg; tablets, 500 and 750 mg.
Dosage
The dosage is 500 to 750 mg twice a day to a maximum daily dose of 4,000 mg.
Sulindac (Clinoril)
Action
Inhibits prostaglandin synthesis.
Metabolism
An indene acetic derivative of indomethacin, sulindac requires hepatic activation to the active sulfide metabolite. The half-life of sulindac is about 8 hours, whereas the half-life of the active sulfide metabolite is 16 to 18 hours. It is tightly protein-bound. The kidney excretes 45% to 50%, and 25% to 30% is found in feces.
Adverse Reactions
Dyspepsia, nausea, gastrointestinal bleeding, tinnitus, headaches, dizziness, hepatitis, rash, and edema may occur. There are reports of relative sparing of renal function in comparison with other NSAIDs, but these remain subject to debate and do not justify unmonitored use in patients at risk for renal impairment.
Caution
Sulindac may potentiate oral hypoglycemic agents, anticoagulants, and other protein-bound drugs. It prolongs bleeding time and should be used with caution in patients receiving anticoagulants. Cross-reactivity in patients with aspirin sensitivity may occur.
Supply
Tablets, 150 and 200 mg.
Dosage
The dosage is 150 mg twice daily, which may be increased to 200 mg twice daily.
Tolmetin Sodium (Tolectin)
Action
Inhibits prostaglandin synthesis.
Metabolism
The half-life of this pyrrole acetic acid derivative is 60 minutes. It is 99% excreted in urine and 99% protein-bound.
Adverse Reactions
Peptic ulcers occur in 2% to 3% of patients. Gastrointestinal bleeding occurs in 1%. Other reactions include diarrhea, abdominal pain, nausea, dyspepsia, rash, sodium retention, lightheadedness, headache, and dizziness.
Caution
False-positive test results for urinary protein are noted when sulfosalicylic acid, but not Albustix (tetrabromophenol blue), is used. It may decrease platelet adhesiveness and prolong bleeding time. Cross-reactivity in patients with aspirin sensitivity occurs.
Supply
Tablets, 200 and 600 mg; capsules, 400 mg.
Dosage
The dosage is 400 mg twice daily, preferably including doses on arising and at bedtime. Daily doses larger than 1,800 mg are not recommended. Tolmetin is approved for use in children.
CORTICOSTEROIDS AND CORTICOTROPIN
Corticosteroids are potent antiinflammatory agents capable of quickly suppressing many disease manifestations of systemic, autoimmune, and inflammatory disorders, and they are available in forms suitable for topical, locally injectable, and systemic use. Corticotropin, or adrenocorticotropic hormone (ACTH), has been used for the treatment of acute crystalline arthritides. Although their ability to modify the ultimate course of disease varies from disease to disease, their side effects with prolonged use are incontrovertible. Among the plethora of adverse effects associated with corticosteroid use are hypertension, weight gain, Cushing's syndrome, glucose intolerance, osteoporosis, osteonecrosis, emotional lability, premature atherosclerosis, immunosuppression , and others. Strong efforts should be made to employ disease-modifying agents to ensure that corticosteroids play as small role as possible in the management of inflammatory arthritis.
Corticosteroids differ with regard to relative antiinflammatory potency and to relative mineralocorticoid potency. A comparison of the properties of different selected corticosteroids is given in Table E-2.
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Table E-2. Glucocorticoid preparations
Corticosteroids
Action
Glucocorticoids suppress inflammation in addition to humoral and cell -mediated immune responses.
Metabolism
Corticosteroids are well absorbed from the gastrointestinal tract. Prednisone is metabolized in the liver to prednisolone, the active compound. Further hepatic metabolism results in the inactivation of steroids. They are 90% protein-bound.
Adverse Reactions
Cutaneous side effects include acne, hirsutism, striae, purpura, and impaired wound healing. Osteoporosis, myopathy, and aseptic necrosis of bone may occur. Gastrointestinal side effects include peptic ulceration with bleeding or perforation and pancreatitis . Hypertension and edema secondary to fluid retention occur. Steroid psychosis and benign intracranial hypertension are the central nervous system adverse reactions. Ocular effects include cataracts and glaucoma. Patients may suffer growth arrest, secondary amenorrhea, impotence, and suppression of the hypothalamic- pituitary - adrenal axis. Glucose intolerance, hyperosmolar nonketotic coma, and centripetal obesity occur. The risk for infection is increased. Intraarticular corticosteroids may cause a crystal-induced transient synovitis. Immobilization and ice compress will facilitate resolution; persistence of the synovitis beyond 24 hours raises the possibility of an arthrocentesis-related infectious arthritis. Topical steroids, especially the more potent fluorinated compounds, may cause cutaneous telangiectasia, striae, epidermal and dermal atrophy, rosacea-like facial eruption, and senile-type purpura. When used with occlusive dressings, infection, folliculitis, and decreased heat exchange may occur.
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Table E-3. Commonly used topical preparations
Caution
Periodic determinations of blood sugar, complete blood cell counts, stool guaiac tests, and blood pressure measurements should be obtained. Diabetes mellitus, hypertension, pregnancy, and psychosis are relative contraindications. In patients receiving long-term steroids, the hypothalamic-pituitary-adrenal axis is suppressed, and they require glucocorticoid supplementation when undergoing surgical procedures or other physiologic stress. Repeated administration of intraarticular injections of corticosteroid may lead to disruption of cartilage and supporting soft-tissue structures. Soft-tissue injections may cause similar effects. Long-term steroid use demands appropriate immunizations and measures to ensure protection against osteoporosis.
Systemic absorption of topical steroid preparations may occur. Prolonged use, especially of the more potent compounds, may lead to suppression of the hypothalamic-pituitary-adrenal axis.
Dosage
The safest steroid regimen is the lowest effective dosage for the shortest time period. Numerous schedules for administering glucocorticoids have been developed to limit side effects and maximize therapeutic response. Single-dose, alternate-day regimens decrease the incidence of side effects but may not suppress disease activity adequately. In such cases, daily therapy (divided or single doses) may be administered. Dosage varies widely according to the specific disease. Intraarticular corticosteroids are useful in patients with involvement of only one or a few joints by inflammatory arthritis. Doses vary from several milligrams for small joints of the hand to 40 mg for large joints, such as the knee. The efficacy of topical steroids is related to both potency and percutaneous penetration. Adequate hydration of the skin, inflammation, and occlusion with plastic wraps enhance penetration. Better biologic activity is often obtained with ointment rather than cream or lotion preparations. As a general principle, therapy is started with stronger preparations and then reduced to less potent strengths once control of skin manifestations is achieved.
Supply
- Selected oral preparations
Prednisone tablets, 1, 2.5, 5, 10, 20, and 50 mg. Prednisolone tablets, 1, 2.5, and 5 mg. Methylprednisolone tablets, 2, 4, 8, 16, 24, and 32 mg. Dexamethasone tablets, 0.25, 0.5, 0.75, 1.5, and 4 mg.
- Selected parenteral preparations
Hydrocortisone vial, 100, 250, 500, and 1,000 mg. Methylprednisolone vial, 40, 125, 500, and 1,000 mg.
- Selected intraarticular preparations
Methylprednisolone acetate, suspension of 20 and 40 mg/mL in 1-, 5-, and 10-mL containers. Triamcinolone acetonide, suspension of 40 mg/mL in 1-, 5-, and 10-mL vials; suspension of 10 mg/mL in 5-mL vials. Triamcinolone hexacetonide, suspension of 20 mg/mL in 1- and 5-mL vials. Prednisolone tertiary butylacetate, suspension of 20 mg/mL in 1-, 5-, and 10-mL vials.
- Selected topical preparations
Very high strength
Betamethasone dipropionate 0.05% (Alphatrex, Diprolene, Maxivate, Psorion)
Clobetasol propionate 0.05% (Temovate)
Diflorasone diacetate 0.05% (Psorcon)
Halobetasol propionate 0.05% (Ultravate)High strength
Desoximetasone 0.25% (Topicort)
Fluocinolone acetonide 0.2% (Synalar-HP)
Fluocinonide 0.05% (Lidex)
Halcinonide 0.1% (Halog)
Triamcinolone acetonide 0.1% (Aristocort A)Moderate strength
Betamethasone valerate 0.1% (Valisone)
Fluocinolone acetonide 0.025% (Synalar)
Flurandrenolide 0.05% (Cordran)
Hydrocortisone valerate 0.2% (Westcort)
Triamcinolone acetonide 0.025% (Kenalog, Aristocort)Low strength
Hydrocortisone 0.25%, 0.5%, 1.0%
Other preparations with cortisone, prednisolone, methylprednisolone acetate
Corticotropin
Action
Stimulates secretion of cortisol by adrenal glands.
Selected Indications
Acute crystal-induced arthritides.
Metabolism
Corticotropin is a polypeptide, usually extracted from the porcine pituitary gland, and is administered either IM or IV. Peak plasma cortisol levels are achieved usually within 1 hour of injection. The metabolism of corticotropin is not fully known, but it is rapidly removed from plasma by many tissues.
Adverse Reactions
Corticotropin may cause immediate hypersensitivity reactions, even without previous exposure; these may range from minor skin reactions to anaphylaxis. With prolonged use, typical toxicities associated with corticosteroid use may occur. Moreover, suppression of endogenous corticotropin release by the pituitary may result in hypothalamic-pituitary insufficiency.
Caution
Corticotropin is contraindicated in patients with known previous hypersensitivity reactions to the medication or to porcine proteins.
Supply
The supply is 25 or 40 units for IM, IV, or SC injection.
Dosage
The dosage is 40 units every 8 hours.
DISEASE-MODIFYING ANTIRHEUMATIC DRUGS
Disease-modifying antirheumatic drugs (DMARDs) are much more readily and promptly utilized than previously for the treatment of systemic rheumatic illnesses. Also called slowly acting antirheumatic drugs (SAARDs) or remittive agents in the medical literature, these drugs are certainly slowly acting but probably do not induce indefinite remissions. In rheumatoid arthritis (RA), for example, the capacity for these agents to modify disease varies greatly from drug to drug and from patient to patient. As a group , their modes of action are poorly understood and probably varied. Some are clearly immunosuppressive or cytotoxic, whereas others may act by reducing systemic inflammation. Their potential for and spectrum of adverse effects are diverse, and so careful monitoring for toxicities is crucial. Although their clinical effect generally becomes apparent only after several weeks to months, they appear capable of ameliorating the course of disease in a significant percentage of patients and reducing cumulative corticosteroid use. Accordingly , DMARDs are commonly used and are also known as steroid-sparing agents. Moreover, there appear to be advantages in using combinations of DMARDs in lower doses to maximize benefit while minimizing toxicities.
Azathioprine (Imuran) and 6-Mercaptopurine (Purinethol)
Action
Inhibition of purine synthesis.
Selected Indications
RA, SLE, vasculitis.
Metabolism
Azathioprine (AZA) is a pro-drug that is converted to the active compound 6-mercaptopurine (6-MP). However, because of better gastrointestinal absorption, AZA is more widely used. Urinary excretion, partial hepatic metabolism, and tissue uptake account for clearance from the blood.
Adverse Reactions
Hematologic toxicity is usually mild leukopenia and thrombocytopenia; aplastic anemia is rare. Drug fever may occur. Hepatitis and pancreatitis may also occur. Nausea, especially during initiation of therapy, is common. Stomatitis may be seen. An increased incidence of late lymphoreticular and hematopoietic malignancy is possible. The immunosuppressive effects of these drugs increases susceptibility to infections.
Caution
Complete blood cell counts and platelet counts should be obtained initially weekly and then monthly. A rapid fall in leukocyte count requires a decrease in dosage or discontinuation of the drug. Liver function tests should be performed periodically. Allopurinol inhibits the metabolism of both AZA and 6-MP, which causes high levels to accumulate; thus, concomitant use of allopurinol should be avoided, or else a significant reduction in the AZA dose by 75% is appropriate. AZA has been used safely in pregnancy, but as with any medication, discontinuation of the drug, if possible, is preferable. Dosages must be adjusted in patients with hepatic or renal impairment.
Supply
AZA tablets, 50 mg.
6-MP tablets, 50 mg.
Dosage
AZA, 2 to 3 mg/kg daily.
6-MP, 1 to 2 mg/kg daily.
Chlorambucil (Leukeran)
Action
Alkylating agent. Interferes with cell function and mitotic activity by inhibition of intracellular macromolecules.
Selected Indications
Severe RA, SLE, vasculitis.
Metabolism
Adequate and reliable oral absorption. Incomplete information concerning metabolism and excretion.
Adverse Reactions
Myelosuppression is usually moderate, gradual, and rapidly reversible. Gastrointestinal discomfort, dermatitis, and hepatotoxicity occasionally occur.
Caution
Frequent complete blood cell counts should be obtained. Delayed occurrence of acute leukemia is reported. Infertility in both sexes may occur.
Supply
Tablets, 2 mg.
Dosage
The dosage is 0.05 to 0.2 mg/kg daily. The total daily dose (usually 4 to 10 mg) is given as a single dose.
Chloroquine (Aralen)
Action
Mode of action is unknown. Potential actions include binding of nucleic acids, stabilization of lysosomal membranes, and trapping of free radicals.
Selected Indications
RA, SLE, cutaneous LE.
Metabolism
Chloroquine is well absorbed from the gastrointestinal tract. The drug is concentrated and retained in body tissues. Peak plasma concentrations are attained within 2 hours, which may be facilitated by administering the drug with food. Chloroquine and its metabolites are slowly excreted by the kidneys. Unabsorbed drug is eliminated in the feces.
Adverse Reactions
The most common side effects are allergic eruptions and gastrointestinal disturbances ( anorexia , nausea, cramps, diarrhea). The most serious complication is ocular toxicity, which appears to be dose-dependent but more common than with hydroxychloroquine. Reversible corneal deposits of the drug are detectable by slit-lamp examination, but retinopathy affecting macular pigmentation may be irreversible. Less common side effects include hyperpigmented rash, hypopigmentation of hair, neuropathy, ototoxicity, and cardiomyopathy. Hematologic toxicity is rare.
Caution
Ophthalmologic examination ( color testing, visual fields, funduscopy, slit-lamp examination) should be performed every 4 to 6 months. Complete blood cell count should be performed periodically. At the first sign of visual disturbance, the drug should be discontinued. Hydroxychloroquine may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency. The drug is contraindicated in patients with significant visual, hepatic, or renal impairment, or porphyria, and during pregnancy.
Supply
Tablets, 300 mg.
Dosage
The dosage is 150 mg daily.
Co-trimoxazole (Bactrim, Septra)
Action
Co-trimoxazole is a fixed combination of sulfamethoxazole (SMX) and trimethoprim (TMP), both of which are synthetic folate antagonists. Although most widely used as an antiinfective agent, it has found use in some cases of limited Wegener's granulomatosis.
Selected Indications
Mild Wegener's granulomatosis, prophylaxis against Pneumocystis carinii infection.
Metabolism
Co-trimoxazole is rapidly absorbed after oral administration, and peak plasma levels of both components are reached within 4 hours. The liver converts TMP to oxide and hydroxylated metabolites, and acetylates and conjugates SMX to its metabolites. Almost all these metabolites are excreted in the urine. Elimination of co-trimoxazole is highly dependent on renal function.
Adverse Reactions
Gastrointestinal intolerance and hypersensitivity skin reactions of all degrees account for the majority of adverse effects. Hypersensitivity reactions may occur more commonly in patients with SLE. Cytopenias may occur, especially in patients with underlying hematologic abnormalities. In patients with renal impairment, potentially life- threatening electrolyte abnormalities may develop, particularly hyperkalemia.
Caution
Co-trimoxazole should be used with caution in the setting of liver or kidney impairment, underlying hematologic problems, and possibly folate or deficiency of glucose-6-phosphate dehydrogenase. Patients with sulfa allergies should not receive cotrimoxazole.
Supply
Tablets, TMP 80 mg/SMX 400 mg and TMP 160 mg/SMX 800 mg.
Dosage
For limited Wegener's granulomatosis, TMP 160 mg/SMX 800 mg twice daily.
For prophylaxis against P. carinii, TMP 160 mg/SMX 800 three times a week.
Cyclophosphamide (Cytoxan)
Action
Alkylating agent. Interferes with nucleic acids and proteins by cross-linking intracellular macromolecules. Cyclophosphamide (CTX) can inhibit secondary immune responses.
Selected Indications
Severe RA, SLE, vasculitis, interstitial lung disease.
Metabolism
Well absorbed from gastrointestinal tract. It requires activation by liver to produce active metabolites. Unchanged drug and metabolites are excreted in the urine.
Adverse Reactions
Bone marrow depression, primarily of white cell series, and predisposition to infection, both of which may be life-threatening but reversible with discontinuation of drug. Alopecia, drug-induced infertility with amenorrhea or defective spermatogenesis, hemorrhagic cystitis (in up to 25% of patients), fibrosing cystitis, carcinoma of the bladder, hematopoietic malignancies, anorexia, nausea, vomiting, and pulmonary fibrosis. Antidiuretic hormone-like activity may occur with large doses and result in hyponatremia.
Caution
Contraindicated in pregnant women and patients with hepatic impairment. Dosage requires adjustment in renal insufficiency. Frequent complete blood cell counts, platelet counts, and urinalyses must be obtained. Maintenance of high urine output and the use of 2-mercaptoethane sulfonate may reduce bladder complications.
Supply
Tablets, 25 and 50 mg; vials, 100, 200, and 500 mg for IV injection.
Dosage
Oral route: 0.5 to 3.5 mg/kg daily given as single morning dose. IV route: For treatment of diffuse proliferative glomerulonephritis associated with SLE or systemic vasculitides, begin with monthly IV treatments at an initial dose of 0.5 mg/m 2 . Doses are then increased by 25% if the 7- to 10-day post-CTX white blood cell count is above 5,000/mL or decreased by 25% if that white blood cell count is below 3,000/mL. The highest dose is 1 mg/m 2 . After six monthly treatments, the treatment interval is reduced to every 2 to 3 months for the second 6 months. Further treatments are defined by the clinical course. Appropriate hydration and anti-emetics are indicated.
Cyclosporin A (Sandimmune, Neoral)
Action
Cyclosporin A is a nonpolar, cyclic oligopeptide. It is a potent inhibitor of early steps in T-cell activation via suppression of early gene transcription.
Selected Indications
RA, psoriatic arthritis, autoimmune diseases.
Metabolism
The unmetabolized drug is active. The absorption of cyclosporin A is variable after oral administration, averaging about 30% of the ingested dose but varying from 2% to 89%, and it is reduced by simultaneous administration of food. Serum levels may followed if indicated. Two oral formulations of cyclosporin A are available, which differ in bioavailability and therefore do not exhibit equivalent dosing. The nonaqueous liquid formulation (Neoral) immediately forms an emulsion in aqueous fluids and has a bioavailability 1.2 to 1.5 times that of the conventional liquid preparation (Sandimmune). Peak levels appear between 3 and 4 hours, and the drug is metabolized on first pass though the liver. More than 90% of cyclosporin A is protein-bound, mostly to lipoproteins. It passes the placenta and into breast milk. About 95% is eliminated via feces.
Adverse Reactions
Nephrotoxicity is the most frequent and clinically significant adverse effect. At prior high doses for the treatment of RA, more than half of treated patients exhibit a significant elevation in serum creatinine, although fewer than 10% require discontinuation of the drug. New or exacerbation of preexisting hypertension is also frequently observed. Other common side effects include gastrointestinal intolerance, infections, gout, hypertrichosis, hyperesthesias, paresthesias, gingival hyperplasia, abnormal serum liver chemistries, and potential oncogenicity.
Caution
The dosage should not exceed 5 mg/kg of body weight; the usual starting dose in RA is 2.5 mg/kg of body weight daily. Renal function and arterial blood pressure should be monitored carefully. The serum creatinine should not be allowed to increase by more than 50% of baseline. Hypertension may be controlled with nifedipine or isradipine, but not with verapamil or diltiazem, both of which interfere with hepatic metabolism. Special caution should be taken with concomitant use of MTX, which can decrease the elimination of cyclosporin A. Additional medications to be avoided because of drug interactions include antifungal azole derivatives (ketoconazole, fluconazole, itraconazole), macrolide antibiotics (erythromycin, clarithromycin), and allopurinol, among many others. Grapefruit juice increases the bioavailability of the drug. Cyclosporin A is contraindicated in premenopausal women who do not practice effective contraception, during pregnancy, and in nursing mothers.
Supply
Capsules (Sandimmune), liquid-filled, 25, 50, and 100 mg.
Capsules (Neoral), liquid-filled, for emulsion, 25 and 100 mg.
Solution (Sandimmune), 100 mg/mL.
Solution (Neoral), for emulsion, 20 mg.
Dosage
The dosage is 2 to 5 mg/kg of body weight daily in twice-daily dosing.
Dapsone
Action
Possible antiinflammatory effects through inhibition of prostaglandin synthesis, complement activation, and myeloperoxidase-mediated pathways .
Selected Indications
Cutaneous LE, SLE.
Metabolism
Dapsone is well absorbed within the gastrointestinal tract. Peak levels are attained within 2 to 8 hours. The half-life of the drug is about 1 day. Dapsone is partially acetylated by the liver. It and its metabolites are mostly excreted in urine; about 20% is unchanged drug.
Adverse Reactions
Dose-dependent hemolytic anemia and methemoglobinemia are the most frequent adverse effects. Hemolysis may occur in patients with or without glucose-6-phosphate dehydrogenase deficiency but is more severe in those with glucose-6-phosphate dehydrogenase deficiency. Supplementation with ascorbic acid, folic acid, and iron may prevent some of the hematologic effects. Cutaneous hypersensitivity and gastrointestinal intolerance may occur. Elevated serum liver enzymes are common, but toxic hepatitis and cholestatic jaundice have been rarely reported.
Caution
Patients with significant anemia should not receive dapsone, and screening for glucose-6-phosphate dehydrogenase deficiency may be indicated in persons suspected to be at high risk for hemolysis (e.g., taking concurrent medications with adverse hematologic effects) or myelosuppression. Complete blood cell counts and serum liver chemistries should be followed weekly for the first month and then regularly thereafter with long-term administration.
Supply
Tablets, 25 and 100 mg.
Dosage
Initial dose of 50 mg daily; increases titrated according to response to a maximum of 400 mg daily.
Gamma Globulin, for Intravenous Use
Action
IV preparations of gamma globulin contain modified polyvalent antibodies with intact opsonic activity but with little or no aggregates. Action in thrombocytopenia may involve blockade of macrophage Fc receptors. Other proposed mechanisms of action include the activity of anti-idiotypic antibodies, effects on cytokine production and cytokine receptors, and induction of increased catabolism of pathogenic immunoglobulin.
Selected Indications
Inflammatory myositis, immune thrombocytopenia purpura, vasculitis.
Metabolism
Gamma globulin is distributed 50% intravascularly and 50% extravascularly after 6 days. Its half-life is 3 weeks. Disaccharides used for stabilization are excreted in the urine.
Adverse Reactions
In fewer than 1% of patients who are not immunodeficient, reactions develop 30 to 60 minutes after the start of infusions, including flushing, fever, dizziness, nausea, and hypotension. Patients should be observed and vital signs monitored throughout infusions.
Caution
Patients with selective IgA deficiency who possess antibodies to IgA should not receive intravenous gamma globulin.
Supply
Gamma globulin is supplied in 1-, 3-, and 6-g vials with sodium chloride for reconstitution.
Dosage
For treatment of inflammatory myositis or idiopathic thrombocytopenia purpura, 2 g/kg body weight (cumulative) in divided doses during 3 to 5 days.
Gold Compounds (Ridaura, Solganal, Aurolate)
Action
Mode of action in RA is unknown. Alters macrophage and complement functions.
Selected Indications
RA, psoriatic arthritis.
Metabolism
Approximately half of the administered IM dose is excreted within 1 week, 30% in the urine and the remainder in the stool. Gold in the circulation rapidly equilibrates with synovial fluid. It is stored by the reticuloendothelial system. It is 90% protein-bound.Approximately 25% of oral gold (auranofin) is absorbed and metabolized, with 15% excreted in urine and the remainder in feces. In blood, it is 60% protein-bound and 40% associated with red blood cells .
Adverse Reactions
Forty percent of patients experience some toxicity. Eosinophilia, although common, does not necessarily predict toxicity. The most common reaction is dermatitis, which may be heralded by pruritus or eosinophilia, or both. Both dermatitis and stomatitis are reversible with discontinuation of drug, and except for the rare instances of exfoliative dermatitis, gold therapy can be reinstituted with low doses. Hematologic abnormalities occur in 1% to 2% of patients. Thrombocytopenia is most common, followed by leukopenia, agranulocytosis, and pancytopenia. Gold should not be restarted. Proteinuria may be seen in 4% of patients, but nephrotic syndrome with membranous glomerulonephritis is much less common. Proteinuria of more than 0.5 g/d requires cessation of therapy. Mild proteinuria or celluria is a signal to interrupt therapy until urinalysis result is normal. Nitritoid reactions characterized by self-limited episodes of sweating, flushing, dizziness, nausea, and shortness of breath after administration of gold may occur with the thiomalate preparation. Treatment of nitritoid reactions involves switching to aurothioglucose and administering gold with the patient supine. Unusual problems include enterocolitis, intrahepatic cholestasis, skin hyperpigmentation, peripheral neuropathy, pulmonary infiltrates, and deposits of gold in the cornea.
Adverse reactions to oral gold (auranofin) are similar to but less common than those with IM gold and include the additional side effects of diarrhea in 50% of patients and abdominal pain in 14%.
Caution
Gold is contraindicated in patients with previous gold allergy or severe toxic skin, kidney, or bone marrow reaction to gold. Relative contraindications include functional impairment of kidneys or liver. Immunosuppressive agents and penicillamine, agents with a potential to suppress the bone marrow, should not be given with gold. Patients should have frequent complete blood cell counts (including platelets) and a urinalysis before each injection during the first few weeks of therapy and periodically thereafter.
Dosage
Initial dose is 10 mg IM to test for idiosyncratic reactions. Thereafter, 25 mg the second week and 50 mg at subsequent weekly intervals are given. In the absence of side effects, a total dose of 1 g may be given. If improvement has occurred, the drug is continued in 50-mg doses with an increasing time interval between injections: every 2 weeks for several months, then every 3 weeks, and finally 50 mg monthly for maintenance therapy. Improvement is gradual but usually begins when the cumulative dose is 300 to 700 mg. Dosage for children and adolescents is 1 m/kg up to 25 mg per injection. Oral gold (auranofin) is initially administered at 3 mg daily and increased to a maximum of 9 mg daily for maintenance therapy.
Supply
Gold thioglucose (Solganal), vials of 50 mg/mL in 10 mL.
Gold sodium thiomalate (Aurolate), 10, 25, 50, and 100 mg/mL in 1-mL ampules; 50 mg/mL in 10-mL ampules.
Auranofin (Ridaura), tablets, 3 mg.
Hydroxychloroquine (Plaquenil)
Action
Mode of action is unknown. Potential actions include binding of nucleic acids, stabilization of lysosomal membranes, and trapping of free radicals.
Selected Indications
RA, SLE, cutaneous LE.
Metabolism
Well absorbed from the gastrointestinal tract. The drug is concentrated and retained in body tissues. Excretion by the kidney is detectable months after therapy is discontinued.
Adverse Reactions
The most common side effects are allergic eruptions and gastrointestinal disturbances (anorexia, nausea, cramps, diarrhea). The most serious complication is ocular toxicity. Reversible corneal deposits of the drug are detectable by slit-lamp examination. Although retinopathy affecting macular pigmentation may be irreversible, it is extremely rare in patients with normal renal function receiving no more than recommended dosages. Less common side effects include hyperpigmented rash, hypopigmentation of hair, neuropathy, ototoxicity, and cardiomyopathy. Hematologic toxicity is rare.
Caution
When administered in daily doses of less than 6.5 mg/kg of body weight in patients with normal renal function, serious adverse effects are uncommon. Ophthalmologic examination (color testing, visual fields, funduscopy, slit-lamp examination) should be performed every 4 to 6 months. Complete blood cell count should be performed periodically. At the first sign of visual disturbance, the drug should be discontinued. Hydroxychloroquine may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency. The drug is contraindicated in patients with significant visual, hepatic, or renal impairment, or porphyria. The question of safety of hydroxychloroquine during pregnancy remains unanswered. There are anecdotal reports of exacerbations of psoriasis with hydroxychloroquine.
Supply
Tablets, 200 mg.
Dosage
Initially, 400 mg in single or divided doses; after a good response (4 to 12 weeks), maintain at 200 mg/d.
Leflunomide (Arava)
Action
Inhibition of pyrimidine synthesis.
Selected Indications
RA.
Metabolism
Following oral administration, leflunomide is converted into its active metabolite, M1, which reaches peak levels after 8 to 12 hours. Administration of cholestyramine or charcoal reduces plasma titers of M1. The metabolite is extensively bound to albumin, and its half-life is about 2 weeks. M1 is excreted in both feces and urine.
Adverse Reactions
Gastrointestinal effects, including diarrhea, occur in more than one-fourth of patients, and elevated serum liver chemistries in 10%. Rash and alopecia are not uncommon. Adverse effects may be more common in patients taking concurrent hepatotoxic substances, such as MTX.
Caution
Leflunomide can cause fetal harm and is contraindicated in pregnancy and in nursing mothers. Women of childbearing potential should use reliable modes of contraception. Significant hepatic insufficiency is also a relative contraindication, and parameters of liver function should be followed regularly, especially during the initial part of therapy. Although concurrent administration with MTX does not demonstrate pharmacokinetic interactions, there may be additive hepatotoxic effects. In patients with renal insufficiency, the levels of M1 may be doubled . Cholestyramine or activated charcoal may be administered to accelerate the elimination of M1.
Supply
Tablets, 10, 20, and 100 mg.
Dosage
A loading dose of 100 mg is given daily for 3 days, followed by 10 to 20 mg as a daily maintenance dose.
Methotrexate (Rheumatrex)
Action
Folate antagonist that inhibits dihydrofolate reductase, resulting in pleiotropic effects that include immunosuppressive and antiinflammatory properties.
Selected Indications
RA, psoriatic arthritis, vasculitis, inflammatory myositis, systemic sclerosis.
Metabolism
MTX is readily absorbed from the gastrointestinal tract in dosages of less than 0.1 mg/kg of body weight. Approximately 50% is protein-bound and is susceptible to displacement by sulfonamides, salicylates, NSAIDs, and other drugs. The kidneys rapidly excrete 50% to 90%; this process is enhanced by urine alkalinization. Impaired renal function significantly affects elimination of MTX.
Adverse Reactions
Patients should be observed for marrow suppression (leukopenia, thrombocytopenia, or complete aplasia) and gastrointestinal injury (ulcerative stomatitis, diarrhea, hemorrhagic enteritis, and hepatic dysfunction, including cirrhosis). Pulmonary infiltrates and pneumonitis, osteoporosis, rashes, and alopecia may occur. Some of the mucocutaneous toxicities may be prevented by daily intake of 1 mg of folic acid.
Caution
Use in nonmalignant disease requires emphasis on long-term side effects. The risk for hepatic cirrhosis supports weekly administration of the drug and careful monitoring of hepatic function, which may include liver biopsy. Renal function, pulmonary function, and complete blood cell counts should also be monitored. Although serial liver biopsies before and during treatment are no longer universally recommended in patients with RA, their utility remains a subject of debate in other diseases, such as psoriatic arthritis. A baseline chest roentgenogram is suggested.
Supply
Tablets, 2.5 mg; vials, 5 and 50 mg for parenteral use.
Dosage
For RA and for psoriatic arthritis, 7.5 to 10 mg weekly may be used initially, administered orally or parenterally, and increased as clinically indicated. The optimal dose for RA may fall in the range of 15 to 25 mg weekly. For inflammatory polymyositis and vasculitides, 10 to 15 mg IV weekly, with a gradual increase in 5-mg increments to 30 to 50 mg weekly. The dosage interval is subsequently increased to 2 weeks, then 1 month. The dosage should be increased for lack of responsiveness but cautiously because of increasing toxicity at higher levels.
Minocycline (Dynacin, Minocin)
Action
Semisynthetic tetracycline derivative that probably inhibits proteolytic enzyme activity in RA.
Selected Indications
RA.
Metabolism
Gastrointestinal absorption is excellent in the fasting state but is reduced with food and antacids. Peak serum levels are reached within 4 hours. The serum half-life is 11 to 26 hours and does not appear to be affected by mild hepatic or renal dysfunction, although dose adjustment may be necessary in severe renal impairment. Elimination is through both urinary and fecal excretion.
Adverse Reactions
As with other tetracyclines, a photosensitive skin rash may occur. Lightheadedness and dizziness may occur, especially early in therapy. Gastrointestinal intolerance is very common. Because minocycline is also an antibiotic, long-term use may result in overgrowth of nonsusceptible organisms, such as fungus or Clostridium difficile. A lupuslike syndrome has been reported in association with long-term use of minocycline.
Caution
Minocycline causes discoloration of dentin and should be avoided in children, pregnant women, and lactating mothers.
Supply
Tablets and capsules, 50 and 100 mg. Suspension, 50 mg/5 mL.
Dosage
The dosage is 100 mg twice daily.
Mycophenolate Mofetil (CellCept)
Action
Immunosuppression via inhibition of guanosine synthesis.
Selected Indications
RA.
Metabolism
Mycophenolate mofetil is rapidly absorbed and then hydrolyzed to its active metabolite, mycophenolic acid. Food does not affect absorption. Mycophenolic acid is later inactivated by hepatic glucuronidation. The inactive metabolites are mostly excreted in urine (93%), with the remainder excreted in feces.
Adverse Reactions
Gastrointestinal effects, including nausea, diarrhea, mucosal hemorrhage, and ulceration, can occur. Leukopenia and infections, especially by opportunistic organisms, are also potential problems. In the renal transplant population, there may be an increased risk for lymphoproliferative and non-melanoma skin carcinomas.
Caution
Complete blood cell counts should be obtained initially weekly and then monthly. A rapid fall in leukocyte count requires a decrease in dosage or discontinuation of the drug. Serum liver chemistries should be checked periodically. Vigilance for infection and malignancy should be maintained . Mycophenolate should be avoided in pregnant and nursing women. Dose adjustment is necessary in severe renal insufficiency.
Supply
Tablets, 250 and 500 mg.
Dosage
Initially 500 mg twice daily; can be increased as indicated to 1,000 mg twice daily.
D-Penicillamine (Cuprimine, Depen)
Action
Mode of action in RA is unknown. D-Penicillamine decreases circulating immune complexes and rheumatoid factor titer and inhibits lymphocyte responsiveness to mitogens. A latent period of 2 to 3 months is often observed between initiation of therapy and clinical response.
Selected Indications
RA, systemic sclerosis.
Metabolism
Well absorbed from gastrointestinal tract and rapidly excreted in urine. It should be administered on an empty stomach (1 to 2 hours after a meal) to avoid interference of absorption by dietary metals.
Adverse Reactions
Pruritus and skin rash represent the most common side effects and can occur at any time. They can be treated by either lowering the dosage or administering antihistamines. If necessary, the therapy may be interrupted until the rash resolves. Stomatitis also occurs. Alteration of taste is frequent, independent of dosage, and self-limited, with resolution in 2 to 3 months despite continued drug administration. Bone marrow depression may occur precipitously at any time. If the platelet count falls below 80,000 to 100,000, therapy must be discontinued. The most common late toxic effect is immune complex nephropathy. Proteinuria may be seen in 20% of patients. If proteinuria exceeds 1 g/d, the dosage should be reduced. Nephrotic syndrome, hypoalbuminemia, or hematuria requires discontinuation of the drug. Less common side effects include autoimmune syndromes (lupus syndromes, Goodpasture's syndrome, myasthenia gravis, pemphigus, stenosing alveolitis, polymyositis), which necessitate prompt discontinuation of the drug.
Caution
Penicillamine administration is contraindicated in patients who are receiving gold compounds, immunosuppressive drugs, or phenylbutazone. Renal insufficiency and pregnancy are further contraindications. A history of penicillin allergy does not preclude use of penicillamine. All patients should have a complete blood cell count, including platelets, and a urinalysis at 2-week intervals for the first 6 months of therapy and monthly thereafter. An unreliable patient is a relative contraindication.
Supply
Capsules, 125 and 250 mg.
Dosage
Initially, a single daily dose of 250 mg, which is increased in 2 to 3 months to 375 or 500 mg daily if clinical response is insufficient. Further increases to the maximum dose of 750 mg daily may be made after 2 to 3 months.
Protein A Immunoadsorption Column (Prosorba)
Action
This is a device consisting of protein A from Staphylococcus bound to a silica matrix. By means of apheresis technology, potentially pathogenic IgG and IgG-containing immune complexes are removed.
Selected Indications
Refractory RA, immune thrombocytopenia purpura.
Metabolism
Extracorporeal passage of plasma through the immunoadsorption column is performed by means of an apheresis machine. The treated plasma is then returned to the patient.
Adverse Reactions
The most common adverse effects are joint pain and swelling, fatigue paresthesias, headache, hypotension, anemia, nausea, sore throat, edema, abdominal pain, hypertension, rash, dizziness, diarrhea, hematoma, flushing, chills, dyspnea, chest pain, and fever. Other complications associated with any procedure involving apheresis may occur, including blood loss, damage to blood cells, and problems arising from mismanagement of fluid balance (e.g., hypertension, hypotension, arrhythmias). In patients with RA, the rate of infection, local thrombosis, or both at the site of central venous catheters is greater than 40%.
Caution
A full discussion with the patient covering reasonable expectations and potential adverse effects of treatment is mandatory before therapy is initiated. This device should be used only at facilities with extensive experience in apheresis. Strict sterile technique is essential, and careful monitoring of vital signs and fluid status is crucial. Concurrent use of ACE inhibitors is contraindicated, and at least 3 days of drug withdrawal is recommended by the manufacturer before the procedure. Patients with previous intolerance to apheresis procedures, hypercoagulable states, or conditions that may become exacerbated by apheresis should not undergo treatment. Treatment may not be advisable in patients with poor peripheral access, impaired renal function, relative hypotension, significant vascular disease, intracranial disease, severe anemia, systemic infections, or significant risk for congestive heart failure and fluid overload. RA patients may be at particular risk for the development of severe anemia.
Supply
Prepackaged sterile polycarbonate columns containing 200 mg of protein A covalently bound to 300 mL of silica matrix.
Dosage
Individualized according to patient status. In general, weekly apheresis may be performed.
Quinacrine Hydrochloride (Atabrine)
Action
Mode of action is unknown. Potential actions include binding of nucleic acids, stabilization of lysosomal membranes, and trapping of free radicals.
Selected Indications
RA, SLE, cutaneous LE.
Metabolism
Well absorbed from the gastrointestinal tract and widely distributed into body tissues, where it is concentrated and retained. Excretion by urine can be detected months after therapy is discontinued.
Adverse Reactions
Common side effects include nausea, vomiting, anorexia, abdominal cramps, rash, and reversible yellow coloration of skin. Less common reactions include central nervous system stimulation, emotional changes, altered pigmentation of skin and nails (black and blue), and cardiomyopathy. Reversible corneal edema and deposits have been reported, but retinopathy is rare. Rare toxicity includes psychosis and aplastic anemia.
Caution
Ophthalmologic examination should be performed periodically. At any sign of visual disturbance, the drug should be discontinued. Quinacrine may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency. It is contraindicated in pregnancy.
Supply
Tablets, 100 mg.
Dosage
The dosage is 100 mg/d.
Sulfasalazine (Azulfidine)
Action
Exact mechanism is unknown, but there is evidence for antiinflammatory, immunomodulatory, antibacterial (in the colon ), and folate metabolism actions.
Selected Indications
RA, seronegative spondyloarthropathies.
Metabolism
Sulfasalazine is partially absorbed (one-third) from the small intestines and extensively metabolized. It is split into 5-aminosalicylic acid and sulfapyridine; the latter is metabolized in the liver. The metabolic products are excreted in the urine.
Adverse Reactions
The most common side effects, occurring in up to one-third of patients, include anorexia, headache, nausea, vomiting, gastric distress, and apparently reversible oligospermia. Rash, pruritus, urticaria, fever, and hemolytic anemia are less frequent. Rare reactions such as blood dyscrasia (especially leukopenia), hypersensitivity reaction, and central nervous system reaction have been reported.
Caution
Azulfidine is contraindicated in patients with porphyria and should be administered with caution in patients with hepatic or renal disease, blood dyscrasia, severe asthma, or allergies. Complete blood cell counts and liver function tests should be performed frequently. Urinalysis results should also be followed. Adequate fluid intake must be maintained to prevent crystalluria and renal stones. Patients with glucose-6-phosphate dehydrogenase deficiency should be followed closely for signs of hemolysis. Azulfidine should be avoided in patients with sulfa allergies and should not be given simultaneously with sulfa drugs.
Supply
Tablets, 500 mg.
Dosage
The dosage is 2 to 3 g/d in divided doses with meals.
BIOLOGIC AGENTS
Although biologic agents may be broadly defined and will certainly be subject to redefinition as their use evolves, they generally describe specific antibodies or recombinant forms of natural inhibitors against modulatory molecules of immunity or inflammation. These agents have been most widely studied in the setting of RA, but they represent a new approach to the treatment of all systemic inflammatory rheumatic diseases. Only etanercept has been approved by the Food and Drug Administration thus far, but many more agents specific for various target molecules are in development.
Etanercept (Enbrel)
Action
Inhibition of tumor necrosis factor-alpha (TNF- a ).
Selected Indications
RA, psoriatic arthritis.
Metabolism
Etanercept is a dimeric recombinant protein consisting of two ligand-binding domains of the human 75-kd (p75) TNF- a receptor fused to the Fc domain of human IgG1. After SC injection, the median half-life is about 115 hours. Maximum serum concentration is reached in 72 hours. Pharmacokinetic differences have not been noted between male and female patients, or between adult and pediatric patients. The effects of hepatic and renal impairment are not known.
Adverse Reactions
Reactions at the local injection site occur in more than a third of patients but may respond to topical corticosteroids and generally do not result in discontinuation of the drug. Some controlled data suggest that minor upper respiratory tract infections may be increased, and there are few anecdotal cases of sepsis and death in patients taking etanercept. As with other immunomodulatory agents, vigilance for infections should be maintained, and discontinuation of the drug is recommended when severe infections are identified. The effects of etanercept in patients with a history of malignancies or on the risk for new malignancies are not known. The development of antibodies against etanercept are common, but only non- neutralizing antibodies have been detected and are not associated with clinical response or adverse effects.
Caution
Caution should be used during pregnancy, and the drug should be discontinued in nursing mothers. Etanercept is contraindicated in the setting of sepsis or in patients with known hypersensitivity to any component of the preparation or to latex. No drug interactions are known, but concurrent live vaccinations should not be given. The risk for the eventual development of neutralizing antibodies is not known.
Supply
Sterile lyophilized powder, 25 mg for reconstitution with 1.0 mL of sterile water.
Dosage
The dosage is 25 mg SC twice weekly.
MEDICATIONS FOR CRYSTALLINE ARTHRITIDES
NSAIDs and corticosteroids are the mainstays in the treatment of acute gout and crystalline arthritides. Colchicine may also be used in the acute setting, but it is more widely used for prophylaxis. Hypo-uricemic agents reduce serum uric acid levels by either inhibiting production or increasing excretion of uric acid and are used primarily in patients with chronic, recurrent gouty arthritis, tophaceous gout, nephrolithiasis, and urate nephropathy.
Allopurinol (Xyloprim, Lopurin)
Action
Allopurinol, an analog of the purine hypoxanthine, inhibits the enzyme xanthine oxidase, which converts hypoxanthine to xanthine and xanthine to uric acid. Plasma and urine concentrations of uric acid are lowered . Hypoxanthine, a more soluble product, and other purine metabolites are excreted in the urine rather than uric acid. Allopurinol also acts by a feedback mechanism to inhibit de novo purine synthesis. The efficacy of allopurinol decreases when the creatinine clearance falls below 20 mL/min.
Selected Indications
Refractory/recurrent gouty arthritis, tophaceous gout, nephrolithiasis, urate nephropathy.
Metabolism
Twenty percent is excreted in the urine unchanged, with the remainder excreted in the urine as alloxanthine. The half-life of the major metabolite, oxypurinol, which also inhibits xanthine oxidase, is 30 hours.
Adverse Reactions
Maculopapular rash is the most common side effect and occurs in 3% of patients. Immune complex dermatitis and hepatitis, occasionally with vasculitis and nephritis, can occur; pruritus is an important warning symptom. Side effects of allopurinol are increased in the presence of marked renal failure (creatinine clearance <20 mL/min).
Caution
Allopurinol inhibits the oxidation of 6-MP. Because 6-MP is the active metabolite of AZA, the concomitant use of either AZA or 6-MP should be avoided with allopurinol, or appropriate dosage reductions of 75% should be made. Allopurinol inhibits hepatic microsomal enzymes for drug metabolism; warfarin derivatives and other drugs metabolized by these enzymes should be given in lower dosages. Concurrent administration of ampicillin and allopurinol leads to a threefold higher incidence of drug rash. The toxicity of cytotoxic agents, such as CTX, appears to be enhanced by the concomitant administration of allopurinol. The dosage of allopurinol should be reduced in renal insufficiency and failure.
Supply
Tablets, 100 and 300 mg.
Dosage
For mild disease, 200 to 300 mg daily is usually adequate, but the dosage should be individualized to achieve the desired serum urate level. It is advisable to start with 100 mg/d and gradually build toward full dosage to lessen the probability of acute gout attacks that may be precipitated by sudden lowering of the serum uric acid. Allopurinol is counterproductive and is to be avoided in acute attacks of gout. For severe tophaceous gout, 400 to 600 mg daily can be used. The maximum single dose should be 300 mg. Total daily doses in excess of 600 mg are associated with increased toxicity. It is advisable to prescribe colchicine (0.6 mg PO daily or twice daily) during the first 3 months of therapy as prophylaxis against acute gout.
To prevent uric acid nephropathy during the treatment of neoplastic disease, a daily dose of 600 to 800 mg may be required, with the maintenance of large volumes of an alkaline urine.
Colchicine (ColBENEMID, Proben-C, Col-Probenecid)
Action
Colchicine inhibits microtubule assembly, which interferes with granulocyte mobility and the inflammatory response to precipitated crystals.
Selected Indications
Acute crystal-induced arthritis, prophylaxis for crystal-induced arthritis.
Metabolism
Although complete metabolism is unknown, colchicine is deacetylated in the liver to inactive metabolites; 10% is excreted unchanged by the kidney. The drug half-life is 90 minutes and is prolonged in patients with renal insufficiency.
Adverse Reactions
Gastrointestinal irritation producing nausea, vomiting, and abdominal pain occurs in up to 80% of patients receiving oral colchicine for acute gout. Bone marrow depression, renal dysfunction, and hemorrhagic colitis may occur, especially with overdose or in the setting of liver or renal disease.
Caution
IV colchicine should be diluted in 10 to 15 mL of normal saline solution and administered slowly during 5 minutes through a free- flowing IV route to decrease the chance of infiltration and soft-tissue necrosis. Fatalities have been reported with IV administration. Reduction in dosage is necessary in liver or renal impairment.
Supply
Tablets, 0.6 mg.
IV ampules, 2 mL containing 1 mg of colchicine.
Also available in combination with probenecid (ColBENEMID), tablets, colchicine 0.5 mg/probenecid 500 mg.
Dosage
For maintenance prophylaxis, 0.6 mg daily or twice daily. For acute attacks, oral colchicine, 0.6 to 1.2 mg initially followed by 0.6 mg hourly until symptoms abate or toxicity occurs. The total cumulative dose should not exceed 8 mg. IV colchicine, 1 to 2 mg initially followed by 0.5 mg every 3 to 6 hours up to a total of 4 mg. The dosage should be reduced significantly in the presence of renal or hepatic disease.
Probenecid (Benemid, ColBENEMID, Proben-C, Col-Probenecid)
Action
A uricosuric agent that inhibits renal tubular resorption of organic acids, including uric acid. Probenecid is not effective with a creatinine clearance of less than 40 mL/min.
Selected Indications
Hyperuricemia associated with refractory or recurrent gouty arthritis.
Metabolism
Excreted in urine in the glucuronide form and as oxidized metabolites. The half-life is dose-dependent and ranges from 6 to 12 hours.
Adverse Reactions
Gastrointestinal irritation occurs in 10% of patients; systemic hypersensitivity characterized by fever and rash is seen in about 3%.
Caution
A large alkaline urine output should be maintained, especially during the first week of therapy, to prevent urate renal stones. A history of renal calculi is a relative contraindication. Probenecid may alter the metabolism of other drugs by decreasing their excretion (indomethacin, ampicillin), reducing their volume of distribution (ampicillin), or delaying metabolism (heparin). Probenecid is antagonized by low-dose salicylates (<3 g/d).
Supply
Tablets, 500 mg.
Also available in combination with colchicine (ColBENEMID, Proben-C, Col-Probenecid), tablets, colchicine 0.5 mg/probenecid 500 mg.
Dosage
The dosage is 250 mg twice daily for 1 week, then 500 mg twice daily. Maintenance colchicine should be given during the first 3 months of probenecid therapy and then can be stopped if the patient is asymptomatic. Probenecid is not useful in acute attacks of gout.
Sulfinpyrazone (Anturane)
Action
A uricosuric agent that inhibits renal tubular reabsorption of organic acids.
Selected Indications
Hyperuricemia associated with refractory or recurrent gouty arthritis.
Metabolism
Rapidly and completely absorbed, with peak plasma levels in about 1 hour. Sulfinpyrazone is 98% protein-bound. The kidney excretes about 40% unchanged.
Adverse Reactions
Gastrointestinal irritation is common. Because sulfinpyrazone is similar in structure to phenylbutazone, it should be avoided in patients with known sensitivity to phenylbutazone.
Caution
A large alkaline urine output should be maintained, especially during the first week of therapy, to decrease the risk for urate calculi formation. Sulfinpyrazone inhibits platelet aggregation and potentiates the action of protein-bound drugs such as oral hypoglycemics and oral anticoagulants. The action of sulfinpyrazone is antagonized by low-dose salicylates, and the drug is ineffective in the presence of renal failure.
Supply
Tablets, 100 mg; capsules, 200 mg.
Dosage
Start with 50 to 100 mg twice daily with meals, and increase gradually during several weeks to a maintenance dosage usually of 300 to 400 mg/d in three to four divided doses. Maximum recommended daily dose is 800 mg. Maintenance colchicine should be given for the first 3 months of therapy to prevent precipitation of an acute attack of gouty arthritis.
ANALGESICS
Acetaminophen
Action
Centrally acting analgesic.
Metabolism
Acetaminophen is rapidly absorbed in the gastrointestinal tract and reaches peak levels within 1 hour. The drug is metabolized by the liver, largely to the glucuronide conjugate, and then excreted in urine.
Adverse Reactions
Although rare, hepatic toxicity, including hepatic failure, is the most dangerous potential adverse effect.
Caution
Alcohol use or abuse, fasting, concurrent use of medications that induce cytochrome P-450 activity, and preexisting liver disease increase the risk for liver toxicity. Reduced doses are necessary in children.
Supply
Tablets, caplets, gelcaps, 160, 325, and 500 mg; liquid, 500 mg/15 mL.
Multiple combinations with other medications are available.
Dosage
The dosage is 325 to 1,000 mg every 6 hours as necessary. Maximum adult daily dose is 4 g.
Amitriptyline (Elavil)
Action
Tricyclic antidepressant thought to block reuptake of a variety of neurotransmitters. Amitriptyline and other tricyclic antidepressants have been used for the adjuvant treatment of neuropathic pain.
Metabolism
Amitryptiline is rapidly absorbed by the gastrointestinal tract. The plasma half-life can range from 10 to 50 hours. Amitriptyline and its metabolites are primarily excreted in urine.
Adverse Reactions
The most common adverse effects are related to anticholinergic activity, such as xerostomia, mydriasis, constipation, and urinary retention, especially in geriatric patients. Central nervous system and neuromuscular symptoms are also common, including cognitive changes, somnolence, and exacerbations of underlying psychiatric disorders. Extrapyramidal symptoms ranging from minor involuntary movements and tardive dyskinesia to parkinsonism may occur. Cardiovascular effects include conduction disturbances and arrhythmias and postural hypotension.
Caution
Acute toxicities relate to extensions of adverse reactions. An acute withdrawal syndrome may result after sudden discontinuation of long-standing therapy. A baseline electrocardiogram is generally recommended. Amitriptyline should be used in elderly patients with extreme caution. Concomitant use of monoamine oxidase inhibitors, hypotensive agents, central nervous system depressants, sympathomimetics, and anticholinergic medications should be avoided.
Supply
Tablets, 10, 25, 50, 75, 100, and 150 mg.
Dosage
For neuropathic pain, initially 10 mg at bedtime, with escalating doses to a maximum of 300 mg daily.
Capsaicin (Zostrix, Dolorac)
Action
Inhibition of substance P.
Metabolism
No information is available.
Adverse Reactions
Capsaicin may cause local skin irritation, burning, and erythema.
Caution
Capsaicin is for external use only and should not be applied to open wounds. Contact with eyes should be avoided, and hands should be washed immediately after application. Dried material may cause irritation to nasal and respiratory mucosa and should not be inhaled.
Supply
Cream, 0.025%, 0.075%, and 0.25%.
Dosage
At lower doses, apply topically to skin up to four times daily; 0.25%, apply topically to skin up to twice daily.
Gabapentin (Neurontin)
Action
Gabapentin is a structural analog of t -aminobulytic acid (GABA), which has been used for neuropathic pain syndromes. Although designed to mimic GABA activity at inhibitory neuronal synapses, gabapentin does not bind to GABA receptors, and its precise mechanism of action is not known.
Metabolism
At therapeutic doses, the bioavailability of gabapentin is about 60%. It is not significantly metabolized in humans and is excreted almost exclusively by the kidneys.
Adverse Reactions
Gabapentin is well tolerated. Nervous system effects are the most common forms of intolerance and include somnolence, dizziness, ataxia, and fatigue.
Caution
Concurrent use with other central nervous system depressants should be avoided. Dose adjustment is necessary in the setting of severe renal insufficiency.
Supply
Capsules, 100, 300, and 400 mg.
Dosage
Initially, 300 mg daily in divided doses, to be titrated up to 2,400 mg daily in divided doses.
Tramadol Hydrochloride (Ultram)
Action
Tramadol is a synthetic, centrally acting analgesic. Although it is not an opiate derivative, it is a selective opiate-receptor agonist. It may also have additional analgesic properties through inhibition of synaptic monoamine reuptake.
Metabolism
The absorption of tramadol is good and is not affected by food. Tramadol is partially metabolized by the liver, and about 90% of the drug and its metabolites are excreted in the urine.
Adverse Reactions
Tramadol shares similar adverse reactions with true opiates, including central nervous system effects (lightheadedness, somnolence), nausea, constipation, xerostomia, and pruritus. It may also potentially cause respiratory depression when administered at high doses and may lower seizure threshold. Tolerance, addiction , and manifestations of withdrawal may also occur, but risks are thought to be relatively small in comparison with those of other opiate agonists.
Caution
Tramadol should be used with extreme caution in conjunction with other medications that may depress the central nervous system, such as other opiates, alcohol, sedatives, and hypnotics, or medications that may reduce seizure threshold, such as monoamine oxidase inhibitors and antipsychotic agents. Patients receiving monoamine oxidase inhibitors should not receive tramadol also because of the drug's inhibitory effects on monoamine reuptake. Dosing should be less frequent in patients with renal or hepatic impairment.
Supply
Tablets, 50 mg.
Dosage
The dosage is 50 to 100 mg every 4 to 6 hours as needed.
DRUGS FOR OSTEOPOROSIS AND METABOLIC BONE DISEASES
Alendronate (Fosamax)
Action
Bisphosphonate that inhibits osteoclast activity and bone resorption but does not interfere significantly with bone mineralization.
Selected Indications
Osteoporosis prevention and treatment, Paget's disease of bone.
Metabolism
Alendronate is poorly absorbed by the gastrointestinal tract, especially when taken with food. Calcium-, aluminum-, and magnesium-containing supplements and antacids interfere with absorption. Absorbed drug is tropic for bone and will persist within the bony skeleton for years. The terminal half-life is about 11 years . Excretion is in the urine.
Adverse Reactions
Gastrointestinal intolerances are the most common adverse effects and include diarrhea, nausea, abdominal pain, and, most importantly, esophagitis and esophageal ulcerations. Adequate calcium repletion before the initiation of therapy may reduce the risk for arthralgias and other musculoskeletal complaints.
Caution
Alendronate must be taken on an empty stomach, while upright, at least a half-hour before eating . Patients with preexisting esophageal reflux or inflammation may not be good candidates for alendronate therapy. It is contraindicated in women of childbearing potential.
Supply
Tablets, 5, 10, and 40 mg.
Dosage
For osteoporosis prevention, 5 mg daily. For osteoporosis treatment, 10 mg daily. For Paget's disease, 40 mg daily with reassessment after 6 months.
Calcitonin (Calcimar, Miacalcin)
Action
Inhibits osteoclast activity and bone resorption.
Selected Indications
Osteoporosis prevention and treatment, Paget's disease of bone, analgesia for acute vertebral fractures, hypercalcemia.
Metabolism
Calcitonin is a protein that is rapidly metabolized to smaller, inactive fragments in the kidneys.
Adverse Reactions
Nausea and vomiting occur in 10% of patients with either the intranasal or SC route. Flushing of face and hands, peripheral paresthesias, urticaria, altered taste, and local skin reactions may be more common with SC calcitonin. Low-dose skin testing is recommended by some before full-dose SC treatment is administered. Irritation of the nasal mucosa, epistaxis, and rarely perforation can be seen with nasal inhalation, so that periodic nasal examinations are indicated.
Caution
Neutralizing antibodies may develop with partial loss of effectiveness.
Supply
Nasal spray, 200 U per spray (14-dose cannisters).
Sterile injectable solution, 1-mL vials.
Dosage
For postmenopausal osteoporosis, 100 U daily by SC or IM injection or 200 U daily intranasally. Each intranasal dose should be taken via the alternate nostril.
For Paget's disease, 100 U daily by SC or IM injection.
Calcium Preparations
Action
Increased calcium pool available for gastrointestinal absorption.
Selected Indications
Osteoporosis prevention and treatment.
Metabolism
Renal excretion of absorbed fraction.
Adverse Reactions
Nausea, constipation, and gastrointestinal irritation may occur.
Caution
Hypercalcemia may occur, especially in patients receiving concomitant vitamin D. Calcium carbonate is ineffective in patients with achlorhydria.
Supply
Calcium carbonate tablets, 500, 650, and 1,250 mg; calcium citrate tablets, 950 mg; calcium gluconate tablets, 450, 500, 600, 900, and 1,000 mg; calcium lactate tablets, 300 and 600 mg. Many preparations are now available with vitamin D.
Dosage
Supplement dietary calcium intake to achieve a total elemental calcium dosage of 1,000 mg/d in divided doses for male and premenopausal female patients; 1,500 mg/d in divided doses for postmenopausal women.
Estrogens
Action
Estrogens are bound by nuclear receptors in various tissues and ultimately affect the transcription of genes that bear the estrogen response element. In bone, inhibition of osteoclast activity is the eventual effect, resulting in reduced bone resorption.
Selected Indications
Prevention and treatment of postmenopausal osteoporosis.
Metabolism
Unconjugated estrogens are rapidly inactivated by the liver after oral administration and so are usually given parenterally. By contrast, conjugated estrogens may be administered orally. Estrogens accumulate in body fat and so may be cleared more slowly in obese patients. Steroidal estrogens are metabolized primarily by the liver via conjugation and then excreted in the urine. A substantial amount is recirculated through the liver from bile for further metabolism.
Adverse Reactions
Malignancies are the most feared potential complication of estrogen therapy (see Caution). It is clear that unopposed prolonged estrogen use increases the risk for endometrial carcinoma in postmenopausal women. However, an association with breast cancers remains a topic of great debate. Other potential adverse effects are manifold and include hypertension, hypercoagulability and thromboembolic disorders, fluid retention, nausea, vomiting, pancreatitis, skin rashes, glucose intolerance, hypercalcemia, hypertriglyceridemia, abnormal serum liver chemistries, cholestasis, gallbladder disease, breakthrough vaginal bleeding, menstrual-type cramping, fibroid enlargement , changes in affect, migraine headaches, mastodynia, and breast secretions.
Caution
Estrogens increase the risk for endometrial carcinoma in postmenopausal women; concomitant administration of progestin in women with intact uteri is recommended to reduce this risk. Estrogens are associated with developmental defects in fetal reproductive organs and are contraindicated in pregnancy. Most physicians regard a past or current history of breast cancer as another contraindication. Other contraindications to estrogen therapy include estrogen-dependent neoplasias, undiagnosed abnormal vaginal bleeding, active or past thrombophlebitis, and severe liver disease. Use in women without a personal history but with a close family history of breast cancer requires careful discussion of the risks and benefits of initiating or withholding therapy. Caution should also be taken in patients with preexisting uncontrolled hypertension, cardiovascular disease, asthma, migraine headaches, seizure disorders, renal dysfunction, depression, gallbladder disease, hypercoagulable states, and fibroids.
Supply
Estradiol: tablets, 0.5, 1, and 2 mg; transdermal patch, 0.025, 0.05, 0.075, and 0.1 mg/ 24 h.
Estradiol/norethindrone acetate combinations: transdermal patch, estradiol 0.05 mg and norethindrone acetate 0.14 mg or 0.25 mg/24 h.
Conjugated estrogens: tablets, 0.3, 0.625, 0.9, and 0.125 mg.
Conjugated estrogens/medroxyprogesterone combinations:
Monophasic regimen, conjugated estrogens 0.625 mg and medroxyprogesterone 2.5 mg.
Monophasic regimen, conjugated estrogens 0.625 mg and medroxyprogesterone 5 mg.
Biphasic regimen, conjugated estrogens 0.625 mg in 28 tablets with medroxyprogesterone 5 mg in 14 tablets.
Estropipate: tablets, 0.75, 1.5, and 3.0 mg.
Esterified estrogens: tablets, 0.3, 0.625, 1.25, and 2.5 mg.
Dosage
The recommended initial dosages for prevention and treatment of postmenopausal osteoporosis are given. Women with intact uteri should receive concomitant cyclical or continuous progestin therapy; for example, oral medroxyprogesterone may be administered either in a cyclical fashion (5 mg daily during the last 2 weeks of a 4-week cycle) or continuously (2.5 mg daily). Women who have undergone hysterectomies may be given estrogen therapy without progestin.
Estradiol:
Oral regimen is 0.5 mg daily.
Transdermal regimen is 0.05 mg/24 h patch applied twice weekly. (Note: Combination patches containing norethindrone acetate 0.14 mg or 0.25 mg/24 h are available.)
Conjugated estrogens: 0.625 mg orally each day. (Note: combination regimens for concomitant continuous or cyclical medroxyprogesterone are available.)
Estropipate: 0.75 mg orally each day.
Esterified estrogens: 0.3 mg orally each day.
Etidronate Disodium (Didronel)
Action
Bisphosphonate compound that inhibits either osteoclast or osteoblast activity and diminishes bone resorption and new bone formation.
Selected Indications
Osteoporosis prevention and treatment, Paget's disease of bone.
Metabolism
Adsorbed to developing apatite crystals during bone formation. Excreted unchanged by the kidneys.
Adverse Reactions
Defective mineralization of bone with accumulation of unmineralized osteoid, and possible onset of new bone pain and pathologic fractures. Mild abdominal cramps, nausea, and diarrhea are common.
Caution
Patients with renal insufficiency should be treated cautiously. Like other bisphosphonates, etidronate is contraindicated in women of childbearing potential.
Supply
Tablets, 200 mg.
Dosage
For Paget's disease, 400 mg daily given as a single dose 2 hours before meals. Reassessment is indicated after 6 months of therapy. Dosages above 10 mg/kg daily should be used cautiously and reserved for suppression of rapid bone turnover or for prompt reduction in elevated cardiac output. For treatment of postmenopausal osteoporosis, the dosage is 400 mg of etidronate daily (2 hours before or after a meal) for 14 days every 3 months.
Fluoride, Sodium
Action
Incorporated into bone, rendering it less soluble. Stimulates new bone formation.
Selected Indications
Osteoporosis prevention and treatment.
Metabolism
Absorbed from gastrointestinal tract and incorporated into bone.
Adverse Reactions
Occasional gastrointestinal upset. Fluorosis, caused by chronic overexposure to fluoride, results in mottling of teeth and formation of thickened bones with poor mechanical quality (osteomalacia and osteosclerosis). Excessive doses, therefore, may result in an increased risk for fractures despite apparent improvement in bone density.
Caution
To prevent precipitation of calcium fluoride, calcium supplements and sodium fluoride are given at separate times of the day. Fluoride supplements should not be given to patients with renal insufficiency.
Supply
Tablets, 1 mg. Larger capsules and oral solution are also available in some pharmacies.
Dosage
The dosage is 10 mg of elemental fluoride twice daily.
Pamidronate (Aredia)
Action
Bisphosphonate that inhibits osteoclast activity.
Selected Indications
Hypercalcemia associated with malignancies, Paget's disease of bone.
Metabolism
After IV administration, pamidronate is immediately retained in bone, preferentially in areas of high turnover. The drug is then slowly cleared by the kidney, with a terminal half-life of about 300 days.
Adverse Reactions
Most adverse effects appear to be dose-related. These include fatigue, somnolence, reactions at the infusion site, anorexia, nausea, gastrointestinal hemorrhage, and electrolyte abnormalities (hypocalcemia, hypokalemia, hypomagnesemia, hypophosphatemia). Cardiopulmonary effects such as hypertension, atrial fibrillation, tachycardia, syncope, and rales may occur with the highest doses. Fever occurs in about one-fifth of patients. Cytopenias may occur rarely.
Caution
Serum electrolytes should be followed closely. In patients with preexisting hematologic conditions, complete blood cell counts should also be followed. Pamidronate should not be given to women of childbearing potential.
Supply
Vials of lyophilized powder, 30 mg, 60 mg, and 90 mg, for reconstitution with sterile water.
Dosage
For Paget's disease, 30 mg daily IV given over 4 hours for 3 days. Higher doses are recommended for hypercalcemia associated with malignancies.
Raloxifene (Evista)
Action
Raloxifene, a benzothiophene compound, is a selective estrogen receptor modulator . It has estrogen agonist activity on bone and antagonist activity on breast and uterine tissue. Its anti-osteoporotic effects are probably a consequence of inhibition of osteoclast activity.
Metabolism
Sixty percent of ingested drug is absorbed. It is glucuronidated on first pass in the liver and excreted almost entirely in the feces. Its half-life is about 27 hours.
Adverse Reactions
Hot flashes and leg cramps occur. As with other estrogens, there is an increased risk for venous thromboembolism.
Caution
Men and premenopausal women are not candidates for raloxifene therapy. The drug is contraindicated in patients with histories of thromboembolic disease and in patients with known hypersensitivity to the drug or components of the tablets. Cholestyramine causes a 60% reduction in absorption and should not be administered together with raloxifene. Risks for breast and gynecologic malignancies have not been adequately studied.
Supply
Tablets, 60 mg.
Dosage
The dosage is 60 mg daily.
Risedronate (Actonel)
Action
Bisphosphonate that inhibits osteoclast activity and bone resorption but does not interfere with bone mineralization.
Selected Indications
Paget's disease of bone.
Metabolism
Risedronate is poorly absorbed by the gastrointestinal tract, especially when taken with food. Fasting absorption is less than 1%. Calcium-, aluminum-, and magnesium-containing supplements and antacids interfere with absorption. Absorbed drug is tropic for bone and will persist within the bony skeleton for years. Excretion is in the urine.
Adverse Reactions
Gastrointestinal intolerances are the most common adverse effects and include diarrhea, nausea, abdominal pain, and esophagitis. About a third of patients may experience arthralgias. Adequate calcium repletion before the initiation of therapy may reduce the risk for musculoskeletal discomfort.
Caution
Risedronate must be taken on an empty stomach, while upright, at least one-half hour before eating. Risedronate is contraindicated in women of childbearing potential.
Supply
Tablets, 30 mg.
Dosage
The dosage is 30 mg daily. For Paget's disease, reassessment is indicated after 2 months of therapy.
Tiludronate (Skelid)
Action
Bisphosphonate that inhibits osteoclast activity and bone resorption but does not interfere with bone mineralization.
Selected Indications
Paget's disease of bone.
Metabolism
Tiludronate is poorly absorbed by the gastrointestinal tract, especially when taken with food. Calcium-, aluminum-, and magnesium-containing supplements and antacids interfere with absorption. Absorbed drug is tropic for bone and will persist within the bony skeleton for years. The drug is not metabolized and is excreted in the urine.
Adverse Reactions
Gastrointestinal intolerances are the most common adverse effects and include diarrhea, nausea, and abdominal pain, but esophagitis and esophageal ulcerations have not been reported.
Caution
Tiludronate must be taken on an empty stomach, while upright, at least 2 hours before eating. Tiludronate is contraindicated in women of childbearing potential.
Supply
Tablets, 200 mg.
Dosage
The dosage is 400 mg daily. For Paget's disease, reassessment is indicated after 3 months of therapy.
Vitamin D
Action
Family of sterol derivatives that increase intestinal absorption of calcium and may increase mobilization of mineral from bone.
Selected Indications
Prevention and treatment of postmenopausal osteoporosis, prevention of drug-induced osteoporosis, osteomalacia, rickets, hypoparathyroidism, hypocalcemia, and renal osteodystrophy.
Metabolism
The activation of vitamin D is effected via sequential hepatic and renal hydroxylation. The metabolites of vitamin D are mostly excreted in bile.
Adverse Reactions
Vitamin D toxicity may produce elevated serum calcium and phosphorus levels, causing drowsiness, gastrointestinal symptoms, metastatic calcifications, renal failure, and hypertension.
Caution
Administration of exogenous calcium may also be necessary for desired effects of vitamin D therapy. Monthly monitoring of serum and urinary calcium to avoid manifestations of vitamin D toxicity is recommended. If urinary calcium rises above 120 mg/d, the dosage of vitamin D should be reduced.
Supply
Many options are available, including the following:
Vitamin D 3 , 200 to 400 IU (contained in many multivitamin preparations).
Ergocalciferol (vitamin D 2 ), 25,000 and 50,000 IU.
Calcitriol capsules, 0.25 and 0.5 g.
Calcifediol capsules, 20 and 50 g.
Dihydrotachysterol tablets, 0.125, 0.2, and 0.4 g.
Dosage
Postmenopausal osteoporosis: at least 400 IU of vitamin D 3 daily.
Prevention of drug-induced osteoporosis: 400 IU of vitamin D 3 twice daily.
The appropriate agent and dosing for other conditions should be adjusted on a clinical basis.
ANTICOAGULANTS
Indications for the use of anticoagulation have grown. In rheumatology specifically , some situations in which anticoagulants are widely utilized include primary treatment in the anti-phospholipid syndrome and other hypercoagulable states, adjuvant therapy in Raynaud's phenomenon and other low-flow states, and prophylaxis against deep venous thrombosis. Warfarin and heparins/heparinoids remain the primary agents currently available.
The major recent advances have been in the development and use of preparations of low-molecular-weight heparin, which appears to be as effective as traditional, unfractionated heparin and also safer and easier to use. All heparins act by enhancing the activity of antithrombin III, which neutralizes thrombin and factor Xa. Three preparations of low-molecular-weight heparin (ardeparin, dalteparin, enoxeparin) are currently available in the United States. They are all depolymerized heparins, but they differ in the degradation process by which they are obtained. An additional agent, danaparoid, is considered to be a low-molecular-weight heparinoid; it too enhances antithrombin III. One major difficulty in the current use of these preparations is the lack of standardization of activity. The drugs are not interchangeable on a milligram-for-milligram basis, and even attempts to standardize according to biochemical activity (e.g., anti-factor Xa activity) have been unsatisfactory. At present, the only approved indication for the low-molecular weight heparins and danaparoid is prophylaxis of deep venous thrombosis. However, many studies have already shown that when administered at higher doses, these compounds are also effective in the treatment of acute deep venous thrombosis.
Although these low-molecular-weight heparins/heparinoids are effective in a twice-daily regimen via the SC route and do not require monitoring of prothrombin times (PT) or partial thromboplastin times (PTT), physicians must appreciate that when they are used at therapeutic doses, they do induce full anticoagulation. Thus, as with IV heparin, significant risks for hemorrhage do exist.
Ardeparin (Normiflo)
Action
Ardeparin is a partially depolymerized heparin prepared by peroxide degradation of porcine intestinal heparin. It potentiates antithrombin III activity.
Selected Indications
Prophylaxis of deep venous thrombosis, hypercoagulable states.
Metabolism
The metabolic fate of ardeparin is not fully known. Most is probably removed by the reticuloendothelial system and by vascular endothelium. A small amount may be excreted in urine.
Adverse Reactions
Hematoma at injection sites is the most common adverse effect. Hemorrhage, although much less frequent than with unfractionated heparin, is still a concern. Hematomas at the site of epidural or spinal anesthesias may result in potentially devastating neurologic compromise, including permanent paralysis. Allergic reactions and skin necrosis are rare. Thrombocytopenia is much less common than with unfractionated heparin.
Caution
Monitoring of PT or PTT is not necessary. Use in patients with underlying thrombocytopenia or another potential bleeding diathesis should be monitored especially closely. Use in the setting of epidural or spinal anesthesia must be carefully considered. Ardeparin is contraindicated in patients with active hemorrhaging or in those with allergies to porcine products. It should not be administered IM.
Supply
Prefilled Tubex syringes, 5,000 U/0.5 mL and 10,000 U/0.5 mL.
Dosage
For deep venous thrombosis prophylaxis, 50 U/kg of body weight injected SC twice daily.
Dalteparin (Fragmin)
Action
Dalteparin is a depolymerized heparin prepared by nitrous acid degradation of porcine intestinal heparin. It potentiates antithrombin III activity.
Selected Indications
Prophylaxis of deep venous thrombosis, hypercoagulable states.
Metabolism
The metabolic fate of dalteparin is not fully known. Most is probably removed by the reticuloendothelial system and by vascular endothelium. A small amount may be excreted in urine.
Adverse Reactions
Hematoma at injection sites is the most common adverse effect. Hemorrhage, although much less frequent than with unfractionated heparin, is still a concern. Hematomas at the site of epidural or spinal anesthesias may result in potentially devastating neurologic compromise, including permanent paralysis. Allergic reactions and skin necrosis are rare. Thrombocytopenia is much less common than with unfractionated heparin.
Caution
Monitoring of PT or PTT is not necessary. Use in patients with underlying thrombocytopenia or another potential bleeding diathesis should be monitored especially closely. Use in the setting of epidural or spinal anesthesia must be carefully considered. Dalteparin is contraindicated in patients with active hemorrhaging and in those with allergies to porcine products. It should not be administered IM.
Supply
Disposable prefilled syringes, 2,500 anti-factor Xa U/0.2 mL and 5,000 anti-factor Xa U/0.5 mL.
Dosage
For deep venous thrombosis prophylaxis, 2,500 to 5,000 U of anti-factor Xa injected SC twice daily.
Danaparoid (Orgoran)
Action
Danaparoid is a depolymerized glycosaminoglycan isolated from porcine intestinal mucosa through a process that specifically excludes heparin and heparin fragments. It potentiates antithrombin III activity.
Selected Indications
Prophylaxis of deep venous thrombosis, hypercoagulable states.
Metabolism
The metabolic fate of danaparoid is not fully known. Most is probably removed by the reticuloendothelial system and by vascular endothelium. A small amount may be excreted in urine.
Adverse Reactions
Hematoma at injection sites is the most common adverse effect. Hemorrhage, although much less frequent than with unfractionated heparin, is still a concern. Hematomas at the site of epidural or spinal anesthesias may result in potentially devastating neurologic compromise, including permanent paralysis. Allergic reactions and skin necrosis are rare.
Caution
Monitoring of PT or PTT is not necessary. Use in patients with underlying thrombocytopenia or other potential bleeding diathesis should be monitored especially closely. Use in the setting of epidural or spinal anesthesia must be carefully considered. Danaparoid is contraindicated in patients with active hemorrhaging and in those with allergies to porcine products. Patients with sulfite sensitivity may also not be good candidates for danaparoid use. It should not be administered IM.
Supply
Disposable prefilled syringes, 750 anti-factor Xa U/0.6 mL.
Dosage
For deep venous thrombosis prophylaxis, 750 U of anti-factor Xa injected SC twice daily.
Enoxeparin (Lovenox)
Action
Enoxeparin is a depolymerized heparin prepared by alkaline degradation of porcine intestinal heparin. It potentiates antithrombin III activity.
Selected Indications
Prophylaxis of deep venous thrombosis, hypercoagulable states.
Metabolism
The metabolic fate of enoxeparin is not fully known. Most is probably removed by the reticuloendothelial system and by vascular endothelium. A small amount may be excreted in urine.
Adverse Reactions
Hematoma at injection sites is the most common adverse effect. Hemorrhage, although much less frequent than with unfractionated heparin, is still a concern. Hematomas at the site of epidural or spinal anesthesias may result in potentially devastating neurologic compromise, including permanent paralysis. Allergic reactions and skin necrosis are rare. Thrombocycotpenia is much less common than with unfractionated heparin.
Caution
Monitoring of PT or PTT is not necessary. Use in patients with underlying thrombocytopenia or other potential bleeding diathesis should be monitored especially closely. Use in the setting of epidural or spinal anesthesia must be carefully considered. Enoxeparin is contraindicated in patients with active hemorrhaging and in those with allergies to porcine products. It should not be administered IM.
Supply
Disposable prefilled syringes, 30 mg/0.3 mL.
Dosage
For deep venous thrombosis prophylaxis, 30 mg injected SC twice daily.
Heparin, Unfractionated
Action
Heparin is a heterogeneous mixture of anionic sulfated glycosaminoglycans, usually extracted from porcine intestinal mucosa or bovine lung. It potentiates antithrombin III activity.
Selected Indications
Prophylaxis and treatment of deep venous thrombosis, hypercoagulable states.
Metabolism
The metabolic fate of heparin is not fully known. Most is probably removed by the reticuloendothelial system and by vascular endothelium. A small amount may be excreted in urine.
Adverse Reactions
Hemorrhage and hematomas are the most common adverse effect. Hematomas at the site of epidural or spinal anesthesias may result in potentially devastating neurologic compromise, including permanent paralysis. Thrombocytopenia may occur in 15% of patients treated with bovine heparin and in 5% of patients treated with porcine heparin. Two reversible mechanisms of thrombocytopenia are identified, both of which are idiosyncratic and not dose-dependent: (a) a direct, non-immunologic effect and (b) a heparin-dependent IgG platelet-aggregating phenomenon. Rarely, a paradoxical thrombogenic white clot syndrome may occur with local or systemic manifestations. Prolonged heparin use may cause osteoporosis.
Caution
Although the PTT is most sensitive to heparin and is used for dose adjustment, the prothrombin time/international normalization ratio (PT/INR) may also be affected, especially at high dosages. Baseline values of PTT and PT/INR should be obtained before continuous IV therapy is instituted. Use in patients with underlying thrombocytopenia or other potential bleeding diathesis should be monitored especially closely. Use in the setting of epidural or spinal anesthesia must be carefully considered. Heparin is contraindicated in patients with active hemorrhaging and in those with allergies to porcine or bovine products. It should not be administered IM. Reversal of hemorrhagic complications may require protamine sulfate.
Supply
Bovine lung:
Vials, 1,000, 5,000, and 10,000 U/mL for SC injection.
Porcine intestine:
Vials, 10, 20, 25, 30, 50, 100, 300, 1,000, 2,500, 5,000, 7,500, 10,000, and 20,000 U/mL for SC injection.
In 5% dextrose, 40, 50, and 100 U/mL for IV administration.
In normal saline solution, 2, 50, and 100 U/mL for IV administration.
Dosage
General guidelines for deep venous thrombosis prophylaxis: 5,000 to 7,500 U injected SC twice daily. Adjustments may be necessary as clinically indicated.
General guidelines for full-dose continuous IV use: loading dose of 50 to 100 U/kg of body weight, followed by continuous infusion of 10 to 15 U/kg of body weight per hour.
Repeat bolus and/or readjust infusion rate to desired PTT initially every 6 hours and then daily after stable dose is achieved. Adjustments may be necessary as clinically indicated.
Warfarin Sodium (Coumadin)
Action
Warfarin indirectly alters the synthesis of functional coagulation factors by interfering with vitamin K activity, which is required for t -carboxylation of factors II, VII, IX, and X.
Selected Indications
Prophylaxis and treatment of deep venous thrombosis, hypercoagulable states, and anti-phospholipid syndrome, and care after cerebrovascular accident .
Metabolism
Warfarin is generally well absorbed by the gastrointestinal tract, but the rate of absorption can be highly dependent on individual variability and the commercial source of the drug. Although peak levels of warfarin occur within hours after ingestion, its antithrombogenic activity does not depend on plasma levels but rather on levels of vitamin K-dependent factors, which may not be affected until at least 2 days after administration. IV administration of warfarin does not hasten the onset of activity. The effects of warfarin may be potentiated or diminished by innumerable foods and medications, all of which should be taken into careful consideration during treatment. Warfarin is inactivated in the liver, and the metabolites are excreted in urine.
Adverse Reactions
Hemorrhage is the most common adverse effect of warfarin. Potentially fatal necrosis of the skin or other tissue is a rare complication, most commonly seen in patients with defects or deficiencies in the antithrombotic factors protein C or protein S. This is usually seen early after initiation of therapy and is thought to be caused the rapid depletion of the vitamin K-dependent protein C, which results in a transient prothrombotic state. Another rare complication is cholesterol microembolization syndrome, which can result in systemic microvascular ischemia. Although the PT/INR is most sensitive to warfarin, the PTT can also be elevated at high doses.
Caution
Close monitoring of the PT/INR is required for appropriate dosing of warfarin, especially at the start of therapy or when changes in concurrent medications are made. Familiarity with drugs that may enhance or reduce the anticoagulant effects of warfarin is advised. Warfarin is contraindicated during pregnancy and in nursing women. IM injections should not be given to patients in an anticoagulated state. Patients with anti-phospholipid syndrome present an additional problem in that circulating antibodies may cause artifacts in the INR, which makes monitoring of anticoagulation difficult.
Supply
Tablets, 1, 2, 2.5, 4, 5, 7.5, and 10 mg.
Injectable solution, 5 mg.
Dosage
Daily dosing as dictated by desired INR. For most indications (e.g., treatment of deep venous thrombosis, atrial fibrillation), an INR of 2.0 to 3.0 is generally recommended. For patients with mechanical heart valves , an INR of 2.5 to 3.5 should be maintained. Patients with anti-phospholipid syndrome may require an INR of 3.0 to 4.0 or higher.
VASOACTIVE AGENTS
Vasoactive agents are useful in the management of systemic and pulmonary hypertension, Raynaud's phenomenon, and congestive heart failure. Vascular tone may be relaxed by (a) inhibition of sympathetic function (e.g., prazocin), (b) direct relaxation of smooth muscle (e.g., hydralazine), (c) calcium channel blockade (e.g., amlodipine, diltiazem, nifedipine, verapamil), and (d) inhibition of ACE (e.g., captopril, enalapril). The use of ACE inhibitors, in particular, has drastically changed the outcome in diffuse systemic sclerosis. Included below is a small sampling of available agents.
Amlodipine (Norvasc)
Action
Calcium channel blocker that dilates coronary and peripheral arteries and arterioles.
Selected Indications
Hypertension, Raynaud's phenomenon.
Metabolism
Dose adjustment is not generally necessary in the setting of renal insufficiency. However, elimination can be reduced in the setting of hepatic impairment and in geriatric patients.
Adverse Reactions
Hypotension, bradycardia, dizziness, headache, congestive heart failure, pedal edema, nausea, and rash may occur. In Raynaud's phenomenon, all vasodilators may precipitate a vascular steal syndrome.
Caution
Avoid in patients with sick sinus syndrome, atrioventricular conduction disturbances, severe congestive heart failure, or hypotension (systolic blood pressure <90 mm Hg).
Supply
Tablets, 2.5, 5, and 10 mg.
Dosage
Initially, 2.5 mg daily.
Captopril (Capoten)
Action
ACE inhibitor that reduces peripheral vascular resistance and venous tone.
Selected Indications
Hypertension, treatment of scleroderma renal crisis, proteinuria.
Metabolism
Rapid oral absorption with peak blood levels at 1 hour. Captopril should be taken 1 hour before meals, as food reduces absorption. The drug is 25% to 30% protein-bound. Excretion is in urine.
Adverse Reactions
Rash occurs in 10%, dysgeusia in 7%, proteinuria in 2%, orthostatic hypotension in 2%, proteinuria in 1% to 2%, angioedema in 1%, cough in 0.5% to 2%, neutropenia in 0.3%, and renal failure in 0.1%. Gastric irritation and fever have been reported. Chronic cough may result in discontinuation of all ACE inhibitors.
Caution
Severe hypotension may be seen in salt-or volume-depleted patients, such as those on diuretics. Patients with congestive heart failure may have elevations in blood urea nitrogen and serum creatinine. Neutropenia with myeloid hypoplasia occurs mainly in patients with SLE or other autoimmune diseases. Complete blood cell count, urinalysis, and renal (especially serum potassium and creatinine) parameters should be checked frequently. Renal function and electrolyte abnormalities in patients with SLE in particular should be watched closely. The dosage should be decreased in patients with renal dysfunction.
Supply
Tablets, 12.5, 25, 50, and 100 mg.
Dosage
Initial dose is 12.5 mg three times daily, then 25 mg three times daily. After 1 to 2 weeks, the dosage may be increased to 50 mg three times daily, then at 1- to 2-week intervals to a maximum of 150 mg three times daily.
Diltiazem (Cardizem)
Action
Calcium channel blocker that dilates coronary and peripheral arteries and arterioles.
Selected Indications
Hypertension, Raynaud's phenomenon.
Metabolism
Diltiazem is absorbed with peak level in 3 hours and a half-life of 4 hours. It is 80% protein-bound. There is extensive hepatic metabolism.
Adverse Reactions
Hypotension, bradycardia, dizziness, headache, congestive heart failure, pedal edema, nausea, and rash may occur. In Raynaud's phenomenon, all vasodilators may precipitate a vascular steal syndrome.
Caution
Avoid in patients with sick sinus syndrome, atrioventricular conduction disturbances, severe congestive heart failure, or hypotension (systolic blood pressure <90 mm Hg). Diltiazem should not be used with cyclosporin A. There are data suggesting that extended-release forms may be safer than rapid-release preparations.
Supply
Tablets, 30, 60, 90, and 120 mg.
Extended-release capsules, 120 mg, 180 mg, 240 mg, and 300 mg.
Dosage
Initially 120 mg daily in single or divided doses. Can be increased as tolerated to 480 mg daily in single or divided doses.
Enalapril/Enalaprilat (Vasotec)
Action
ACE inhibitors that reduce peripheral vascular resistance and venous tone.
Selected Indications
Hypertension, treatment of scleroderma renal crisis, proteinuria.
Metabolism
Enalapril is the ethyl ester of enalaprilat. The gastrointestinal absorption of enalapril is good (about 55% to 75%) and does not appear to be affected by foods. In contrast, enalaprilat is poorly absorbed and is administered IV. Enalapril is a pro-drug that is activated by hepatic hydrolysis. Two-thirds of the drug and its metabolites are excreted in urine, and the remainder is eliminated in feces.
Adverse Reactions
Fewer than 5% of patients discontinue enalapril for adverse effects. These may include neurologic complaints (dizziness, vertigo), postural hypotension, deterioration of renal function, hypersensitivity reactions, leukopenia, dysgeusia, hyperkalemia, and chronic cough.
Caution
Severe hypotension may be seen in salt-or volume-depleted patients, such as those on diuretics. Patients with congestive heart failure may have elevations in blood urea nitrogen and serum creatinine. Complete blood cell count, urinalysis, and renal (especially serum potassium and creatinine) parameters should be checked frequently. Renal function and electrolyte abnormalities in patients with SLE in particular should be watched closely. Conversion between IV and oral dosing requires careful attention.
Supply
Enalapril tablets, 2.5, 5, 10, and 20 mg.
Enalaprilat injectable solution for IV use, 1.25 mg/mL.
Dosage
The initial dose of enalapril is 2.5 mg daily; the maximum is generally 40 mg daily in once- or twice-daily dosing. The initial dose of enalaprilat is 1.25 mg every 6 hours, which can be raised to 5 mg every 6 hours as indicated.
Nifedipine (Procardia, Adalat)
Action
Calcium channel blocker. Coronary and peripheral arterial vasodilation.
Selected Indications
Hypertension, Raynaud's phenomenon.
Metabolism
Well absorbed, with peak levels in 1 to 2 hours. Highly protein-bound. Completely metabolized in liver before excreted in urine.
Adverse Reactions
Hypotension, dizziness, headache, tachycardia, fatigue, edema, flushing, nausea, nasal congestion, and leg cramps have been noted. In Raynaud's phenomenon, all vasodilators may precipitate a vascular steal syndrome.
Caution
Close monitoring of blood pressure is recommended. There are data suggesting that extended-release forms of calcium channel blockers may be safer than rapid-release preparations.
Supply
Capsules, 10 and 20 mg.
Extended-release tablets, 30, 60, and 90 mg.
Dosage
Initially 30 mg daily in single or divided doses, which can be raised to 90 mg daily.
Prazocin (Minipress)
Action
Arterial and venous dilator that may act via a -adrenergic receptor blockade.
Selected Indications
Hypertension, Raynaud's phenomenon.
Metabolism
Peak plasma levels in 3 hours with half-life of 2 1/2 hours. It is highly protein-bound and extensively metabolized in the liver.
Adverse Reactions
Orthostatic hypotension, syncope, peripheral edema, fatigue, headache, dizziness, and nausea may occur. Rarely, urinary frequency, impotence, rash, and nasal congestion have been noted.
Caution
Symptomatic orthostatic hypotension with syncope may occur after the first dose. Therefore, the first dose should not exceed 1 mg and should be given at bedtime with instructions for the patient to remain in bed at least 3 hours. The dosage may be increased to 1 mg twice daily, then three times daily, with further gradual increments. Tolerance to hemodynamic effects may develop during long-term treatment.
Supply
Capsules, 1, 2, and 5 mg.
Dosage
The dosage is 1 mg three times daily, gradually increased to 20 mg/d in divided doses.
Verapamil (Calan, Covera, Isoptin, Verelan)
Action
Calcium channel blocker that reduces coronary and peripheral vascular resistance.
Selected Indications
Hypertension, Raynaud's phenomenon.
Metabolism
Excellent oral absorption with peak levels in 1 to 2 hours. It is 90% protein-bound. Half-life is 3 to 6 hours, with marked prolongation in patients with hepatic dysfunction. Extensive metabolism in the liver and excretion of active metabolites in urine.
Adverse Reactions
Hypotension, peripheral edema, bradycardia, heart block, congestive heart failure, headaches, dizziness, constipation, and abnormal serum liver chemistries may occur. In Raynaud's phenomenon, all vasodilators may precipitate a vascular steal syndrome.
Caution
Verapamil increases digoxin levels by 50% to 70%. It should be avoided in patients with sick sinus syndrome, severe congestive heart failure, or hepatic or renal impairment. There are data suggesting that extended-release forms of calcium channel blockers may be safer than rapid-release preparations.
Supply
Tablets, 40, 80, and 120 mg.
Extended-release tablets, 120, 180, and 240 mg.
Dosage
Initially 120 mg daily in single or divided dose; can be increased up to 480 mg daily.
SUPPLEMENTS AND MISCELLANEOUS
Chondroitin Sulfate/Glucosamine Sulfate
In the United States, chondroitin sulfate and glucosamine sulfate are regarded as nutritional supplements rather than as medicines and so have not been as rigorously studied for metabolism, efficacy, and toxicity.
Selected Indications
Osteoarthritis .
Action
Usually taken together, these agents are thought possibly to maintain synovial joint integrity by optimizing synthesis of collagen and glycosaminoglycans, stimulating hyaluronic acid secretion by chondrocytes, and inhibiting degradative enzymes.
Metabolism
Both agents are absorbed in the gastrointestinal tract. At least some of the compounds can then be traced to synovial joints.
Adverse Reactions
Mild gastrointestinal intolerances such as bloating and flatus are common but generally do not result in discontinuation.
Caution
No data are available on effects on fertility, pregnancy, or lactation.
Supply
Glucosamine sulfate, capsules and tablets, 500 mg.
Chondroitin sulfate, capsules and tablets, 400 mg.
Also available in combined forms.
Dosage
Glucosamine sulfate, 1,500 to 2,000 mg daily in divided doses.
Chondroitin sulfate, 1,200 to 1,600 mg daily in divided doses.
Cisapride (Propulsid)
Action
Cisapride is thought to enhance the release of acetylcholine at the myenteric plexus, thus promoting peristalsis.
Selected Indications
Gastrointestinal dysmotility, systemic sclerosis.
Metabolism
Cisapride is rapidly absorbed via the gastrointestinal tract, and peak plasma levels are reached within 2 hours. Gastrointestinal absorption is enhanced by concomitant administration of cimetidine and ranitidine. The mean half-life is between 6 and 12 hours. It is metabolized by the cytochrome P-450 3A4 enzyme. Its metabolites are excreted in both feces and urine. Although hepatic or renal impairment may cause accumulation of metabolites within plasma, no dose adjustments are generally necessary.
Adverse Reactions
Headache, sedation, nausea, and diarrhea are the most commonly reported adverse effects. These problems appear to be dose-dependent.
Caution
Rare cases of serious cardiac arrhythmias, including ventricular arrhythmias and torsades de pointes, have been reported; therefore, the use of cisapride in patients with conditions associated with QT prolongation should be avoided. Concomitant administration of drugs that inhibit cytochrome P-450 3A4 activity (e.g., ketoconazole, itraconazole, micronazole, erythromycin, and troleandomycin) may raise cisapride levels to cause prolongation of the QT interval and so is contraindicated. Cisapride may enhance the effects of sedatives.
Supply
Tablets, 10 and 20 mg.
Dosage
The dosage is 10 to 20 mg up to four times daily, taken orally 15 to 30 minutes before meals.
Hyaluronans (Hyalgan, Synvisc)
Action
Increases viscoelasticity of synovial fluid and possibly reduces cartilage degradation.
Selected Indications
Osteoarthritis.
Metabolism
High-molecular-weight fractions of sodium hyaluronate for sterile intraarticular injection are derived from chicken combs and are available in a buffered physiologic sodium chloride solution. The intraarticular half-life of sodium hyaluronate is less than 24 hours. Hylan G-F is a cross-linked derivative of sodium hyaluronate and appears to have a longer half-life. Hyaluronans are degraded by intraarticular enzymes, free radicals, and sheer forces. The degradation products are removed through lymphatics and undergo hepatic catabolism.
Adverse Reactions
Most adverse effects are related to symptoms associated with the site of injection, including pain, swelling, effusion, warmth, and redness. Some of these cases are exacerbations of gout or pseudogout. Self-limited allergic reactions have been reported.
Caution
At present, hyaluronans are approved only for osteoarthritis of the knee. Increases in knee inflammation after administration in the setting of inflammatory arthritides (e.g., RA and gout) have been noted. Because the source of the agent is rooster combs, precaution should be taken in patients with allergies to avian proteins, feathers, and egg products. Strict sterile technique is to be observed, and no injection should be attempted through skin that appears infected. Disinfectants containing quarternary ammonium salts should not be used for skin preparation.
Supply
Sodium hyaluronate (Hyalgan), sterile 2-mL vials.
Hylan G-F 20 (Synvisc), sterile 2-mL prefilled syringes.
Dosage
Sodium hyaluronate, 2 mL administered weekly by intraarticular injections during 5 weeks.
Hylan G-F 20, 2 mL administered weekly by intraarticular injections during 3 weeks.
Lansoprazole (Prevacid)
Action
Lansoprazole is a substituted benzimidazole that specifically inhibits the proton pump system on the secretory surface of the gastric parietal cell.
Selected Indications
Gastroesophageal reflux, gastroprotection against NSAIDs, systemic sclerosis.
Metabolism
Absorption of lansoprazole occurs after the drug leaves the stomach and is diminished when the drug is taken after eating. Lansoprazole is transformed into two active metabolites that act locally at the parietal cell, and so plasma levels do not reflect activity at the gastric mucosa. The drug is extensively metabolized by the liver, and its metabolites are excreted in both feces (67%) and urine (33%). Dose adjustment should be considered in patients with hepatic impairment.
Adverse Reactions
Lansoprazole is generally well tolerated. Minor reported adverse effects include gastrointestinal intolerance, diarrhea, nausea, vomiting, headache, dizziness, and rashes.
Caution
Lansoprazole may increase clearance of theophylline. It may also interfere with absorption of drugs (such as ketoconazole, ampicillin esters, and digoxin) for which gastric pH is an important determinant of bioavailability.
Supply
Delayed-release capsules, 15 and 30 mg.
Dosage
The dosage is 15 to 30 mg daily.
Lyme Disease Vaccine (LYMErix)
Action
Lyme disease vaccine is a recombinant form of the 257-amino acid outer surface protein A (Osp A) of Borrelia burgdorferi, the spirochete that causes Lyme disease. Immunoglobulins stimulated by the vaccine are thought to prevent infection via interaction with the bacterium, either within the human host or possibly within the tick vector after uptake of antibody into its midgut during a blood meal.
Selected Indications
Prevention of Lyme disease.
Metabolism
Optimal vaccination requires at least three doses during a 1-year period.
Adverse Reactions
Most adverse reactions usually occur within the first month after immunization. These include pain or local reaction at the injection site, myalgias, chills, rigors, fever, rash and influenza-like symptoms.
Caution
Patients with histories of hypersensitivity reactions to any components of the vaccine or to natural rubber should not receive the vaccine. Persons receiving immunosuppression therapy may not mount an optimal immune response. Only IM administration should be used, and so anticoagulation therapy is a relative contraindication. An association of unclear significance has been observed between antibiotic-resistant Lyme arthritis and immune reactivity to Osp A; accordingly, Lyme disease vaccination is not currently recommended in such patients.
Supply
Single-dose vials and prefilled syringes, 30 g/0.5 mL.
Dosage
Three IM injections of 30 g at 0, 1, and 12 months.
Metoclopramide (Reglan)
Action
Metoclopramide stimulates upper gastrointestinal peristalsis without stimulating gastric, biliary , or pancreatic secretions, possibly by sensitizing tissue to the effects of acetylcholine.
Selected Indications
Gastrointestinal dysmotility, systemic sclerosis.
Metabolism
Metoclopramide is rapidly absorbed via the gastrointestinal tract, and peak plasma levels are reached within 2 hours. The mean half-life is about 6 hours. It is partially metabolized by hepatic conjugation and is excreted primarily in urine. Patients with renal impairment may require dose adjustment.
Adverse Reactions
Central nervous system effects, including sedation, headache, restlessness, and cognitive or affective changes, may occur in more than 10% of patients. Extrapyramidal reactions, including acute dystonic reactions, akathisia, parkinsonian symptoms, and tardive dyskinesia, may occur.
Caution
Metoclopramide should not be used in patients with poorly controlled hypertension or in patients with pheochromocytoma. It is also contraindicated when acceleration of gastrointestinal motility is not desired, as in patients with acute hemorrhages. Patients at risk for extrapyramidal symptoms should not receive metoclopramide.
Supply
Tablets, 5 and 10 mg.
Syrup, 1 mg/mL.
Injectable, 5 mg/mL in 2-, 10-, and 30-mL vials.
Dosage
The dosage is 10 to 20 mg up to four times daily, taken orally 15 to 30 minutes before meals. A dose of 10 mg may be administered parenterally (either IM or IV) during 1 to 2 minutes.
Misoprostol (Cytotec)
Action
Misoprostol is a synthetic analog of prostaglandin E 1 with protective properties against gastric inflammation and ulceration induced by NSAIDs.
Selected Indications
Gastroprotection against NSAIDs.
Metabolism
Absorption of misoprostol is rapid but is diminished by food or antacids. It is converted into its active form via de-esterification. Most of the drug is excreted in urine, but dose adjustment is generally not necessary in the setting of renal impairment.
Adverse Reactions
Abdominal discomfort, flatulence, and diarrhea are commonly reported. Gynecologic symptoms, including spotting, cramps, hypermenorrhea, and dysmenorrhea, may also occur. Postmenopausal vaginal bleeding requires thorough evaluation.
Caution
Misoprostol has abortifacient properties and is contraindicated in pregnant women. Women of childbearing age must be warned of these properties and must comply with effective contraceptive methods before taking misoprostol.
Supply
Tablets, 100 and 200 g.
Dosage
The dosage is 200 g four times daily. It may be reduced to 100 g four times daily if the higher dose is not tolerated.
Omeprazole (Prilosec)
Action
Omeprazole is a substituted benzimidazole that specifically inhibits the proton pump system on the secretory surface of the gastric parietal cell.
Selected Indications
Gastroesophageal reflux, gastroprotection against NSAIDs, systemic sclerosis.
Metabolism
Omeprazole is absorbed after leaving the stomach. Although the drug is easily absorbed after oral administration, extensive first-pass hepatic metabolism results in an absolute bioavailability of about 30% to 40% of that from an equivalent IV dose. Accordingly, bioavailability increases in persons with chronic liver disease. About three-fourths of the administered drug is excreted in urine, and the remainder is excreted in feces.
Adverse Reactions
Omeprazole is generally well tolerated. Minor reported adverse effects include gastrointestinal intolerance, diarrhea, nausea, vomiting, headache, dizziness, and rashes.
Caution
Omeprazole may interfere with the metabolism and increase plasma levels of warfarin, phenytoin, and diazepam. It may also interfere with absorption of drugs (such as ketoconazole, ampicillin esters, and digoxin) for which gastric pH is an important determinant of bioavailability.
Supply
Delayed-release capsules, 20 and 40 mg.
Dosage
The dosage is 20 to 40 mg daily.
Pilocarpine Hydrochloride (Salagen)
Action
Cholinergic parasympathomimetic agent that increases salivary gland secretions in Sjgren's syndrome.
Selected Indications
Xerostomia.
Metabolism
Peak levels are achieved within 1 hour after oral administration but are delayed with high-fat meals. Pilocarpine does not bind to serum proteins. It is thought to be inactivated at neuronal synapses and in plasma. Pilocarpine and its metabolites are excreted in urine.
Adverse Reactions
At dosages recommended for xerostomia, excessive sweating is the most commonly reported adverse effect, occurring in 40% of patients. Urinary frequency, flushing, and chills can also occur.
Caution
Pilocarpine is contraindicated and should be avoided in patients with underlying cardiovascular disease, in whom transient hemodynamic changes may not be tolerated, and in patients with uncontrolled asthma or chronic obstructive pulmonary disease. It should also not be used when miosis is undesirable. Concomitant use of b -adrenergic antagonists may result in conduction disturbances. Toxicity is caused by exaggeration of parasympathetic and cholinergic effects and may require treatment with atropine and hemodynamic support. Pregnant and nursing women should not be given pilocarpine. Pilocarpine should be avoided in patients with narrow-angle glaucoma.
Supply
Tablets, 5 mg.
Dosage
The dosage is 5 mg four times daily.
Sunscreens
Action
Absorption of ultraviolet (UV) light. Medium-wave (UVB, 280 to 320 nm) light is the major cause of sunburn and probably lupus-related skin reactions. Long-wave light (UVA, 320 to 400 nm) is the major cause of photosensitivity reactions.
Selected Indications
SLE, prevention of sun exposure while on medications.
Metabolism
Topical use only.
Adverse Reactions
Local hypersensitivity reactions to active compounds, vehicle, or both; contact dermatitis; photocontact dermatitis. Sunscreens may prevent cutaneous synthesis of vitamin D, especially in the elderly.
Caution
Patients allergic to thiazides, sulfa drugs, benzocaine, procaine, aniline dyes, and paraphenylenediamine may have allergic reactions to paraaminobenzoic acid (PABA), a common active ingredient. PABA-free preparations are available.
Dosage
Sunscreens are rated by sun protection factor (SPF, 0 to 50). Higher values reflect greater degrees of protection; preparations with an SPF of 30 or greater are recommended. Apply 1 to 2 hours before sun exposure and several times during exposure, especially after sweating or swimming. Reapplication does not extend the period of protection.
Books@Ovid
Copyright 2000 by Lippincott Williams & Wilkins
Stephen A. Paget, M.D., Allan Gibofsky, M.D., J.D. and John F. Beary, III, M.D.
Manual of Rheumatology and Outpatient Orthopedic Disorders
EAN: N/A
Pages: 315