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243 Cards in this Set

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Nonsteroidal Anti-inflammatory Drugs (NSAIDS) are divided into two categories:
Nonselective Cyclooxygenase Inhibitors
and
Selective Cyclooxygenase-2 Inhibitors
Aspirin and other salicylates
Nonselective Cyclooxygenase Inhibitors
Acetaminophen
Nonselective Cyclooxygenase Inhibitor
Acetaminophen trade name?
Tylenol
Ibuprofen
Nonselective Cyclooxygenase Inhibitor
Ibuprofen trade name?
Motrin, Advil
Ketoprofen
Nonselective Cyclooxygenase Inhibitor
Ketoprofen trade name?
Orudis
Naproxen
Nonselective Cyclooxygenase Inhibitor
Naproxen trade name?
Naprosyn, Aleve
indomethacin
Nonselective Cyclooxygenase Inhibitors
indomethacin trade name?
Indocin
sulindac
Nonselective Cyclooxygenase Inhibitors
sulindac trade name?
Clinoril
ketorolac
Nonselective Cyclooxygenase Inhibitors
ketorolac trade name?
Toradol
piroxicam
Nonselective Cyclooxygenase Inhibitors
piroxicam trade name?
Feldene
nabumetone
Nonselective Cyclooxygenase Inhibitors
nabumetone trade name?
Relafen
etodolac
Nonselective Cyclooxygenase Inhibitors
etodolac trade name?
Lodine
meloxicam
Nonselective Cyclooxygenase Inhibitors
meloxicam trade name?
Mobic
diclofenac
Nonselective Cyclooxygenase Inhibitors
diclofenac trade name?
Flector, Voltaren Gel
Celecoxib
Selective Cyclooxygenase-2 Inhibitors
Celecoxib trade name?
Celebrex
Disease-modifying Antirheumatic Drugs (DMARDS) are divided into thre categories:
Gold Salts
Glucocorticoids
Other Disease-Modifying Antirheumatic Drugs
Auranofin
Gold Salt
Gold sodium thiomalate
Gold Salt
Gold sodium thiomalate trade name?
Myochrysine, Aurolate
Aurothioglucose
Gold Salt
Aurothioglucose trade name?
Solganal
Prednisone
Glucocorticoid
Prednisone trade name?
Deltasone
Methotrexate
Disease-Modifying Antirheumatic Drug
Methotrexate trade name?
Rheumatrex
Leflunomide
Disease-Modifying Antirheumatic Drug
Leflunomide trade name?
Arava
Hydroxychloroquine
Disease-Modifying Antirheumatic Drug
Hydroxychloroquine trade name?
Plaquenil
Penicillamine
Disease-Modifying Antirheumatic Drug
Penicillamine trade name?
Cuprimine
Sulfasalazine
Disease-Modifying Antirheumatic Drug
Sulfasalazine trade name?
Azulfidine
Etanercept
Disease-Modifying Antirheumatic Drug
Etanercept trade name?
Enbrel
Drugs for Gout are divided into two categories:
Drugs to Prevent Gout Attacks
and
Drugs to Treat Gout Attacks
Probenecid
Drug to Prevent Gout Attacks
Probenecid trade name?
Benemid
Sulfinpyrazone
Drug to Prevent Gout Attacks
Sulfinpyrazone trade name?
Anturane
Allopurinol
Drug to Prevent Gout Attacks
Allopurinol trade name?
Zyloprim
Colchicine
Drug to Treat Gout Attacks
Indomethacin and other Nsaids
Drugs to Treat Gout Attacks
Nonsteroidal anti-inflammatory drugs (NSAIDs), which are widely used to alleviate the symptoms of
rheumatoid arthritis, osteoarthritis, and gout, as well as to relieve the pain and fever that accompany many nonarthritic disorders. They are also used by millions on a daily basis for the occasional headache.
Rheumatoid arthritis (RA) is an
autoimmune disorder of unknown etiology.
The hallmark symptom of RA is
joint inflammation
most patients with RA experience a chronic, fluctuating course of disease that, despite therapeutic measures, can result in
progressive joint destruction, deformity, disability, and premature death. RA affects 2% to 3% of the U.S. population, making it the most common systemic inflammatory disease. It is three times more common in women than in men.
RA is characterized by
symmetrical joint inflammation that most frequently affects the small joints of the hands, wrists, and feet, but also the joints of the ankles, elbows, hips, knees, and shoulders. Cardiopulmonary, neurologic, and ocular inflammation are also often found in patients with RA, and many patients develop rheumatoid nodules on the extensor surfaces of the elbows, forearms, and hands. In addition, many patients have extra-articular manifestations, such as vasculitis, lymphadenopathy, and splenomegaly.
RA is triggered by autoimmune mechanisms that lead to the destruction of
synovial tissue and other connective tissue. Both humoral and cellular immune mechanisms are involved in the pathogenesis of the disease. These mechanisms include the cytokine-mediated activation of T and B lymphocytes and the recruitment and activation of macrophages. The inflammatory leukocytes then release a variety of prostaglandins, cytotoxic compounds, and free radicals that cause joint inflammation and destruction.
Patients with RA show elevated levels of
immunoglobulin G-rheumatoid factor (IgG-RF) complexes; extracorporeal filtering of these complexes using immunoabsorption apheresis has helped some patients.
In patients with RA, NSAIDs are used to
relieve pain and inflammation
In patients with RA, DMARDs are used to
suppress the underlying disease process and slow the progression of joint destruction.
RA is an autoimmune disease that causes chronic, symmetrical inflammation of the joints. The disease can begin at any age, but most often starts after age
40 and before age 60
There are two main classes of medications used in treating RA:
the anti-inflammatory agents and the DMARD agents
celecoxib, aspirin, or cortisone are
anti-inflammatory agents, used to reduce pain and inflammation
methotrexate, leflunomide, hydroxychloroquine are
DMARD agents, which promote disease remission and prevent progressive joint destruction.
infliximab, anakinra, and adalimumab are
newer immunomodulating DMARD agents that are administered by the intravenous route
The most common DMARD used to treat RA is
Methotrexate
The use of the selective COX-2 inhibitor, celecoxib, is warranted given no stated history of
cardiovascular disease in the patient.
Osteoarthritis is also called
degenerative joint disease
Osteoarthritis, also called degenerative joint disease, is the
most common joint disease in the world. It affects about 10% of persons over 60 years of age, and radiographic evidence of osteoarthritis can be found in most persons over 65.
Factors that increase the risk for osteoarthritis include
obesity, osteoporosis, smoking, heredity, repetitive use of joints through work or leisure activities, and joint trauma.
Osteoarthritis primarily affects
weight-bearing joints and causes deformity, limitation of motion, and progressive disability. The cartilage undergoes thickening, inflammation, splitting, and thinning. Eventually, the cartilaginous layer is completely destroyed, leading to erosion and microfractures in the underlying bone.
The major symptoms of osteoarthritis are
pain, stiffness, and muscle weakness around affected joints.
Nonpharmacologic measures for treating osteoarthritis include
joint protection and splinting, physiotherapy, orthotic prostheses to support the feet, and joint replacement surgery.
Pharmacologic measures for treating osteoarthritis include
NSAIDs, local glucocorticoid injections, and experimental chondroprotective drugs (e.g., chondroitin sulfate and glucosamine). Recently, sodium hyaluronate (Supartz) was approved for intra-articular injection as a type of joint fluid replacement in the treatment of osteoarthritis. It is a sterile, viscoelastic solution prepared from chicken combs (the fleshy growths on top of chicken heads).
Gout is an
arthritic syndrome caused by an inflammatory response to crystals of monosodium urate monohydrate in joints, renal tubules, and other tissues. The deposition of these crystals occurs as a consequence of hyperuricemia, which can result from overproduction or underexcretion of uric acid.
Risk factors for gout include
obesity, alcohol consumption, and hypertension.
Acute gout is treated with
an NSAID or colchicine to relieve joint inflammation. Subsequent attacks of gout can be prevented by long-term therapy with a drug that either increases uric acid excretion or inhibits uric acid formation and thereby reduces the serum level of uric acid.
The nonsteroidal anti-inflammatory drugs comprise a large family of weak acidic drugs whose pharmacological effects result primarily from the inhibition of
cyclooxygenase (COX), an enzyme that catalyzes the first step in the synthesis of prostaglandins from arachidonic acid and other precursor fatty acids. COX is a microsomal enzyme, existing as a dimer (two molecules linked to form a functional unit) in the lumen and membrane of the endoplasmic reticulum. NSAIDs decrease COX activity primarily by competitive inhibition; however, aspirin forms a covalent, irreversible inhibition of COX. The net effect of NSAID administration is a decrease in the production of prostaglandins and other autacoids.
Prostaglandins play an important role in the development of
pain, inflammation, and fever
Prostaglandins are released from cells in response to
chemical stimuli or physical trauma. They sensitize sensory nerve endings to nociceptive stimuli and thereby amplify the generation of pain impulses. They also promote tissue inflammation by stimulating inflammatory cell chemotaxis, causing vasodilation and increasing capillary permeability and edema.
Bacterial toxins and other pyrogens stimulate the production of cytokines by leukocytes, and these cytokines increase prostaglandin synthesis in the preoptic area of the hypothalamus. The prostaglandins then act to
reset the body's thermostat to a new point above 37° C. This, in turn, activates temperature-raising mechanisms, such as a reduction in heat loss via cutaneous vasodilation, and causes the temperature to rise. All NSAIDs relieve fever by inhibiting prostaglandin synthesis in the hypothalamus, but these drugs are not capable of reducing body temperature below normal.
Cyclooxygenase is now known to occur in two major isoforms:
cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2)
COX-1 is a
constitutive or "housekeeping" enzyme that is found in relatively constant levels in various tissues. COX-1 participates in the synthesis of prostaglandins that have a cytoprotective effect on the gastrointestinal (GI) tract. It also catalyzes the formation of thromboxane A2 in platelets, leading to platelet aggregation and hemostasis.
COX-2 is an
inducible enzyme. Its levels are normally very low in most tissues but are rapidly up-regulated during the inflammatory process by proinflammatory substances (e.g., cytokines, endotoxins, and tumor promoters). Both COX-1 and COX-2 appear to participate in renal homeostasis.
Most of the NSAIDs available today are nonselective inhibitors of
COX-1 and COX-2. The discovery of COX isozymes led to the development of selective COX-2 inhibitors, the first one being celecoxib. These selective inhibitors are effective anti-inflammatory drugs, and they produce less GI bleeding and ulcers than do the nonselective COX inhibitors.
A third COX isozyme (COX-3), which was recently discovered, appears to be an alternative splice variant of
COX-1
Acetaminophen potently inhibits COX-3, and this finding likely explains the reason that acetaminophen has little
anti-inflammatory action.
Among the nonselective COX inhibitors are many well-known NSAIDs that are available without a prescription, including
aspirin, ibuprofen, ketoprofen, and naproxen. Acetaminophen is a weak anti-inflammatory agent, but it is also included in this class of drugs because it exerts analgesic and antipyretic effects via inhibition of COX.
NSAIDs vary greatly in potency and half-life, but most of them are administered
from two to four times a day with food.
Lower doses of NSAIDs are usually sufficient to treat mild to moderate pain and counteract fever, whereas higher doses are generally needed to relieve
inflammation associated with arthritic disorders and injuries
NSAIDs are particularly effective in relieving pain caused by
tissue inflammation or bone or joint trauma, and they can be combined with opioid analgesics to obtain a greater analgesic effect and reduce the need for higher doses of opioids.
NSAIDs are widely used in the treatment of postoperative pain, either alone or in combination with an
opioid
Acetaminophen
Nonselective COX Inhibitor
Relative Potency: 1
Half-Life (Hours): 3
Daily Doses: 4
Aspirin
Nonselective COX Inhibitor
Relative Potency: 1
Half-Life (Hours): 2
Daily Doses: 4
Ibuprofen
Nonselective COX Inhibitor
Relative Potency: 4
Half-Life (Hours): 2
Daily Doses: 2-4
Indomethacin
Nonselective COX Inhibitor
Relative Potency: 40
Half-Life (Hours): 4
Daily Doses: 1-3
Ketoprofen
Nonselective COX Inhibitor
Relative Potency: 20
Half-Life (Hours): 2
Daily Doses: 2-4
Ketorolac
Nonselective COX Inhibitor
Relative Potency: 100
Half-Life (Hours): 7
Daily Doses: 4
Naproxen
Nonselective COX Inhibitor
Relative Potency: 4
Half-Life (Hours): 14
Daily Doses: 2
Celecoxib
Selective COX-2 Inhibitors
Relative Potency: 20
Half-Life (Hours): 11
Daily Doses: 2
Although NSAIDs are effective in relieving the pain of chronic disorders, their long-term use is associated with a number of adverse effects, including
GI bleeding, peptic ulcers, and renal and hepatic dysfunction.
Acetaminophen produces fewer GI problems than do other nonselective COX inhibitors, but it also lacks
significant antiplatelet and anti-inflammatory activity.
Although acetaminophen can be used concurrently with another NSAID for supplemental analgesia, alternative combinations of two NSAIDs should generally be avoided, not only because they increase the risk of GI and other side effects but also because they sometimes have
adverse interactions. For example, aspirin and other salicylates displace some NSAIDs (e.g., ketorolac) from plasma proteins and thereby increase their serum levels significantly.
NSAIDs can interact with a large number of other drugs through pharmacokinetic and pharmacodynamic mechanisms. Most NSAIDs inhibit the renal excretion of
lithium and can increase lithium serum levels and toxicity.
NSAIDs can reduce the clearance of
methotrexate and aminoglycoside drugs.
NSAIDs can also interfere to varying degrees with the antihypertensive effect of
diuretics, β-adrenoceptor antagonists, angiotensin inhibitors, and other antihypertensive drugs.
When given with potassium-sparing diuretics, NSAIDs can cause
potassium retention and lead to hyperkalemia.
High doses of salicylates exert a
hypoglycemic effect that can alter the effects of antidiabetic drugs.
Indomethacin reduces the
natriuretic effect of diuretics and can cause nephrotoxicity when given with triamterene.
Low doses of acetaminophen can be safely used for
analgesia and antipyresis during pregnancy.
The use of other NSAIDs during the second half of pregnancy
is generally not recommended, however, because of potential adverse effects to the fetus. These effects result from prostaglandin inhibition and include GI bleeding, platelet inhibition, renal dysfunction, and premature closure of the ductus arteriosus.
The therapeutic value of salicylates was originally recognized when they were identified as the
active ingredients of willow bark and other plant materials used in folk medicine to relieve pain and fever.
Aspirin was synthesized in 1899 during a search for a salicylate derivative that would be
less irritating to the stomach than salicylic acid. Aspirin soon became widely used around the world as an analgesic, antipyretic, and anti-inflammatory drug.
Salicylic acid derivatives include
aspirin (acetyl-salicylic acid) and several nonacetylated drugs, such as salsalate, choline magnesium salicylate, and methyl salicylate (oil of wintergreen).
In adults, the salicylates can be used in the management of
pain, fever, and inflammation, as well as in the prophylaxis of myocardial infarction, stroke, and other thromboembolic disorder.
In children, the use of salicylates should be avoided, because
the risk of Reye's syndrome appears to be increased in virus-infected children who are treated with these drugs.
The analgesic, antipyretic, and anti-inflammatory effect of aspirin and other salicylates result from
nonspecific inhibition of COX in peripheral tissues and the CNS. Aspirin irreversibly acetylates platelet COX and has a longer-lasting effect on thromboxane synthesis than do other salicylates. The antiplatelet effect of aspirin persists for about 14 days, whereas that of most other NSAIDs is much shorter. The effect is long-lived, because platelets lack a nucleus and do not make new COX enzyme.
The salicylates are usually administered orally, but formulations are also available for
topical and rectal administration
The oral dosage of aspirin that is needed to inhibit platelet aggregation is
somewhat lower than the oral dosage needed to obtain analgesic and antipyretic effects, and it is much lower than the oral dosage needed to relieve inflammation caused by arthritic and other inflammatory disorders.
Aspirin is
well absorbed from the gut.
Aspirin is rapidly hydrolyzed to
salicylic acid (salicylate) by plasma esterase, and this accounts for its short plasma half-life (about 15 minutes). Most of the pharmacologic effects of aspirin are attributed to its salicylate metabolite, which has a half-life of about 2 hours. Aspirin itself, however, is responsible for irreversible inhibition of platelet COX and platelet aggregation.
Most of the salicylic acid formed from aspirin and other salicylate drugs is conjugated with
glycine to form salicyluric acid. This substance is then excreted in the urine, along with about 10% of free salicylate and a similar amount of glucuronide conjugates. The rate of excretion of salicylate is affected by urine pH. For this reason, alkalinization of the urine by administration of sodium bicarbonate has been used to increase the ionization and elimination of salicylic acid in cases of drug overdose
When a therapeutic dose of aspirin or other salicylate drug is ingested, the rate of metabolism and the rate of excretion of salicylate are proportional to the drug's
plasma concentration (first-order elimination)
When an excessive dose is taken, the elimination pathways become saturated, giving rise to
zero-order elimination. For this reason, larger doses can rapidly elevate plasma salicylate concentrations to toxic levels, especially in the elderly, who are at greatest risk of aspirin toxicity.
The use of aspirin in children with chickenpox and other viral infections has been associated with
Reye's syndrome
Therapeutic doses of aspirin can cause
gastric irritation and contribute to GI bleeding and peptic ulcers. Moderately high therapeutic doses can cause tinnitus, which is described as an abnormal auditory sensation or buzzing noise, and considered an early sign of salicylate toxicity.
Excessive doses of aspirin produce the toxic effects like
Hyperventilation which is caused by direct and indirect stimulation of the respiratory center in the medulla, and it often leads to increased exhalation of carbon dioxide and respiratory alkalosis. Higher plasma salicylate concentrations can cause fever, dehydration, and severe metabolic acidosis. If not treated promptly, these events can culminate in shock, coma, organ system failure, and death. Excessive doses of aspirin also cause hypoprothrombinemia, which is an impairment of hemostasis and causes bleeding.
Aspirin hypersensitivity is an uncommon but serious condition that can result in
severe and potentially fatal anaphylactic reactions
Symptoms of aspirin intolerance include
vasomotor rhinitis, angioedema, and urticaria (hives).
Aspirin sensitivity occurs most frequently in persons with
asthma, nasal polyps, or chronic urticaria.
Persons who have had a severe hypersensitivity reaction to aspirin or another salicylate should not be treated with another type of NSAID, because
a 5% risk of cross-sensitivity exists between salicylates and other NSAIDs.
The treatment of salicylate poisoning may include the following:
(1) induction of vomiting and gastric lavage to remove unabsorbed drug; (2) intravenous administration of sodium bicarbonate to counteract metabolic acidosis, increase the ionization of salicylate in the kidneys, and thereby enhance the rate of excretion of salicylate; and (3) administration of fluids, electrolytes, and other supportive care, as needed.
For more than 100 years, acetaminophen has been available for the treatment of
mild pain and fever. The drug is a p-aminophenol derivative that exerts analgesic and antipyretic effects at doses that are well tolerated and produce remarkably few adverse effects during short-term administration. Unlike aspirin use, acetaminophen use has not been associated with Reye's syndrome, so acetaminophen can be safely given to children with fever caused by viral illnesses.
Acetaminophen has only weak
anti-inflammatory activity, partly because it is inactivated by peroxides produced in the cells of inflamed tissue. Recent evidence suggests the existence of a third COX isoform, designated COX-3, with roles in mediating pain and fever, and subject to inhibition by acetaminophen. Acetaminophen has little effect on COX-1 or COX-2 and, thus, lacks anti-inflammatory activity.
Although acetaminophen is not considered a first-line drug for patients with arthritic disorders, it is sometimes used as an analgesic in those with
mild arthritis
Because acetaminophen lacks the ability to inhibit thromboxane synthesis and platelet aggregation, it is not used for the prophylaxis of
myocardial infarction, stroke, or other thromboembolic disorders.
Acetaminophen is rapidly absorbed from the gut, exhibits minimal binding to plasma proteins, and is
widely distributed to peripheral tissues and the CNS.
acetaminophen is extensively metabolized by several pathways in the liver. Most of the drug is conjugated with
sulfate and glucuronide, and these metabolites are excreted in the urine. A small amount of acetaminophen is converted by cytochrome P450 to a potentially hepatotoxic quinone intermediate.
When a therapeutic dose of acetaminophen is taken, the quinone intermediate is rapidly inactivated by conjugation with glutathione. Toxic doses of acetaminophen, however,
deplete hepatic glutathione, cause accumulation of the quinone intermediate, and lead to hepatic necrosis. To prevent liver damage, patients who ingest an overdose and are determined to be at risk for hepatotoxicity can be given acetylcysteine, a sulfhydryl compound that conjugates the quinone intermediate and renders it harmless.
Some epidemiologic evidence indicates that long-term use of acetaminophen is associated with an increased risk of
renal dysfunction
Although therapeutic doses of acetaminophen are remarkably nontoxic,
the ingestion of 20 to 30 tablets is sufficient to cause life-threatening hepatotoxicity.
Because hepatotoxicity gradually progresses over several days following an acetaminophen overdose,
prompt treatment with acetylcysteine can prevent or significantly reduce hepatotoxicity.
Ibuprofen, ketoprofen, and naproxen are among the most widely used NSAIDs for pain and inflammation caused by
trauma, infection, autoimmune disorders, neoplasms, joint degeneration, and other causes. By reversibly and nonselectively inhibiting COX isozymes, these drugs exert analgesic, antipyretic, and anti-inflammatory effects. Low-dose formulations of the drugs are available without prescription for the treatment of mild pain and inflammation. Formulations with higher doses are used to treat most arthritic disorders and still require a prescription.
Ibuprofen, ketoprofen, and naproxen are
administered orally, are widely distributed, and are extensively metabolized to inactive metabolites in the liver before undergoing renal excretion. Naproxen has a longer half-life (14 hours) than does ibuprofen or ketoprofen (2 hours each). For this reason, naproxen is given twice daily, whereas ibuprofen or ketoprofen is usually administered from two to four times a day.
Ibuprofen and related drugs produce
dose-dependent gastric irritation, nausea, dyspepsia, and bleeding. Long-term administration of high doses has been associated with peptic ulcer disease, but short-term use of low doses causes very few serious adverse effects. Among the serious effects that have been reported are hepatic toxicity and renal toxicity. In some cases, acute renal failure occurred following short-term use of therapeutic doses by patients who failed to ingest adequate fluids and became dehydrated.
Indomethacin, an indoleacetic acid derivative, is one of the most potent
inhibitors of COX isozymes. Because of its greater tendency to cause adverse effects, this drug is usually reserved for the management of moderate to severe acute inflammatory conditions. It is also used to treat infants with a patent ductus arteriosus. In these infants, indomethacin inhibits the synthesis of prostaglandins and thereby causes closure of the ductus arteriosus.
The incidence of GI and CNS side effects is higher with the use of
indomethacin than with the use of many other NSAIDs. Indomethacin therapy is also associated with a risk of serious hematological toxicity. Hence, therapy should be limited to short-term use whenever possible, and patients should be closely monitored.
Sulindac, which is structurally related to indomethacin, is actually a
prodrug converted to an active sulfide metabolite. The parent compound, sulindac sulfoxide, is inactive in COX inhibition assays done in vitro as biotransformation in the liver produces the active metabolite. It is noted for having a "renal-sparing" effect such that moderate doses alter renal prostaglandin production less than other NSAIDs. Besides sulindac use in the treatment of RA, it is also administered to treat adenomas in polyp disease.
Ketorolac is an arylacetic acid derivative. It has potent
analgesic activity and is one of the few NSAIDs that is available for parenteral use for either intravenous or intramuscular administration. In studies of mild to moderate postoperative pain, ketorolac produced a level of analgesia comparable to that produced by morphine but caused less nausea, vomiting, and drowsiness. Ketorolac, therefore, has been widely used for the short-term management of moderate pain, such as postoperative pain associated with dental surgery. Although the drug has also been used to treat migraine headaches, it does not appear to be superior to ibuprofen for treatment of musculoskeletal pain. The ophthalmic solution for ketorolac is used to treat allergic conjunctivitis and postoperative ocular inflammation.
Ketorolac causes fewer adverse GI and CNS effects than do opioid analgesics, but it poses a significant risk of
hematologic toxicity and other adverse effects. For this reason, oral or parenteral therapy with the drug must be limited to 5 or fewer days. In patients with renal or hepatic disease, ketorolac should be used with caution because it is associated with an increased risk of severe renal or hepatic impairment. A similar drug, bromfenac (Duract), was withdrawn from the market in 1998, following postmarketing reports of hepatic failure and death.
Piroxicam is an effective anti-inflammatory agent with potency equal to
aspirin or naproxen for the chronic treatment of RA. The main advantage of piroxicam is its 50-hour plasma half-life. This allows a single daily dose in most patients, although it can take up to 2 weeks to achieve maximal therapeutic effect.
One of the few nonacid NSAIDs, nabumetone, is a
ketone prodrug with weak COX inhibitory activity in vitro. It is converted to one or more active metabolites in vivo and a potent inhibition of COX activity occurs with these metabolites. It also has the advantage that a half-life of 20 hours allows once-daily dosing in most patients.
Other NSAIDs, including meloxicam and etodolac, which have been marketed in Europe or the United States as safer NSAIDs, were found after the discovery of COX-2 to be
preferential inhibitors of this enzyme. They are more selective for COX-2 than typical NSAIDs but not as selective as the remaining COX-2 inhibitor, celecoxib.
Diclofenac is available in a number of preparations including immediate-release, extended-release, a transdermal patch (Flector), and a new formulation for topical administration (Voltaren Gel). The latter formulation contains 1% diclofenac sodium indicated for treating
pain associated with osteoarthritis in joints amenable to topical treatment.
The selective COX-2 inhibitors are a new group of drugs that provide potent anti-inflammatory activity without causing
significant GI toxicity. Celecoxib (Celebrex), the first selective COX-2 inhibitor to be marketed, was soon followed by the release of rofecoxib (Vioxx) and valdecoxib (Bextra). Together, these agents are known as "coxibs."
In late 2004, the makers of rofecoxib voluntarily withdrew the drug from the market after data were analyzed from a clinical trial testing rofecoxib's effectiveness in preventing recurrence of colorectal polyps. This study found an increased relative risk for
confirmed cardiovascular events (e.g., heart attack and stroke) beginning after 18 months of treatment in the patients taking rofecoxib compared with those taking placebo.
Valdecoxib also showed an increased risk for
cardiovascular events in patients after heart surgery. Serious skin reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme) were reported in patients receiving valdecoxib. Some of these reactions resulted in fatalities. For these reasons, the U.S. Food and Drug Administration (FDA) removed valdecoxib from the market in 2005.
With regard to celecoxib, patients in a colon cancer clinical trial taking 400 mg of celecoxib twice daily had a
3.4 times greater risk of cardiovascular events compared with those taking placebo. For patients in the trial taking 200 mg of celecoxib twice daily, the risk was 2.5 times greater. As a result, the FDA recently strengthened the warnings for cardiovascular risk of the only remaining selective COX-2 inhibitor, celecoxib, and for all NSAID agents except aspirin.
While cardiovascular risk may dampen wider use of coxibs and other NSAID agents, recent studies show that NSAIDs can delay or slow the progress of
Alzheimer's disease. The neurodegeneration that occurs in this disease is accompanied by inflammatory mechanisms that involve COX and the activation of the complement cascade.
Increased expression of COX-2 is seen in some cancer cells and the angiogenesis essential to tumor growth requires COX-2 activity. Overexpression of COX-2 leads to increased expression of vascular endothelial growth factor, a factor vital to tumor angiogenesis. Regular use of NSAIDs may therefore decrease the risk of
developing cancer (particularly colon cancer), and especially so with the use of a COX-2 selective inhibitor.
Celecoxib is a potent
analgesic, antipyretic, and anti-inflammatory agent. This drug does not inhibit platelet aggregation, because platelets contain only the COX-1 isozyme.
In clinical studies of osteoarthritis and rheumatoid arthritis, celecoxib was shown to be
as efficacious as naproxen without causing significant side effects. In a study of postoperative pain management, however, celecoxib was reported to provide insufficient analgesia to control pain after general surgery. In laboratory studies, investigators found that celecoxib was more effective than nonselective COX inhibitors in protecting against colon carcinogenesis. This finding suggested a role for prophylactic coxib use in persons with a high risk of colon cancer; however, clinical trials were halted because of cardiovascular events
Celecoxib is available for
oral administration and is usually taken twice daily. The drug is rapidly absorbed from the gut, is metabolized by cytochrome P450 isozyme CYP2C9, and is excreted in the feces and urine. The half-life is about 11 hours.
Besides the risk of cardiovascular events, celecoxib appears to cause
a low incidence of adverse reactions, the most common of which are diarrhea, dyspepsia, and abdominal pain. This drug is associated with a much lower incidence of gastroduodenal ulcers than the nonselective NSAIDs (e.g., ibuprofen and naproxen).
Because celecoxib is metabolized by CYP2C9, drugs such as
fluconazole, fluvastatin, and zafirlukast may inhibit its metabolism and increase its serum concentration. Lower doses of celecoxib should be used in patients treated concurrently with these interacting drugs.
DMARDs are
DISEASE-MODIFYING ANTIRHEUMATIC DRUGS
DMARDs are agents capable of slowing the progression of
joint erosions in patients with RA.
Examples of DMARDs are
gold salts, glucocorticoids, hydroxychloroquine, methotrexate, and a number of newer immunologic agents, including leflunomide, etanercept, and infliximab. These drugs have a delayed onset of action and require several weeks to months before their antirheumatic benefits are observed. Several studies suggest that using a combination of DMARDs is more effective than using a single DMARD in many patients with RA.
Disease-modifying antirheumatic drugs act by various mechanisms to suppress the
proliferation and activity of lymphocytes and polymorphonuclear leukocytes and thereby counteract their ability to cause joint inflammation and destruction.
Because joint erosion is usually found within the first 2 years of RA, many rheumatologists prescribe DMARDs at
the time of diagnosis. The utility of DMARDs, however, is often limited by their toxicity or by their loss of efficacy over time, and many patients must cease taking them within 5 years of commencing therapy.
Gold salts were first used to treat RA in the late 1920s, from the finding of Robert Koch in 1890 that elemental gold inhibited the growth of
Mycobacterium tuberculosis and the mistaken belief that the swollen joints characteristic of RA were caused by these bacteria. They were once used extensively in the management of this disease, but their popularity has declined with the introduction of newer DMARDs, which tend to be more efficacious and less toxic.
The oral compound, auranofin, is
poorly absorbed from the gut, however, and may be less efficacious than parenteral preparations, such as gold sodium thiomalate (also called sodium aurothiomalate). A second preparation of gold for intravenous administration is available as aurothioglucose.
The antirheumatic effects of gold salts are usually not observed until
3 to 6 months after starting therapy.
Gold salts can cause
a variety of adverse hematologic, dermatologic, GI, and renal effects. Flushing, hypotension, and tachycardia are sometimes observed. Skin rash and stomatitis are commonly observed and require discontinuation of treatment until they resolve.
For many years, prednisone and other glucocorticoids have played an important role in the treatment of
RA. These drugs induce the formation of lipocortin, a protein that inhibits phospholipase A2 activity. By this mechanism, they inhibit the release of arachidonic acid from cell membranes and the formation of prostaglandins. Glucocorticoids also inhibit the production of numerous cytokines, including interleukins and tumor necrosis factor, by synthesis of proteins that inhibit their action.
Glucocorticoids act more rapidly than
other DMARDs, but their long-term use is limited by the development of serious adverse effects. In light of these facts, glucocorticoids have been used in various ways to manage patients with RA or other inflammatory joint diseases. For example, they have been used to induce a remission in the disease at the time that therapy with another (slower-acting) DMARD is started; to provide short courses of therapy during disease flare-ups; and to provide continuous low-dose background therapy in patients being treated with other DMARDs and NSAIDs.
Methotrexate is an
antineoplastic and immunomodulating drug
Methotrexate has several mechanisms of action. It inhibits
human folate reductase and thereby reduces the availability of active forms of folate that are required for thymidylate and DNA synthesis. It also inhibits lymphocyte proliferation and the production of cytokines and rheumatoid factor. In addition, it interferes with polymorphonuclear leukocyte chemotaxis and reduces the production of cytotoxins and free radicals that damage the synovial membrane and bone.
Methotrexate is considered the DMARD of choice for most patients with
RA. The drug can be given orally or intramuscularly and has a fairly rapid onset of action, with benefits observed as early as 2 to 3 weeks after therapy is started. From 45% to 55% of patients continue therapy for at least 5 to 7 years, and sustained efficacy for up to 15 years has been demonstrated in some patients. The combined use of methotrexate and other DMARDs is often more effective than single-drug therapy.
Treatment with methotrexate is generally well tolerated by patients with RA, but it can cause
adverse GI, hematologic, hepatic, and pulmonary reactions. Elevated liver enzyme levels are found in up to 15% of patients treated with methotrexate, but serious hepatotoxicity is rare. The administration of folic acid supplements does not reduce the drug efficacy and may prevent some of these adverse effects. The use of methotrexate is contraindicated in pregnancy.
Leflunomide is a newer immunosuppressive drug that acts as a powerful inhibitor of
leukocyte and T-cell proliferation. The active metabolite of leflunomide inhibits a key enzyme in pyrimidine synthesis, dihydroorotate dehydrogenase, and thereby prevents replication of DNA and synthesis of RNA and protein in immune cells. Leflunomide is converted to its active metabolite in the intestinal wall and liver. The active metabolite is further metabolized and excreted in the urine and feces, with an elimination half-life of about 2 weeks.
Leflunomide is marketed as an alternative to methotrexate for the first-line management of
RA. In a controlled trial, 41% of patients treated with leflunomide showed significant improvement in tender and swollen joints, compared with 35% of those treated with methotrexate and 19% given a placebo.
The adverse effects of leflunomide include
diarrhea and reversible alopecia (baldness). The drug can increase serum levels of hepatic enzymes and increase the risk of hepatotoxicity when it is used in combination with methotrexate. The active metabolite of leflunomide inhibits CYP2C9 and may thereby increase the serum level of many drugs, including ibuprofen and some of the other NSAIDs. Leflunomide is teratogenic, so its use is contraindicated in pregnancy.
Hydroxychloroquine, an antimalarial drug related to chloroquine, is extensively used as a
DMARD. It reduces the chemotaxis and phagocytosis of polymorphonuclear leukocytes and decreases the production of superoxide radicals by these cells. The drug has a slow onset of action and can require 6 months of therapy before benefits are observed. It does not produce the myelosuppressive, hepatic, and renal toxicities that many other DMARDs produce.
Hydroxychloroquine occasionally causes
GI disturbances, and patients undergoing hydroxychloroquine treatment must be monitored for adverse ocular effects, including blurred vision, scotomas, and night blindness.
Etanercept, Infliximab, Adalimumab, Anakinra and Abatacept are
Immunomodulators
Etanercept, infliximab, and adalimumab are immunomodulating agents that exert their effects by
binding to and inactivating tumor necrosis factor (TNF). TNF is one of the proinflammatory cytokines produced by macrophages and activated T cells. Elevated levels of TNF are found in the synovial fluid of joints and play an important role in both the pathologic inflammation and the joint destruction that are hallmarks of RA. Anakinra and abatacept have novel mechanisms of action and prevent interleukin binding T-cell activation respectively.
Etanercept is a protein formed by recombining human p75 (75-kd) TNF receptors with Fc fragments of human immunoglobulin G1 (IgG1). In comparison with the original protein, the recombined protein can
antagonize TNF to a greater extent and has a longer half-life. Experimental studies in several animal models of RA have found etanercept treatment to be effective, as have subsequent clinical trials in patients with this disease. According to a 3-month clinical study, 75% of patients with RA had a significant improvement in the signs and symptoms of their disease. The drug was generally well tolerated, although injection site reactions were common.
Etanercept must be administered
subcutaneously twice a week and is expensive (a 6-month supply costs about $6300 in the United States). The drug is currently intended for use in patients whose RA is refractory to treatment with methotrexate or other DMARDs. Etanercept can be used alone or in combination with methotrexate in these patients.
Infliximab is a
chimeric human-murine (mouse) monoclonal antibody that inactivates TNF. It is used in the treatment of Crohn's disease and RA. In one clinical trial, infliximab treatment resulted in an improvement of RA manifestations in 80% of patients whose disease was refractory to other drugs. In another study, infliximab was found to be more effective when combined with methotrexate than when used alone. Infliximab is administered intravenously at 4- to 12-week intervals.
Adalimumab is a human IgG1 monoclonal antibody specific for
for human TNF. It is made by recombinant DNA technology in a mammalian cell expression system and purified to exclude viral particles. For adult patients, adalimumab (40 mg) is administered every other week as a subcutaneous injection. During adalimumab treatment, administration of methotrexate, glucocorticoids, salicylates, NSAIDs, analgesics or other DMARDs can continue safely. Some patients not taking concomitant methotrexate may see additional benefits by increasing the frequency of adalimumab to 40 mg every week.
All TNF blocking agents, including adalimumab, produced
serious infections and sepsis, some fatal, during clinical trials. Many of the serious infections were seen in patients on concomitant immunosuppressive therapy that, in addition to their RA, could predispose them to infections. Tuberculosis and invasive opportunistic fungal infections were also noted during treatment with TNF blockers.
Lymphomas were also reported in patients treated with
TNF blocking agents. In clinical trials, patients with RA, particularly those with highly active disease, were at increased risk for the development of lymphoma. The role of TNF blockers in the development of this malignancy is not known.
Anakinra is a recombinant form of
the human interleukin-1 receptor antagonist (IL-1Ra), differing only by the addition of a single methionine residue at its amino terminus. It blocks the biologic activity of IL-1 by competitively inhibiting IL-1 binding to the interleukin-1 type I receptor (IL-1RI). IL-1 production is induced in response to inflammatory stimuli and mediates inflammatory and immunologic responses. IL-1 has a broad range of activities, including cartilage degradation by its induction of the rapid loss of proteoglycans, as well as stimulation of bone resorption. The levels of the naturally occurring IL-1Ra in synovial fluid of patients with RA are not sufficient to compete with the increased production of IL-1.
The recommended dose of anakinra is
100 mg/day administered daily by subcutaneous injection. The adverse effects are the same as for the TNF blockers, with serious infections and lymphoma of most concern.
Abatacept is a selective costimulation modulator and inhibits T-cell activation by
binding to cell surface markers (proteins) on leukocytes. Activated T lymphocytes are involved in the etiology of RA and are found in the synovial fluid of patients with RA. Abatacept is a recombinant protein made by joining the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) to the modified Fc portion of human IgG1. It is the CTLA part of the molecule that binds to specific cell surface proteins of T-lymphocytes to prevent their activation.
Sulfasalazine was developed and is a formulation combining an anti-inflammatory drug, 5-amino salicylic acid, with an
antibacterial drug, sulfapyridine. Recent experiments suggest that it is sulfapyridine that is active against RA, but the exact mechanism is not known.
D-penicillamine is a penicillin-derived compound used frequently in the past, but its use today has declined with the increasing use of other disease modifying anti-rheumatic drugs (e.g., methotrexate). It is not understood exactly how penicillamine provides a benefit in RA, but it is known to reduce
the blood levels of inflammatory cytokines. Penicillamine effects can take up to 3 months to manifest; however, if no effect is seen in a year, it should be stopped.
The effective management of gout often requires the use of various agents to
prevent and treat acute attacks.
Gout attacks can be prevented by
lowering the serum concentration of uric acid. Probenecid and sulfinpyrazone accomplish this goal by increasing the excretion of uric acid, whereas allopurinol does so by inhibiting the synthesis of uric acid.
Probenecid, is used to prevent gout attacks in persons who
under-excrete uric acid, as indicated by a 24-hour uric acid excretion that is less than 800 mg.
Probenecid is a weak acid that
competitively inhibits the reabsorption of uric acid by renal tubules and thereby increases the excretion of uric acid. The drug is taken orally and should be swallowed with a full glass of water to ensure adequate fluid intake. Treatment should begin with a low dose, and the dosage should be gradually increased until an adequate uricosuric effect is obtained or the maximal dosage is reached. Probenecid treatment is usually well tolerated.
The use of aspirin and other salicylates can alter or interfere with the
uricosuric effect of probenecid, so patients should avoid concurrent use of these agents. High doses of salicylates inhibit uric acid reabsorption and exert a uricosuric effect. Low doses of salicylates, however, inhibit uric acid secretion by renal tubules and thereby increase serum concentrations of uric acid.
Sulfinpyrazone is another uricosuric agent that
competitively inhibits the active reabsorption of urate at the proximal renal tubule. As with probenecid, it increases the urinary excretion of uric acid and lowers serum urate concentrations. Although sulfinpyrazone lacks clinically useful anti-inflammatory or analgesic activity, it inhibits prostaglandin synthesis and shares some of the risks associated with NSAIDs, including the potential for causing GI, renal, or hematologic adverse effects.
Allopurinol is used to prevent gout attacks in persons who
overproduce uric acid, as indicated by a 24-hour uric acid excretion that is greater than 800 mg. It is also sometimes used to prevent hyperuricemia and gout in persons who are having cancer chemotherapy and whose rate of purine catabolism is high because of the death of neoplastic cells.
Allopurinol and its active metabolite, oxypurinol (also called alloxanthine), decrease the production of uric acid by inhibiting
xanthine oxidase, the enzyme that converts hypoxanthine to xanthine and xanthine to uric acid. Allopurinol is a competitive inhibitor of xanthine oxidase. In contrast to uricosuric drugs, allopurinol causes a decrease in uric acid excretion and a corresponding increase in the urinary excretion of hypoxanthine.
Allopurinol increases reutilization of hypoxanthine and xanthine for nucleotide and nucleic acid synthesis via inhibition of hypoxanthine-guanine phosphoribosyltransferase. The resultant increase in nucleotide concentration leads to increased feedback inhibition of de novo purine synthesis. By lowering both serum and urine concentrations of uric acid below its solubility limits, allopurinol prevents or decreases
urate deposition, thereby preventing the occurrence or progression of both gouty arthritis and urate nephropathy.
Allopurinol is administered
orally. Most of the drug is rapidly converted to its active metabolite, oxypurinol, in the liver. Oxypurinol has a half-life of about 20 hours; most of this metabolite is excreted unchanged in the urine.
About 25% of patients are unable to tolerate allopurinol because of its adverse effects, which include
nausea, vomiting, hepatitis, skin rashes, and other forms of hypersensitivity. Because allopurinol inhibits the catabolism of azathioprine and mercaptopurine, doses of these drugs may need to be reduced if allopurinol is given concurrently with either of them.
In patients with acute gout
indomethacin is given for the rapid relief of pain.
Colchicine was traditionally used to treat acute gout, but it is less frequently used today because of its unpleasant side effects, which include
nausea, vomiting, diarrhea, and abdominal cramps. The drug is believed to act by disrupting microtubules and inhibiting the motility of inflammatory leukocytes and thereby blocking their ability to cause urate crystal-induced joint inflammation. Colchicine is rapidly absorbed after oral administration. It is partly metabolized in the liver, and the drug and its metabolites are excreted by the biliary and fecal route. If colchicine treatment causes the adverse effects noted above, treatment should be stopped to avoid more serious toxicity.
NSAIDs act primarily by inhibiting
COX and the synthesis of prostaglandins. The drugs exhibit varying degrees of analgesic, anti-inflammatory, and antipyretic activity. Most of them also inhibit platelet aggregation.
Long-term use of NSAIDs can lead to
renal or hepatic toxicity.
Nonselective COX inhibitors include
acetaminophen, aspirin, ibuprofen, indomethacin, ketoprofen, ketorolac, and naproxen. Except for acetaminophen, the agents in this group can cause gastric irritation and bleeding, and their long-term use can lead to peptic ulcers.
Acetaminophen is an effective analgesic and antipyretic agent, but it lacks
significant anti-inflammatory and antiplatelet activity.
A minor metabolite of acetaminophen is a
potentially hepatotoxic quinone. This quinone metabolite is normally inactivated by conjugation with glutathione, but toxic doses of acetaminophen can deplete glutathione and cause fatal liver failure.
Acetylcysteine, a sulfhydryl compound that conjugates and inactivates the quinone metabolite of acetaminophen, is used as an
antidote for acetaminophen hepatotoxicity
Low doses of aspirin have potent antiplatelet effects because they
acetylate and irreversibly inhibit platelet COX.
Low doses of aspirin also produce analgesic and antipyretic effects, but higher doses are needed to
counteract inflammation.
High therapeutic doses of aspirin can cause
tinnitus. Toxic doses cause hyperventilation and respiratory alkalosis, followed by metabolic acidosis.
In cases of severe aspirin toxicity,
sodium bicarbonate can be given to counteract acidosis and increase urinary excretion of salicylic acid.
Ibuprofen, ketoprofen, and naproxen are potent NSAIDs that are widely used as
analgesic, antipyretic, and anti-inflammatory agents.
Ketorolac is a potent analgesic that can be given
orally or parenterally. To avoid hematologic toxicity, ketorolac use should be limited to a few days.
Indomethacin is a potent
COX inhibitor that can be used to treat moderate to severe acute inflammatory conditions. It is also used to cause closure of the ductus arteriosus in infants.
Celecoxib, the first and only selective COX-2 inhibitor now available, is a potent
analgesic, antipyretic, and anti-inflammatory drug. Its incidence of GI bleeding and peptic ulcers is lower than that of nonselective COX inhibitors. Increased risk of cardiovascular events for celecoxib and all nonaspirin NSAIDs is now a concern with chronic administration.
DMARDs are agents capable of
slowing the progression of joint erosions in patients with RA. These drugs have a slow onset of action and can cause considerable toxicity.
DMARDs act by
inhibiting the proliferation and activity of lymphocytes and polymorphonuclear leukocytes.
Methotrexate, the most widely used and effective DMARD, can be
combined with other drugs in this class for enhanced activity. It is generally well tolerated and can be used effectively for many years.
Etanercept, infliximab, and adalimumab are DMARDs that
bind to and inactivate TNF.
Abatacept decreases
T-cell activation.
Anakinra blocks the biologic activity of
IL-1 by competitively inhibiting IL-1 binding to IL-1RI. These drugs are administered intermittently by injection and appear to benefit many patients with RA, but all carry the risk of increased infections.
Other DMARDs include
gold salts, glucocorticoids, leflunomide, hydroxychloroquine, sulfasalazine, and penicillamine.
Gout is caused by
hyperuricemia and the deposition of urate crystals in joints.
Uricosuric drugs (e.g., probenecid and sulfinpyrazone) increase
uric acid excretion
allopurinol inhibits
uric acid formation. These drugs are used to prevent gout attacks.
Acute gout is treated with
an NSAID (e.g., indomethacin) or colchicine.
Colchicine inhibits
the motility of leukocytes and thereby prevents their migration into joints and their ability to cause urate crystal-induced joint inflammation.