I. OVERVIEW• Inflammation is a normal protective response to tissue injury caused

by physical trauma, noxious chemicals, or microbiologic agents.

• Inflammation is the body's effort to inactivate or destroy invading organisms, remove irritants. When healing is complete, the inflammatory process usually subsides.

• However, inflammation is sometimes inappropriately triggered by an innocuous agent, such as pollen, or by an autoimmune response, such as in asthma or rheumatoid arthritis. In such cases (asthma or rheumatoid arthritis), the defense reactions themselves may cause progressive tissue injury, and anti-inflammatory or immuno-suppressive drugs may be required to modulate the inflammatory process.

II. Prostaglandins• All NSAIDs act by inhibiting the synthesis of

prostaglandins.

• A. Role of prostaglandins as local mediators• Prostaglandins and related compounds are produced in

minute quantities by virtually all tissues. They generally act locally on the tissues in which they are synthesized, and they are rapidly metabolized to inactive products at their sites of action. Therefore, the prostaglandins do not circulate in the blood in significant concentrations.

B. Synthesis of prostaglandins• Arachidonic acid is present as a component of the

phospholipids of cell membranes-primarily phosphatidyl inositol and other complex lipids.

• Free arachidonic acid is released from tissue phospholipids by the action of phospholipase A2.

• There are two major pathways in the synthesis of the eicosanoids from arachidonic acid.

Cyclooxygenase pathway• Two related isoforms of the cyclooxygenase

enzymes have been described.

• Cyclooxygenase-1 (COX-1) • Cyclooxygenase-2 (COX-2)

LTD4LTC4LTB4TXA2PGI2PGF2PGE2Effects

أو أو؟Vascular tone

؟Bronchial tone

؟؟؟

(uterus tone)

أو ؟؟؟؟Platelet agglutination

؟؟؟؟؟؟Chemotaxis

?= Unknown effects

1. Cyclooxygenase pathway• All prostaglandins, thromboxanes, and prostacyclins, are

synthesized via the cyclooxygenase (COX) pathway.

• Two related isoforms of the COX enzymes have been described:

• COX-1 is responsible for the physiologic production of prostanoids. COX-1 is described as a "housekeeping enzyme" that regulates normal cellular processes, such as gastric cytoprotection, vascular homeostasis, platelet aggregation, and kidney function.

• COX-2 causes the elevated production of prostanoids that occurs in sites of disease and inflammation. COX-2 is constitutively expressed in some tissues, such as the brain, kidney, and bone.

COX-1physiologic production

of prostanoids

housekeeping enzymeregulates normal cellular

processes(gastric cytoprotection, vascular homeostasis,

platelet aggregation, and kidney function)

COX-2 increases production of prostanoids in sites of

disease and inflammation.

Structural differences between COX-1 and COX2 permitted development of

COX-2-selective inhibitors.

COX-2 inhibited by glucocorticoidssignificant anti-

inflammatory effects of these drugs.

Cyclooxygenase pathway

2. Lipoxygenase pathway• Alternatively, several lipoxygenases can act on arachidonic

acid to form 5-HPETE, 12-HPETE, and 15-HPETE, which are unstable peroxidated derivatives that are converted to the corresponding hydroxylated derivatives (the HETES) or to leukotrienes or lipoxins, depending on the tissue.

• Antileukotriene drugs, such as zileuton, zafirlukast, and montelukast, are useful for the treatment of moderate to severe allergic asthma.

C. Actions of prostaglandins• Actions of prostaglandins are mediated by their binding

to cell membrane receptors that operate via G proteins, which subsequently activate or inhibit adenylyl cyclase or stimulate phospholipase C.

• This causes an enhanced formation of diacylglycerol and inositol 1,4,5-trisphosphate (IP3).

• Prostaglandin F2α (PGF2α), the leukotrienes, and thromboxane A2 (TXA2) mediate certain actions by activating phosphatidylinositol metabolism and causing an increase of intracellular Ca2+.

• D. Functions of prostaglandins in the body• Prostaglandins functions vary widely depending on the

tissue. • Release of TXA2 from platelets triggers recruitment of

new platelets for aggregation (first step in clot formation).

• Elevated levels of TXA2 in certain smooth muscle, this compound induces contraction.

• Prostaglandins are released in allergic and inflammatory processes.

Summary of anti-inflammatory drugs • COX-2 INHIBITORS• Celecoxib• OTHER ANALGESICS• Acetaminophen• DRUGS FOR ARTHRITIS• Adalimumab Anakinra

Chloroquine Etanercept Gold salts Infliximab Leflunomide Methotrexate D-Penicillamine

• DRUGS FOR GOUT• Allopurinol Colchicine

Probenecid Sulfinpyrazone

• ANTI-INFLAMMATORY DRUGS

• NSAIDs• Aspirin Diflunisal • Diclofenac Etodolac • Fenamates Fenoprofen

Flurbiprofen Ibuprofen Indomethacin Ketoprofen Meloxicam Methylsalicylate Nabumetone Naproxin Nimesulide Oxaprazin Piroxicam Sulindac Tolmetin

III. Nonsteroidal Anti-inflammatory Drugs

• NSAIDs are a group of chemically dissimilar agents that differ in their antipyretic, analgesic, and anti-inflammatory activities.

• They act primarily by inhibiting the cyclooxygenase enzymes that catalyze the first step in prostanoid biosynthesis. This leads to decreased prostaglandin synthesis.

• Long-term treatment with COX-2 inhibitors have been shown to increase risks of myocardial infarctions and strokes, and several of these drugs have been withdrawn.

• Many experts believe that long-term therapy with older, nonspecific NSAIDs (not including aspirin) may also cause similar problems.

• Patients are now advised to take the lowest dose that is effective for as short a period as possible.

• A. Aspirin and other salicylates• B. Propionic acid derivatives (Ibuprofen, naproxen,

fenoprofen, ketoprofen , fIurbiprofen, oxaprozin).• C. Acetic acid derivatives (indomethacin , sulindac,

etodolac)• D. Oxicam derivatives (Piroxicam and meloxicam)• E. Fenamates (Mefenamic acid, meclofenamate)• F. Other agents (diclofenac, ketorolac, tolmetin and

nabumetone, diflunisal).

NSAID (Nonsteroidal antiinflammatory drugs)

A. Aspirin and other salicylates• Aspirin is prototype of traditional NSAIDs. It is

commonly used and is the drug to which all other anti-inflammatory agents are compared.

• However, about 15% of patients show an intolerance to aspirin. Therefore, these individuals may benefit from other NSAIDs.

• Advantages of newer NSAIDs compared with aspirin

• greater anti-inflammatory activity• less gastric irritation• taken less frequently

• Disdvantages of newer NSAIDs compared with aspirin• More expensive• More toxic in other ways.

1. Mechanism of action

• Aspirin is a weak organic acid that is unique among the NSAIDs in that it irreversibly acetylates (and thus inactivates) cyclooxygenase.

• The other NSAIDs are all reversible inhibitors of cyclooxygenase.

• Aspirin is rapidly deacetylated by esterases in the body, producing salicylate, which has anti-inflammatory, antipyretic, and analgesic effects.

• The antipyretic and anti-inflammatory effects of the salicylates are due primarily to blockade of prostaglandin synthesis at the thermoregulatory centers in the hypothalamus and at peripheral target sites.

• Furthermore, by decreasing prostaglandin synthesis, the salicylates also prevent sensitization of pain receptors to both mechanical and chemical stimuli.

• Aspirin may also depress pain stimuli at subcortical sites (that is, the thalamus and hypothalamus).

2. Actions

• The NSAIDs, including aspirin, have three major therapeutic actions.

• They reduce inflammation (anti-inflammation), pain (analgesia), and fever (antipyrexia).

• However not all NSAIDs are equally potent in each of these actions.

2. Actions

• a. Anti-inflammatory actions• b. Analgesic action• c. Antipyretic action• d. Respiratory actions• e. Gastrointestinal effects• f. Effect on platelets• g. Actions on the kidney

• a. Anti-inflammatory actions:Because aspirin inhibits COX activity, it diminishes formation of PGs .

• Aspirin inhibits inflammation in arthritis, but it neither arrests the progress of the disease nor induces remission.

• Acetaminophen has weak anti-inflammatory activity, and is not useful in treatment of inflammation, such as that seen with rheumatoid arthritis.

• b. Analgesic action: PGE2 is thought to sensitize nerve endings to chemical mediators (e.g., bradykinin, histamine), which are released locally by the inflammatory process.

• By decreasing PGE2 synthesis, aspirin and other NSAIDs block the sensation of pain. Salicylates are used for management of pain of low to moderate intensity arising from integumental (cutaneous) structures rather than that arising from the viscera.

• NSAIDs are superior to opioids for management of pain in which inflammation is involved. However, combinations of opioids and NSAIDs are effective in treating pain caused by a malignancy.

c. Antipyretic action: • Fever occurs when the set-point of the anterior

hypothalamic thermoregulatory center is elevated.

• Fever can be caused by PGE2 synthesis, stimulated when an endogenous fever-producing agent (pyrogen), such as a cytokine, is released from white cells that are activated by infection, hypersensitivity, malignancy, or inflammation.

• The salicylates lower body temperature in patients with fever by impeding PGE2 synthesis and release.

• Aspirin resets the "thermostat" toward normal, and it rapidly lowers the body temperature of febrile patients by increasing heat dissipation as a result of peripheral vasodilation and sweating.

• Aspirin has no effect on normal body temperature.

• d. Respiratory actions:• Therapeutic doses of aspirin increases alveolar

ventilation. Salicylates uncouple oxidative phosphorylation, which leads to elevated CO2 and increased respiration.

• Higher doses work directly on respiratory center in the medulla, resulting in hyperventilation and respiratory alkalosis.

• At toxic levels, central respiratory paralysis occurs, and respiratory acidosis due to continued production of CO2.

e. Gastrointestinal effects:• Prostacyclin (PGI2) inhibits gastric acid secretion,

whereas PGE2 and PGF2α stimulate synthesis of protective mucus in both stomach and small intestine.

• Aspirin, these prostanoids are not formed, resulting in increased gastric acid secretion and diminished mucus protection. This may cause epigastric distress, ulceration, and/or hemorrhage.

• At ordinary aspirin doses, as much as 3 to 8 ml of blood may be lost in the feces per day.

• Buffered and enteric-coated preparations are only marginally helpful in dealing with this problem.

• The PGE1 derivative misoprostol, the proton pump inhibitor omeprazol, and H2-antihistamines also reduce the risk of gastric ulcer, and are used in the treatment of gastric damage induced by NSAIDs.

f. Effect on platelets:• TXA2 enhances platelet aggregation, whereas

PGI2 decreases it.

• Low doses (60-80 mg daily) of aspirin can irreversibly inhibit thromboxane production in platelets without markedly affecting TXA2 production in the endothelial cells of the blood vessel.

f. Effect on platelets:• The acetylation of COX is irreversible. • Because platelets lack nuclei, they cannot

synthesize new enzyme, and the lack of thromboxane persists for the lifetime of the platelet (3- 7days).

• This contrasts with the endothelial cells, which have nuclei and, therefore, can produce new COX.

• As a result of the decrease in TXA2, platelet aggregation is reduced, producing an anticoagulanteffect with a prolonged bleeding time.

• g. Actions on the kidney:• COX inhibitors prevent synthesis of PGE2 and PGl2-

prostaglandins (responsible for maintaining renal blood flow) particulary in presence of circulating vasoconstrictors.

• Decreased synthesis of prostaglandins can result in retention of sodium and water and may cause edema and hyperkalemia in some patients.

• Interstitial nephritis can also occur with all NSAIDs except aspirin.

3. Therapeutic usesa. Antipyretics and analgesicsb. External applications: used topically to treat corns, calluses, and

epidermophytosisc. Cardiovascular applications: Salicylates are used to inhibit

platelet aggregation. Low doses of aspirin are used prophylactically to decrease the incidence of transient ischemic attack and unstable angina in men as well as that of coronary artery thrombosis.

d. Colon cancer: There is evidence that chronic use of aspirin reduces the incidence of colorectal cancer.

Aspirin: Doses and Uses• Low dose (160 to 325 mg/day) reduces the incidence of recurrent

myocardial infarction, and to reduce the mortality in post-myocardial infarction patients.

• 650 mg aspirin tablets administered four times a day produce analgesia.

• Higher doses (> 4 grams/day) produce both analgesic and anti-inflammatory activity.

• At normal low dosages, aspirin is hydrolyzed to salicylate and acetic acid by esterases in tissues and blood.

• Salicylate is converted by the liver to water-soluble conjugates that are rapidly cleared by the kidney, resulting in elimination with first-order kinetics and a serum half-life of 3.5 hours.

• At anti-inflammatory dosages (>4 g/day), the hepatic metabolic pathway becomes saturated, and zero-order kinetics are observed, with the drug having a halflife of 15 hours or more. Saturation of hepatic enzymes requires treatment for several days to one week.

5. Adverse effects• a. Gastrointestinal: epigastric distress, nausea, and

vomiting and GI bleeding. • b. Blood: prolonged bleeding time. • c. Respiration: respiratory depression and metabolic

acidosis (in toxic doses).• e. Hypersensitivity: urticaria, bronchoconstriction, or

angioneurotic edema. Fatal anaphylactic shock is rare.• f. Reye syndrome: fatal, fulminating hepatitis with

cerebral edema.

5. Adverse effects• a. Gastrointestinal: The most common gastrointestinal (GI) effects

of the salicylates are epigastric distress, nausea, and vomiting. Microscopic GI bleeding is almost universal in patients treated with salicylates.

• Aspirin is an acid. At stomach pH, aspirin is uncharged; consequently, it readily crosses into mucosal cells, where it ionizes (becomes negatively charged) and becomes trapped, thus potentially causing direct damage to the cells. Aspirin should be taken with food and large volumes of fluids to diminish GI disturbances. Alternatively, misoprostol may be taken concurrently.]

• b. Blood: The irreversible acetylation of platelet COX reduces the level of platelet TXA2, resulting in inhibition of platelet aggregation and a prolonged bleeding time. For this reason, aspirin should not be taken for at least one week prior to surgery. When salicylates are administered, anticoagulants may have to be given in reduced dosage.

• c. Respiration: In toxic doses, salicylates cause respiratory depression and a combination of uncompensated respiratory and metabolic acidosis.

• e. Hypersensitivity: Approximately 15% of patients taking aspirin experience hypersensitivity reactions. Symptoms of true allergy include urticaria, bronchoconstriction, or angioneurotic edema. Fatal anaphylactic shock is rare.

• f. Reye syndrome: Aspirin given during viral infections has been associated with an increased incidence of Reye syndrome, which is an often fatal, fulminating hepatitis with cerebral edema. This is especially encountered in children, who therefore should be given acetaminophen instead of aspirin when such medication is required to reduce fever.

• g. Drug interactions:Concomitant administration of salicylates with many classes of drugs may produce undesirable side effects (Figure).

6. Toxicity• Salicylate intoxication may be mild or severe. • The mild form is called salicylism, and is characterized

by nausea, vomiting, hyperventilation, headache, mental confusion, dizziness, and tinnitus.

• When large doses of salicylate are administered, severe salicylate intoxication may result. The symptoms listed above are followed by restlessness, delirium, hallucinations, convulsions, coma, respiratory and metabolic acidosis, and death from respiratory failure.

• Children are particularly prone to salicylate intoxication.

• Ingestion of as little as 10 g of aspirin (or 5 g of methyl salicylate) can cause death in children. Treatment of salicylism should include measurement of serum salicylate concentrations and of pH to determine the best form of therapy.

• In mild cases, symptomatic treatment is usually sufficient. Increasing the urinary pH enhances the elimination of salicylate.

• In serious cases, mandatory measures include the intravenous administration of fluid, dialysis, and the frequent assessment and correction of acid-base and electrolyte balances. Diflunisal does not cause salicylism.

B. Propionic acid derivatives• Ibuprofen, naproxen, fenoprofen, ketoprofen , fIurbiprofen.• All these drugs possess anti-inflammatory, analgesic, and

antipyretic activity. They have gained wide acceptance in the chronic treatment of rheumatoid arthritis and osteoarthritis, because their gastrointestinal effects are generally less intense than that of aspirin.

• These drugs are reversible inhibitors of the cyclooxygenases, inhibit synthesis of prostaglandins but not of leukotrienes.

• Adverse effects: GI, ranging from dyspepsia to bleeding. Side effects involving CNS, such as headache, tinnitus, and dizziness, have also been reported.

C. Acetic acid derivatives• indomethacin , sulindac , etodolac . • They have anti-inflammatory, analgesic, and antipyretic activity. • They act by reversibly inhibiting cyclooxygenase. • They are generally not used to lower fever. • Toxicity of indomethacin limits its use to the treatment of acute

gouty arthritis, ankylosing spondylitis, and osteoarthritis of the hip. • Sulindac is an inactive prodrug that is closely related to

indomethacin. Although the drug is less potent than indomethacin, it is useful in the treatment of rheumatoid arthritis, ankylosingspondylitis, osteoarthritis, and acute gout.

• The adverse reactions caused by sulindac are similar to, but less severe than, those of the other NSAIDs, including indomethacin. Etodolac has effects similar to those of the other NSAIDs. GI problems may be less common.

D. Oxicam derivatives• Piroxicam and meloxicam are used to treat rheumatoid

arthritis, ankylosing spondylitis, and osteoarthritis. They have long half-lives, which permit administration once a day. GI disturbances are encountered in approximately 20% percent of patients treated with piroxicam.

• Meloxicam is relatively COX-2 selective and at low to moderate doses shows less GI irritation than piroxicam. However, the ability of meloxicam at therapeutic dosage to spare COX-1 is dose-related.

• At high doses, meloxicam is a nonselective NSAID, inhibiting both COX-1 and COX-2.

E. Fenamates• Mefenamic acid and meclofenamate have no advantages

over other NSAIDs as anti-inflammatory agents.

• Mefenamic acid – use for short-term relief of mild to moderate pain including primary dysmenorrhea

• Their side effects, such as diarrhea, can be severe, and are associated with inflammation of the bowel. Cases of hemolytic anemia have been reported.

• Other NSAIDs• Diclofenac is approved for long-term use. Diclofenac

accumulates in synovial fluid. An ophthalmic preparation is also available.

• Ketorolac: oral route, intramuscularly in treatment of postoperative pain.

• Diflunisal: A derivative of salicylic acid, diflunisal is not metabolized to salicylate and, therefore, cannot cause salicylate intoxication.

• Diflunisal is 3-4 fold more potent than aspirin as an analgesic and an anti-inflammatory agent, but it has no antipyretic properties. Diflunisal does not enter the CNSand, therefore, cannot relieve fever.

Cox-2-Selective NSAIDs• The structural difference between COX-1 and COX-2 has

allowed the development of COX-2-selective agents, such as celecoxib and valdecoxib.

• Most of traditional NSAIDs inhibit both COX-1 and COX-2. • Some traditional NSAIDs (etodolac, meloxicam, and nimesulide)

display some level of COX-2 selectivity. • COX-2 drugs • Have no significant effects on platelets• May cause renal insufficiency and increase risk of

hypertension• Chronic use of NSAIDs in high risk patients for NSAID-

related gastroduodenal toxicity, therapy with a COX-2-selective inhibitor is a reasonable option.

A. Celecoxib• Celecoxib is significantly more selective for reversible

inhibition of COX-2 than of COX-1. • Celecoxib was approved for treatment of osteoarthritis and

rheumatoid arthritis. • Celecoxib does not inhibit platelet aggregation and does

not increase bleeding time.• Its half-life is about eleven hours; thus, the drug is usually

taken once a day.• Celecoxib is contraindicated in patients who are allergic to

sulfonamides. If there is a history of sulfonamide drug allergy, then use of a nonselective NSAID along with a protonpump inhibitor is recommended.

The incidence of gastroduodenal ulcers in patients taking celecoxib was less that found in patients taking naproxen, diclofenac, or ibuprofen.

• 2. Adverse effects: Abdominal pain, diarrhea, and dyspepsia are most common adverse effects.

• Patients who have had anaphylactoid reactions to aspirin or nonselective NSAIDs may be at risk for similar effects when challenged with COX-2 selective agents.

• Inhibitors of CYP2C9, such as fluconazole, fluvastatin, and zafirlukast, may increase serum levels of celecoxib.

• Celecoxib has the ability to inhibit CYP2D6 and, thus, could lead to elevated levels of some -blockers, antidepressants, and antipsychotic drugs.

A. Acetaminophen• Acetaminophen inhibits prostaglandin synthesis in

the CNS. This explains its antipyretic and analgesic properties.

• Acetaminophen has less effect on cyclooxygenase in peripheral tissues, which accounts for its weak anti-inflammatory activity.

• Acetaminophen does not affect platelet function or increase blood clotting time.

• 1. Therapeutic uses: Acetaminophen is substitute for the analgesic and antipyretic effects of aspirin for those patients with gastric complaints, for those for whom prolongation of bleeding time would be a disadvantage, or those who do not require the anti-inflammatory action of aspirin.

• Acetaminophen is the analgesic/antipyretic of choice for children with viral infections or chickenpox (aspirin increases risk of Reye syndrome).

• Acetaminophen does not antagonize the uricosuric agent probenecid and, therefore, may be used in patients with gout who are taking that drug.

• 2. Pharmacokinetics: Acetaminophen is rapidly absorbed from the GI tract. A significant first-pass metabolism occurs in the luminal cells of the intestine and in the hepatocytes.

• Under normal circumstances, acetaminophen is conjugatedin the liver to form inactive glucuronidated or sulfated metabolites.

• A portion of acetaminophen is hydroxylated to form N-acetylbenzoiminoquinone-a highly reactive and potentially dangerous metabolite that reacts with sulfhydryl groups.

• At normal doses of acetaminophen, the N-acetylbenzoiminoquinone reacts with the sulfhydryl group of glutathione, forming a nontoxic substance. Acetaminophen and its metabolites are excreted in the urine.

• 3. Adverse effects: With normal therapeutic doses, acetaminophen is virtually free of any significant adverse effects. Skin rash and minor allergic reactions occur infrequently.

• Renal tubular necrosis and hypoglycemic coma are rarecomplications of prolonged, large-dose therapy.

• With large doses of acetaminophen, the available glutathione in the liver becomes depleted, and N-acetylbenzoiminoquinone reacts with the sulfhydryl groups of hepatic proteins, forming covalent bonds. Hepatic necrosis, a very serious and potentially life-threatening condition, can result. Renal tubular necrosis may also occur.

• N-acetylcysteine , Administration of, which contains sulfhydryl groups to which the toxic metabolite can bind, can be lifesaving if administered within ten hours of the overdose.

N-acetylcysteine

DOSAGE FORMS: Antidote, Mucolytic Agent• Injection, solution:• Acetadote®: 20% [200 mg/mL] (30 mL)

• Solution, inhalation/oral: 10% [100 mg/mL]; 20% [200 mg/mL

Disease-Modifying Antirheumatic Agents (DMARDs)

• DMARDs, or slow-acting anti-rheumatic drugs (SAARDs) have the potential to reduce or prevent joint damage.

• They have a long onset of action, sometimes taking 3-4 months. These drugs are used for rheumatic disorders, in inflammatory disease does not respond to COXIs.

• The DMARDs slow course of the disease and can induce remission, preventing further destruction of the joints and involved tissues.

A. Choice of drug• Most experts begin DMARD therapy with one of the

traditional small molecules, such as methotrexate or hydroxychloroquine.

• Inadequate response to traditional agent may be followed by use newer DMARDs, such as leflunomide, adalimumab, anakinra, etanercept, and infliximab.

• Combination therapies are both safe and efficacious. In most cases, methotrexate is combined with one of the other DMARDs.

B. Methotrexate• Treatment patients with severe rheumatoid or

psoriatic arthritis who have not responded adequately to NSAIDs.

• Effective in arthritis, and an autoimmune disease (immunosuppressant).

• Doses of methotrexate required for this treatment are much lower than those needed in cancer chemotherapy and are given once a week.

• Most common side: mucosal ulceration, nausea. • Cytopenias (particularly depression of white-blood-cell count), cirrhosis of the liver, and an acute

pneumonia-like syndrome may occur on chronic administration.

C. Leflunomide• Leflunomide is an immunomodulatory agent that

preferentially causes cell arrest of the autoimmune lymphocytes.

• It not only reduces pain and inflammation associated with the disease but also appears to slow the progression of structural damage.

• Leflunomide can be used in monotherapy as an alternative to methotrexate or as an addition to methotrexate in combination therapy.

• Leflunomide is teratogenic in experimental animals and, therefore, is contraindicated in pregnancy and in women of child-bearing potential.

D. Chloroquine and hydroxychloroquine

• These drugs are used in the treatment of malaria. • They are reserved for rheumatoid arthritis that has been

unresponsive to NSAIDs or are used in conjunction with an NSAID, which allows a lower dose of chloroquine or hydroxychloroquine to be administered.

• These drugs have been shown to slow progression of erosive bone lesions and may induce remission. They do cause serious adverse effects.

E. D-Penicillamine• D-Penicillamine slows the progress of bone destruction and

rheumatoid arthritis. • Prolonged treatment with penicillamine has serious side

effects, ranging from dermatologic problems to nephritis and aplastic anemia; therefore, it is used primarily in the treatment of rheumatoid arthritis after use of gold salts has failed but before use of corticosteroids has been attempted.

• D-Penicillamine is used as a chelating agent in the treatment of poisoning by heavy metals. It is also of benefit in treating cystinuria.

• Dosage Forms: Capsule (Cuprimine®): 125, 250 mg. Tablet (Depen®): 250 mg

F. Gold salts (Capsule: Ridaura®: 3 mg )

• Gold compounds, like other drugs in this group, cannot repair existing damage. Rather, they can only prevent further injury. The currently available gold preparations are gold sodium thiomalate and aurothioglucose.

• Gold compounds are being used less by rheumatologists, because of need for monitoring for serious toxicity and costs of administration and monitoring.

VII. Anticytokine Therapies In Rheumatoid Arthritis

• Interleukin-1 b (IL-1 b) and tumor necrosis factor- α (TNF-α) are proinflammatory cytokines involved in the pathogenesis of rheumatoid arthritis.

•• When secreted by synovial macrophages, IL-1 band TNF-a stimulate synovial cells

to proliferate and synthesize collagenase, thereby degrading cartilage, stimulating bone resorption, and inhibiting proteoglycan synthesis.

• Drug antagonists of these cytokines are proving to be effective in treating rheumatoid arthritis.

•

• Etanercept is protein composed of two chains of recombinant human TNF-receptor. Etanercept is given subcutaneously twice a week.

• Adalimumab is a recombinant monoclonal antibody.• Infliximab is a monoclonal antibody, and has been

approved for Crohn disease and for the treatment of rheumatoid arthritis.

• Anakinra is an IL-1 receptor antagonist.

VII. Anticytokine Therapies In Rheumatoid Arthritis

VIII. Drugs Used in Treatment Of Gout• Gout is a metabolic disorder characterized by high levels

of uric acid in the blood.

• This hyperuricemia results in the deposition of sodium urate crystals in tissues, especially the kidney and joints.

• The cause of hyperuricemia is an overproduction of uric acid relative to the patient's ability to excrete it.

VIII. Drugs Used in Treatment Of Gout• Most therapeutic strategies for gout involve lowering the

uric acid level below the saturation point, thus preventing the deposition of urate crystals.

• This can be accomplished by• 1) interfering with uric acid synthesis with allopurinol, • 2) increasing uric acid excretion with probenecid or

sulfinpyrazone, • 3) inhibiting leukocyte entry into the affected joint with

colchicine, or • 4) administration of NSAIDs.

A. Treating acute gout• Acute attacks are treated with indomethacin to

decrease movement of granulocytes into the affected area and with NSAIDs to decrease pain and inflammation.

• Colchicine is reserved for treatment of acute gouty attacks.

• Aspirin is contraindicated, because it competes with uric acid for the organic acid secretion mechanism in the proximal tubule of the kidney.

B. Treating chronic gout• Chronic gout can be caused by 1) a genetic defect (an

increase in the rate of purine synthesis; 2) renal deficiency; 3) Lesch-Nyhan syndrome; or

• 4) excessive synthesis of uric acid associated with cancer chemotherapy.

• (a disorder of purine metabolism due to deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT); characterized by hyperuricemia, uric acid renal stones, mental retardation, spasticity, choreoathetosis, and self-mutilation of fingers and lips by biting; X-

linked inheritance, caused by mutation in the HPRT gene).

• Treatment strategies for chronic gout include the use of uricosuric drugs that increase the excretion of uric acid, thereby reducing its concentration in plasma, and the use of allopurinol, which is a selective inhibitor of the terminal steps in the biosynthesis of uric acid. Allopurinol is preferred in patients with excessive uric acid excretion, with previous histories of uric acid stones.

C. Colchicine• Colchicine is reserved for treatment of acute gouty attacks. • Colchicine does reduce frequency of acute attacks and

relieves pain. It is neither a uricosuric nor an analgesic agent. Colchicine :

1. blocks cell division by binding to mitotic spindles.2. inhibits the synthesis and release of the leukotrienes.

• Indomethacin has largely replaced colchicine in the treatment of acute gouty attacks.

• 4. Adverse effects: nausea, vomiting, abdominal pain, and diarrhea, myopathy, agranulocytosis, aplastic anemia, and alopecia. The drug should not be used in pregnancy.

Allopurinol reduces production of uric acid by competitively inhibiting last two steps in uric acid biosynthesis that are catalyzed by xanthine oxidase.

D. Allopurinol

• Allopurinol is completely absorbed after oral administration. The primary metabolite is alloxanthine (oxypurinoI), which is also a xanthine oxidase inhibitor.

• Pharmacologic effect of administered allopurinol results from combined activity of these two compounds. The plasma half-life of allopurinol is short (two hours), whereas the half-life of oxypurinol is long (fifteen hours).

• Thus, effective inhibition of xanthine oxidase can be maintained with once-daily dosage.

E. Uricosuric agents• Uricosuric drugs are weak organic acids that

promote renal clearance of uric acid by inhibiting the urate-anion exchanger in the proximal tubule that mediates urate reabsorption.

• Uric acid is freely filtered at the glomerulus. Like many other weak acids, it is also both reabsorbed and secreted in the middle segment (S2) of the proximal tubule.

E. Uricosuric agents• Probenecid, inhibitor of tubular secretion of

organic acids, and sulfinpyrazone, a derivative of phenylbutazone, are two most commonly used uricosuric agents.

• At therapeutic doses, they block proximal tubular resorption of uric acid.

• Probenecid `blocks the tubular secretion of penicillin and is sometimes used to increase levels of the antibiotic.