INFLAMMATION• Inflammation is a defense reaction caused by tissue damageor injury• Can be elicited by numerous stimuli including:• infectious agents• antigen-antibody interaction• ischemia• thermal and physical injury• Noxious chemicals
Inflammatory responses occur in three distinct phases:1. An acute transient phase, characterized by:– local vasodilation and its resulting increased bloodflow causes the redness (rubor) and increased heat(calor)– Increased permeability of the blood vessels results inan exudation (leakage) of plasma proteins and fluidinto the tissue (edema), which manifests itself asswelling (tumor).2. A delayed phase, most prominently characterized by:– infiltration of leukocytes and phagocytic cells tothe injured /inflammed tissue3. A chronic proliferative phase, in which:– tissue degeneration and fibrosis occur
4 signs of inflammation• Redness –due to vasodilation of capillaries to increase blood flow.• Heat - due to local vessel dilatation.• Swelling –due to Increased vascular permeability and influx ofplasma proteins and phagocytic cells into the tissuespaces• Pain – due to-Hyperalgesia, sensitization of nociceptors-local release of enzymes and-increased tissue pressure
i)Complement system- The complement system is a biochemical cascade thathelps, or “complements”, the ability of antibodies to clear pathogens from anorganism. It is part of the immune system called the innate immune system that is notadaptable and does not change over the course of an individuals lifetime.ii)histamine – Secreted from mast cell.increases gap junction spacecauses tissue congestion & swellingcauses bronchoconstrictioncauses sneezing, watery eyes, itchingcauses pressure & painiii) serotoniniv)bradykinin - major contributors to symptoms of inflammation. A vasoactiveprotein which is able to induce vasodilation, increase vascular permeability, causesmooth muscle contraction, and induce painMediators of the inflammatory response
v)leukotrienes- increase vascular permeability and leakiness- increase mobilization of endogenous mediators of inflammationvi)ProstaglandinsPGE2 - promote Vasodilation, Bronchodilation leukocyte infiltration,Directly Cause Pain and Induces FeverPGI2 - increase vascular permeability, enhance pain producingproperties of bradykininvii) Thromboxane A2 (TXA2)- Thromboxane is a member of the family oflipids known as eicosanoids. The two major thromboxanes are thromboxaneA2 and thromboxane B2.cause platelets to aggregatecauses vasoconstrictioncauses smooth muscle contractionenhances function of inflammatory cells
Prostaglandins• Prostaglandins are unsaturated fatty acidderivatives containing 20 carbons that includea cyclic ring structure.• Note: These compounds are sometimesreferred to as eicosanoids; whichrefers to the20 carbon atoms.
Synthesis of prostaglandins• Arachidonic acid, a 20-carbon fatty acid, is the primaryprecursor of the prostaglandins and relatedcompounds.• Arachidonic acid is present as a component of thephospholipids of cell membranes ,primarilyphosphatidylinositol and other complex lipids.• Free arachidonic acid is released from tissuephospholipids by the action of phospholipase A2 andother acyl hydrolases via a process controlled byhormones and other stimuli.• There are two major pathways in the synthesis of theeicosanoids from arachidonic acid.
• Cyclooxygenase pathway:• All eicosanoids with ring structures that is, theprostaglandins, thromboxanes, and prostacyclins aresynthesized via the cyclooxygenase pathway.• Two related isoforms of the cyclooxygenase enzymes havebeen described. Cyclooxygenase-1 (COX-1) is responsiblefor the physiologic production of prostanoids, whereascyclooxygenase-2 (COX-2) causes the elevated productionof prostanoids that occurs in sites of disease andinflammation.• COX-1 is described as a housekeeping enzyme• thatregulates normal cellular processes, such as gastriccytoprotection, vascular homeostasis, plateletaggregation, and kidney function.• COX-2 is constitutively expressed in tissues such as thebrain, kidney, and bone.
• Lipoxygenase pathway:• Alternatively, several lipoxygenases can act onarachidonic acid to form 5-HPETE, 12-HPETE, and15-HPETE, which are unstable peroxidatedderivatives that are converted to thecorresponding hydroxylated derivatives (theHETEs) or to leukotrienes or lipoxins, dependingon the tissue .• Antileukotriene drugs, such aszileuton, zafirlukast, and montelukast, are usefulfor the treatment of moderate to severe allergicasthma.
Two main forms of Cyclooxygenases (COX)• Cyclooxygenase-1 (COX-1)• Produces prostaglandins thatmediate homeostatic functions• Constitutively expressed• HomeostaticProtection of gastricmucosaPlatelet activationRenal functionsMacrophagedifferentiation• Cyclooxygenase-2 (COX-2)• Produces prostaglandins thatmediate inflammation, pain, andfever.• Induced mainly in sites ofinflammation by cytokines• PathologicInflammationPainFeverDysregulatedproliferation
NSAID• The NSAIDs are a group of chemicallydissimilar agents that differ in theirantipyretic, analgesic, and anti-inflammatoryactivities.• They act primarily by inhibiting thecyclooxygenase enzymes that catalyze the firststep in prostanoid biosynthesis. This leads todecreased prostaglandin synthesis with bothbeneficial and unwanted effects.
Mechanism of action of NSAIDs1. Antiinflammatory effect– due to the inhibition of the enzymes cyclooxygenase, orCOX, which converts arachidonic acid toprostaglandins, and to TXA2 and prostacyclin.– Aspirin irreversibly inactivates COX-1 and COX-2 byacetylation of a specific serine residue.– This distinguishes it from other NSAIDs, which reversiblyinhibit COX-1 and COX-2.
2. Analgesic effectA. The analgesic effect of NSAIDs is thought to be relatedto:– the peripheral inhibition of prostaglandinproduction– may also be due to the inhibition of pain stimuli ata subcortical site.B. NSAIDs inhibits bradykinin from stimulating painreceptors
3. Antipyretic effect– The antipyretic effect of NSAIDs is believed to be relatedto:• inhibition of production of prostaglandins induced bycytokines such as interleukin-1 (IL-1) and interleukin-6 (IL-6) in the hypothalamus• the “resetting” of the thermoregulatorysystem, leading to vasodilatation and increased heatloss.
Aspirin and other salicylic acidderivatives• Pharmacologic properties:– Salicylates are weak organic acids;– aspirin has a pKa of 3.5.– These agents are rapidly absorbed from the intestine aswell as from the stomach, where the low pH favorsabsorption.
• Mechanism of action:• Aspirin is a weak organic acid that is uniqueamong the NSAIDs in that it irreversiblyacetylates (and, thus, inactivates) cyclooxygenase(Figure). The other NSAIDs, includingsalicylate, are all reversible inhibitors ofcyclooxygenase.• Aspirin is rapidly deacetylated by esterases in thebody producing salicylate, which has anti-inflammatory, antipyretic, and analgesic effects.
– Salicylates are hydrolyzed rapidly by plasma andtissue esterases to acetic acid and the activemetabolite salicylic acid.esterases
– Salicylates have a t1/2 of 3—6 hours after short-term administration.– Long-term administration of• high doses (to treat arthritis) or• toxic overdose– increases the t1/2 to 15—30 hours because theenzymes for glycine and glucuronide conjugationbecome saturated.
– Unmetabolized salicylates are excreted by thekidney.– If the urine pH is raised above 8, clearance isincreased approximately fourfold as a result ofdecreased reabsorption of the ionized salicylatefrom the tubules.
Pharmacological Effects1. InflammationBecause aspirin inhibits cyclooxygenaseactivity, it diminishes the formation ofprostaglandins and, thus, modulates thoseaspects of inflammation in whichprostaglandins act as mediators. Aspirininhibits inflammation in arthritis, but itneither arrests the progress of the disease norinduces remission.
2. Analgesia• NSAIDs alleviate mild-to-moderate pain by:– decreasing PGE- and PGF-mediated increases in painreceptor sensitivity.• They are more effective against pain associated withintegumental structures (pain of muscular and vascularorigin, arthritis, and bursitis) than with pain associatedwith the viscera.
3. Antipyresis• NSAIDs reduce elevated body temperaturewith little effect on normal bodytemperature.
3.Respiratory actions: At therapeutic doses, aspirinincreases alveolar ventilation.• [Note: Salicylates uncouple oxidativephosphorylation, which leads to elevated CO2 andincreased respiration.]• Higher doses work directly on the respiratory center inthe medulla, resulting in hyperventilation andrespiratory alkalosis that usually is adequatelycompensated for by the kidney.• At toxic levels, central respiratory paralysis occurs, andrespiratory acidosis ensues due to continuedproduction of CO2
4. Gastrointestinal effects:• Normally, prostacyclin (PGI2) inhibits gastric acid secretion, whereas PGE2 andPGF2Î± stimulate synthesis of protective mucus in both the stomach and smallintestine.• In the presence of aspirin, these prostanoids are not formed, resulting in increasedgastric acid secretion and diminished mucus protection.• This may cause epigastric distress, ulceration, hemorrhage, and iron-deficiencyanemia.• Aspirin doses of 1 to 4.5 g/day can produce loss of 2 to 8 mL of blood in the fecesper day. Buffered and enteric-coated preparations are only marginally helpful indealing with this problem.• Agents used for the prevention of gastric and/or duodenal ulcers include the PGE1-derivative misoprostol and the proton-pump inhibitors (PPIs);esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole);• PPIs can also be used for the treatment of an NSAID-induced ulcer and areespecially appropriate if the patient will need to continue NSAID treatment.• H2-antihistamines (cimetidine, famotidine, nizatidine, and ranitidine) relievedyspepsia due to NSAIDS, but they may mask serious GI complaints and may notbe as effective as PPIs for healing and preventing ulcer formation.
5.Effect on platelets:• TXA2 enhances platelet aggregation, whereas PGI2 decreases it.• Low doses (60 to 81 mg daily) of aspirin can irreversibly inhibitthromboxane production in platelets via acetylation ofcyclooxygenase. Because platelets lack nuclei, they cannotsynthesize new enzyme, and the lack of thromboxane persists forthe lifetime of the platelet (7 days).• As a result of the decrease in TXA2, platelet aggregation (the firststep in thrombus formation) is reduced, producing an anticoagulanteffect with a prolonged bleeding time.• Finally, aspirin also inhibits cyclooxygenase in endothelialcells, resulting in reduced PGI2 formation; however, endothelial cellspossess nuclei able to re-synthesize new cyclooxygenase.Therefore, PGI2 is available for antiplatelet action.
6. Actions on the kidney:Cyclooxygenase inhibitors prevent the synthesis ofPGE2 and PGI2 prostaglandins that are responsiblefor maintaining renal blood flow, particularly inthe presence of circulating vasoconstrictors.Decreased synthesis of prostaglandins can result inretention of sodium and water and may causeedema and hyperkalemia in some patients.Interstitial nephritis can also occur with all NSAIDsexcept aspirin
Therapeutic Use– NSAIDs are first-line drugs used to arrest inflammationand the accompanying pain of rheumatic andnonrheumatic diseases, including rheumatoidarthritis, juvenile arthritis, osteoarthritis, psoriaticarthritis, ankylosing spondylitis, Reiter syndrome, anddysmenorrhea.– Pain and inflammation of bursitis and tendonitis alsorespond to NSAIDs.
– NSAIDs:• do not significantly reverse the progress of rheumaticdisease• they slow destruction of cartilage and bone• allow patients increased mobility and use of theirjoints.
– Treatment of chronic inflammation requires use of theseagents at doses well above those used for analgesia andantipyresis– the incidence of adverse drug effects is increased.
– Drug selection is generally dictated by thepatients ability to tolerate the adverseeffects, and the cost of the drugs.– Antiinflammatory effects may develop only afterseveral weeks of treatment.
Adverse effectsi)Gastrointestinal: The most common GI effects of thesalicylates are epigastric distress, nausea, and vomiting.Microscopic GI bleeding is almost universal in patientstreated with salicylates.• [Note: Aspirin is an acid. At stomach pH, aspirin isuncharged; consequently, it readily crosses into mucosalcells, where it ionizes (becomes negatively charged) andbecomes trapped, thus potentially causing direct damageto the cells. Aspirin should be taken with food and largevolumes of fluids to diminish dyspepsia.Additionally, misoprostol or a PPI may be takenconcurrently.]
ii) Blood: The irreversible acetylation of plateletcyclooxygenase reduces the level of platelet TXA2, resultingin inhibition of platelet aggregation and a prolongedbleeding time.For this reason, aspirin should not be taken for at least 1week prior to surgery. When salicylates areadministered, anticoagulants may have to be given inreduced dosage, and careful monitoring and counseling ofpatients are necessary.iii) Respiration: In toxic doses, salicylates cause respiratorydepression and a combination of uncompensatedrespiratory and metabolic acidosis.iv) Metabolic processes: Large doses of salicylates uncoupleoxidative phosphorylation.4 The energy normally used forthe production of adenosine triphosphate is dissipated asheat, which explains the hyperthermia caused bysalicylates when taken in toxic quantities.
v) Reyes syndrome:– Aspirin and other salicylates given during viral infections has beenassociated with an increased incidence of Reyes syndrome, which is apotentially fatal disease that causes numerous detrimental effects tomany organs, especially the brain and liver, as well as causing a lowerthan usual level of blood sugar (hypoglycemia).– The classic features are a rash, vomiting, and liver damage.– The exact cause is unknown and, while it has been associatedwith aspirin consumption by children with viral illness, it also occurs inthe absence of aspirin use.-The disease causes fatty liver with minimal inflammation andsevere encephalopathy (with swelling of the brain).-The liver may become slightly enlarged and firm, and there is a change inthe appearance of the kidneys. Jaundice is not usually present-This is especially encountered in children, who therefore should be givenacetaminophen instead of aspirin when such medication is required toreduce fever. Ibuprofen is also appropriate.
vi) Drug interactions:Concomitant administration of salicylates with many classes of drugs may produceundesirable side effects. Because aspirin is found in many over-the-counteragents, patients should be counseled to read labels to verify aspirin content to avoidoverdose.Salicylate is 90 to 95 percent protein bound and can be displaced from its protein-bindingsites, resulting in increased concentration of free salicylate; alternatively, aspirin coulddisplace other highly protein-bound drugs, such as warfarin, phenytoin, or valproicacid, resulting in higher free concentrations of the other agent .Chronic aspirin use should be avoided in patients receiving probenecid orsulfinpyrazone, because these agents cause increased renal excretion of uric acidwhereas aspirin (<2 g/day) cause reduced clearance of uric acid.Concomitant use of ketorolac and aspirin is contraindicated because of increased risk of GIbleeding and platelet aggregation inhibition. Children who have received live varicellavirus vaccine should avoid aspirin for at least 6 weeks after vaccination to prevent Reyessyndrome.vii) In pregnancy:Aspirin is classified as FDA pregnancy category C risk during Trimesters 1 and 2 and categoryD during Trimester 3. Because salicylates are excreted in breast milk, aspirin should beavoided during pregnancy and while breast-feeding.
• B. Propionic acid derivatives• Ibuprofen [eye-byoo-PROE-fen] was the first in this class of agents tobecome available in the United States.• It has been joined by naproxen [nah-PROX-en], fenoprofen [fen-oh-PROE-fen], ketoprofen [key-toe-PROE-fen], flurbiprofen [flur-bye-PROE-fen], andoxaprozin [ox-ah-PROE-zin].• All these drugs possess anti-inflammatory, analgesic, and antipyreticactivity;• additionally, they can alter platelet function and prolong bleeding time.• They have gained wide acceptance in the chronic treatment of RA andosteoarthritis, because their GI effects are generally less intense thanthose of aspirin.• These drugs are reversible inhibitors of the cyclooxygenasesand, thus, like aspirin, inhibit the synthesis of prostaglandins but not ofleukotrienes. All are well absorbed on oral administration and are almosttotally bound to serum albumin.• [Note: Oxaprozin has the longest half-life and is administered once daily.]They undergo hepatic metabolism and are excreted by the kidney. Themost common adverse effects are GI, ranging from dyspepsia to bleeding.Side effects involving the central nervous system (CNS), such asheadache, tinnitus, and dizziness, have also been reported.
• Acetic acid derivatives• This group of drugs includes indomethacin [in-doe-METH-a-sin], sulindac [sul-IN-dak], andetodolac [eh-TOE-doh-lak].• All have anti-inflammatory, analgesic, andantipyretic activity.• They act by reversibly inhibitingcyclooxygenase.• They are generally not used to lower fever.
IndomethacinUse: As anti-inflammatoryTreatment of• Ankylosing spondylitis• Reiter syndrome• Acute gouty arthritis.to speed the closure of patent ductus arteriosus inpremature infants (otherwise, it is not used in children);• it inhibits the production of prostaglandins that prevent closure ofthe ductus.
– Indomethacin is not recommended as a simple analgesicor antipyretic because of the potential for severe adverseeffects.– Bleeding, ulceration– Headache– Occasional:Tinnitus, dizziness, or confusion
• Sulindac is an inactive prodrug that is closelyrelated to indomethacin.• Although the drug is less potent thanindomethacin, it is useful in the treatment ofRA, ankylosing spondylitis, osteoarthritis, andacute gout.• The adverse reactions caused by sulindac aresimilar to, but less severe than, those of the otherNSAIDs, including indomethacin.• Etodolac has effects similar to those of the otherNSAIDs. GI problems are less common.
Oxicam derivatives• Piroxicam [peer-OX-i-kam] and meloxicam [mel-OX-i-kam] are used totreat RA, ankylosing spondylitis, and osteoarthritis.• They have long half-lives, which permit once-dailyadministration, Piroxicam has t1/2 of 45 hours.• The parent drug as well as its metabolites are renally excreted in the urine.•• GI disturbances are encountered in approximately 20 percent of patientstreated with piroxicam.• Meloxicam inhibits both COX-1 and COX-2, with preferential binding forCOX-2, and at low to moderate doses shows less GI irritation thanpiroxicam.• However, at high doses, meloxicam is a nonselective NSAID, inhibitingboth COX-1 and COX-2. Meloxicam excretion is predominantly in the formof metabolites and occurs equally in the urine and feces.
Meclofenamate, mefenamic acid– They have no advantages over other NSAIDs asanti-inflammatory agent.– t1/2 of 2 hours.– A relatively high incidence of gastrointestinaldisturbances is associated with these agents, suchas diarrhea, can be severe, and they areassociated with inflammation of the bowel
Nabumetone– Compared with NSAIDs, nabumetone is associated withreduced:• inhibition of platelet function• incidence of gastrointestinal bleeding.– Nabumetone inhibits COX-2 more than COX-1.Other NSAIDS includeflurbiprofen, diclofenac, and etodolac.Flurbiprofen is also available for topical ophthalmic use.
COX-2 Selective agents– Celecoxib [Celebrex]– Rofecoxib [Vioxx]– Valdecoxib [Bextra]– that inhibit COX-2 more than COX-1 have been developedand approved for use.– The rationale behind development of these drugs wasthat:A. inhibition of COX-2 would reduce the inflammatory responseand painB. not inhibit the cytoprotective action of prostaglandins in thestomach, which is largely mediated by COX-1.
– Rofecoxib and valdecoxib have been removed from themarket due to a doubling in the incidence of heart attackand stroke– Celecoxib remains on the market and is approved for:– Osteoarthritis and rheumatoid arthritis– Pain including bone pain, dental pain, and headache– Ankylosing spondylitis.
• Celecoxib• Celecoxib [sel-eh-COCKS-ib] is significantly more selective for inhibition of COX-2than of COX-1 (Figure 41.10).• In fact, at concentrations achieved in vivo, celecoxib does not block COX-1.• Unlike the inhibition of COX-1 by aspirin (which is rapid and irreversible), theinhibition of COX-2 is time dependent and reversible.• Celecoxib is approved for treatment of RA, osteoarthritis, and pain.• Unlike aspirin, celecoxib does not inhibit platelet aggregation and does notincrease bleeding time.• Celecoxib has similar efficacy to NSAIDs in the treatment of pain and the risk forcardiovascular events.• Celecoxib, when used without concomitant aspirin therapy, has been shown to beassociated with less GI bleeding and dyspepsia;• however, this benefit is lost when aspirin is added to celecoxib therapy. In patientsat high risk for ulcers (that is, history of peptic ulcer disease), use of PPIs withcelecoxib and aspirin may be necessary to avoid gastric ulcers.
• Pharmacokinetics:• Celecoxib is readily absorbed, reaching a peak concentration in about 3hours.• It is extensively metabolized in the liver by cytochrome P450 (CYP2C9)and is excreted in the feces and urine.• Its half-life is about 11 hours; thus, the drug is usually taken once aday but can be administered as divided doses twice daily.• The daily recommended dose should be reduced by 50 percent inthose with moderate hepatic impairment, and celecoxib should beavoided in patients with severe hepatic and renal disease.•
`• Adverse effects: Headache, dyspepsia, diarrhea, and abdominalpain are the most common adverse effects.• Celecoxib is contraindicated in patients who are allergic tosulfonamides.• [Note: If there is a history of sulfonamide drug allergy, then use of anonselective NSAID along with a PPI is recommended.]• As with other NSAIDs, kidney toxicity may occur.• Celecoxib should be avoided in patients with chronic renalinsufficiency, severe heart disease, volume depletion, and/orhepatic failure.• Patients who have had anaphylactoid reactions to aspirin ornonselective NSAIDs may be at risk for similar effects whenchallenged with celecoxib.• Inhibitors of CYP2C9, such as fluconazole, fluvastatin, andzafirlukast, may increase serum levels of celecoxib. Celecoxib hasthe ability to inhibit CYP2D6 and, thus, could lead to elevated levelsof some antidepressants, and antipsychotic drugs.
Acetaminophen (Paracetamol):– does not displace other drugs from plasma proteins– Acetaminophen [a-SEAT-a-MIN-oh-fen] inhibits prostaglandinsynthesis in the CNS. This explains its antipyretic and analgesicproperties.– Acetaminophen has less effect on cyclooxygenase in peripheraltissues, which accounts for its weak anti-inflammatory activity.– Acetaminophen does not affect platelet function or increase bloodclotting time.– it causes minimal gastric irritation– has little effect on platelet adhesion and aggregation– Acetaminophen has no significant antiinflammatory activity.
– Acetaminophen is administered orally and is rapidlyabsorbed.– It is metabolized by hepatic microsomal enzymes to sulfateand glucuronide.– Acetaminophen is a substitute for aspirin to treat mild-to-moderate pain for selected patients who are:• intolerant to aspirin• have a history of peptic ulcer or hemophilia• are using anticoagulants or a uricosuric drug to managegout• are at risk for Reyes syndrome.
• Pharmacokinetics• Acetaminophen is rapidly absorbed from the GI tract.• A significant first-pass metabolism occurs in the luminal cells of theintestine and in the hepatocytes.• Under normal circumstances, acetaminophen is conjugated in theliver to form inactive glucuronidated or sulfated metabolites.• A portion of acetaminophen is hydroxylated to form N-acetylbenzoiminoquinone, a highly reactive and potentiallydangerous metabolite that reacts with sulfhydryl groups.• At normal doses of acetaminophen, the N-acetylbenzoiminoquinone reacts with the sulfhydryl group ofglutathione, forming a nontoxic substance Acetaminophen and itsmetabolites are excreted in the urine.
• Adverse effects• With normal therapeutic doses, acetaminophen is virtually free of anysignificant adverse effects.• Skin rash and minor allergic reactions occur infrequently.• There may be minor alterations in the leukocyte count, but these aregenerally transient.• Renal tubular necrosis and hypoglycemic coma are rare complications ofprolonged, large-dose therapy.• With large doses of acetaminophen, the available glutathione in the liverbecomes depleted, and N-acetylbenzoiminoquinone reacts with thesulfhydryl groups of hepatic proteins, forming covalent bonds (see Figure41.12).• Hepatic necrosis, a very serious and potentially life-threateningcondition, can result.• Renal tubular necrosis may also occur.• [Note: Administration of N-acetylcysteine, which contains sulfhydrylgroups to which the toxic metabolite can bind, can be lifesaving ifadministered within 10 hours of the overdose.]• This agent should be avoided in patients with severe hepatic impairment.Periodic monitoring of liver enzymes tests is recommended for those onhigh-dose acetaminophen.
Overdose with acetaminophen:accumulation of a minor metabolite, N-acetyl-p-benzoquinone,which is responsible for hepatotoxicity.
• Overdose is treated by:– emesis or gastric lavage– oral administration of N-acetyl cystine within 1 day toneutralize the metabolite.• Long-term use of acetaminophen has beenassociated with:– a 3-fold increase in kidney disease– women taking more than 500 mg/day had a doubling inthe incidence of hypertension.
Disease-Modifying AntirheumaticAgents• Disease-modifying antirheumatic drugs (DMARDs) are used inthe treatment of RA .• They have been shown-- to slow the course of the disease by preventing furtherdestruction of the joints and involved tissues.-induce remission,When a patient is diagnosed with RA, the American College ofRheumatology recommends initiation of therapy withDMARDs within 3 months of diagnosis (in addition toNSAIDs, low-dose corticosteroids, physical therapy).Therapy with DMARDs is initiated rapidly to help stop theprogression of the disease at the earlier stages.
• Choice of drug• No one DMARD is efficacious and safe in every patient, and trials ofseveral different drugs may be necessary.• Most experts begin DMARD therapy with one of the traditionaldrugs, such as methotrexate or hydroxychloroquine.• These agents are efficacious and are generally well tolerated, withwell-known side-effect profiles.• Inadequate response to the traditional agents may be followed byuse of newer DMARDs, such as leflunomide, anakinra, and TNF-inhibitors (adalimumab, etanercept, and infliximab).• Combination therapies are both safe and efficacious.• In most cases, methotrexate is combined with one of the otherDMARDs.• In patients who do not respond to combination therapy withmethotrexate plus TNF inhibitors, or other combinations, treatmentwith rituximab or abatacept may be tried.• Most of these agents are contraindicated for use in pregnantwomen.
• Methotrexate• Methotrexate [meth-oh-TREX-ate], used alone or in combination therapy, hasbecome the mainstay of treatment in patients with rheumatoid or psoriaticarthritis.• Methotrexate slows the appearance of new erosions within involved joints.• Response to methotrexate occurs within 3 to 6 weeks of starting treatment.• It is an immunosuppressant, and this may account for its effectiveness in anautoimmune disease.• The other DMARDs can be added to methotrexate therapy if there is partial or noresponse to maximum doses of methotrexate.• Doses of methotrexate required for this treatment are much lower than thoseneeded in cancer chemotherapy and are given once a week; therefore, theadverse effects are minimized.• The most common side effects observed after methotrexate treatment of RA aremucosal ulceration and nausea.• Cytopenias (particularly depression of the WBC count), cirrhosis of the liver, andan acute pneumonia-like syndrome may occur on chronic administration.• [Note: Taking leucovorin once daily after methotrexate reduces the severity of theadverse effects.]
• Leflunomide• The mechanism of action by which leflunomide works is by blocking the bodysability to make certain nucleotide, which is a building block of DNAsynthesis, by blocking the enzyme dihydroorotate dehydrogenase.• People who have rheumatoid arthritis have a type of immune cell (called a Tcell) that is overactive.• T cells produce chemicals that cause inflammation and damage joint tissue.• T cells need DNA to divide, or reproduce.• By stopping the production of DNA, leflunomide prevents T cells fromreproducing, thereby reducing inflammation and preventing joint damage.• Leflunomide has been approved for the treatment of RA.• It not only reduces pain and inflammation associated with the disease but alsoappears to slow the progression of structural damage.
• Hydroxychloroquine• This agent is also used in the treatment of malaria.• It is used for early, mild RA and has relatively few side effects.• When used alone, it does not slow joint damage, therefore, it is oftenused in combination with methotrexate.• Its mechanism of action may include inhibition of phospholipase A2 andplatelet aggregation, membrane stabilization, effects on the immunesystem, and antioxidant activity.• It may cause renal toxicity• Sulfasalazine• Sulfasalazine [sull-fa-SAH-la-zeen] is also used for early, mild RA incombination with hydroxycholoroquine and methotrexate.• Onset of activity is 1 to 3 months, and it is associated with leukopenia.• D-Penicillamine• D-Penicillamine [pen-ih-SILL-a-meen], an analog of the amino acidcysteine, slows the progression of bone destruction and RA.• This agent is used as add-on therapy to existing NSAID/glucocorticoidtherapy.
• Gold salts• Gold compounds, like the other drugs in thisgroup, cannot repair existing damage.• They can only prevent further injury.• The currently available gold preparation is auranofinfor oral administration.• This agent will suppress phagocytosis and lysosomalenzyme activity.• This mechanism retards the progression of bone andarticular destruction, and beneficial effects may beseen in 3 to 6 months.• The gold compounds are being used infrequently byrheumatologists because of the need for meticulousmonitoring for serious toxicity (forexample, myelosuppression) and the costs ofmonitoring.
• Other Therapies in Rheumatoid Arthritis• Interleukin-1b and TNF- α are proinflammatory cytokines involved in the pathogenesis of RA.• When secreted by synovial macrophages, IL-1b and TNF-α stimulate synovial cells toproliferate and synthesize collagenase, thereby degrading cartilage, stimulating boneresorption, and inhibiting proteoglycan synthesis.• The TNF inhibitors (etanercept, adalimumab, and infliximab) have been shown to decreasesigns and symptoms of RA, reduce progression of structural damage, and improve physicalfunction; clinical response can be seen within 2 weeks of therapy.• If a patient has failed therapy with one TNF inhibitor, a trial with a different TNF inhibitor isappropriate.• Many experts propose that a TNF inhibitor plus methotrexate be considered as standardtherapy for patients with rheumatoid and psoriatic arthritis.• Indeed, TNF inhibitors can be administered with any of the other DMARDs, except foranakinra, an IL-1 receptor antagonist.• Patients receiving TNF inhibitors are at increased risk for infections (tuberculosis, andsepsis), fungal infections, and pancytopenia.• These agents should be used very cautiously in those with heart failure, because these agents
• Gout• Gout is a metabolic disorder characterized by high levelsof uric acid (end product of purine metabolism) in theblood.• Hyperuricemia can lead to deposition of sodium uratecrystals in tissues, especially the joints and kidney.• The cause of hyperuricemia is an overproduction of uricacid relative to the patients ability to excrete it.• The deposition of urate crystals initiates aninflammatory process involving the infiltration ofgranulocytes that phagocytize the urate crystals(Figure).• This process generates oxygen metabolites, whichdamage tissues, resulting in the release of lysosomalenzymes that evoke an inflammatory response.• In addition, there is increased production of lactate inthe synovial tissues.• The resulting local decrease in pH fosters furtherdeposition of urate crystals.
Figure: Role of uric acid in the inflammation of gout.
• Most therapeutic strategies for gout involve lowering the uricacid level below the saturation point (<6 mg/dL), thuspreventing the deposition of urate crystals.• This can be accomplished by 1) interfering with uric acidsynthesis with allopurinol, 2) increasing uric acid excretionwith probenecid or sulfinpyrazone, 3) inhibiting leukocyteentry into the affected joint with colchicine, or 4)administration of NSAIDs.
• Treating acute gout• Acute gouty attacks can result from a number ofconditions, including excessive alcoholconsumption, a diet rich in purines, or kidneydisease.• Acute attacks are treated with indomethacin todecrease movement of granulocytes into theaffected area;• NSAIDs other than indomethacinare also effective at decreasing pain andinflammation.• [Note: Aspirin is contraindicated, because itcompetes with uric acid for the organic acidsecretion mechanism in the proximal tubule ofthe kidney.]
• Treating chronic gout• Chronic gout can be caused by 1) a genetic defect, such as oneresulting in an increase in the rate of purine synthesis; 2) renaldeficiency; 3) Lesch-Nyhan syndrome; or 4) excessive production ofuric acid associated with cancer chemotherapy.• Treatment strategies for chronic gout include-the use of uricosuric drugs : That increase the excretion of uricacid, thereby reducing its concentration in plasma.Uricosuric agents are first-line agents for patients with goutassociated with reduced urinary excretion of uric acid.- inhibits uric acid production : Allopurinol, which is a selectiveinhibitor of the terminal steps in the biosynthesis of uric acid.Allopurinol is preferred in patients with excessive uric acidsynthesis, with previous histories of uric acid stones, or with renalinsufficiency.
• Colchicine– Colchicine is an alkaloid– It is used for relief of inflammation and pain in acute goutyarthritis.– Reduction of inflammation and relief from pain occur 12—24 hours after oral administration.– The mechanism of action in acute gout is unclear.– Colchicine:• Colchicine binds to tubulin, a microtubularprotein, causing its depolymerization. This disruptscellular functions, such as the mobility ofgranulocytes, thus decreasing their migration into theaffected area.• Furthermore, colchicine blocks cell division by bindingto mitotic spindles.• Colchicine also inhibits the synthesis and release of theleukotrienes
– The adverse effects after oral administration, which occurin 80% of patients at a dose near that necessary to relievegout, include nausea, vomiting, abdominal pain, andparticularly diarrhea.– IV administration reduces the risk of gastrointestinaldisturbances and provides faster relief (6—12 h) butincreases the risk of sloughing skin and subcutaneoustissue.– Higher doses may (rarely) result in liver damage.
• Probenecid and sulfinpyrazone• are organic acids• reduce urate levels by preventing reabsorption of uric acid inthe renal tubule .• These agents are used for chronic gout, often in combinationwith colchicine.• Probenecid and sulfinpyrazone undergo rapid oral absorption.
• These agents inhibit the excretion of other drugs that are activelysecreted by renal tubules, including penicillin, NSAIDs,cephalosporins, and methotrexate.• Increased urinary concentration of uric acid may result in theformation of urate stones (urolithiasis).• This risk is decreased with:1. the ingestion of large volumes of fluid or2. alkalinization of urine with potassium citrate.• Common adverse effects include gastrointestinal disturbancesand dermatitis; rarely, these agents cause blood dyscrasias
• Allopurinol• Allopurinol inhibits the synthesis of uric acid by inhibitingxanthine oxidase, an enzyme that converts hypoxanthine toxanthine and xanthine to uric acid.• Allopurinol is metabolized by xanthine oxidase toalloxanthine, which also inhibits xanthine oxidase. Allopurinol alsoinhibits de novo purine synthesis.• Allopurinol commonly produces gastrointestinal disturbances anddermatitis. This agent more rarely causes hypersensitivity, includingfever, hepatic dysfunction, and blood dyscrasias.• Allopurinol should be used with caution in patients with liverdisease or bone marrow depression.
Mechanism of action:Allopurinol inhibits xanthine oxidase enzymewhich is required for the synthesis of Uric acid.This enzyme is required when purine is oxidizedto Uric acid.
1. Anti-TNF- drugsA. Infliximab:• is a recombinant antibody with human constant and murinevariable regions that specifically binds TNF-α, therebyblocking its action.– Approved for use for rheumatoid arthritis, Crohnsdisease, psoriasis, and other autoimmune diseases– Administered by IV infusion at 2-week intervals initiallyand repeated at 6 and 8 weeks
B. Adalimumab• is approved for the treatment of rheumatoid arthritis.• It is a humanized (no murine components) anti-TNF-α antibodyadministered subcutaneously every other week.C. Etanercept• is a fusion protein composed of the ligand-binding pocket of a TNF-αreceptor fused to an IgG1 Fc fragment.• The fusion protein has two TNF-binding sites per IgG molecule and isadministered subcutaneously weekly.• The most serious adverse effect is infection includingtuberculosis, immunogenicity, and lymphoma.• Injection site infections are common.
2. Anti-IL1 drugs– Anakinra is a recombinant protein essentially identical toIL-1 , a soluble antagonist of IL-1 that binds to the IL-1receptor but does not trigger a biologic response.– Anakinra is a competitive antagonist of the IL-1 receptor.– It is approved for use for the treatment of rheumatoidarthritis.– It has a relatively short half-life and must beadministered subcutaneously daily.
Characterized by:1. Redness (rubor): vasodilation of capillaries to increaseblood flow2. Heat (calor): vasodilation3. Pain (dolor): Hyperalgesia, sensitization of nociceptors4. Swelling (tumor): Increased vascular permeability(microvascular structural changes and escape ofplasma proteins from the bloodstream)5. Loss of function (functio laesa)• Inflammatory cell transmigration through endotheliumand accumulation at the site of injury
Other antiinflammatory drugs are used in the more advancedstages of some rheumatoid diseases.• Gold compounds:– Aurothioglucose– Gold sodium thiomalate– Auranofin– may retard the destruction of bone and joints by anunknown mechanism.– These agents have long latency.– Aurothioglucose and gold sodium thiomalate areadministered intramuscularly.– Auranofin is administered orally and is 95% bound toplasma proteins.
Side effects: Gold compounds Serious:• gastrointestinal disturbances, dermatitis, and mucous membranelesions. Less common effects:• aplastic anemia• proteinuria Occasional:• nephrotic syndrome.
Penicillamine– Penicillamine is a chelating drug (will chelate gold) that is ametabolite of penicillin.– Penicillamine has immunosuppressant activity, but itsmechanism of action is unknown.– This agent has long latency.– The incidence of severe adverse effects is high; theseeffects are similar to those of the gold compounds.
• Methotrexate– Methotrexate is an antineoplastic drug used forrheumatoid arthritis that does not respond well to NSAIDsor glucocorticoids.– Methotrexate commonly produces hepatotoxicity.• Chloroquine and hydrochloroquine– Chloroquine and hydrochloroquine are antimalarial drugs.– These agents have immunosuppressant activity, but theirmechanism of action is unknown.– Used to treat joint pain associated with lupus and arthritis• Adrenocorticosteroids