Anti-inflammatory

Anti-inflammatory DrugsBy Chinedu ike-morris Inflammation It is a biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants.

Quick OverviewEicosanoids are cell-regulating polyunsaturated fatty acids primarily synthesized from arachidonic acid and released by the action of phospholipase A2 from lipids in cell membranes.Eicosanoids are present in low concentrations in most cells but are synthesized and released on demand in response to stimuli, including IgE-mediated reactions, inflammatory mediators, trauma, heat, and toxins. Eicosanoids interact with specific receptors, which are G-protein coupled to second messenger effector systems.

Drugs acting on Eicosanoids

NSAIDS

All of the NSAIDS act by inhibiting the synthesis of Prostaglandins (by primarily inhibiting cyclooxygenase enzymes).Aspirin (AcetylSalicylic acid derivative) Causes irreversible inhibition of COX (Both) by covalent acetylation (Unique to only Aspirin).NonselectiveIt is quickly deacetylated by esterases in the body, thereby producing salicylate, which has anti-inflammatory, antipyretic, and analgesic effects.The actions of Aspirin is dose dependent:Antiplatelet aggregation: Low dose (Post-MI prophylaxis)(80mg/day).Analgesia and antipyresis: Moderate dose (320-650mg/day).Anti-inflammatory: High dose (3-6g/day).Adverse effects: GI (gastritis, Ulcers, bleeding).Salicylism (tinnitus, vertigo, reduced hearing--- often 1st sign of toxicity).Bronchoconstriction: exacerbation of asthma.Hypersensitivity.Reye syndrome: Encephalopathy.Increased bleeding time.6Continuation Toxic doses: Inhibits respiratory center- decrease respiration increased pCO2 respiratory acidosis (decrease pH,HCO3 , normalization of pCO2) plus inhibition of Krebs cycle and severe uncoupling of oxidative phosphorylation (decrease ATP) metabolic acidosis, hyperthermia , and hypokalemia.

Overdose management: No specific antidote, Management includes gastric lavage (+/- activated charcoal), plus ventilatory support , acid-base and electrolyte imbalance management, and the hyperthermia and resulting dehydration. Increased urine volume and its alkalinization facilitate salicylate renal elimination.Drug interactionsEthanol (increases GI bleeding)Warfarin (increases effect)Uricosurics (Decreases effect)ContraindicationChronic liver diseaseDiabeticsAvoided during pregnancy and breast feeding.Stopped 48 hours before surgery.Other NSAIDSReversible inhibitors of COX(both),nonselective, with analgesic, antipyretic, and anti-inflammatory actions, Include:Ibuprofen (Propionic acid derivatives)Naproxen (Propionic acid derivatives)Indomethacin (Acetic acid derivatives)Ketorolac (Heteroaryl acetic acid derivatives)Sulindac (Acetic acid derivatives)Comparisons with Aspirin:Analgesic: Ketorolac > ibuprofen/naproxen > AspirinGI irritation: < Aspirin, but still occurs.Minimal effects on acid-base balance; no effects on uric acid elimination.Allergy: Common, possible cross-hypersensitivity with Aspirin.Renal: Chronic use may cause nephritis, nephritic syndrome, acute failure----- does not occur with Sulindac.Specific toxicities:Indomethacin: thrombocytopenia, agranulocytosis, and > CNS effects.Sulindac: Stevens-Johnson syndrome, hematotoxicity. CelecoxibSelective COX 2 Inhibitors: Compared with conventional NSAIDs, it is no more effective as an anti-inflammatory agent.Primary differences are:Less gastrointestinal toxicity Less antiplatelet actionHowever, it may possibly exert prothrombotic effects via inhibition of endothelial cell function (MI and strokes).Cross-hypersensitivity between celecoxib and sulfonamides

ACetaminophenNo inhibition of COX in peripheral tissues (Unlike ASA which has both CNS & Peripheral inhibition of COX) and lacks significant anti-inflammatory effects.Equivalent analgesic and antipyretic activity to ASA due to inhibition of cyclooxygenases in the CNS.Not an NSAID.Comparisons with ASA:No antiplatelet actionNot implicated in Reye syndromeNo effects on uric acidNot bronchospastic (safe in NSAID hypersensitivity and asthmatics)Gastrointestinal distress is minimal at low to moderate dosesContinuation Overdose and management:Hepatotoxicity: Acetaminophen is metabolized mainly by liver glucuronyl transferase to form the inactive conjugate. A minor pathway (via P450) results in formation of a reactive metabolite (N-acetylbenzoquinoneimine), which is inactivated by glutathione (GSH). In Overdose situations, the finite stores of GSH are depleted. Once this happens, the metabolite reacts with hepatocytes, causing nausea and vomiting, abdominal pain, and liver failure due to centrilobular necrosis. Chronic use of ethanol enhances liver toxicity via induction of P450.Management of the hepatotoxicity: N-acetylcysteine (supplies---SH group), preferably within the first 12 hours (N-acetylcysteine is also used as a mucolytic for cystic fibrosis).

Prostaglandins: Therapeutic usesThey play a role in modulating pain, inflammation, and fever.They affect acid secretion and mucus production in GI, Uterine contractions, and renal blood flow. They are also released in allergic and inflammatory processes.

DRUGMOAUSEADVERSE EFFECTMisoprostol(PGE1 analog)Interacts with prostaglandins receptors on parietal cells (reduce Gastric acid secretion),GI cytoprotective effect.Counteract NSAID-induced stomach ulcers, Increases uterine contractions.Induce abortion, diarrhea, abdominal pain, headache, maternal or fetal death, infection, uterine damage and fetal bradycardia.Iloprost(a synthetic analog of PGI2)Causes a reduction in pulmonary arterial resistance with a subsequent increase in cardiac index and oxygen deliveryPulmonary arterial hypertension(potent pulmonary vasodilator)Dizziness, headache, flushing, fainting, bronchospasm and cough may also occur. Latanoprost, travoprost, and bimatoprost (PGF2a analog)Binds to the prostaglandin FP receptors, increase uveoscleral outflow, reducing intraocular pressure.open angle glaucoma, elevated intraocular pressure. Also increase eyelash prominence, length and darkness (eyelash hypothrichosis)bimatoprost.Blurred vision, iris color change, increased number and pigment of eyelashes, ocular irritation, and foreign body sensation.Alprostadil (PGE1)Urethra (suppository), corpus cavernosa (injection), IV .

Increase in intracellular cAMP leading to activation of protein kinase and smooth muscle relaxation.Erectile dysfunction, keep ductus arteriosus open in neonates.Symptomatic hypotension, dizziness and syncope (ED). Priapism. Apnea, fever, sepsis and seizures (neonates). Lubiprostone (PGE1)Stimulates chloride channels in the luminal cells of the intestinal epithelium, thereby increasing the intestinal fluid secretion.Chronic idiopathic constipation, IBS with constipationNausea (decreased if taken with food), Diarrhea , headache and abdominal pain. Disease-modifying antirheumatic agents (DMARDs)They are used in the treatment of RA.They have been shown to slow the progression of the disease, induce remission, thereby allowing these agents prevent further destruction of the joints and surrounding tissues.No specific DMARDS is efficacious and safe in every patient.Treatment is usually started with a single 1st line drug (methotrexate or hydroxychloroquine), due to their well documented profiles. In some cases combination therapy is used. DrugMOAUSEADVERSE EFFECTMethotrexate (MONO/COMB)It is an immunosuppressant, and this may account for its effectiveness in autoimmune diseasesRheumatoid or psoriatic arthritisMucosal ulceration, nausea, cytopenias, cirrhosis of the liver and acute pneumonia-like syndrome may occur with chronic administration.Leflunomide (MONO/COMB-methotrexate)Is an immunomodulatory agent that preferentially causes cell arrest of the autoimmune lymphocytes through its action on dihydroorotate dehydrogenase (DHODH), RA (it reduces pain & inflammation , also slow the progression of structural damage by inhibiting osteoclast production)Headache, diarrhea, nausea, weight loss, allergic rxn.Contraindicated in Pregnancy and not given to woman of child bearing age as it is a tetratogenic agent.Hydrochloroquine (MONO does not slow joint damage/ COMB-methotrexate)Inhibits phospholipase A2 and platelet aggregation, membrane stabilization, effects on the immune system, and antioxidant activity.Malaria , early/mild RAOcular toxicity, irreversible retinal damage, corneal deposit, CNS disturbances, GI upset , Skin discoloration and eruptions.Sulfasalazine (COMB-methotrexate & Hydrochloroquine)Its MOA in treating RA is unclear. Early/mild RA

Leukopenia D-penicillamine (add-on therapy to existing NSAID/glucocorticoid therapy but avoided in patients on DMARD therapy.)An analog of the amino acid cysteine, slows the progression of bone destruction and RA.RA, treatment of poisoning by heavy metals, cystinuria.Dermatologic problems , nephritis and aplastic anemia.GlucocorticoidsPotent anti-inflammatory which inhibits phospholipase A2 and COX2.Used in patients with RA to bridge the time until DMARDs are effective.Adverse effects are associated with long-term use.CyclophosphamideProduces a cytotoxic effects on Both B & T cells and selectively suppresses B-lymphocyte.RA (off-label use)Cytotoxic to kidneys & heart, myelosuppressive effects increase risk for infection or bleeding. GI disturbance, alopecia and infertility. Contraindicated in Pregnancy and not given to woman of child bearing age as it is a tetratogenic agentAzathioprine (COMB- aspirin, NSAIDs and/or low dose glucocorticoids in Tx of RA)Immunosuppressive agentKidney transplant rejection prophylaxis, RA , lupus nephritis and psoriatic arthritisContraindicated in Pregnancy and not given to woman of child bearing age as it is a tetratogenic agentBiologic therapies in Rheumatoid arthritisIL-1 and TNF-a are pro-inflammatory cytokines involved in the pathogenesis of RA.The TNF inhibitors (etanercept, adalimumab, infliximab, golimumab, and certolizumab) have been shown to decrease the signs and symptoms of RA.Experts propose that TNF inhibitors plus methotrexate be considered as standard therapy for RA and psoriatic arthritis.TNF inhibitors can not be administered with anakinra (IL-1 receptor antagonist).TNF inhibitors increase the risk of infections (TB-check for latent TB before starting Tx & sepsis), fungal opportunistic infections, and pancytopenia.Live vaccines should by avoided by patients on TNF inhibitor therapy.They can cause or exacerbate preexisting heart failure. Increase risk of lymphoma and other cancers has been observed with use of TNF-a inhibitors.DrugMOAUSEPHARMACOKINETICS ADVERSE EFFECTEtanercept (MONO/COMB-methotrexate)Binds to TNF-a, thereby blocking its interaction with cell surface TNF receptorsModerate to severe RA, juvenile RA, psoriatic arthritis, ankylosing spondylitis and psoriasisSubcutaneously twice a week. Time to max serum conc after a single dose is about 72hrs. Median t1/2 is 115hrsLocal inflammation at site of injectionInfliximab (COMB-methotrexate)Antibody binds specifically to human TNF-a, and inhibits binding with its receptors.RA, psoriatic arthritis, ankylosing spondylitis, crohn disease, ulcerative colitis.Infused IV over at least 2hrs. T1/2 9.5days.Fever , chills, pruritus and Urticaria. Pneumonia, activation of latent tuberculosis, leukopenia, neutropenia, thrombocytopenia, and pancytopenia.Adalimumab (MONO/COMB-methotrexate)Binds to TNF-a, thereby interfering with endogenous TNF-a activity by blocking its binding to the surface receptors.Moderate to severe RA, psoriatic arthritis, ankylosing spondylitis, crohn disease.Subcutaneously weekly or every other week. Average absolute bioavailability is 64% & conc in the synovial fluid may reach 31 to 96 percent of serum conc.Headache, nausea, agranulocytosis, rash, rxn at the injection site, increased risk of infection.Golimumab (COMB-methotrexate or other nonbiologic DMARD)Neutralizes the biological activity of TNF-a by binding to it and blocking its interaction with cell surface receptors. Binds to both the soluble and the transmembrane bioactive forms of human TNF-a.RASubcutaneously once a month.Increase risk of malignancies and serious infections, including TB. Erythema, itching and burning at site of injection.Rituximab (COMB-methotrexate )Antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes, resulting in B-cell depletion.Moderate to severe RA in adult patients who have had an inadequate response to one or more TNF-inhibitors.Administered as two 1000-mg IV infusion separated by 2 weeks. The mean terminal elimination half-life after the second dose is 19 daysInfusion rxn (Urticaria, hypotension, and angioedema).Anakinra (MONO/COMB-DMARD)IL-1 receptor antagonistModerate to severe RA in adult who have failed one or more DMARDsInfection, neutropeniaDrugs used in the treatment of goutDrugMOAUSEPHARMACOKINETICSADVERSE EFFECTColchicine (a plant alkaloid)Binds to tubulin, causing its depolymerization. This disrupts cellular functions, such as the mobility of granulocytes, thus decreasing their migration into the affected area.Prophylaxis of recurrent gout.Administered orally followed by rapid GI absorption. Use should be avoided in patients with a creatinine clearance of less than 10 mL/minNausea, vomiting, abdominal pain and diarrhea, Chronic use- myopathy, neutropenia, aplastic anemia and alopecia. Allopurinol (a purine analog)It reduces the production of uric acid by competitively inhibiting the last two steps in uric acid biosynthesis that are catalyzed by xanthine oxidase.Primary hyperuricemia of gout and hyperuricemia secondary to other conditions (malignancies or renal disease).Completely absorbed orally. t1./2 2hrs.Hypersensitivity rxn-skin rash. GI side effects, such as nausea and diarrhea. FebuxostatXanthine oxidase inhibitor (structurally unrelated to allopurinol)Same as allopurinolSame as allopurinol

Same as allopurinol

Probenecid and Sulfinpyrazone (Uricosuric agents)Weak organic acids that promote renal clearance of uric acid by inhibiting the urate-anion exchanger in the proximal tubule that mediates urate reabsorption. Gout Gastric distress (Probenecid), avoid in patients with creatinine clearance less than 50 ml/min.Sulfinpyrazone is contraindicated in patients with bone marrow suppression THE END