Management of Inflammation - Pharmacology PDF

management of inflammation PHARMACOLOGY Paul Benzo I. Sia, DMD Assistant Professor I National University MOA- College of Dentistry inflammation immune system’s protective response to an injurious stimulus can be evoked by noxious agents, infections, and physical injuries inflammation may be ex...

management of inflammation PHARMACOLOGY Paul Benzo I. Sia, DMD Assistant Professor I National University MOA- College of Dentistry inflammation immune system’s protective response to an injurious stimulus can be evoked by noxious agents, infections, and physical injuries inflammation may be exaggerated and sustained without apparent benefit and even with severe adverse consequences e.g., hypersensitivity, automimmune diseases, chronic inflammation inflammation the inflammatory response is characterized mechanistically by transient local vasodilation and increased capillary permeability; infiltration of leukocytes and phagocytic cells; and resolution with or without tissue degeneration and fibrosis. inflammation PGE2 and PGI2 are the primary prostanoids that mediate inflammation increase local blood flow, vascular permeability, and leukocyte infiltration fever hypothalamus regulates the set point at which body temperature is maintained elevation results from tissue damage, inflammation, graft rejection, or malignancy NSAIDs suppress this response by inhibiting COX-2–dependent PGE2 synthesis NSAIDs non-steroidal antiinflammatory drugs for management of inflammation, fever, pain, hyperuricemia, gout act by inhibiting cyclooxygenases (COX) cox-1- expressed throughout the body cox-2- induced at sites of inflammation role in blood pressure regulation endogenous inhibitors of hemostasis ADME absorption rapidly absorbed following oral ingestion peak plasma concentrations are reached within 2–3 h Food intake may delay absorption and systemic availability Antacids, commonly prescribed to patients on NSAID therapy, variably delay absorption ADME distribution Most NSAIDs are extensively bound (95%–99%) to plasma proteins, usually albumin Most NSAIDs are distributed widely throughout the body and readily penetrate arthritic joints, yielding synovial fluid concentrations in the range of half the plasma concentration sufficient concentrations in the CNS to have a central analgesic effect ADME metabolism and excretion Hepatic biotransformation and renal excretion therapeutic effect antipyretic can reduce fever in most situations no effect on the circadian variation in temperature or the rise in response to exercise or increased ambient temperature therapeutic effect analgesic low-to-moderate intensity maximal efficacy is generally less than the opioids NSAIDs lack the unwanted adverse effects of opiates in the CNS can be coadministered with opioids not effective against pain arising from hollow viscera except menstrual pain lacks efficacy in neuropathic pain therapeutic effect anti-inflammatory rheumatoid arthritis and osteoarthritis NOTE: acetaminophen antipyretic and analgesic largely devoid of anti-inflammatory activity therapeutic effect closing of patent ductus arteriosus e.g. indomethacin, ibuprofen therapeutic effect cardioprotection aspirin prolongs bleeding time Aspirin reduces the risk of serious vascular events in high-risk patients by 20%–25%; subsequent thrombotic strokes roughly 10%–15% cardioprotection is lost when combining low-dose aspirin with NSAIDs adverse effects Gastrointestinal Abdominal pain dysplasia nausea vomiting, and rarely, ulcers or bleeding inhibition of cox-1 in gastric epithelial cells adverse effects cardiovascular COX-2 inhibitors depress formation of PGI2 but do not inhibit the COX-1– catalyzed formation of platelet TxA increased risk of MI and CVA adverse effects renal events hypertension (5%); more on cox-2 retention of salt and water adverse effects Reye’s syndrome acute onset of encephalopathy, liver dysfunction, and fatty infiltration of the liver and other viscera aspirin and other salicylates are contraindicated in children and young adults less than 20 years of age with viral illness–associated fever may use acetaminophen and ibuprofen NSAIDs classifications Non-selective COX inhibitors selective Cox-1 inhibitors selective Cox-2 inhibitors do not affect platelet function at their usual doses may increase incidence of edema and hypertension improved GI safety aspirin and other salicylates aspirin and other salicylates aspirin aka ASA (acetylsalicylic acid) irreversible inhibitors of cox activity duration of aspirin’s effects is related to the turnover rate of the COXs in different target tissues Inhibition of platelet COX-1–dependent TxA2 formation is cumulative with repeated doses of aspirin (at least as low as 30 mg/d) and takes 8–12 days (the platelet turnover time) to recover fully once therapy has been stopped analgesic-antipyretic dose of aspirin for adults is 325–1000 mg orally every 4–6 h. maximum recommended daily dose of aspirin for adults and children 12 years or older is 4 g aspirin and other salicylates Low-dose aspirin (≤100 mg daily) lowers cardiovascular risk and is recommended for the prevention of myocardial infarction and stroke in patients at elevated risk use of salicylates is contraindicated in patients with chronic liver disease Patients with severe hepatic damage, hypoprothrombinemia, vitamin K deficiency, or hemophilia should avoid aspirin If possible, aspirin therapy should be stopped at least 1 week before surgery ototoxic acetaminophen acetaminophen aka paracetamol active metabolite of phenacetin non-selective cox inhibitor not an NSAID raises the threshold to painful stimuli well tolerated but can be hepatotoxic acetaminophen conventional oral dose of acetaminophen is 325–650 mg every 4–6 h; total daily doses should not exceed 4 g (2 g/d for chronic alcoholics). Single doses for children 2–11 years old depend on age and weight (~10–15 mg/kg); no more than five doses should be administered in 24 h. toxicity may be managed with n-acetylcysteine acetic acid derivatives diclofenac potency is substantially greater than that of other NSAIDs. Although it was not developed to be a COX-2 selective drug, the selectivity of diclofenac for COX-2 resembles that of celecoxib 50% reaches circulation accumulates in synovial fluid for management of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, pain, primary dysmenorrhea, and acute migraine indomethacin non-selective cox-inhibitor closure of patent ductus arteriosus others sulindac etodolac ketorolac nabumetone proprionic acid derivatives proprionic acid derivatives nonselective COX inhibitors with the effects and side effects common to other NSAIDs approved for use in the symptomatic treatment of rheumatoid arthritis, juvenile arthritis, and osteoarthritis Ibuprofen and naproxen have been shown to interfere with the antiplatelet effects of aspirin ibuprofen An injectable formulation of ibuprofen is approved to close patent ductus arteriosus in premature infants 200 mg or less are available without a prescription usual dose for mild-to-moderate pain is 400 mg every 4–6 h as needed Ibuprofen is better tolerated than aspirin and indomethacin and has been used in patients with a history of GI intolerance to other NSAIDs Ibuprofen can be used occasionally by pregnant women; however, the concerns apply regarding third-trimester effects, including delay of parturition. Excretion into breast milk is thought to be minimal ibuprofen 200–800 mg 3–6 times/d with food (maximum 3.2 g/d); Children: 4–10 mg/kg/dose, 3–4 times/d naproxen for juvenile and rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, pain, primary dysmenorrhea, tendonitis, bursitis, and acute gout. 250 mg 3–4 times/d; 250–550 mg 2 times/d; 750–1000 mg daily (extended release) Children: 5 mg/kg 2 times/d (max 15 mg/kg/d) fenamates fenamates pharmacological properties of the fenamates are those of typical NSAIDs, and therapeutically, they have no advantages over others in the class drugs are not recommended for use in children or pregnant women e.g. mefenamic acid, meclofenamate, flufenamic acid enolic acids enolic acids oxicams Piroxicam nonselective COX inhibitor with the longest t1/2 approved for the treatment of rheumatoid arthritis andosteoarthritis usual daily dose is 20 mg Meloxicam shows modest COX-2 selectivity comparable to celecoxib and was approved as a COX-2–selective NSAID in some countries 7.5 mg/d of meloxicam coxibs cox-2 selective inhibitors -coxibs Most are restricted in their use or withdrawn from the market in view of their adverse cardiovascular risk profile Celecoxib currently is the only COX-2 inhibitor licensed for use in the U.S. e.g. celecoxib, rofecoxib, valdecoxib and its prodrug parecoxib, etoricoxib, and lumiracoxib Some older NSAID compounds—diclofenac, etodolac, meloxicam, and nimesulide—exhibit selectivity for COX-2 that is close to that of celecoxib celecoxib elimination t1/2 is about 11 h management of acute pain for the treatment of osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, and primary dysmenorrhea recommended dose for treating osteoarthritis is 200 mg/d as a single dose or divided as two doses treatment of rheumatoid arthritis, the recommended dose is 100–200 mg twice daily. Due to cardiovascular hazard, physicians are advised to use the lowest possible dose for the shortest possible duration celecoxib confers a risk of myocardial infarction and stroke, and this appears to relate to dose and the underlying risk of cardiovascular disease Chronic use of celecoxib may decrease bone mineral density, particularly in older male patients