Pharmacology Anti-inflammatory drugs PDF

Pharmacology Anti-inflammatory drugs Lec 1 ASPIRIN DICLOFENAS NSAIDS NAPROXEN IBUPROFEN Pharmacology | Anti-inflammatory drugs Contents : Inflammation 3 Prostaglandins 6 Non-steroidal anti-inflammatory drugs (NSAIDs) 11 Therapeutic uses of NSAIDs 20 Pharmacokinetics 26 Adverse effects of NSAIDs 30 P...

Pharmacology Anti-inflammatory drugs Lec 1 ASPIRIN DICLOFENAS NSAIDS NAPROXEN IBUPROFEN Pharmacology | Anti-inflammatory drugs Contents : Inflammation 3 Prostaglandins 6 Non-steroidal anti-inflammatory drugs (NSAIDs) 11 Therapeutic uses of NSAIDs 20 Pharmacokinetics 26 Adverse effects of NSAIDs 30 Pharmacology | Anti-inflammatory drugs Inflammation: 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, and set the stage for tissue repair. When healing is complete, the inflammatory process usually subsides. Pharmacology | Anti-inflammatory drugs However, inappropriate activation of the immune system can result in inflammation and immune-mediated diseases such as rheumatoid arthritis (RA). In RA, white blood cells (WBCs) initiate an inflammatory attack WBC activation leads to stimulation of T lymphocytes, which recruit and activate monocytes and macrophages. These cells secrete proinflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-1, into the synovial cavity, ultimately leading to joint destruction and other systemic abnormalities characteristic of RA. Pharmacology | Anti-inflammatory drugs In addition to T lymphocyte activation, the B lymphocytes are also involved and produce rheumatoid factor and other autoantibodies to maintain inflammation. Pharmacotherapy for RA includes antiinflammatory and/or immunosuppressive agents that modulate/reduce the inflammatory process, with the goals of reducing inflammation and pain, and halting or slowing disease progression. Pharmacology | Anti-inflammatory drugs Prostaglandins: Prostaglandins are unsaturated fatty acid derivatives containing 20 carbons that include a cyclic ring structure. Thromboxanes, leukotrienes, and the hydroperoxyeicosatetraenoic and hydroxyeicosatetraenoic acids (HPETEs and HETEs, respectively) are related lipids, synthesized from the same precursors as the prostaglandins, and use interrelated pathways. Note: These compounds are sometimes referred to as eicosanoids Pharmacology | Anti-inflammatory drugs Synthesis of prostaglandins: Arachidonic acid, a 20-carbon fatty acid, is the primary precursor of the prostaglandins and related compounds. There are two major pathways in the synthesis of the eicosanoids from arachidonic acid. Cyclooxygenase pathway: All eicosanoids with ring structures that is, the prostaglandins, thromboxanes, and prostacyclins are synthesized via the cyclooxygenase pathway. Pharmacology | Anti-inflammatory drugs Two related isoforms of the cyclooxygenase enzymes have been described. Cyclooxygenase-1 (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. Cyclooxygenase-2 (COX-2) causes the elevated production of prostanoids that occurs in sites of disease and inflammation. COX-2 is constitutively expressed in tissues such as the brain, kidney, and bone. Its expression at other sites is increased during states of inflammation. Pharmacology | Anti-inflammatory drugs Pharmacology | Anti-inflammatory drugs Lipoxygenase pathway: Alternatively, several lipoxygenases can act on arachidonic acid to form leukotrienes or lipoxins, depending on the tissue. Pharmacology | Anti-inflammatory drugs Functions of prostaglandins in the body: Prostaglandins and their metabolites produced endogenously in tissues, they control many physiological functions, such as acid secretion and mucus production in the gastrointestinal (GI) tract, uterine contractions, and renal blood flow. Prostaglandins are also among the chemical mediators that are released in allergic and inflammatory processes. Intradermal, intravenous, or intra-arterial injections of small amounts of prostaglandins mimic many components of inflammation.. Pharmacology | Anti-inflammatory drugs Non-steroidal anti-inflammatory drugs (NSAIDs): All NSAIDs, including the traditional nonselective drugs and the subclass of selective cyclooxygenase-2 (COX-2) inhibitors, have the following actions: anti-inflammatory, analgesic, and antipyretic. NSAIDs are a chemically heterogeneous group of organic acids that share certain therapeutic actions and adverse effects. All of the NSAIDs act by inhibiting the cyclooxygenase enzymes that catalyze the first step in prostanoid biosynthesis. This leads to decreased prostaglandin synthesis with both beneficial and unwanted effects. Pharmacology | Anti-inflammatory drugs Aspirin and other NSAIDs: Aspirin can be thought of as a traditional NSAID, but it exhibits anti-inflammatory activity only at relatively high doses that are rarely used. It is used more frequently at lower doses to prevent cardiovascular events such as stroke and myocardial infarction (MI). Aspirin is often differentiated from other NSAIDs since it is an irreversible inhibitor of cyclooxygenase activity Pharmacology | Anti-inflammatory drugs Mechanism of action: Aspirin is a weak organic acid that irreversibly acetylates and, thus, inactivates cyclooxygenase, the other NSAIDs are reversible inhibitors of cyclooxygenase. The NSAIDs, including aspirin, have three major therapeutic actions: they reduce inflammation (anti-inflammatory), pain (analgesic effect), and fever (antipyretic effect). However, not all NSAIDs are equally effective in each of these actions. Pharmacology | Anti-inflammatory drugs Actions of Aspirin and other NSAIDs: 1. Anti-inflammatory effect: Anti-inflammatory actions: inhibition of cyclooxygenase diminishes the formation of prostaglandins since PGE2 induce acute inflammation through mast cell activation via the EP3 receptors. Aspirin inhibits inflammation in arthritis, but it neither arrests the progress of the disease nor induces remission. Pharmacology | Anti-inflammatory drugs 2. Analgesic action: PGE2 is thought to sensitize nerve endings to the action of bradykinin, histamine, and other chemical mediators released locally by the inflammatory process. Thus, by decreasing PGE2 synthesis, the sensation of pain can be decreased, as COX-2 is expressed during times of inflammation and injury, it is thought that inhibition of this enzyme is responsible for the analgesic activity of NSAIDs. Note: No single NSAID has demonstrated superior efficacy over another, and they are generally considered to have equivalent analgesic efficacy. Pharmacology | Anti-inflammatory drugs The NSAIDs are used mainly for the management of mild to moderate pain arising from musculoskeletal disorders. One exception is ketorolac, which can be used for more severe pain, but for only a short duration. Pharmacology | Anti-inflammatory drugs 3. Antipyretic action: Fever occurs when the set-point of the anterior hypothalamic thermoregulatory center is elevated. Lipoxygenase pathway: Alternatively, several lipoxygenases can act on arachidonic acid to form leukotrienes or lipoxins, depending on the tissue. This can be caused by PGE2 synthesis, which is stimulated when endogenous fever-producing agents (pyrogens), such as cytokines, are released from WBCs that are activated by infection, hypersensitivity, malignancy, or inflammation. Pharmacology | Anti-inflammatory drugs The NSAIDs lower body temperature in patients with fever by impeding PGE2 synthesis and release, resetting the “thermostat” back toward normal. This rapidly lowers the body temperature of febrile patients by increasing heat dissipation through peripheral vasodilation and sweating. NSAIDs have no effect on normal body temperature. Therapeutic uses of NSAIDs Pharmacology | Anti-inflammatory drugs Therapeutic uses of NSAIDs: Anti-inflammatory and analgesic uses: NSAIDs are used in the treatment of osteoarthritis, gout, RA, and common conditions requiring analgesia (for example, headache, arthralgia, myalgia, and dysmenorrhea). Combinations of opioids and NSAIDs may be effective in treating pain caused by malignancy. Furthermore, the addition of NSAIDs may lead to an opioidsparing effect, allowing for lower doses of opioids to be utilized. Pharmacology | Anti-inflammatory drugs The salicylates exhibit analgesic activity at lower doses. Only at higher doses do these drugs show anti-inflammatory activity. For example, two 325-mg aspirin tablets administered four times daily produce analgesia, whereas 12 to 20 tablets per day produce both analgesic and anti-inflammatory activity Pharmacology | Anti-inflammatory drugs Antipyretic uses: Aspirin, ibuprofen, and naproxen may be used to treat fever. Note: Aspirin should be avoided in patients less than 19 years old with viral infections, such as varicella (chickenpox) or influenza, to prevent Reye syndrome—a syndrome that can cause fulminating hepatitis with cerebral edema, often leading to death. Pharmacology | Anti-inflammatory drugs Cardiovascular applications: Aspirin irreversibly inhibits COX-1–mediated production of TXA2, thereby reducing TXA2-mediated vasoconstriction and platelet aggregation and the subsequent risk of cardiovascular events. The antiplatelet effects persist for the life of the platelet. Low doses of aspirin (75 to 162 mg—commonly 81 mg) are used prophylactically to reduce the risk of recurrent cardiovascular events, transient ischemic attacks (TIAs) , stroke, and death in patients with a history of previous MI, TIA, or stroke. Pharmacology | Anti-inflammatory drugs Chronic use of aspirin allows for continued inhibition as new platelets are generated. Aspirin is also used acutely to reduce the risk of death in acute MI and in patients undergoing certain revascularization procedures. Pharmacology | Anti-inflammatory drugs External applications: Salicylic acid is used topically to treat corns, calluses, and warts. Methyl salicylate is used externally as a cutaneous counterirritant in liniments, such as arthritis creams and sports rubs. Diclofenac is available in topical formulations (gel or solution) for treatment of osteoarthritis in the knees or hands. In addition, ocular formulations of ketorolac are approved for management of seasonal allergic conjunctivitis and inflammation and pain related to ocular surgery. Pharmacology | Anti-inflammatory drugs Pharmacokinetics: a) Aspirin. b) Other NSAIDs Aspirin: After oral administration, aspirin is rapidly deacetylated by esterases in the body to produce salicylate. Unionized salicylates are passively absorbed mainly from the upper small intestine. Pharmacology | Anti-inflammatory drugs Salicylates (except for diflunisal) cross both the blood–brain barrier (BBB) and the placenta and are absorbed through intact skin (especially methyl salicylate). Salicylate is converted by the liver to water-soluble conjugates that are rapidly cleared by the kidney, resulting in first-order elimination and a serum half-life of 3.5 hours. At anti-inflammatory dosages of aspirin (more than 4 g/day), the hepatic metabolic pathway becomes saturated, and zeroorder kinetics are observed, leading to a half-life of 15 hours or more. Pharmacology | Anti-inflammatory drugs Salicylate is secreted into the urine and can affect uric acid excretion. Therefore, aspirin should be avoided in gout, if possible, or in patients taking probenecid. Pharmacology | Anti-inflammatory drugs Other NSAIDs: Most NSAIDs are well absorbed after oral administration and circulate highly bound to plasma proteins. The majority are metabolized by the liver, mostly to inactivate metabolites. Few (for example, nabumetone and sulindac) have active metabolites. Excretion of active drug and metabolites is primarily via the urine. Pharmacology | Anti-inflammatory drugs Adverse effects of NSAIDs: Because of the adverse event profile, it is preferable to use NSAIDs at the lowest effective dose for the shortest duration possible. a) Gastrointestinal: These are the most common adverse effects of NSAIDs, ranging from dyspepsia to bleeding. Normally, production of prostacyclin (PGI2) inhibits gastric acid secretion, and PGE2 and PGF2α stimulate synthesis of protective mucus in both the stomach and small intestine. Pharmacology | Anti-inflammatory drugs Agents that inhibit COX-1 reduce beneficial levels of these prostaglandins, resulting in increased gastric acid secretion, diminished mucus protection, and increased risk for GI bleeding and ulceration. Agents with a higher relative selectivity for COX-1 may have a higher risk for GI events compared to those with a lower relative selectivity for COX-1 (that is, higher COX-2 selectivity). NSAIDs should be taken with food or fluids to diminish GI upset. Pharmacology | Anti-inflammatory drugs If NSAIDs are used in patients at high risk for GI events, proton pump inhibitors or misoprostol should be used concomitantly to prevent NSAID-induced ulcers. Pharmacology | Anti-inflammatory drugs b) Increased risk of bleeding (antiplatelet effect): As aspirin inhibits COX-1–mediated formation of TXA2 and reduces platelet aggregation for the lifetime of the platelet (3 to 7 days). Platelet aggregation is the first step in thrombus formation, and the antiplatelet effect of aspirin results in a prolonged bleeding time. For this reason, aspirin is often withheld for at least 1 week prior to surgery Pharmacology | Anti-inflammatory drugs NSAIDs other than aspirin are not utilized for their antiplatelet effect but can still prolong bleeding time, especially when combined with anticoagulants Concomitant use of NSAIDs and aspirin can prevent aspirin from binding to cyclooxygenase. Patients who take aspirin for cardioprotection should avoid concomitant NSAID use if possible or take aspirin at least 30 minutes prior to the NSAID. Pharmacology | Anti-inflammatory drugs c) Renal effects: NSAIDs prevent the synthesis of PGE2 and PGI2, prostaglandins that are responsible for maintaining renal blood flow, that the synthesis of PGE2 and PGI2 normally antagonizes the intra-renal effect of vasoconstrictors. NSAIDs leave the actions of vasoconstrictors unopposed. Decreased synthesis of prostaglandins can result in retention of sodium and water and may cause edema. Pharmacology | Anti-inflammatory drugs Patients with a history of heart failure or kidney disease are at particularly high risk. These effects can also decrease the beneficial effects of antihypertensive medications. In susceptible patients, NSAIDs have led to acute kidney injury. Pharmacology | Anti-inflammatory drugs Glomeruli and arterioles synthesize not only the vasodilatory prostaglandins PGE2 and PGI2, but also the vasoconstrictor, thromboxane A2. The primary renal cortical actions of these prostaglandins are renal vasodilatation and maintenance of GFR (PGE2 and PGI2) or renal vasoconstriction and reduction of GFR (thromboxane A2). Vasodilatory renal prostaglandins are relatively unimportant under normal circumstances but play a modulatory role after ischemia or in the presence of increased concentrations of vasoconstrictor substances such as angiotensin II (ANG II) , vasopressin or norepinephrine. Pharmacology | Anti-inflammatory drugs Conversely, arachidonic acid reduces the glomerular contractile effect of ANG II. It is, therefore, concluded that renal prostaglandins play an important vasoregulatory role.