Pharmacology lec.2.pdf

Pharmacology Anti-inflammatory drugs Lec 2 ASPIRIN DICLOFENAS NSAIDS NAPROXEN IBUPROFEN Pharmacology | Anti-inflammatory drugs Contents : Adverse effects of NSAIDs(cont.) 3 Selective COX-2 inhibitor 10 Acetaminophen 16 Traditional Disease-Modifying Antirheumatic Drugs 23 Choice of drug 24 Methotrexa...

Pharmacology Anti-inflammatory drugs Lec 2 ASPIRIN DICLOFENAS NSAIDS NAPROXEN IBUPROFEN Pharmacology | Anti-inflammatory drugs Contents : Adverse effects of NSAIDs(cont.) 3 Selective COX-2 inhibitor 10 Acetaminophen 16 Traditional Disease-Modifying Antirheumatic Drugs 23 Choice of drug 24 Methotrexate 25 Hydroxychloroquine 28 Leflunomide 30 Sulfasalazine 33 Glucocorticoids 34 Pharmacology | Anti-inflammatory drugs d) Cardiac effects: Agents such as aspirin, with a very high degree of COX-1 selectivity at low doses, have a cardiovascular protective effect thought to be due to a reduction in the production of TXA2. Agents with higher relative COX-2 selectivity have been associated with an increased risk for cardiovascular events, possibly by decreasing PGI2 production mediated by COX-2. An increased risk for cardiovascular events, including MI and stroke, has been associated with all NSAIDs except aspirin. Pharmacology | Anti-inflammatory drugs Use of NSAIDs, other than aspirin, is discouraged in patients with established cardiovascular disease. For patients with cardiovascular disease in whom NSAID treatment cannot be avoided, naproxen may be the least likely to be harmful. Pharmacology | Anti-inflammatory drugs e) Other adverse effects: NSAIDs are inhibitors of cyclooxygenases and, therefore, inhibit the synthesis of prostaglandins but not of leukotrienes. For this reason, NSAIDs should be used with caution in patients with asthma, as inhibition of prostaglandin synthesis can cause a shift toward leukotriene production and increase the risk of asthma exacerbations. Central nervous system (CNS) adverse events, such as headache, tinnitus, and dizziness, may occur. Pharmacology | Anti-inflammatory drugs Approximately 15% of patients taking aspirin experience hypersensitivity reactions. Symptoms of true allergy include urticaria, bronchoconstriction, and angioedema. Patients with severe hypersensitivity to aspirin should avoid using NSAIDs. Pharmacology | Anti-inflammatory drugs f) Drug interactions: Salicylate is roughly 80% to 90% plasma protein bound (albumin) and can be displaced from protein-binding sites, resulting in increased concentration of free salicylate. Alternatively, aspirin can displace other highly protein-bound, drugs, such as warfarin, phenytoin, or valproic acid, resulting in higher free concentrations of these agents Pharmacology | Anti-inflammatory drugs g) Toxicity: Mild salicylate toxicity is called salicylism and is characterized by nausea, vomiting, marked hyperventilation, headache, mental confusion, dizziness, and tinnitus (ringing or roaring in the ears). When large doses of salicylate are administered, severe salicylate intoxication may result). Restlessness, delirium, hallucinations, convulsions, coma, respiratory and metabolic acidosis, and death from respiratory failure may occur. Pharmacology | Anti-inflammatory drugs Children are particularly prone to salicylate intoxication ingestion of as little as 10 g of aspirin can be fatal. h) Toxicity: NSAIDs should be used in pregnancy only if benefits outweigh risks to the developing fetus. In the third trimester, NSAIDs should generally be avoided due to the risk of premature closure of the ductus arteriosus. Note: Acetaminophen is preferred if analgesic or antipyretic effects are needed during pregnancy Pharmacology | Anti-inflammatory drugs Selective COX-2 inhibitor: Celecoxib: a selective COX-2 inhibitor, is significantly more selective for inhibition of COX-2 than COX-1. Unlike the inhibition of COX-1 by aspirin (which is irreversible), the inhibition of COX-2 is reversible. Pharmacology | Anti-inflammatory drugs Therapeutic uses: Celecoxib is approved for the treatment of RA, osteoarthritis, and acute pain. Celecoxib has similar efficacy to NSAIDs in the treatment of pain. Pharmacology | Anti-inflammatory drugs Pharmacokinetics: Celecoxib is readily absorbed after oral administration. It is extensively metabolized in the liver by cytochrome P450 (CYP2C9), and the metabolites are excreted in feces and urine. The half-life is about 11 hours, and the drug may be dosed once or twice daily. The dosage should be reduced in those with moderate hepatic impairment, and celecoxib should be avoided in patients with severe hepatic or renal disease. Pharmacology | Anti-inflammatory drugs Adverse effects: Headache, dyspepsia, diarrhea, and abdominal pain are the most common adverse effects. Celecoxib is associated with less GI bleeding and dyspepsia than other NSAIDs. However, this benefit is lost when aspirin is added to celecoxib therapy. Pharmacology | Anti-inflammatory drugs Patients who are at high risk of ulcers and require aspirin for cardiovascular prevention should avoid the use of celecoxib. Patients who have had anaphylactoid reactions to aspirin or nonselective NSAIDs may be at risk for similar effects with celecoxib. Inhibitors of CYP2C9, such as fluconazole, may increase serum levels of celecoxib. Like other NSAIDs, celecoxib has a similar risk for cardiovascular events. Pharmacology | Anti-inflammatory drugs Pharmacology | Anti-inflammatory drugs Acetaminophen: Acetaminophen (N-acetyl-p-aminophenol or APAP) inhibits prostaglandin synthesis in the CNS, leading to antipyretic and analgesic effects. Acetaminophen has less effect on cyclooxygenase in peripheral tissues (due to peripheral inactivation), which accounts for its weak anti-inflammatory activity. Acetaminophen does not affect platelet function or increase bleeding time. It is not considered an NSAID. Pharmacology | Anti-inflammatory drugs Therapeutic uses: Acetaminophen is used for the treatment of fever and the relief of pain. It is useful in patients with gastric complaints/risks with NSAIDs and those who do not require the anti-inflammatory action of NSAIDs. Acetaminophen is the analgesic/antipyretic of choice for children with viral infections or chickenpox (due to the risk of Reye syndrome with aspirin). Pharmacology | Anti-inflammatory drugs Pharmacokinetics: Acetaminophen is rapidly absorbed from the GI tract and undergoes significant first-pass metabolism. It is conjugated in the liver to form inactive glucuronidated or sulfated metabolites. A portion of acetaminophen is hydroxylated to form N-acetyl-pbenzoquinoneimine, or NAPQI, a highly reactive metabolite that can react with sulfhydryl groups and cause liver damage. Pharmacology | Anti-inflammatory drugs At normal doses of acetaminophen, NAPQI reacts with the sulfhydryl group of glutathione produced by the liver, forming a nontoxic substance. Acetaminophen and its metabolites are excreted in urine. The drug is also available in intravenous and rectal formulations. Pharmacology | Anti-inflammatory drugs Adverse effects: At normal therapeutic doses, acetaminophen has few significant adverse effects. With large doses of acetaminophen, the available glutathione in the liver becomes depleted, and NAPQI reacts with the sulfhydryl groups of hepatic proteins. Hepatic necrosis, a serious and potentially life-threatening condition, can result. Pharmacology | Anti-inflammatory drugs Patients with hepatic disease, viral hepatitis, or a history of alcoholism are at higher risk of acetaminophen-induced hepatotoxicity. Acetaminophen should be avoided in patients with severe hepatic impairment. Note: N-acetylcysteine is an antidote in cases of overdose. Traditional Disease-Modifying Antirheumatic Drugs: Pharmacology | Anti-inflammatory drugs Traditional Disease-Modifying Antirheumatic Drugs: Traditional DMARDs (methotrexate, hydroxychloroquine, leflunomide, or sulfasalazine) are used in the treatment of RA, slow the course of the disease. Induce remission, and prevent further destruction of the joints and involved tissues. Following diagnosis of RA, these agents should be started as soon as possible to delay progression of the disease. Pharmacology | Anti-inflammatory drugs Choice of drug: Mono-therapy may be initiated with any of the traditional DMARDs, although methotrexate is generally preferred. For patients with inadequate response to monotherapy, a combination of traditional DMARDs, or use of a TNF inhibitor or non-TNF biologic agent may be needed. Combination therapies are both safe and efficacious, NSAIDs or glucocorticoids can also be used for their anti-inflammatory actions. Pharmacology | Anti-inflammatory drugs Methotrexate: Methotrexate is a folic acid antagonist that inhibits cytokine production and purine nucleotide biosynthesis, leading to immunosuppressive and anti-inflammatory effects. Other traditional DMARDs, TNF inhibitors, or non-TNF biologic agents can be added to methotrexate if there is inadequate response to mono-therapy with this agent. Mainstay of treatment in patients with rheumatoid or psoriatic arthritis. Pharmacology | Anti-inflammatory drugs Response to methotrexate occurs within 3 to 6 weeks of starting treatment. Doses of methotrexate required for this treatment are much lower than those needed in cancer chemotherapy and are given once a week, thereby minimizing adverse effects. adverse effects: mucosal ulceration and nausea. Pharmacology | Anti-inflammatory drugs Cytopenias (particularly depression of the WBC count), cirrhosis of the liver, and an acute pneumonia-like syndrome taking leucovorin once daily after methotrexate reduces the severity of the adverse effects. Periodic liver function tests, complete blood counts, and monitoring for signs of infection are recommended. Methotrexate is contraindicated in pregnancy. Note: Supplementation with folic acid may improve tolerability of methotrexate and reduce GI and hepatic adverse effects. Pharmacology | Anti-inflammatory drugs Hydroxychloroquine: Hydroxychloroquine is used for early, mild RA, and may be combined with methotrexate. Its mechanism of action in autoimmune disorders is unknown, and onset of effects takes 6 weeks to 6 months. Hydroxychloroquine has less adverse effects on the liver and immune system than other DMARDs. Pharmacology | Anti-inflammatory drugs However, it may cause 1. ocular toxicity, including irreversible retinal damage and corneal deposits. 2. CNS disturbances. 3. GI upset. 4. skin discoloration and eruptions. Pharmacology | Anti-inflammatory drugs Leflunomide Leflunomide is an immune-modulatory agent, causes cell arrest of the autoimmune lymphocytes through its action on dihydroorotate dehydrogenase (DHODH), after biotransformation, leflunomide becomes a reversible inhibitor of DHODH, an enzyme necessary for pyrimidine synthesis. It not only reduces pain and inflammation associated with the disease but also appears to slow the progression of structural damage. Pharmacology | Anti-inflammatory drugs Leflunomide may be used as monotherapy in patients who have intolerance or contraindications to use of methotrexate in RA, or it may be used in combination with methotrexate for patients with suboptimal response to methotrexate alone. Common adverse effects include: Headache, diarrhea , and nausea. Other effects are weight loss, allergic reactions, including a flu-like syndrome, skin rash, alopecia, and hypokalemia. Pharmacology | Anti-inflammatory drugs The drug is not recommended in patients with liver disease as it can be hepatotoxic. Leflunomide is contraindicated in pregnancy. Monitoring parameters include signs of infection, complete blood count, electrolytes, and liver enzymes. Pharmacology | Anti-inflammatory drugs Sulfasalazine: Sulfasalazine has recommendations for use similar to leflunomide in the treatment of RA. Its mechanism of action in treating RA is unclear. Onset of activity is 1 to 3 months. it is associated with GI adverse effects (nausea, vomiting, anorexia) and leukopenia. Pharmacology | Anti-inflammatory drugs Glucocorticoids: Glucocorticoids are potent anti-inflammatory drugs that are commonly used in patients with RA to provide symptomatic relief and bridge the time until other DMARDs become effective. Glucocorticoids should always be used at the lowest dose and for the shortest duration possible to avoid adverse effects associated with long-term use.