Lecture 1 Pharma 2 D Mahmoud PDF

Non-Opioid Analgesics (Non-steroidal anti-inflammatory drugs "NSAIDs", Aspirin- like drugs, or Antipyretic Analgesics) Introduction: Non-opioid analgesics, particularly NSAIDs, represent a class of drugs widely employed in the treatment of pain, inflammation, and fever. Their...

Non-Opioid Analgesics (Non-steroidal anti-inflammatory drugs "NSAIDs", Aspirin- like drugs, or Antipyretic Analgesics) Introduction: Non-opioid analgesics, particularly NSAIDs, represent a class of drugs widely employed in the treatment of pain, inflammation, and fever. Their primary mechanism of action involves the inhibition of cyclooxygenase (COX) enzymes, which are essential for converting arachidonic acid into eicosanoids such as prostaglandins, thromboxanes, and leukotrienes. NSAIDs are characterized by their ability to provide analgesia without the risk of addiction or respiratory depression seen with opioid analgesics. Types of Cyclooxygenase (COX) Enzymes: Type Constitutive enzyme Inducible enzyme Variant of COX-1 Expression Continuously Upregulated in Primarily expressed in expressed in various response to the central nervous tissues inflammatory stimuli system (CNS) Tissues Stomach, kidneys, Predominantly at sites Mainly in the brain platelets of inflammation, injury, or infection Physiological - Gastric protection: - Mediates - Central regulation of Functions stimulates mucus inflammation, pain, and pain and fever and bicarbonate fever secretion - Platelet - Contributes to - Suggested target for aggregation: vasodilation, increased analgesic and produces vascular permeability, antipyretic drugs like thromboxane A2 and immune cell acetaminophen (TxA2) for clot recruitment formation - Renal function: maintains renal perfusion through vasodilation Role in Not primarily Major role in mediating Limited involvement; Inflammation involved in inflammatory processes primarily associated inflammatory with pain and fever responses regulation Dr. Mahmoud Elsaid | Pharmacology II 1 Pharmacological Actions of NSAIDs: NSAIDs exhibit a broad range of pharmacological effects, with their primary actions being anti-inflammatory, analgesic, and antipyretic. These effects are mediated through the inhibition of prostaglandin synthesis by blocking COX enzymes.’ Category Mechanism of PGs Role of NSAIDs Clinical Implications Anti- ▪ Inflammatory processes trigger ▪ NSAIDs inhibit COX-2, reducing ▪ Effective in treating Inflammatory the release of arachidonic acid, pro-inflammatory prostaglandin inflammatory conditions Action converted into pro-inflammatory production, leading to decreased (e.g., arthritis, injury-related prostaglandins by COX-2. vasodilation, edema, and pain. pain) by reducing ▪ Prostaglandins mediate inflammation and pain. vasodilation, increase vascular permeability, and promote immune cell migration to inflammation sites. Analgesic Effect ▪ Peripheral Mechanism: ▪ NSAIDs decrease nociceptor ▪ Effective for managing mild Prostaglandins sensitize sensitivity by reducing peripheral to moderate pain (e.g., peripheral nociceptors to painful prostaglandin synthesis, headache, dental pain) stimuli, enhancing pain providing pain relief. ▪ but less effective for severe perception. pain (e.g., major trauma). ▪ Central Mechanism: ▪ - NSAIDs block prostaglandin ▪ Used in postoperative pain In the CNS, prostaglandins synthesis in the spinal cord, management and chronic enhance the transmission of pain reducing pain transmission from pain conditions, but signals along afferent neurons. peripheral nerves to the CNS. monitoring for side effects is essential. Dr. Mahmoud Elsaid | Pharmacology II 2  Category Mechanism of PGs Role of NSAIDs Clinical Implications Antipyretic ▪ Fever results from pyrogens ▪ NSAIDs inhibit COX enzymes in ▪ Widely used to treat fever in Effect stimulating IL-1 release by the hypothalamus, reducing PGE2 infections, inflammatory activated immune cells during synthesis, thereby lowering the diseases, and post- infection or inflammation. hypothalamic set point and vaccination in both adults ▪ IL-1 stimulates PGE2 production reducing fever. and children. in the hypothalamus, raising the body temperature set point and causing fever. Gastrointestinal ▪ COX-1-derived prostaglandins ▪ COX-1 inhibition ▪ Chronic NSAID use (GI) Effects protect gastric mucosa by 1. reduces protective effects significantly increases the stimulating mucus and 2. increasing gastric acid secretion risk of peptic ulcer disease, bicarbonate secretion and 3. reducing mucus production necessitating gastric reducing gastric acid production. 4. raising the risk of gastric ulcers. protection measures (e.g., co-administration of antiulcer drugs). Renal Effects ▪ Prostaglandins maintain renal ▪ NSAIDs reduce renal ▪ Risk of acute kidney injury blood flow and glomerular prostaglandin-mediated (AKI) in susceptible patients filtration, especially during low vasodilation, potentially ▪ renal function should be perfusion states. decreasing renal blood flow and monitored during long-term glomerular filtration. NSAID therapy, particularly in patients with pre-existing kidney disease Bronchial Effects ▪ COX-1 inhibition may lead to ▪ NSAIDs can exacerbate bronchial ▪ Patients with asthma or increased leukotriene constriction in susceptible known NSAID sensitivity production, which causes individuals due to shifts in should avoid these drugs or bronchoconstriction. arachidonic acid metabolism. use them with caution Dr. Mahmoud Elsaid ǀ Pharmacology-II 3  Category Mechanism of PGs Role of NSAIDs Clinical Implications Hematological ▪ Prostaglandin I2 (PGI2): ▪ By inhibiting COX-1, NSAIDs ▪ NSAID use is associated with effects o Synthesized in endothelial reduce the production of TXA2, increased gastrointestinal cells leading to decreased platelet bleeding and hemorrhagic o PGI2 is a potent aggregation and an increased risk events, particularly in vasodilator and an of bleeding. This effect is patients with underlying inhibitor of platelet particularly pronounced with conditions or those on non-selective NSAIDs that inhibit aggregation. anticoagulants. both COX-1 and COX-2. ▪ Thromboxane A2 (TXA2): ▪ Careful management is o Produced by activated essential, especially in platelets surgical settings, o TXA2 promotes vasoconstriction and platelet aggregation, facilitating clot formation. Dr. Mahmoud Elsaid ǀ Pharmacology-II 4 General Adverse Effects 1. Gastrointestinal: Dyspepsia, nausea, vomiting, ulcers, and GI bleeding are common side effects. The risk is greater with non-selective NSAIDs 2. Cardiovascular: NSAIDs, particularly selective COX-2 inhibitors, are associated with fluid retention, hypertension, and an increased risk of cardiovascular events, including myocardial infarction and stroke. 3. Renal: NSAIDs can impair renal function by interfering with prostaglandin-mediated regulation of renal blood flow, leading to conditions such as acute kidney injury, hyperkalemia, and proteinuria. 4. Hepatic: Hepatotoxicity, though rare, can occur with prolonged NSAID use. 5. Hematologic: Risk of bleeding in addition to rare adverse effects include thrombocytopenia, neutropenia, and aplastic anemia. 6. Respiratory: NSAIDs can trigger asthma in sensitive individuals, especially those with aspirin-exacerbated respiratory disease (AERD). 7. Dermatologic: Skin reactions, including rashes and pruritus, are possible. Contraindications NSAIDs should be avoided or used with caution in the following conditions: 1. Peptic Ulcer Disease: Due to the increased risk of GI bleeding and ulceration. 2. History of GI Bleeding: Particularly with non-selective NSAIDs, which increase the risk of GI hemorrhage. 3. Cardiovascular Disease: Patients with a history of myocardial infarction, stroke, or congestive heart failure are at increased risk for cardiovascular events when using NSAIDs, particularly COX-2 inhibitors. 4. Chronic Kidney Disease (CKD): NSAIDs can worsen renal function in patients with pre-existing kidney disease. 5. Liver Disease: Caution is advised in patients with liver dysfunction due to the potential for hepatotoxicity. 6. Asthma or Aspirin Sensitivity: NSAIDs, especially aspirin, may precipitate bronchospasm in susceptible individuals. Dr. Mahmoud Elsaid | Pharmacology II 5  7. Coagulation Disorders: Aspirin and non-selective NSAIDs inhibit platelet aggregation, increasing bleeding risk in individuals with coagulation disorders such as hemophilia. 8. Pregnancy: NSAIDs are contraindicated, particularly in the third trimester, due to the risk of premature closure of the fetal ductus arteriosus and prolonged labor. 9. Heart Failure: NSAIDs may exacerbate heart failure by causing fluid retention and increased blood pressure. Dr. Mahmoud Elsaid ǀ Pharmacology-II 6 Dr. Mahmoud Elsaid ǀ Pharmacology-II 7