Tissue Block 22 Lecture Notes PDF

**ILOs** ***By the end of this lecture, students will be able to*** 1. Appraise the role of pharmacological inhibition of prostaglandins (PGs) actions in suppression of inflammation, pain, and fever. 2. 3. Correlate the drugs differential inhibitory effects on COX enzymes to their clin...

**ILOs** ***By the end of this lecture, students will be able to*** 1. Appraise the role of pharmacological inhibition of prostaglandins (PGs) actions in suppression of inflammation, pain, and fever. 2. 3. Correlate the drugs differential inhibitory effects on COX enzymes to their clinical uses, adverse reactions, and contraindications. 4. 1. **The steroidal anti-inflammatory,** i.e., **Corticosteroids**, which are very effective anti-inflammatory drugs in addition to their immunosuppressant and anti-allergic properties. (*Refer to drugs in allergy and anaphylaxis, Drugs modulating immune disorders*). Corticosteroids suppress PGs production by preventing the release of their precursor, arachidonic acid, from the cell membrane phospholipid via inhibition of phospholipase A2 (PLA2). 2. **The non-steroidal anti-inflammatory drugs (NSAIDs)**, which suppress PGs production by directly inhibiting their synthesis through the COX enzyme system, i.e., they are **COX inhibitors**. Non-steroidal anti-inflammatory drugs (NSAIDs) ---------------------------------------------- - Anti-inflammatory effect in different types of inflammatory disorders as ***arthritis, myositis***, etc. - Analgesic effect for mild to moderate painful conditions as ***headache, toothache, rheumatic*** pain, - Antipyretic effect to reduce body temperature in case of ***fever.*** I. #### Non-selective COX inhibitors, which can further be categorized into A. ###### Reversible non-selective COX inhibitors (Conventional non-salicylates NSAIDs), e.g., **Ibuprofen, diclofenac,** etc. These drugs differ from each other in their chemical nature, B. ***Irreversible non-selective COX inhibitor* (Aspirin = Acetyl salicylic acid):** Though it is the prototype NSAID, its use is replaced for most of the clinical indications by the other non- salicylates NSAIDs and is now mostly limited for its antiplatelet action by using a low dose. The **low dose aspirin** inhibits only thromboxane (TXA2) synthesis in the platelet, while it does not affect that of prostacyclin (PGI2) by the endothelial cells, favoring an antiaggregatory effect. The irreversible COX inhibition by aspirin ensures a maintained antiplatelet action for the lifetime of the platelet as being non-nucleated it can't synthesize COX-1 again. On the other hand, if any minor inhibition of endothelial prostacyclin occurs, the endothelial cells are capable of synthesizing new enzyme. Therefore, the main use of aspirin now is the primary or secondary prophylaxis against thrombotic event in patients at risk as those with ischemic ***cardiovascular*** or ***cerebrovascular diseases***. Adverse reactions: ------------------ 1. **The stomach:** leading to gastric irritation, ulceration, and bleeding. Moreover, the acidic nature of some NSAIDs, like **aspirin**, minorly contributes to the gastric irritation, therefore they are better given with meals. Concomitant administration of **proton pump inhibitors** (drugs which inhibit gastric acid formation) can be used to provide prophylaxis against NSAIDs-induced injury in patients at risk of peptic ulcer. 2. **The kidney:** leading to analgesic nephropathy especially with prolonged use. 3. **Hypersensitivity reactions:** Blocking of the COX inflammatory pathway leads to diversion of the arachidonic acid pathway to the LOX pathway with further production of leukotrienes that may precipitate allergic reactions in the form of bronchospasm, urticaria, or angioedema in predisposed individuals. 4. **The platelets:** leading to increased risk of bleeding or thrombosis according to the drug used. II. **Selective COX inhibitors (Coxibs)** e.g., **celecoxib** - Less or minimal gastric injury. - No antiplatelet action, conversely, they can increase thrombotic risk by inhibiting the endothelial PGI2 in favor of the effect of platelet TXA2. Therefore, they are contraindicated in patients at cardiovascular risk of thrombosis, e.g., diabetic hypertensive patients. Paracetamol (Acetaminophen) --------------------------- - Weak or no anti-inflammatory activity - No effect on platelet aggregation - No gastric or renal injury