Drugs Combating Acute Inflammation PDF

22 Drugs Combating Acute Inflammation 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. Distinguish the benefits and hazards of...

22 Drugs Combating Acute Inflammation 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. Distinguish the benefits and hazards of inhibiting PGs on variable tissues. 3. Correlate the drugs differential inhibitory effects on COX enzymes to their clinical uses, adverse reactions, and contraindications. 4. Recommend a suitable drug in different relevant clinical scenarios. As previously discussed, prostaglandins (PGs) are considered the main mediators involved in inducing the manifestations of acute inflammatory response (Refer to mediators of acute inflammation). Therefore, drugs that can suppress the production of PGs are generally used in the management of acute inflammatory conditions. Suppression of PGs production can pharmacologically be achieved by two major classes of drugs, which differ in their chemical nature, and site and mechanism of action as shown in figure 1. 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. Fig. 1: Sites of action of drugs targeting the arachidonic acid pathway for anti-inflammatory and anti-allergic effects. Both classes of drugs are not specific to a particular disease and can be used in the vast majority of acute inflammatory disorders to relieve the manifestations of inflammation. It should be noted that Page 1 of 4 these drugs do not correct the underlying pathology and therefore, may be combined, when necessary, with other lines of treatment directed to the etiopathogenesis of the disease; for e.g., the use of antimicrobial drugs if inflammation is infectious in origin, etc. Another important principle is that though these drugs are first line in acute inflammation, there chronic use is not preferred, where they can be used only during periods of acute flare of chronic diseases to avoid the serious adverse effects of their long-term use. In the next section, the NSAIDs are discussed in more details, while the corticosteroids will be further studied in the Endocrine block. Non-steroidal anti-inflammatory drugs (NSAIDs) The key point to understand the actions of NSAIDs is to recognize and distinguish the consequences of inhibiting the COX enzyme non selectively (both COX-1 and COX-2) versus the selective inhibition of COX-2 alone, and also to relate these actions to the distribution of COX enzymes in the different tissues (Refer to mediators of acute inflammation). From the known functions of COX enzyme, it could be concluded that the therapeutic benefits of NSAIDs are related to inhibition of the excessive PGs produced by the induced COX-2 in response to the injurious agent. These PGs are mediators of inflammation and are responsible for the cardinal signs of the acute inflammatory response, including fever and pain. Therefore, the NSAIDs are used clinically for their: ▪ 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, dysmenorrhea, etc. ▪ Antipyretic effect to reduce body temperature in case of fever. Accordingly, NSAIDs are commonly referred to as analgesic antipyretic drugs or sometimes as non- opioid analgesics, to differentiate them form the opioid analgesics, which are used in severe types of pain and have potential for drug dependence. On the other hand, most of the adverse reactions of NSAIDs would be generally related to inhibition of the physiologically important prostanoids (PGs, prostacyclin, and thromboxane), which are the products of the constitutively active COX-1 enzyme (and in some instances COX-2) under normal conditions and play important roles in various tissues, including gastric protection, regulation of platelet activity, and renal functions. In this respect, it may be predicted that the selective COX-2 inhibitors are better drugs with less adverse effects. However, it was proven, after their wide clinical use, that they have more cardiovascular hazards than the non-selective agents because of their unopposed activating effect on platelet aggregation, as will be discussed below. Therefore, broadly the NSAIDs can be classified into: 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, Page 2 of 4  pharmacokinetics, and their affinity to COX-1 and COX-2. Therefore, they have variable analgesic, anti-inflammatory activities, as well as variable severity of their adverse reactions. For example, Ketorolac is the most effective analgesic up to the analgesic effect of opioids and can be used to relief moderately severe pain as post-operative pain, but it is the most gastric injurious agent. Ibuprofen is less effective but a more tolerable NSAID. 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. At moderate doses, aspirin exerts an analgesic effect, while at high doses, it shows its anti- inflammatory activity, which justifies its use in some cases of rheumatic fever to prevent complications. Adverse reactions: As explained above, the adverse effects of NSAIDs are due to their inhibitory effect on the constitutively produced COX enzyme system that plays a role in normal physiological functions resulting in: 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. Many of the members of this class are available as topical formulations to provide some benefit, while avoiding the systemic adverse effects. II. Selective COX inhibitors (Coxibs) e.g., celecoxib This drug subclass has the same properties as the conventional NSAIDs, but are characterized by: ▪ Less or minimal gastric injury. Page 3 of 4  ▪ 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) Paracetamol is an analgesic antipyretic drug that lacks the anti-inflammatory activity that is why, it does not belong to the NSAID group. The key point to understand the difference between paracetamol and NSAIDs is that it mainly inhibits the COX enzyme centrally (in the CNS) and does not affect the peripheral COX present elsewhere in the body. This, in turn, accounts for the following properties: ▪ Weak or no anti-inflammatory activity ▪ No effect on platelet aggregation ▪ No gastric or renal injury Therefore, paracetamol is preferably used for fever or pain in absence of inflammation or in combination with NSAIDs in inflammatory disorders to decrease their doses and hence their adverse effects. It is also a safe analgesic antipyretic for children and during pregnancy. N.B., Acute overdose of paracetamol carries the risk of hepatic toxicity (Acute necrotizing hepatitis that could be fatal). Therefore, the maximum allowed dose of paracetamol is 3-4 g daily in healthy adults. Page 4 of 4