PHA 403_STEROIDAL & NSAIDs_On pharmacology And therapeuticpptx

On pharmacology And therapeutic

1. STEROIDAL & NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (PHA 403- IMMUNOPHARMACOTHERAPY, INFLAMMATION, ALLERGY & ANAPHYLAXIS) Dr. Kazeem Adeola Oshikoya , MB;BS, MSc, PhD

2. INFLAMMATION & ITS MEDIATORS Inflammation is a physiologic response against noxious stimuli and microbial invaders. The basic elements of inflammation include: host cells, blood vessels, proteins and lipid mediators.

3. They all work together to eliminate the inflammatory stimulus as well as initiate the resolution and repair. During an inflammatory response, molecular patterns are sensed by receptors from innate immunity leading to the production of inflammatory mediators. The aim of inflammation is to eliminate the initial cause of cell injury, such as the necrotic cells/tissues that result from the original damage and, by doing so, paving the way to start the resolution and repair processes, restoring tissue homeostasis.

4. Although inflammation helps in the removal of infectious or sterile stimuli and in the initiation of repair, it can cause considerable tissue damage if it is overshooting or if there is failure in the resolution process. Mediators of inflammation are regulatory molecules that control the generation, maintenance and resolution of this response, which is triggered after recognition of infection or injury.

5. The initial recognition of the inflammatory stimuli leads to the production of pro-inflammatory mediators. Clinically, acute inflammation is classically characterized by symptoms known as the cardinal signs of inflammation: rubor (redness), calor (increased heat), tumor (swelling), dolor (pain), and functio laesa (loss of function).

6. The physiological basis of these signs is centered in the migration of leukocytes out of blood vessels and into the surrounding tissue, in order to eliminate the inflammatory stimuli and clear the inflammatory site from damaged cells and dead tissues. This is allowed by vascular changes characteristic of an acute inflammatory response, such as vasodilation and plasma leakage.

7. Inflammatory mediators of a vast range of nature, structure and cellular origins are involved in the basis of all the cardinal signs of inflammation and the physiological events associated to the inflammatory response. The immune system deals with infection and tissue damage through a sequence of events involving molecular, cellular and physiological alterations.

8. In order to coordinate these sequences of events, inflammatory mediators are produced by blood or local-derived inflammatory cells in response to a noxious stimulus. The major cell types that produce mediators of acute inflammation are platelets, neutrophils, monocytes /macrophages and mast cells, but cells such as fibroblasts, endothelial cells and smooth muscle cells, can be activated to produce some of these mediators.

9. These mediators are derived from immune cells: vasoactive amines, lipid mediators, platelet-activating factor (PAF), reactive oxygen species, nitric oxide, cytokines and chemokines OR are acute phase proteins produced by the liver that circulate in the plasma (e.g. the complement, coagulation ( fibronolysis ) and kallikrein-kinin systems).

10. Together, the mediators of inflammation orchestrate all the inflammatory events such as blood vessel dilatation, vascular permeability, leukocyte migration to the affected tissue and pain. Inflammation covers a host of pathophysiological events and means different things to different people – acute or chronic, organ-specific such as asthma, reversible or irreversible.

11. Irrespective of the types of inflammatory conditions, the same mediators are involved and are many. They include Amines histamine and 5-hydroxytryptamine, Short peptides bradykinin,

12. Long peptides Interleukin-1 (IL-1) Lipids Prostaglandins (PGs) and Leukotrienes (LTs) Enzymes released from migrating cells Complement factors The importance of these putative mediators can be determined by eliminating the mediator, preventing its generation with enzyme inhibitors, or by preventing its pharmacological effects with a selective antagonist.

13. SPECIFIC MEDIATORS Vasoactive Amines Histamine The release of histamine from mast cells during antigen-antibody reactions is well known, as is its involvement in the inflammatory response to skin injury and asthma. Also, increased numbers of mast cells are present in the rheumatoid synovium and the asthmatic lung, correlated with raised levels of histamine.

14. Invariably, histamine plays an important role in inflammatory responses, mainly in hypersensitive responses. It is a vasoactive amine released mostly by mast cells that causes vasodilation, edema and smooth muscle contraction. Antihistamines found a role in the treatment of hay fever and some cutaneous inflammation; they are, however, ineffective in arthritis or asthma, so that histamine did not seem to play a major part in these conditions.

15. Clinical manifestations of histamine-mediated hypersensitive reactions vary from anaphylactic reaction and urticaria, to local wheal and are reactions. Serotonin Although serotonin is best known for its activity in the central nervous system (CNS), it is mostly produced by enterochromaffin cells and predominantly found in the periphery and in the gastrointestinal tract.

16. It is also produced by neuronal cells, T-lymphocytes, monocytes and mast cells but all these sources combined are still smaller than enterochromaffin production. Besides the cells that produce serotonin, it can also be present in other cells, like blood platelets, dendritic cells and B lymphocytes, due to the uptake mechanism. Serotonin functions as a hormone, an immune modulator and a neurotransmitter.

17. Therefore, it contributes to the regulation of many physiological functions, like vasoconstriction, inflammatory responses, intestinal motility and wound healing Serotonin may induce multiple effects in different tissues. These effects are due to the presence of different receptors that will activate distinct signaling pathways.

18. Serotonin receptor family (5-HTR) comprises at least 13 receptors classified in subfamilies from 5-HTR1 until 5-HTR7, they are G-protein coupled receptors (GPCRs) and one is a Cys -loop ligand-gated ion channel receptor. Activation of 5-HTR1 downregulate cyclic AMP. On the other hand, activation 5-HTR4, 5-HTR6 and 5-HTR7 upregulate cAMP.

19. Serotonin is responsible for the regulation of many aspects of cognition and behavior, platelet coagulation, gastrointestinal motility and immunity. 5-HTRs expression in neutrophils, eosinophils, monocytes, macrophages, dendritic cells (DCs), mast cells and natural killer (NK) cells highlight the importance of serotonin in immunological responses.

20. Besides all physiological functions, serotonin can be involved in many pathological processes due to the deregulation of the serotonin-signaling pathway. These diseases can vary from neuro- logical to inflammatory disorders. It was recently suggested that serotonin uptake by lymphocytes may trigger serotonylation .

21. This process is described as the covalent linkage of serotonin to small intracellular GTPases, such as RhoA and Rab4, by intracellular transglutaminase leading to constitutive activation of G-protein-dependent signaling pathways. As these GTPases are also present in other immune cells, serotonylation may help explain the pathophysiological effects of enhanced intracellular serotonin in various inflammatory diseases.

22. In addition, serotonylation subsequently downregulates efferocytosis, resulting in the progression of some chronic inflammatory diseases, like systemic lupus erythematosus, rheumatoid arthritis, obesity, cardiovascular disease, neurodegenerative disease, asthma and chronic obstructive pulmonary disease. It has been recently identified that platelet, and not mast cell-derived, serotonin contributes to allergic airway inflammation

23. Bradykinins Small amounts of bradykinin cause pain, vasodilation, and edema, all contributory to inflammation. Bradykinin-like immunoreactivity has been detected in rat pleural inflammatory exudates. Kinins are also present in nasal secretions after immunological challenge. Kininologenase is released from human lung mast cells.

24. Inhaled bradykinin causes bronchospasm in normal and asthmatic individuals. Lack of antagonists makes it difficult to assess the extent of involvement of kinins in inflammation and asthma. There is also no evidence of inhibitors of the inactivation of bradykinin, such as captopril or enalapril, exacerbate bronchospasm.

25. Prostaglandins (PG) Apart from RBCs (non-nucleated cells), all cells are capable of synthesizing PGs, which are release in response to many kinds of trauma or any disturbance of the cell membrane. Pathological release of PGs that contribute to inflammation, fever, and pain is inhibited by aspirin and other NSAIDs.

26. Thromboxane A 2 and Prostacyclin Platelets arachidonic acid (AA) is metabolized to the pro-aggregatory thromboxane (TX) A 2 . Aspirin has been shown to inhibit the formation of the endoperoxide intermediate in this pathway. Prostacyclin is another prostaglandin that showed opposite activity to that TXA2. Prostacyclin relaxes blood vessels and inhibits aggregation of platelets

27. The Leukotrienes They are slow-reacting substances of anaphylaxis (SRS-A) They are products of lipoxygenase pathway of AA metabolism. NSAIDs inhibits cyclooxygenase pathway but not lipoxygenase pathway, therefore LTs synthesis is not inhibited. Some evidence had shown that lipoxygenase products contribute to vascular changes in inflammation.

28. Platelet-activating factors (PAF) PAF is released by the actions of phospholipase A2 from most proinflammatory cells, vascular endothelial cells and platelets. It induces inflammatory reactions in various animal species and in human skin It also mimics the main clinical features of asthma and is particularly effective in producing hyperactivity and accumulation of eosinophils in lung tissues.

29. Interleukin-1 IL-1) It is a polypeptide produced by activated macrophages that mimics the symptoms of chronic inflammation. IL-1 like activity has been detected in synovial fluids from patients with rheumatoid arthritis. Its action include activation of of lymphocytes and production of fever, which is also mediated by PGE2.

30. STEROIDAL ANTI-INFLAMMATORY DRUGS Corticosteroids exert a potent anti-inflammatory effect. Corticosteroids are steroid hormones classified as glucocorticoids (anti-inflammatory), which suppress inflammation and immunity and assist in the breakdown of fats, carbohydrates, and proteins.

31. They may also be classified as mineralocorticoids (salt retaining) that regulate the balance of salt and water in the body. Corticosteroids are used to treat conditions such as arthritis, colitis, bronchiolitis, allergic reactions, and skin rashes.   Common corticosteroids include prednisolone, cortisone, and methylprednisolone.

32. Mechanism of Action of Steroids in Inflammation Corticosteroids inhibit phospholipase A2 activity, which is necessary for the release of arachidonic acid (AA). Consequently, they inhibit the formation of PGs, TXA2 and LTs.

33. The predominant effect of corticosteroids is to switch off multiple inflammatory genes (encoding cytokines, chemokines, adhesion molecules, inflammatory enzymes, receptors and proteins) that have been activated during the chronic inflammatory process. In higher concentrations they have additional effects on the synthesis of anti-inflammatory proteins and postgenomic effects. 

34. Molecular Mechanisms of Chronic Inflammation Chronic inflammatory diseases, such as asthma, COPD rheumatoid arthritis and inflammatory bowel disease, involve the infiltration and activation of many inflammatory and immune cells, which release multiple inflammatory mediators that interact and activate structural cells at the site of inflammation.

35. The pattern of inflammation clearly differs between these diseases, with the involvement of many different cells and mediators, but all are characterised by increased expression of multiple inflammatory proteins, some of which are common to all inflammatory diseases, whereas others are more specific to a particular disease.

36. The increased expression of most of these inflammatory proteins is regulated at the level of gene transcription through the activation of proinflammatory transcription factors, such as nuclear factor- κ B (NF- κ B) and activator protein-1 (AP-1).  These proinflammatory transcription factors are activated in all inflammatory diseases and play a critical role in amplifying and perpetuating the inflammatory process.

37. Thus, NF- κ B is activated in the airways of asthmatic patients and COPD patients and is activated in the joints of patients with rheumatoid arthritis and the vessels of patients with atherosclerosis. The molecular pathways involved in regulating inflammatory gene expression are now being delineated and it is now clear that chromatin remodeling plays a critical role in the transcriptional control of genes.

38. Stimuli that switch on inflammatory genes do so by changing the chromatin structure of the gene, whereas corticosteroids reverse this process. Corticosteroids exert their physiological effects via activation of either glucocorticoid  receptor (GR) or the mineralocorticoid  receptor (MR) in target tissues to alter the expression of corticosteroid-responsive genes.

39. NON-STEROIDAL ANTI-INFLAMMATORY DRUGS NSAIDs are used due to their potent analgesic, anti-inflammatory, and antipyretic effects. Inhibition of cyclooxygenase (COX) enzyme, which takes part in the biosynthesis of prostaglandins (PGs) and thromboxane (TX), is the mechanism of action of NSAIDs.

40. PGs and TXs are important mediators of fever, pain, and inflammation. Inflammation has a major role in the pathophysiology of various diseases. NSAIDs affect the synthesis and action of inflammatory mediators including PGs, coagulation cascade-derived peptides, interleukin (IL)-2, IL-6, and tumor necrosis factor (TNF).

41. The synthesis of prostanoids that are produced from arachidonic acid causes inflammatory pain. Arachidonic acid mainly exists as esterified phosphatidylcholine and phosphatidylethanolamine phospholipid forms in the membranes. It is released from the cell membrane by phospholipase A 2  (PLA 2 ), which is the overall rate-limiting step for eicosanoids.

42. There are two isoforms of PLA 2  classified as secretory and cytoplasmic. This multiple isoform existence allows for various biological responses for different tissues. PLA 2 isoforms can be stimulated by TNF- α, granulocyte-macrophage colony-stimulating factor, interferon (IFN), and various growth factors, such as mitogen-activated protein kinase (MAPK) and phosphokinase C.

43. COX enzymes (cyclooxygenases) convert arachidonic acid to PGs, prostacyclins , and TXs. Specifically, TXs play a role in platelet adhesion, PGs cause vasodilation, increase the temperature set-point in the hypothalamus, and play a role in anti-nociception. 

44. Mechanism of Action of NSAIDs The main mechanism of action of NSAIDs is the inhibition of the enzyme cyclooxygenase (COX). The therapeutic effects of NSAIDs are attributed to the lack of these eicosanoids. There are two cyclooxygenase isoenzymes, COX-1 and COX-2.

45. COX-1 gets constitutively expressed in the body, and it plays a role in maintaining gastrointestinal mucosa lining, kidney function, and platelet aggregation. COX-2 is not constitutively expressed in the body; and instead, it inducibly expresses during an inflammatory response. Most of the NSAIDs are non-selective and inhibit both COX-1 and COX-2.

46. However, COX-2 selective NSAIDs (e.g. celecoxib) only target COX-2 and therefore have a different side effect profile. Importantly, because COX-1 is the prime mediator for ensuring gastric mucosal integrity and COX-2 is mainly involved in inflammation, COX-2 selective NSAIDs should provide anti-inflammatory relief without compromising the gastric mucosa.

47. NSAIDs are typically divided into groups based on their chemical structure and selectivity: Non-selective COX-Inhibitors Acetylated salicylates (aspirin), Non-acetylated salicylates (diflunisal, salsalate ), Propionic acids (naproxen, ibuprofen, ketoprofen) Pyrazolone derivatives (phenylbutazone,

48. Indole derivatives (indomethacin, sulindac) Acetic acids (diclofenac, ketorolac, indomethacin), Enolic acids/ Oxicams (meloxicam, piroxicam, tenoxicam) Anthranilic acids/ Fenamates (meclofenamate, mefenamic acid), and Naphthylalanine ( nabumetone ),

49. selective COX-2 inhibitors Celecoxib Etoricoxib   Rofecoxib (withdrawn in 2004) Valdecoxib (withdrawn in 2005)