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1. INFLAMMATION PHA 405

2. Local or protective response of living tissues or cells to injury due to any agent. Essential for wound healing. Goal is to rid body of initial cause of cell injury The body’s defender against foreign invaders are plasma proteins, leucocytes and phagocytes.

3. inflammatory changes occur because of dilatation of local blood vessels, which lead to increased permeability and increased receptiveness for leucocytes. This causes accumulatio n of inflammatory cells at the site of injury. The main cells seen in an acute inflammatory response are neutrophils and macrophages. Lymphocytes, basophils and eosinophils also accumulate.

4. Inflammatory responses are produced and controlled by inflammator y mediators, some derived from leucocytes, some from the damaged tissues. Examples include: • Histamine • Kinins (bradykinin) • Neuropeptides (substance-P, calcitonin gene-related peptide) • Cytokines (e.g. interleukins (ILs)) • Arachidonic acid metabolites (eicosanoids).

5. Cardinal Signs of inflammation: Rubor (redness) Tumor (swelling) Calor or calus (heat) Dolor (pain) Functio laesa (loss of function)

6. Calor Consequence of increased blood supply. Also results from increased metabolic activity. Tumor Increased vascularity . Accumulation of fluid and cells in injured tissue. Fluid can be edema or pus.

7. Dolor Consequence of release of mediators that stimulate nerve endings. Type depends on extent of stimulus. Causes of inlammation : Bacteria. Viruses. Protozoa. Fungi.

8. Chemicals Foreign body. Burns Trauma Ionizing radiation. Idiopathic.

9. Types of inflammation : Acute inflammation : - immediate response of tissue to an injurious agent - it delivers mediators of host defense, leukocytes and plasma proteins to injury site. - has short duration -characterized by exudation of fluid , plasma proteins (edema) and emigration of leucocytes . Chronic inflammation : prolonged duration whereby active inflammation, tissue destruction, attempts at repair proceeding simultaneously.

10. Three major components of acute inflammation Vascular dilation and increased blood flow(causing erythema and warmth) Structural changes in the microvasculature that permit plasma proteins and leucocytes to leave the microcirculation Leucocytes emigration and accumulation at the site of injury.

11. Events in acute inflammation are divided into vascular events cellular events Chemical mediators of inflammation Vascular event: Changes in vascular flow and caliber Transcient vasoconstriction stasis Increased vascular permeability.

12. Changes in vascular flow and caliber Vasodilatation in the arterioles (induced by mediators such as nitric oxide and histamine) followed by a brief vasoconstriction Vasodilation causes increased vascular permeability of the microvasculature leading to pouring out of proteins into the tissues Stasis (vascular congestion) occurs when there is Loss of fluid Increase in vessel diameter which leads to slower blood flow Red cells concentrate in small blood vessels Increased blood viscosity

13. Stasis (vascular congestion) occurs when there is Loss of fluid Increase in vessel diameter which leads to slower blood flow Red cells concentrate in small blood vessels Increased blood viscosity Increased vascular permeability Occurs mainly at the arterioles, venules and cappillaries Endothelial contraction -

14. Cellular events are: Exudation ( Escape of fluid, protein, and blood cells from vascular system into interstitial tissue/body cavities ) phagocytosis.

15. Cellular events - Leucocyte extravasation -Adhesion and transmigration - Chemotaxis - Leucocyte activation

16. Adhesion molecules in inflammation 1. Selectins : these are 3 closely related proteins designated P, E, L. L- selectin are found leukocytes and lymphocytes. E- selectin are found on cytokine activated endothelial cells. P- selectin are present on secretory granules of platelets and in granules of endothelial cells.

17. 2. Integrins These are 30 structurally homologous proteins. They promote cell-cell and cell-matrix interactions. 3. Immunoglobulin super family adhesion molecules (intracellular adhesion molecules (ICAM) and vascular cell adhesion molecules (VCAM))

18. Chemotaxis Movement of immune cells to a site of inflammation. Facilitated by chemokines which stimulate leukocyte recruitment and control normal migration of cells through various tissues. -C-X-C chemokines /alpha chemokine-neutrophils . -C-C-Chemokine/beta chemokine- oesinophils , basophils, monocytes, lymphocytes. -C- Chemokine -lymphocytes

19. Effect of chemokines mediated by binding to receptors: -CXCR -CCR -CR CXCR-4, CCR-5 are co-receptors for viral envelope glycoprotein of HIV and are involved in entry and binding.

20. Phagocytosis - engulfment of solid particulate material by cells and involves: -Recognition and attachment -Engulfment -Digestion/degradation/killing.

21. Killing and degradation Oxygen dependent- by production of reactive oxygen metabolites, HOCL, HOI, HOBR, Hydrogen peroxide, hydroxyl. Myeloperoxidase (MPO) dependent killing. -MPO acts on hydrogen peroxide in the presence of halides to form hypohalous acid. - Hypohalous acid is a potent antibacterial.

22. MPO independent killing MPO not present in mature macrophages. Bactericidal action is by formation of hydroxyl ions. Oxygen independent killing Ki lling by agents released from phagocytic cells which include: - Lysosomal hydrolases -Permeability increasing factors. - Defensins . -Cationic proteins.

23. Chemical mediators of inflammation. They are also known as permeability factors. Two types: -Cell derived -Plasma derived

24. Cell derived Vasoactive amines Arachidonic acid metabolites Lysosomal components PAF Cytokines. Nitric oxide.

25. Vasoactive amines Histamine Formed by decarboxylation of histidine First autacoid discovered. Found in all tissues but more in skin, lungs, GIT. High concentration in mast cells and basophils . Involved in inflammation and anaphylactic reactions.

26. Effects mediated by H1 and H2 receptors -Increased secretion of pancreas, sweat, salivary, lacrimal glands, increased gastric (H2) receptors and bronchial secretion. -Increased vasodilation (H1 and H2 receptors). and permeability of arterioles, capillaries and venules . -Increased bronchial, uterine and GIT contraction.

27. H3 and H4 receptors Expressed mainly in the CNS. H3 receptors fxn as autoreceptors on histaminergic neurons. H3 antagonists promote wakefulness while H3 agonists promote sleep. H4 receptors are found on oesinophils and neutrophils , GIT, CNS. H4 antagonists are used as inhibitors of allergic and inflammatory responses.

28. Histamine antagonists Inhibit histamine action by receptor blockade. Inhibit histidine decarboxylase . H1 antagonists divided into first ( chlorpheniramine , diphenylhydramine , promethazine , hydroxyzine ) and second ( fexofenadine , loratidine , levocetirizine ) generations. They are used in treatment of allergic reactions.

29. Serotonin (5-HT) Formed from tryptophan. Present in platelets and enterochromaffin cells. Similar actions to histamine. Less potent as a vasodilator

30. Arachidonic acid metabolites: the eicosanoids T he eicosanoids are involved in most inflammatory reactions . The eicosanoids are a family of polyunsaturated fatty acids (PUFA) formed from arachidonic acid. Arachidonic acid is derived from phospholipids of cell membranes, from which it is m etabolized by the action of the enzyme phospholipase A2. Arachidonic acid is then furthe r metabolized: • By cyclooxygenase to produce prostaglandins, thromboxane and prostacyclin , collectively known as the prostanoids • By lipoxygenase to produce the leukotrienes

31. Arachidonic acid metabolites They are 20 carbon PUFA. They are derived from dietary sources. Do not occur freely in cells but esterified in membrane phospholipids.

32. Biosynthetic pathway of the eicosanoids. (HETE, hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid; LT, leukotrienes; NSAID, non-steroidal anti-inflammatory drug; PG, prostaglandin.)

33. Cyclooxygenase exists in two enzyme isoforms: • COX-1 : Expressed in most tissues, platelets, gastric mucosa and renal vasculature . Are involved in physiological cell signalling. Most adverse effects of NSAIDs are caused by inhibition of COX-1. • COX-2: Induced at sites of inflammation and produces the prostanoids involved in inflammatory responses. Analgesic and anti-inflammatory effects of NSAIDs are largely due to inhibition of COX-2.

34. COX-2-specific inhibitors have a reduced incidence of gastric side-effects. However, they are associated with an increased incidence of adverse cardiovascular events (such as myocardial infarction).

35. Anti-inflammatory drugs The main drugs used for their broad-spectrum antiinflammatory effects are: • Non-steroidal anti-inflammatory drugs (NSAIDS) . • Steroidal anti-inflammatory drugs (glucocorticoids) They exert their actions by inhibiting the formation of eicosanoids some other drug classes have more restricted anti-inflammatory actions. These are: • Disease-modifying antirheumatic drugs (DMARDs) • Drugs used to treat gout • Antihistamines • Drugs used to treat skin disorders.

36. NSAIDs NSAIDs all possess the ability to inhibit both forms of the enzyme cyclooxygenase, an action The first drugs of this type were the salicylates (e.g. aspirin) , extracted from the bark of the willow tree.

37. Mechanism of action of NSAIDS inhibition of the enzyme cyclooxygenase . Inhibition of cyclooxygenase can occur by several mechanisms: • Irreversible inhibition – e.g. aspirin causes acetylation of the active site. • Competitive inhibition – e.g. ibuprofen acts as a competitive substrate. • Reversible, non-competitive inhibition – e.g. paracetamol has a free radical trapping action that interferes with the production of hydroperoxidases, which are believed to have an essential role in cyclooxygenase activity.

38. The inhibitin g action of NSAIDS on the cyclooxygenase s producing three major clinical actions : analgesia anti-inflammatory action antipyretic action However paracetamol does not possess anti-inflammatory activity .

39. A spirin inhibit s platelet aggregation , due to reduced thromboxane synthesis. It is used in the primary and secondary prevention of cardiovascular and cerebrovascular events. Indications —NSAIDs are widely used for managing musculoskeletal and joint diseases (strains, sprains, rheumatic problems, arthritis, gout, etc.), analgesia for mild to moderate pain relief and symptomatic relief in fever. Contraindications —gastrointestinal ulceration or bleeding, or a previous hypersensitivity to any NSAID. Caution : should be used in asthma and in renal impairment. Adverse effects —Less commonly, liver disorders and bone marrow depression.

40. Salicylic acids, e.g. aspirin: Used for mild pain , has antiplatelet action Produces tinnitus in toxic doses a n d has GIT side effects Propionic acids, e.g. ibuprofen: Has a low incidence of side-effects. Acetic acids, e.g. indometaci in. A h ighly potent inhibitor of COX . May cause neurological effects such as dizziness and confusion, gastrointestinal upsets. Oxicams, e.g. piroxicam: used for chronic inflammatory conditions . Is given only once daily, but causes high incidence of GIT problems. Pyrazolones, e.g. phenylbutazone Very potent agent but can produce a fatal bone marrow aplasia. For this reason it is reserved for the treatment of intractable pain in ankylosing spondylitis.

41. Fenemates, e.g. mefenamic acid: Is a moderately potent drug . Commonly causes gastrointestinal upsets and occasional skin rashes. para-Aminophenols, e.g. paracetamol: Is used as an analgesic and antipyretic but not an anti-inflammatory drug. Is effective for pain, headaches, and fever. This is probably due to its mechanism of action in trapping free radicals and interfering with the production of hydroperoxidases, which have essential role in cyclooxygenase activity. COX-2 specific inhibitors, e.g.lumiracoxib and celecoxib: Preferentially inhibit the inducible COX-2 enzyme, limiting COX-1-mediated side-effects observed with other, non-specific NSAIDs. They are contraindicated in inflammatory bowel disease, ischaemic heart disease or cerebrovascular disease

42. Steroidal anti-inflammatory drugs (glucocorticoids) There are two main groups of corticosteroids, the glucocorticoids the mineralocorticoids. The glucocorticoids (such as cortisone and cortisol), posses ses powerful anti-inflammatory actions that make them useful in several diseases, e.g. rheumatoid arthritis, inflammatory bowel conditions, bronchial asthma and inflammatory conditions of the skin. Their inhibitory effects is due to inflammatory responses from the effects of corticosteroids in altering the activity of certain

43. The anti-inflammatory action results from : • Reduced production of acute inflammatory mediators, like the eicosanoid s. Corticosteroids prevent the formation of arachidonic acid from membrane phospholipids by inducing the synthesis of a polypeptide called lipocortin . Lipocortin inhibits phospholipase A2, the enzyme responsible for m etabolizing arachidonic acid from cell membrane phospholipids, and thus inhibits the formation of both prostaglandins and leukotrienes. • Reduced numbers and activity of circulating immunocompetent cells, neutrophils and macrophages. • Decreased activity of macrophages and fibroblasts involved in the chronic stages of inflammation, leading to decreased inflammation and decreased healing.

44. Nitric oxide . Endothelial derived relaxing factor. Synthesis from L– arginine by nitric oxide synthetase . It reduces inflammatory response. 3 types eNOS – endothelial. nNOS - neuronal. iNOS – inducible.

45. Roles in inflammation Potent vasodilator. Microbicidal . Reduces platelet aggregation. Reduces leucocyte adhesion. Inhibit mast cell induced inflammation.

46. Plasma derived factors

47. Bradykinin Nonapeptide . Generated from kininogens by kallikreins . Causes pain. Increases vascular permeability. Causes smooth muscle contraction. Potent vasodilator. Short lived action. Inactivated by kininase

48. Also inactivated by ACE.

49. INFLAMMATORY DISEASES Rheumatoid arthritis I s a chronic, progressive and destructive inflammatory disease of the joints Disease modifying anti-rheumatic drugs (DMARDs) used in the treatment of rheumatoid arthritis . The mechanism of action of the DMARDs is often unclear – they appear to have a long-term depressive effect on the inflammatory response as well as modulat e other aspects of the immune system. All DMARDs have a slow onset of action . C linical improvement is apparent until 4–6 months after the initiation of treatment. They are believed to slow erosive damage at joints. use d in severe, active, progressive rheumatoid arthritis when NSAIDs alone have proved inadequate. DMARDs are frequently used in combination with an NSAID and/or low-dose glucocorticoids.

50. Gold salts Examples of gold salts include sodium aurothiomalate and auranofin. Mechanism of action —The mechanism of action of gold salts is unknown – they may be taken up by, and inhibit, mononuclear macrophages, or may affect the production of free radicals. Route of administration —Sodium aurothiomalate is given by intramuscular injection, and auranofin orally. Adverse effects —Rashes, proteinuria, ulceration, diarrhoea, bone marrow suppression. Therapeutic notes —Careful patient monitoring, including blood counts and urine analysis, is necessary. If any serious adverse effects develop, treatment must be stopped.

51. Penicillamine Mechanism of action —The mechanism of action of penicillamine is unknown. It c helates metals and has immunomodulatory effects , suppression of immunoglobulin production and effects on immune complexes . Penicillamine may also d ecrease synthesis of interleukin (IL). Route of administration —Oral. Adverse effects— Rashes, proteinuria, ulceration, gastrointestinal upsets, fever, transient loss of taste, bone marrow suppression. Therapeutic notes —As for gold salts

52. Antimalarials Examples of antimalarials include chloroquine and hydroxychloroquine Mechanism of action —The mechanism of antimalarials is unclear. They interfere with a wide variety of leucocyte functions, including IL-1 production by macrophages, lymphoproliferative responses and T-cell cytotoxic responses. Route of administration —Oral. Adverse effects —At the low doses currently recommended for antimalarials, toxicity is rare. The majo r adverse effect is retinal toxicity. Therapeutic notes —People on antimalarials should have their vision monitored.

53. Sulfasalazine Mechanism of action —Sulfasalazine is broken down in the gut into its two component molecules, 5-aminosalicylate (5-ASA) and sulfapyridine . The 5-ASA moiety is believed to be a free radical scavenger and responsible for most of this drug’s antirheumatic effects. Route of administration —Oral. Adverse effects—Side-effects of sulfasalazine are mainly due to sulfapyridine; they are common, but rarely serious. These include nausea, vomiting, headache and rashes. Rarely, blood disorders and oligospermia are reported. Therapeutic notes —People on sulfasalazine should f have their blood counts monitored.

54. Immunosuppressants These include azathioprine, ciclosporin and corticosteroids they work by suppressing the autoimmune component of rheumatoid arthriti s . Cytokine inhibitor s Cytokine inhibitors retard destruction of joints caused by rheumatoid arthritis. They are usuall y used for highly active rheumatoid arthritis in those who have failed to respond to at least two standard DMARDs. The primary pro-inflammatory cytokines are tumour necrosis factor (TNF)-a and IL-1 . The inflammatory role in diseases, such as rheumatoid arthritis can be reduced via cytokine inhibitors

55. Monoclonal antibodies Examples of monoclonal antibodies include adalimumab, tocilizumab and infliximab . Mechanism of action —The monoclonal antibodies bind TNF-a, preventing its interaction with cell surface receptors and the subsequent proinflammatory events. Indications —Moderate to severe rheumatoid arthritis, after DMARDs have not provided an adequate response. Contraindications —Pregnancy, breastfeeding, severe infections, heart failure. Route of administration —Subcutaneous injection. Adverse effects —Tuberculosis, septicaemia, gastrointestinal disturbance, worsening heart failure, hypersensitivity reactions, blood disorders. Interactions —Avoid concomitant use of live vaccines. Therapeutic note s—Monitor for infections, discontinue if active tuberculosis is suspected.

56. Soluble TNF-a blocker An example is etanercept. Mechanism of action —Contains the ligand-binding component of the human TNF receptor. It, therefore, competes with the patient’s own receptors, thereby acting like a sponge to remove most of the TNF-a molecules from the joints and blood. Indications —Moderate to severe rheumatoid arthritis, after DMARDs have not provided an adequate response. Contraindications —Pregnancy, breastfeeding, severe infections, heart failure. Route of administration —Subcutaneous injection. Adverse effects—Predisposition to infections, exacerbation of heart failure or demyelinating central nervous system (CNS) disorders, blood disorders. Interactions —Avoid concomitant use of live vaccines. Therapeutic notes —Monitor for infections.

57. Gout Gout is a condition in which uric acid (monosodium urate) crystals are deposited in tissues, especially in the joints, provoking an inflammatory response that manifests as an extremely painful acute arthritis. Uric acid crystallizes in the tissues when plasma urate levels are high, due to either excessive production or reduced renal excretion. There are two treatment strategies for gout – treatment of an acute attack and prophylaxis against further attacks

58. Treatment of an acute attack Non-steroidal anti-inflammatory drugs Aspirin and other salicylates are not used in gout as they inhibit uric acid excretion in the urine, exacerbating serum concentrations.

59. Colchicine Mechanism of action —Colchicine helps in gouty arthritis by inhibiting the migration of leucocytes such as neutrophils into the inflamed joint. This effect is achieved as a result of the action of colchicine binding to tubulin, the protein monomer of microtubules, resulting in their depolymerization. The end result is that cytoskeletal movements and cell motility are severely inhibited. The inhibition of microtubular function inhibits mitotic spindle formation, giving colchicine a cytotoxic effect on dividing cells. This cytotoxic effect is responsible for the side-effects of colchicine. Route of administration —Oral, rarely intravenously. Adverse effects —Side-effects of colchicine include gastrointestinal toxicity, with nausea, vomiting and diarrhoea, occurring in 80% of people. Rarely, bone marrow suppression and renal failure occur.

60. Prophylaxis against recurrent attacks Preventative management of gout includes diet and lifestyle changes, use of drugs that reduce plasma uric acid concentration. These drugs should not be used during an acute attack, as they will initially worsen symptoms. NSAIDs or colchicine should be co-administered for the first 3 months of treatment, as initiation of prophylactic treatment may precipitate an acute attack.

61. Agents that reduce uric acid synthesis Allopurinol and febuxostat (xanthine oxidase inhibitors) are examples of a drug that reduces uric acid synthesis. Mechanism of action —Allopurinol inhibits the enzyme xanthine oxidase, which converts purines (from DNA breakdown) into uric acid, thus reducing uric acid production. Route of administration —Oral. Adverse effects —Headaches, dyspepsia, diarrhoea, rash, drug interactions and acute exacerbation of gout initially. Rarely, life-threatening hypersensitivity occurs. Therapeutic notes —Febuxostat is indicated in hyperuricaemia where urate deposition has occured (in the form of tophi or arthritis).

62. Agents that increase uric acid excretion Uricosurics are drugs that increase uric acid excretion. Examples of uricosurics include sulfinpyrazone and probenecid. Mechanism of action —Uricosurics compete with uric acid for reabsorption in the proximal tubules, preventing uric acid reabsorption and resulting in uricosuria. Route of administration —Oral. Adverse effects— Gastrointestinal upset, deposition of uric acid crystals in the kidney, interference with excretion of certain drugs, and acute exacerbation of gout initially. Therapeutic notes —Uricosurics should not be used during an acute attack of gout. NSAIDs or colchicine should be co-administered for the first 3 months o f treatment, as initiation of treatment may precipitate an acute attack.

63. IMMUNOMODULATION The process of altering or modifying the immune response to achieve an objective. Drugs used to achieve this aim are called Immunomodulators . Augmentation or immunostimulation. Immunosuppression .

64. P harmacological suppression of the immune system is used in the following three main clinical areas: • To suppress undesirable autoimmune responses (e.g. systemic lupus erythematosus or rheumatoid arthritis), where the host immune system is ‘attacking’ host tissue • To suppress host immune rejection responses to donor organ grafts or transplants • To suppress donor immune responses against host antigens (prevention of graft versus host disease after bone marrow transplant (GVHD)).

65. Immunosuppressive agents Calcineurin inhibitors • Anti-proliferatives • Glucocorticoids. note : Solid organ transplant patients require immunosuppression to prevent organ rejection. They are usually maintained on a corticosteroid combined with a calcineurin inhibitor (ciclosporin) or with an antiproliferative drug (azathioprine or mycophenolate mofetil), or with both

66. Calcineurin inhibitors Eg ciclosporin . Mechanism of action —Ciclosporin is a cyclic peptide, derived from fungi . It has a selective inhibitory effect on T cells by inhibiting the T-cell receptor (TCR)-mediated signal transduction pathway. C iclosporin enter s the T cell and prevent s the transcription of specific genes

67. Ciclosporin ent ers into the T cell and specifically binds to its cytoplasmic binding protein, cyclophilin and forms a complex . This cyclosporin-cyclophilin complex then binds to calcineurin , inhibiting its phosphatase activity. Calcineurin is normally activated when intracellular calcium ion levels rise following T-cell-receptor binding to major histocompatibility complex: antigen complex. When calcineurin is active it dephosphorylates the cytoplasmic component of the nuclear factor of activated T cells (NF-ATc) into a form that migrates to the nucleus and induces transcription of genes such as IL-2 that are involved in T-cell activation. Inhibition of calcineurin by the ciclosporin - cyclophilin complex prevents the nuclear translocation of NF-ATc and the transcription of certain genes essential for the activation of T cells. Hence stopping the production of IL-2 by T-helper cells, the maturation of cytotoxic T cells and the production of some other lymphokines, such as interferon-g, are all inhibited.