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1

MEDIATORS OF INFLAMMATION

- Inflammatory mediators (initiate and control inflammation) include histamine, kinins (bradykinin), neuropeptides, cytokines, eicosanoids etc
- What are eicosanoids? (prostaglandins)
- Group of polyunsaturated fatty acids
- Formed from arachidonic acid in phospholipid layer of cell membranes
- Important→ involved in majority of inflammatory reactions
- Most anti-inflammatory therapy is based on the manipulation of their biosynthesis

2

PROSTAGLANDINS (PGs) (eicosanoids)

- Kidney→ maintaining renal blood flow
- Inflammation → vasodilation and increased capillary permeability
- Stomach→ Lowers acid/ pepsin secretion, increases mucus secretion
- Platelets→ Aggregation
- Pain→ Central and peripheral mediator release
- Fever→ Pyrogen production
- Pregnant uterus→ Smooth muscle contraction

3

ANTI-INFLAMMATORY DRUGS

- Main drugs used for their broad spectrum anti-inflammatory effects are: NSAIDS and Steroidal anti-inflammatory drugs (glucocorticoids)
- Both classes exert their effect by inhibiting the formation of eicosanoids
- Anti inflammatory drugs used under more limited circumstances include:
- Disease modifying anti rheumatic drugs (DMARDS)
- Drugs used to treat gout
- Antihistamines

4

NSAIDs (Non steroidal anti-inflammatory drugs) OVERVIEW

- Grouped based on common mechanism of action- inhibition of cyclooxygenase (COX)
- Mixture of synthetic and semisynthetic drugs, >50 on the market
- First- generation NSAIDs-- aspirin & Second generation NSAIDs- coxibs

5

NSAIDs (Non steroidal anti-inflammatory drugs) Pharmacological actions of NSAIDs

- Drugs share common therapeutic properties; analgesia (pain), anti-inflammatory (inflammation) anti-pyretic (fever)
- Antiplatelet effect; aspirin inhibits platelet aggregation; irreversible inhibition of COX1→ reduced thromboxane synthesis→ use after myocardial infarction and stroke to prevent vascular occlusion

6

NSAIDs (Non steroidal anti-inflammatory drugs) ANALGESIC ACTIONS

- Peripheral effects→anti-inflammatory action→ inhibits PG production at site of pain and inflammation
- PGs (E&F) sensitise nociceptive fibre nerve endings to other inflammatory mediators (e.g. histamine) amplifying basic pain message
- Small component of analgesic action is due to a central effect (mainly in the spinal cord) reducing PG synthesis

7

NSAIDs (Non steroidal anti-inflammatory drugs) ANTI-INFLAMMATORY ACTIONS

- PGs produce vasodilation; facilitates actions of other mediators → Increased vascular permeability leading to oedema
- Inhibition of PG synthesis reduces this part of inflammatory reaction
- NSAIDs do not inhibit other mediators involved in an inflammatory reaction; thus inflammatory cell accumulation for example, is not inhibited

8

NSAIDs (Non steroidal anti-inflammatory drugs) ANTIPYRETIC ACTIONS

- During a fever, leukocytes release inflammatory pyrogens (e.g IL-1) as part of the immune response
- IL-1 stimulates generation of PAGEs in hypothalamus which cause the set-point for temp to increase
- The antipyretic effect of NSAIDs is largely through their inhibition of PGE production
- NSAIDs do not affect temperature under normal circumstances or in heat stroke

9

NSAIDs (Non steroidal anti-inflammatory drugs) ANTIPLATELET ACTION

- Aspirin inhibits platelet aggregation due to irreversible inhibition of COX-1→ reduced thromboxane (TXA2) synthesis
- Use after myocardial infarction and stroke to prevent vascular occlusion; Increased bleeding time as a side effect
- Antiplatelet action may link to the chemopreventive properties of NSAIDs against colorectal cancer

10

NSAIDs (Non steroidal anti-inflammatory drugs) MECHANISMS OF ACTION

- All NSAIDs possess the ability to inhibition the enzyme cyclooxygenase
- COX is involved in the metabolism of arachidonic acid to form the prostanoids i.e. the classical prostaglandins (PGs) prostacyclin (PGI2) and thromboxane A2 (TXA2)

Mechanisms for Inhibition of COX
- Most NSAIDs enter the long channel in COX enzymes and bind with hydrogen bonds to an arginine halfway down
- Reversibly inhibits the enzymes by preventing access of arachidonic acid

11

ISOFORMS OF CYCLOOXYGENASE: COX 1

- Expressed in most tissues and involved in physiological cell signalling
- Most adverse effects are caused by inhibition of COX-1

12

ISOFORMS OF CYCLOOXYGENASE: COX 2

- Mainly 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

13

ASPIRIN

- Drug of choice for many sorts of mild pain despite a relatively high incidence of GI effects
- Used for antiplatelet action following MI → Low doses of aspirin used prophylactically to decrease the incidence of transient ischaemic attack
- Used as antipyretics and analgesics in the treatment of rheumatic fever, and rheumatoid arthritis

14

IBUPROFEN AND PIROXICAM

- Ibuprofen is effective and well tolerated→ Drug of choice for inflammatory joint disease, owing to its low incidence of side effects
- Used for pain- dysmenorrhea
- Piroxicam - is a potent drug widely used for chronic inflammatory conditions (e.g. arthritis)
- Given only once daily (t1/2 50 hr) but causes a relatively high incidence of gastrointestinal problems (COX-2 Selective)

15

PARACETAMOL

- Used as an analgesic and antipyretic only and not as an anti-inflammatory drug (no anti-inflammatory effect)
- Effective for pain, especially headaches and fever
- Used in combination of aspirin (Excedrin)
- Causes a serious, potentially fatal hepatotoxicity in toxic doses (>2-3 times therapeutic)
- Saturates normal liver conjugation systems
Formation of a toxic metabolite, N-acetyl-p-benzoquinone (NPBQI)
- Treat with N-acetyl cysteine to increase GSH levels - neutralises

16

ADVERSE EFFECTS OF NSAIDS:

- Common, particularly in the elderly and chronic users
- Primarily arise from non-selective inhibition of COX1 and COX2 synthesis
- Most common and serious side effects are:
- Epigastric distress- peptic ulcer, nausea and vomiting
- Microscopic bleeding- almost all patients treated with aspirin
- Renal impairment
- Aspirin should be taken with food and large volumes of fluids to minimise GI disturbances

17

ADVERSE EFFECTS OF NSAIDS: ACTIONS ON GIT

- Normally→ PGI2 inhibits gastric acid secretion, whereas PGE2 and PGF2a stimulate synthesis of protective mucus
- Aspirin causes a decrease in PGS and causes: Increase in gastric acid secretion and decrease in mucus protection → May cause pangastritis, ulceration and/or haemorrhage

18

ADVERSE EFFECTS OF NSAIDS: ACTIONS ON KIDNEY

- Aspirin can cause acute reversible renal impairment because prostaglandins promote renal blood flow
- Inhibition of PGs may lead to
- Decreased glomerular filtration
- Fluid and NA+ retention- hypertension
- Oedema and hyperkalaemia
- Precipitating renal failure in compromised patients and athletes

19

ADVERSE EFFECTS OF NSAIDS: ADVERSE EFFECTS ON BLOOD

- Prolonged bleeding time resulting from inhibition of platelet aggregation → contraindicated for patients with bleeding disorders
- Aspirin (high dose) should not be taken for at least 1 week before surgery
- If taking salicylates, anticoagulants may have to be given at lower dosages

20

ISSUES WITH COX-2 SELECTIVE INHIBITORS

- Developed on the theory that selective inhibition of COX-2 only should be able to suppress pain and inflammation posing little or no risk of gastric ulceration
- With coxibs, patients can develop significant gastroduodenal ulcer and bleeding
- Coxibs increase the risk of heart attack since the protective anti-coagulative effect of PGF2 is decreased
- 2 coxibs (rofecoxib and valdecoxib) have been withdrawn as a result. Sales of remaining agents declined since then
- They also slow healing of peptic ulcers

21

IMMUNOSUPPRESSIVE DRUGS: OVERVIEW

- Drugs that inhibit immune responses
- Prevention and treatment of organ rejection and autoimmune disorders
- 2 major toxicities: increased risk of infection and increased risk of cancer

22

IMMUNOSUPPRESSIVE DRUGS: CLASSIFICATIONS

- Inhibitors of IL-2 production or action → Cyclosporine and tacrolimus
- Inhibitors of cytokine gene expression → Corticosteroids e.g. prednis(ol)one
- Inhibitors of purine or pyrimidine synthesis (block DNA synthesis) → Azathioprine and leflunomide
- Blockers of T-cell surface molecules involved in signaling → bDMARDS/anti cytokines e.g. infliximab and anakinra

23

IMMUNOSUPPRESSIVE DRUGS: CLINICAL USES

- Suppress rejection of transplanted organs and tissues
- Suppress graft-vs-host disease in bone marrow transplantation
- Treat conditions with an autoimmune components including rheumatoid arthritis, ulcerative colitis, systemic lupus erythematosus etc

24

CYCLOSPORINE: OVERVIEW

- Most important immunosuppressive agent in transplantation
- Cyclic peptide of 11 amino acids derived from the fungus Tolypocladium inflatum Gams
- Crucial for the development of transplant surgery

25

CYCLOSPORINE: MECHANISM OF ACTION

- Selective inhibitory effect on lymphocytes, inhibits IL- 2 gene transcription→ decreased proliferation of B cells and cytotoxic T cells
- Decreased expression of IL-2 receptors

26

CYCLOSPORINE: USES

- Key drug used in prevention and treatment of transplant rejection (kidney, heart, liver etc)
- Used routinely with corticosteroids
- Also used in the treatment of autoimmune disorders

27

CYCLOSPORINE: ADVERSE EFFECTS

- Nephrotoxicity is the major side effect, up to 75% of treated patients. Renal damage can be intensified by concurrent use of other nephrotic drugs
- Infections: Risk increase for infectious complications in 74% of patients
- Hepatotoxicity occurs in 4-7% of patients
- Hypertension (reduced by fish oil)
- Gum hyperplasia
- Increased risk of lymphomas

28

CYCLOSPORINE: PHARMACOKINETICS DRUG INTERACTIONS

- Most of cyclosporine in the body is bound, - 60-70% to RBC, 10-20% to WBC and plasma protein
- Can be administered orally or IV
- Undergo extensive metabolism by hepatic microsomal enzymes. CYP3A4 inhibitors (diltiazem ketoconazole, erythromycin) increased levels and enzyme inducer (phenytoin, rifampicin, st john's wort) decreased levels
- Grapefruit juice→ increases cyclosporine by 50%-200%

29

CYCLOSPORINE: Tacrolimus (FK506)

- Also known as FK506 is alternative to cyclosporine
- A macrolide antibiotic of fungal origin with similar mechanism of action
- Comparatively new, more potent (ug/kg) and more effective than cyclosporine
- Side effects: More toxic, more patients discontinue the drug due to its toxicity
- Therapeutic use: Prophylaxis of organ rejection in patients receiving liver, kidney or heart transplants

30

GLUCOCORTICOIDS: OVERVIEW

- Early phase of inflammation→ inhibit initial redness, heat, pain, swelling
- Late phase of inflammation inhibit→ wound healing and repair (adverse effects) and proliferative reactions in chronic inflammation (therapeutic)
- Reverse inflammation caused by→ Pathogens, Chemical/physical stimuli, Inappropriate immune responses in hypersensitivity and autoimmunity