GM6677 Principles of Pharmacology for Nursing Inflammation, Analgesics Opioids

1. GM6677 Principles of Pharmacology for Nursing Inflammation, Analgesics & Opioids Roger McFadden 2010

2. Inflammation Inflammation manifests itself by redness swelling heat pain alteration of function We will examine how inflammation causes these signs and symptoms

3. Inflammation The inflammatory response involves three key processes… Vasodilation resulting in increased blood flow 2. Increase vascular permeability – plasma leaks from blood vessels into the damaged area 3. Emigration of neutrophil leucocytes from blood into the damaged area

5. Inflammation Redness and Heat… Chemicals* released in inflammation cause vasodilation More blood flows to the damaged area Blood makes the area red and warm Swelling and Pain Chemicals* released in inflammation cause blood vessels to ‘leak’ Plasma enters interstitial fluid Plasma causes swelling in tissues Pressure on nerves causes pain Inflammatory chemicals* also cause pain* Prostaglandins, histamine and bradykinin

6. Mast cells Mast cells (granulocytes) are found in connective tissue adjacent to blood vessels. Trauma, chemical agents or the immune system causes them to release mediators (locally acting chemicals). Some mediators are pre-formed in granules and released very quickly in a process termed degranulation. Other mediators are synthesised by the mast cell and released over a longer period Other leucocytes, basophils, eosinophils also release these mediators

7. Mast cells

8. Early Mediators in Inflammation Products of degranulation include histamine which causes vasodilation and increased permeability of small blood vessels. Chemotactic factors are also released in degranulation which attract neutrophils (early response leucocytes) which mature into phagocytes.

9. Neutrophils Mast cells release LTB4, a leukotriene that attracts neutrophils from the blood Neutrophils congregate on the endothelium of small blood vessels They then squeeze through the endothelium and migrate towards the area of inflammation Here they mature and phagocytose micro-organisms

10. Neutrophils and Macrophages

11. Fluid Exudate Exudation of plasma from the small blood vessels results in the familiar oedema (swelling) observed in inflammation This serves the function of bringing plasma proteins into intimate contact with the damaged area These proteins help heal wounds and prevent infection

12. Fluid Exudate - Proteins Proteins in the inflammatory exudate include… Clotting proteins - especially fibrinogen that forms blood clots and prevents further loss of blood Fibrinolytic proteins – plasminogen will degrade the clot when the wound has resolved Complement – plasma proteins that stimulate immune responses and destroy bacteria Kinin cascade – kinins cause vasodilation, increase the permeability of blood vessels and stimulate pain receptors

13. Kinin cascade Kinins cause vasodilation, increase the permeability of blood vessels and stimulate pain receptors Prostaglandins produced in inflammation potentiate the action of bradykinin

14. Prostaglandins Prostaglandins are members of a large family of chemical mediators derived from phospholipids and are found in most tissues of the body. Prostaglandin biochemistry is complex, as are the actions of prostaglandins themselves. Prostaglandins belong to a family that includes prostaglandins, thromboxanes and leukotrienes. Prostaglandins have inflammatory and non-inflammatory actions

15. Prostaglandin E2 in inflammation Prostaglandin E2 (PGE2) main prostanoid involved in inflammation and secreted by mast cells and macrophages. Resulting in… vasodilation increased vascular permeability pain receptors becoming more sensitive to bradykinin

16. Prostaglandins in inflammation Mast cells and macrophages produce large amounts of PGE2 that is released into the inflamed area Increased synthesis of PGE2 results from the upregulation of an enzyme – cyclo-oxygenase 2 (COX-2) COX-2 is part of a family of cyclo-oxygenase enzymes (isozymes) COX-1 is perhaps the most common, being produced constitutively in most cells of the body and producing the prostaglandins involved in normal homoeostasis

17. Prostaglandin E2 synthesis

18. Non-steroidal anti-inflammatory drugs Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin are amongst the oldest drugs known to Western European medicine They appear in 16C herbals such as Culpeper in the form of willow bark – Salix alba. This is where aspirin’s chemical name of acetylsalicylic acid originates Modern NSAIDs include ibuprofen, indometacin, naproxen and diclofenac

19. NSAIDs NSAIDs reduce the production of inflammatory prostaglandins and so attenuate their inflammatory effects… reduction in oedema reduces dull pain reduction of bradykinin induced pain reduction in allodynia (tenderness of skin)

20. NSAIDs – side-effects COX-1 and COX-2 are isozymes – very similar in structure Anti-inflammatory drugs that target COX-2 are thus likely to bind to COX-1 Inflammatory PGE2 prostaglandin levels are reduced Unfortunately, so are the prostaglandins produced by COX-1 – the non-inflammatory “housekeeping” prostaglandins

22. NSAIDs – side-effects A reduction in levels of “housekeeping” prostaglandins can produce disturbances in homoeostasis – side effects The most common side-effect is…GI discomfort - PGE2 protects the stomach by promoting gastric mucus secretion and inhibiting gastric acid secretion NSAIDs are contra-indicated in patients with peptic ulcers, hypersensitivity reactions to aspirin, coagulation defects* etc. (refer to BNF for full list) *Aspirin is an anti-coagulant

23. COX-2 inhibitors These drugs are highly specific for COX-2 enzyme and do not inhibit COX-1 produced prostaglandins Long-term use is possible with less chance of side-effects, particularly GI problems Selective COX-2 inhibitors have been useful in the treatment of chronic inflammatory diseases such as rheumatoid arthritis. At the time of writing (September 2009) celecoxib (Celebrex) and etoricoxib (Arcoxia) appear in the BNF Current COX-2 inhibitors are contra-indicated in coronary artery disease (earlier versions promoted MI)

24. Paracetamol Paracetamol is a non-anti-inflammatory analgesic that has mainly anti-pyretic and analgesic properties It may (or may not) inhibit COX-3 isozymes in the central nervous system or attenuate pain transmission pathways. A reduction in prostaglandins in the hypothalamus reduces pyresis The short-term usage of paracetamol at therapeutic doses produces relatively few side effects But… hepatotoxicity can occur at only 2-3 times the therapeutic dose. The toxic metabolite (N-acetyl-p-benzoquinoneimine) accumulates causing necrosis in the liver

25. Opioids The body has its own analgesic system that has evolved to kick-in when an animal is injured This in-built analgesia provides short-term relief from pain that enables an animal to escape from predators or extract themselves from a dangerous situation without being crippled with pain Opioid analgesics utilise this system to provide controlled pain-relief This system is stimulated by other stimuli beside pain, including exercise and stress

27. Opioids Descending neurons synapse with the first order afferent neurons in the spinal cord Here they release neurotransmitters which block the synaptic transmission of the incoming pain neurons and so reduce the experience of pain Neurotransmitters include endogenous opioid peptides including b-endorphin, dynorphin and enkephalins This area is a key target for analgesic drugs including opioids and (probably) paracetamol

28. Pain transmission synapse in the spinal cord

29. Opioids – mechanism of action Opioids bind to m (mu) receptors associated with these channels This firstly enhances the opening of K+ channels and secondly inhibits the opening of Ca2+ channels This hyperpolarises the membrane and inhibits the release of neurotransmitters respectively Both of these events inhibit the transmission of nociceptive signals to ascending pathways to the brain

30. Effect of opioids on pain transmission synapse in the spinal cord

31. Opioids – side-effects Most opioid side effects associated with m receptors respiratory depression (reduces sensitivity of  respiratory centres in brain stem to CO2) euphoria sedation dependence reduction in GI motility bronchoconstriction (histamine release stimulated) Different opioid drugs interact with different subspecies of receptor producing different actions and side effects

32. End of Presentation