Department of Nursing and Women s Health The Pharmacology of Pain Relief and Anti-clotting Drugs

1. Department of Nursing and Women�s HealthThe Pharmacology of Pain Reliefand Anti-clotting Drugs Roger McFadden Click on the mouse to begin

3. Pain classification Pain is broadly divided into two types - nociceptive pain and neuropathic pain Nociceptive pain � injury, disease or infection that results in the stimulation of nociceptive neurons that transmit pain signals into the CNS Neuropathic pain - caused by neurological dysfunction that results in the perception of pain e.g. neuralgia

4. Afferent nerves Afferent nerves carry sensory information into the CNS Some information can be from inside the body e.g. blood pressure Some information can be from outside the body e.g. temperature Damage information is carried into the CNS along pain neurons called nociceptive neurons

5. Nociceptive Pain Nociceptive pain is transmitted along a relay of neurons, from the site of injury, into the spinal cord and up to the brain where the pain is conceptualised

6. Nociceptors These are pain sensing nerve endings found at the distal end of afferent pain neurons - often called nociceptive neurons. Nociceptors are divided into two broad categories� Ad type neurons transmit information at relatively high speeds between 5 - 25 m sec-1. These generally transmit sharp, well localised pain. � C type neurons transmit information at relatively low speeds between 1 - 2 m sec-1. These generally transmit dull, burning pain that is less well localised.

7. Spinal tracts Nociceptive neurons enter the spinal cord via the dorsal route and synapse with ascending neurons that are grouped in bundles called tracts Some nociceptive neurons synapse with interneuronsand motor neurons that produce reflex arcs, fast withdrawal responses to noxious stimuli

9. Synaptic transmission in the spinal cord

10. Endogenous analgesia 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

12. Neuromodulation of nociceptive pathways The body�s analgesic system is centred in the periaqueductal grey matter of the brain Efferent neurons descend from the brain to the synapses between first and second order afferent neurons in the spinal cord Here they release neurotransmitters which block the synaptic transmission of the afferent fibres and so attenuate the experience of pain This area is a key target for analgesic drugs including opioids and (probably) paracetamol

13. Pharmacology of Pain Attenuation There are various groups of drugs used to attenuate nociceptive pain� NSAIDs � diclofenac etc. COX-II inhibitors � etoricoxib etc. Non-anti-inflammatory analgesics - paracetamol Opiates � morphine etc.

14. NSAIDs NSAIDs reduce the production of inflammatory prostaglandin E2 and so attenuate its inflammatory effects� reduction in oedema reduces dull pain reduction in bradykinin induced pain reduction in allodynia (tenderness of skin) reduction in fever (anti-pyretic effect)

16. NSAIDs � side-effects Anti-inflammatory drugs that target COX-2 are likely to bind to COX-1 because COX-1 and COX-2 are very similar in structure The prostaglandins produced by COX-1 are the non-inflammatory �housekeeping� prostaglandins � important in many physiological functions Main side effect of NSAIDs is GI discomfort (prostaglandins protect 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)

17. Selective 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 (Sept 2009) celecoxib, etoricoxib and paracoxib appear in the BNF

18. Paracetamol Paracetamol is a non-anti-inflammatory analgesic that has mainly anti-pyretic and analgesic properties It probably inhibits COX-3 isozymes in the central nervous system. A reduction in prostaglandins in the hypothalamus reduces pyresis The short-term usage of paracetamol at therapeutic doses produces relatively few side effects Hepatotoxicity can occur at only 2-3 times the therapeutic dose. The toxic metabolite (N-acetyl-p-benzoquinonimine) accumulates causing necrosis in the liver

19. Opioid analgesics Morphine and its relatives make up the opioid analgesics, the strongest and most effective pain killers in current use. Closely related to heroin but less lipid soluble so less able to cross the blood-brain barrier and produce the euphoric effects of heroin. Obtained from opium, the sap of the poppy Papaver somniferum Current opioids include morphine, buprenorphine, codeine, diamorphine, fentanyl, methadone, pethidine and tramadol.

20. The Body�s own analgesic system

21. Action of Opioids Opioids inhibit synaptic transmission on the pre-synaptic membrane by binding to opiate receptors and inhibiting the opening of calcium channels and so prevent the release of the neurotransmitter On the post-synaptic membrane, opioids bind to opiate receptors and make the membrane less responsive to stimulation by neurotransmitters.

22. Opioids � side-effects Opioid receptors are found in various parts of the body and it is the action of opioid drugs on these receptors that is responsible for most of the side-effects. Nausea and vomiting, especially after initial administration Respiratory depression with some opioids, believed to be due to a reduction in the sensitivity of respiratory centres in brain stem to carbon dioxide, the main driver of breathing. A decrease in gastro-intestinal motility is another problem with opioids, especially codeine.

23. Clotting and anticoagulants

24. Platelets Platelets (or thrombocytes) are small cell-like structures that circulate in the blood. They circulate in an inactive form until they come into contact with a damaged blood vessel. When a blood vessel is damaged, collagen in the vessel wall is exposed. The platelet becomes active on contact with collagen Active platelets change shape and are then able to bind to fibrin, trapping other blood cells and forming a blood clot

25. Platelets binding to fibrin

26. Oral anti-platelet drugs - aspirin Aspirin is used in the prevention of stroke and MI Aspirin strongly (irreversibly) inhibits the platelet enzyme cyclo-oxygenase 1 (COX I) This inhibits the pathway that produces thromboxane Thromboxane makes platelets bind to fibrin Inhibition of thromboxane will therefore inhibit clotting

27. Action of aspirin

28. Oral Anti-platelet drugs � Clopidogrel and Dipyridamole The expression of GPIIb/IIIa platelet receptors depends on ADP and thromboxane Clopidogrel (Plavix�) is an ADP receptor antagonist and so inhibits the ADP mediated expression of GPIIb/IIIa receptors Dipyridamole* is a phosphodiesterase inhibitor that blocks the ADP signalling pathway and so inhibits the ADP mediated expression of GPIIb/IIIa receptors *Persantin�, Persantin� Retard and Asasantin� Retard (dipyridamole and aspirin)

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30. Oral anticoagulants - warfarin Warfarin - used for prevention of DVT and pulmonary embolism Mechanism - Warfarin prevents the reduction of vitamin K by the enzyme Vitamin K reductase Being similar in structure to vitamin K, it binds to and inhibits Vitamin K reductase This prevents the production of various clotting factors, II, VII, IX and X.

31. Oral anticoagulants - warfarin

32. Warfarin The effects of warfarin take 48 - 72 hours for the anticoagulant effect to develop fully This is because warfarin inhibits the synthesis of new clotting factors but does not affect those in circulation. Note that many, many drugs and foods interact with warfarin (not a complete list)� Rifampicin, carbamazepine, St John�s wort, cabbage and broccoli decrease anticoagulant effect Cimetidine, NSAIDs and cranberry juice increase anticoagulant effect

33. Parenteral Anticoagulants Heparin - as in standard or unfractionated form is used for initial treatment of DVT and pulmonary embolism Low molecular weight heparins (LMWH) enoxaparin (Clexane), dalteparin (Fragmin) etc. Used for prevention of DVT and prophylaxis of clotting during surgery. They have longer duration of action than standard heparin

34. The Clotting Cascade

35. Action of heparins