Birmingham City University Prescribing from the Community Practitioner Formulary V100 V150 Roger McFadden Pharmacolo

1.  Birmingham City University Prescribing from the Community Practitioner Formulary (V100 & V150) Roger McFaddenPharmacology II Analgesia and Anti-constipation drugs Click mouse to begin

2. Part IInflammation The inflammatory response occurs immediatelyafter trauma and� prevents the spread of pathogens minimises further damage to tissues promotes repair and healing

3. The Inflammatory Response The inflammatory response involves two key processes� Vasodilation resulting in increased blood flow 2. Increase vascular permeability � plasma leaks from blood vessels into the damaged area

4. Inflammation � signs and symptoms Redness and Heat� Inflammation results in vasodilation More blood flows to the damaged area Blood makes the area red and warm We will see later what causes vasodilation

5. Inflammation � signs and symptoms 2 Swelling and Pain Chemicals released in inflammation cause small blood vessels to �leak� Plasma enters interstitial fluid Plasma causes swelling in tissues Pressure on nerves causes pain Inflammatory chemicals also cause pain We will discuss inflammatory chemicals later

7. Mast cells

8. Inflammatory Pain Swelling puts pressure on pain receptors causing pain Prostaglandins produced in inflammation make the pain receptors more sensitive to pain

9. Prostaglandins Prostaglandins are members of a large family of chemical mediators derived from arachidonic acid (a fatty acid) and are found in all 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.

10. There�s a whole journal dedicated to prostaglandins and leukotrienes (and fatty acids) �!!!Good for insomnia�!!!

11. Prostanoids - function Prostanoids have many housekeeping roles unconnected with inflammation, including� Prostaglandin E2 (PGE2) � promotion of gastric mucus secretion and inhibition of gastric acid secretion Prostaglandin I2 (PGI2) - inhibition of platelet aggregation in the clotting process, vasodilation Prostaglandin D2 (PGD2) � inhibition of platelet aggregation in the clotting process, sleep regulation  Thromboxane A2 (TXA2) � (produced in platelets) promotes their aggregation in the clotting process Plus many, many more useful functions

12. Prostaglandins in Inflammation Prostaglandin E2 (PGE2) main prostaglandin involved in inflammation Secreted by mast cells and macrophages. PGE2 acts synergistically with histamine and other mediators Resulting in� vasodilation increased vascular permeability Make pain receptors more sensitive to stimuli pain transmission in dorsal horn of spinal cord pyresis (fever)

13. Prostanoids 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

15. NSAIDs - Effects NSAIDs target COX II They reduce the production of inflammatory prostaglandin E2 and so reduce inflammatory effects� reduction in oedema reduces dull pain reduction in allodynia (tenderness of skin) reduction in fever (anti-pyretic effect in hypothalamus)

16. Modern NSAIDs include Aceclofenac Acemetacin Azapropazone Dexibuprofen Dexketoprofen Diclofenac sodium Etodolac Fenbufen Flurbiprofen Ibuprofen Indometacin

17. NSAIDs � Which drug is suitable for which patient must be made by the clinical practitioner but around 60% of patients will respond to any NSAID (BNF 2009) Anti-inflammatory action may take longer to become effective than the analgesic action Note that NSAIDs give continuous anti-inflammatory action � not just pain relief

18. 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

19. NSAIDs � side effects Inhibiting COX-I reduces levels of �housekeeping� prostaglandins and can produce disturbances in homoeostasis � side effects The most common side-effect is�GI discomfort (remember 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, severe heart failure etc. (refer to BNF for full list)

20. Selective COX-2 Inhibitors These drugs are highly specific for COX-2 enzyme and do not inhibit COX-1 produced prostanoids 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 (November 2010) celecoxib (Celebrex) and etoricoxib (Arcoxia) appear in the BNF plus parecoxib (Dynastat) � post-operative pain only

21. Paracetamol (US � acetaminophen) Paracetamol is a non-anti-inflammatory analgesic that has mainly anti-pyretic and analgesic properties Its mechanism of action is subject to much pharmacological speculation but somehow it reduces prostaglandin synthesis 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-benzoquinoneimine) accumulates causing necrosis in the liver Acetylcysteine is used to treat paracetamol overdosage

24. Principles of Digestion The digestive system is basically a tube that runs from the mouth to the anus During the passage of food along this tube, various chemicals and enzymes are added to break down the food into its component parts The muscular walls of the gut squash and squeeze the food along the system which aids the process of breakdown

25. Disorders of the Gastro-intestinal system - indigestion Vague feeling of abdominal discomfort - possibly involving pain and a feeling of fullness. Rarely a serious health problem, unless accompanied by other symptoms. May be triggered by eating particular foods or drinks. Symptoms may be worsened by anxiety and depression. Treatment is usually by OTC preparations, antacids, alginates or combinations of both.

26. Disorders of the Gastro-intestinal system Gastro-oesophageal reflux disease - GORD (heartburn & dyspepsia) Discomfort caused by the reflux of acidic chyme from the stomach into the oesophagus which can become inflamed Causes of GORD are various but commonly it is the inappropriate relaxation of the gastro-oesophageal sphincter that allows chyme to enter the oesophagus. The symptoms may be worsened by coughing, lifting or by certain foods.

27. Drugs used in the treatment of GORD Antacids - these usually contain aluminium or magnesium compounds that increase the pH of chyme, making it less acid and reducing its irritating effect on the oesophagus. Simeticone acts as an anti-foaming agent Alginates - form a raft that floats on top of the stomach contents that reduces reflux and protects the oesophageal mucosa. They are usually combined with an antacid. Most are available OTC such as Gaviscon (sodium alginate, sodium bicarbonate, calcium carbonate)

28. H2 receptor antagonists and Proton-pump inhibitors (PPIs) H2 antagonists include; cimetidine, famotidine, nizatidine and ranitidine. H2 antagonists block the H2 receptors from the stimulatory effect of histamine and thus reduce gastric secretions PPIs include; esomeprazole, lansoprazole, omeprazole, pantoprazole and rabeprazole. These drugs irreversibly inhibit proton pumps in the parietal cells of the mucosa and so reduce stomach acid

29. Diarrhoea Diarrhoea is the frequent passage of liquid faeces. It can range from minor discomfort to emergency requiring fluid and electrolyte replacement. Diarrhoea involves either an increase in fluid secretion into the gut, a reduction of fluid absorption from the gut or an increase in motility

30. Anti-diarrhoea drugs First there is a need to identify and remedy the cause of the problem, not just to relieve the symptoms. For example, in the case of bacterial infection, an antibiotic may be required plus any necessary rehydration. Anti-diarrhoea drugs can either � reduce motility eg. opiates absorb excess fluid eg. kaolin

31. Constipation Difficult or infrequent defecation that can have many causes including� abdominal muscle weakness eg. from surgery pain eg. from haemorrhoids low fibre diet sedentary lifestyle depression antidepressants (anticholinergics block parasympathetic system) opiates dehydration

32. Treatment - laxatives Treatment is primarily directed at cause e.g. diet Bulk forming laxatives - increases faecal mass and stimulates peristalsis eg. ispaghula husk, methylcellulose and sterculia Osmotic laxatives - pulls water into gut and softens stools and increases faecal mass eg. lactulose, magnesium hydroxide and macrogols (polyethylene glycols) Stimulant laxatives - increases fluid secretion into gut and stimulates peristalsis eg. bisacodyl, docusate sodium, sodium picosulfate & senna

33. End of presentation