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55 Cards in this Set
- Front
- Back
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What is inflammation? |
A common tissue response to injury Associated with chemical, physical, immunological, biological damage. |
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What does inflammation look like? |
Redness, heat, swelling pain, loss of function |
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Beneficial effects of inflammatory response (5) |
1. Increased blood flow to injured tissue 2. Oedema formation in damaged tissue 3. Attraction of leucocytes and macrophages 4. Generation of antibodies at the site of infection 5. Increased supply of nutrients and O2 |
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Adverse effects of inflammation (4) |
1. Significant pain 2. Long lasting hyperalgesia 3. Loss of function 4. Mediators can induce a cycle inflammatory cell attraction--> further mediator release--> chronic inflammatory response |
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Inflammatory Mediators(5) |
1. Granular (histamine, 5HT) 2. Eicosanoids (PGE2, PGI2, L-B4) 3. Platelet activating factor 4. Plasma derived mediators (bradykinin, complement) 5. Cytokines (ILs) |
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Histamine (origin/comments) |
Released from mast cells, basophils, eosinophils. Increase vasodilation. Increase vascular permeability. |
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5 HT |
Released from mast cells and platelets. Increase vasoconstriction. |
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Bradykinin |
Formed from kininogen plasma by Factor 12. Increase vascular dilation. Mediator of pain. |
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Prostaglandin |
From many cell types. Normal physiological functions i.e. Protection of GIT, kidney, role in inflammation |
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Thromboxanes |
From many platelets. Platelet aggregation Vasoconstriction. |
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Leukotrines |
Platelets and mast cells. Increased vascular permeability. |
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Platelet activating factor |
Macrophages, eosinophils, neutrophils, mast cells, basophils. Platelet aggregation Promote adherence of leukocytes to endothelial cells. Stimulate release of lysosomal enzymes. |
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Complement |
Proteins contained in plasma.
Chemotaxis. Opsonisation. |
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Cytokines |
Macrophages and mast cells. Effector cytokines and chemokines. Initiation of inflammation. Chemotaxis. |
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Use of anti-inflammatory drugs (6) |
C, E, A(4x) 1. Control adverse effects of inflammatory drugs 2. Anaphylaxis (acute allergic rxn) 3. Arthritis, synovitis 4. Endotoxemia 5. Asthma 6. Anti-thrombosis |
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Definition: NSAID |
Agents which inhibit formation of eicosanoids from arachidonic acid. Prostaglandins and thromboxanes. |
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NSAID classification (2) |
1. Enolic acids 2. Carboxylic acids |
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Enolic acids |
1. Pyrazolones 2. Oxicams |
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Carboxylic acids |
*many *Classified as COX 2 selective inhibitors |
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How do NSAID's work? (graph) |
Need first insult in cell membrane to release arachidonate from phospholipid. Cyclo-oxygenase reacts with arachidonate in cytoplasm to bring about PGs. Cyclo-oxygenase targetted by NSAIDs. |
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NSAID's and its inhibition on COX |
2 COX enymes: 1. COX 1- constitutive enzyme 2. COX 2- inducible (can be switched on and off) produced by inflammatory cells. *NSAID's mainly non-selective reversible inhibitors of COX 1 and COX2 |
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NSAID actions: central |
Analgesic Antipyretic |
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NSAID actions: Peripheral |
Anti-inflammatory Analgesic Anti-thrombotic Anti-endotoxic Cartilage effects |
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NSAID Central effect: Analgesia |
Could be acute, persistent, chronic. Post-operative pain effective. Good where inflammation has sensitised pain receptors (hyperalgesia) Bradykinin, cytokines liberate PGs. |
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NSAID Central effect: Antipyretic |
Hypothalamus regulates set point. IL release--> prostaglandin release--> elevates setpoint in hypothalamus-->PYREXIA. *NSAID blocks PG release |
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Endotoxic shock |
LPS G- Damage WBC, vascular endothelium, release vasoactive mediators. *NSAIDs prevent the generation of vasoactive mediators during endotoxemia. |
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Caprofen, Flunixin, PBZ |
See table in p.47 *note that the body is chiral. |
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NSAID absorption |
Orally or parenterally. Weak acids well absorbed after oral administration. Food may interfere with absorption. |
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NSAID distribution. |
Highly protein bound (99%). Small Vd (accumulate in sites of inflammation) Short half life (length of time it is in blood). Long Duration (bind to COX). |
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NSAID metabolism |
Liver. Some excretion of unaltered drug. Some metabolites are active. Slow metabolism/excretion in young (up to 6 weeks old) Some are zero order kinetics. |
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Side effects (4) |
Mainly from COX 1 inhibition 1. GIT ulceration 2. Nephrotoxicity 3. Hepatotoxicity 4. Coagulation effects |
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Side effects: GIT ulceration |
NSAIDS reduce synthesis of GI prostaglandin. PGs inhibit gastric acid secretion and promote mucus secretion. PBZ> flunixin> ketoprofen |
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Side effects: Nephrotoxicity |
NSAIDs inhibit PGs on renal blood flow. 1. *However, in the face of relative hypovolemia/hypotension -PGs dilate afferent arteriole -Allow activation of RAAS to constrict efferent arteriole 2. COX inhibition leads to increased apoptosis of the medullary interstitial cells. Suggests COX plays a role in protecting these cells. |
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Side effects: Hepatotoxicity |
Nearly all NSAIDs potential to induce hepatic injury. Some cases idiosyncratic. Aspirin, paracetamol are dose dependent. |
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Side effects: Coagulation effects |
Aspirin and Ketoprofen.
Not described for flunixin, carprofen, or PBZ. |
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Drug Interactions |
2 cyclo-oxygenase inhibitors- additive efficacy and toxicity. Slower clearance in combination with some other NSAIDs. Highly protein bound drugs. |
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What NSAIDs are in our pharmacy? |
Paracetamol Caroprofen Meloxicam Firocoxib Robenacoxib Mavacoxib |
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Aspirin |
Active form: Salicylate Irreversibly binds cyclo-oxygenase (byacetylation) -selectivity for platelet COX |
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Aspirin side effects |
GIT erosions Haemorrhage Emesis |
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Aspirin dose |
Dogs 25-35mg/kg every 8h Cats 25mg/hr every 24 hrs. |
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Aspirin metabolism |
Oxidised Some conjugated to glucoronide or sulphate |
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Antirhombotic effect of aspirin |
More effective at low doses. Low doses: TXA2 inhibited, PGI2, not High doses: PGI2 inhibited. *PGI2 is for platelet disaggregation *TXA2 promotes clotting formation |
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Paracetamol metabolism |
1. Glucoronidation 2. Sulphate conjugation 3. N- Hydroxylation Yields: NABQI *NABQI binds to gluthathione. If gluthathione is saturated, it binds to hepatic proteins causes necrosis. *Treatment: N-acetylcysteine, precursoe to gluthathione that provides substrate for pathway 3. |
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Paracetamol properties |
Good antipyretic and analgesic. Poor anti-inflammatory. *Paracetamol interferes in the cyclic endoperoxides. |
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Phenylbutazone |
More potent anti-inflammatory. Cyclo-oxygenase inhibition. Concentrated in inflammatory exudate. Toxic in humans-- causes aplastic anemia. |
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Phenylbutazone pharmacokinetics |
Absorption reduced by food. Large interspecies differences. Active metabolite-- oxyphenbutazone Zero order kinetics. |
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Caprofen |
Poor cyclo-oxygenase inhibitor. Racemic mix of S and R. COX 1 sparing. Well tolerated. Peri-operative analgesic with reduced risk of nephropathy. |
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Robenacoxib |
A "coxib" Safe. "Coxibs" develop to increase GI safety. Once daily admin. Liver metabolism. Biliary excretion. |
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Mavacoxib |
COX2 inhibitor. Oral. Linear kinetics. Highly boung plasma protein. Eliminated unchanged in the biles. Extended half life given therapeutic levels for one month after single dose. |
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New horizons for NSAIDs. |
See p.51 |
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Hyaluronan |
Ubiquitous molecule Non-sulphated proteoglycan. Naturally occuring, imparts structural characteristics to synovial fluid and cartilage. Classed as chondroprotective agent. Intraarticular and iv admin. Dogs and horses. |
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Hyaluronic acid effects |
Increased proteoglycan synthesis Free radical scavenger Decreased PGE2 synthesis Decreased IL 1 induced PG release Decrease WBC and macrophage activity |
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Polysulphated glycosaminoglycan and Pentosan polysulphate |
Similar structure to heparin. Horse: intra-articular, im Dogs: sc Stimulates matrix production by chondrocytes May reduce MMP production. Drug not retained in cartilage. Excreted by kidney. |
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MMPs |
proteolytic enzymes. Matrix degradation. Endogenous inhibitors called TIMPs. Play a role in joint disease. Potential role of MMP inhibitors in management of inflammatory joint disease. |
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Nutraceuticals |
1. Proteins-Superoxide dismutase 2. Fish oils- anti-inflammatory 3. Polysaccharides- chondroitin sulphate 4. Perna Canaliculus: green lipped mussel 5. EPA- omega 3 *all supposed to have anti-inflammatory properties *be careful, may not contain important ingredient. |
