---start---- pharm 2/16/98 washabau dr washabau is wondering why no one is here... hmmm. mechanisms of emesis, examples, therapies... we left off looking at that diagram and going over pathways for mediating emesis - the neural pathway, and the humoral pathway. structures in periphery - viscera, afferent pathways into CNS into emetic center in brainstem which has lots of receptors. also CRTZ. motion sickness - semicircular canals - synapse in CRTZ in dog, emetic center in cat. efferent information to mediate events in GI tract examples of drugs - moving forward... Motion sickness: animals who get sick, nauseated, vomit during motion. how do we treat/prevent it? in dog, there is a path from semicircular canals to emetic center, involving histamine H1 receptors. histamine H1 antagonists work in the dog, but not in the cat, to treat motion sickness. treatment for motion sickness: 1. dimenhydramine 2. diphenhydramine both of those are classic H1 antagonists, used in dog, but not the cat. will diminish nausea associated with vomiting in dog but not cat. don't worry about doses right now. 3. chlorpromazine - a phenothiazine, which can antagonize A1 and A2 receptors and many many other receptors, as discussed. diminishes motion sickness signs in cats - probably due to action at one or more receptors in the emetic center. slide: bottle of diphenhydramine (benadryl). understanding pharmacologic principles, knowing pathways, etc is very useful. uremia treatment: metabolic derangements during end stage renal failure cause severe nausea. these animals generally have elevated BUN, creat, low PCV, and deranged electrolytes. animals with kidney failure have nausea and vomiting - why? the toxins that accumulate with CRF can activate receptors in the CRTZ. we think they activate the D2 dopaminergic receptors there. so we should tx with dopamine D2 receptor antagonist. this is an example of humoral emesis. the key thing to remember is not only do these animals have mechanism for vomiting at CRTZ, but also in the periphery - they get gastritis, ulcers, etc which also stimulate vomiting as you recall from previous discussion. we have to remember the peripheral mechanism - there are a number of effects of uremia on the gastric mucosal barrier - something to do with metabolism of gastrin - with uremia, there is loss of the barrier, permitting back diffusion of H+ into mucosa/submucosa, leading to full thickness ulcers. we have to treat this also, so: 1. D2 dopaminergic antagonist to treat humoral emesis mediated by CRTZ - metoclopramide aka reglan is a good choice to do this. another drug used in europe and newly used here is domperidon (?) which is 25x more potent than reglan in experiments in healthy dogs. 2. H2 histaminergic antagonists - to treat the gastric ulcer induced emesis. this inhibits acid secretion, diminishing acid that gets into ulcers 3. diffusion barrier - sucralfate - to cover the ulcers. remember, these bind necrotic tissue proteins, preventing acid from entering damaged areas. slide: ad for metoclopramide slide: ad for zantac (H2 receptor antagonist) (ranitidine is generic name) cancer chemotherapy induced emesis: slide: lateral and dorsoventral projection of radius and ulna of doberman with a mixed productive and lytic lesion which turned out to be osteosarcoma, which spreads easily. dog put on chemo: cisplatinum and adriamycin. this may prolong life. but these drugs - esp cisplatinum - cause profound nausea and vomiting. this was a huge problem for people for a long time. many people would in fact d/c their treatment because it was so awful. so, new antiemetics were developed. these chemo drugs stimulate serotonin release from GI tract, which binds 5HT3 receptors in smooth muscle, epi, etc. activates afferent pathway to emetic center, causing emesis. also some serotonin is absorbed and may activate the 5HT3 receptor in the CRTZ - this is the main mechanism of chemo related emesis in the cat, which does not have the peripheral 5HT3 receptor and which is less susceptible to the cisplatinum induced emesis. 1. ondansetron (zofran) and granisetron (kytril) these are fairly selective 5HT3 antagonists. in wide use in human cancer patients. tropezatron - used in europe 2. butorphanol - mixed mu delta enkephalonergic drug - has some antiemetic effects in animals on chemo - need more studies. may be useful, but have to use near-sedative doses 3. metoclopramide - a classic D2 dopaminergic antagonist, also binds 5HT receptors and is an antagonist of the 5HT3 and agonist of 5HT4 receptor. has been used but isn't as good as zofran et al. CNS effects occur at therapeutic doses. delayed gastric emptying: this is something out in the periphery that can induce nausea/vomiting. slide: lateral abdominal radiograph w/barium fed to animal - stomach is massively distended. when do we see delayed gastric emptying? 1. inflammatory or infectious disorders - should tx these. sometimes the delayed emptying persists and you need to use prokinetic drugs 2. neoplasia 3. ulcer 4. electrolyte disturbances - hypocalcemia, hypokalemia 5. endocrine/metabolic disorders - chronic hypothyroid in dogs 6. drugs eg anticholinergics et al. therapies in order of preference to tx delayed emptying: 1. 5HT4 serotonergic agonists eg cisapride (propulsid) - binds receptor in gastric myenteric neuron, causing depolarization and ACH release, and contraction. metoclopramide - mild agonist, not as potent as cisapride. 2. motilin agonists eg erythromycin is the best example. when used at antimicrobial doses it stimulates nausea and vomiting. scientists have shown that erythromycin acts like motilin in stimulating motility. when used at antimicrobial doses, it stimulates retrograde peristalsis and vomiting. when used at lower doses, it stimulates antegrade motility and promotes gastric emptying. 3. H2 histaminergic antagonists - just these two: ranitidine, nizatidine - these inhibit ACHesterase, increasing ACH activity and promoting contraction. these are the main things you reach for to tx delayed emptying. cisapride - has a number of properties. most important for tx this disorder is it binds and activates the 5HT4 receptor on myenteric neuron leading to ACH release and contraction of gastric sm muscle. other studies show that this drug in the colon of dogs/cats stimulates 5HT2 receptors directly on sm muscle, not involving neuron. this drug is marketed as propulsid and is the first choice for txing delayed gastric emptying. erythromycin - note in dog, this activates 5HT3 receptors on myenteric neuron causing ACH release from neuron and contraction of sm muscle. in cat, it acts on motilin receptor on sm muscle - like in most other spp. dog is unusual. ranitidine, nizatidine: third and last thing to consider. these inhibit ACHesterase, allow ACH to accumulate in synaptic space, causing more depolarization and contraction of gastric smooth muscle. both of these drugs are useful for txing gastric emptying and also stimulate feline colonic motility. Pregnancy: this isn't a disease but is a physiologic perturbation: slide: Mrs Washabau very pregnant. what drugs treat pregnancy related nausea? you don't want to harm fetus. pregnancy hormones have many effects, often reducing tone of lower esoph sphincter and doing other things that promote nausea and vomiting. what can we use to tx this? rx: brown paper bag. carry that around with you. ha. Criteria for antiemetic usage in the undiagnosed patient: your best success is when you dx disease and treat the disease specifically. however, sometimes you don't have a definitive dx. so sometimes you have to treat- eg, when you have: 1. frequent or severe vomiting 2. risk of aspiration pneumonia or acid/base disorders 3. no evidence of obstruction or toxicity - may want to promote vomiting to remove toxin. also don't want to promote motility in cases of obstruction - may cause rupture. 4. client does not desire definitive dx. irrational uses of antiemetics: when not to use them: 1. GI bacterial infection - eg, people go to some country and get bacteria in GI tract and get sick - using antiemetics prolongs infection. well, what about in puppies with parvo? good question. that's a virus. we don't seem to be prolonging it. 2. GI obstruction 3. GI toxicity 4. systemic hypotension - those A2 antagonists shouldn't be used in animals with systemic hypotension. a phenothiazine for example would really screw things up. 5. epilepsy - phenothiazines lower the seizure threshold. choose something else. medical management of refractory vomiting take hom epoints: 1. mechanisms - neural (emetic center) and humoral (CRTZ) 2. receptors - a lot of them - A2, D2, 5HT3, etc 3. motion sickness, uremia, cancer chemo, delayed emptying strategies: you have no definitive dx: 1. start with A2 adrenergic antagonist - broad spectrum,works at both sites. 2. if fails - try D2 antogonist or 5HT3 antagonist 3. if fails try motilin agonist, cisapride most cases will resolve on one of those therapies. cases: 6 yr old male boxer - hx of wt loss, anorexia, loose black feces x 3 wks, "skin lesions" and weakness. PE: pale mms, holosystolic heart murmur II/V, melena, large ulcerated skin masses. [ddx: mast cell tumors? -->histamine release, heparin release, GI ulceration, etc? assuming physiologic murmur. this is my guess at this point - hrg] slide: large round ulcerated skin masses. slide: dermal nodules that look hivelike slide: bleeding underneath skin labwork: leukocytosis w/left shift 39,200. anemia - HCT = 18. hypoproteinemia at 3.8 w/low albumin and low globulins. these go along with the clinical signs. animal seems to have GI hemorrhage. why? what can we do about it? there are also elevations of cholestatic and leakage liver enzymes. BUN elevated, creat is ok. urine is ok. BUN is elevated due to GI hemorrhage. the PT/PTT are both prolonged. FSP are within normal limits. gastrogram shows a filling defect - likely a gastric ulcer. endoscopy shows multiple gastric ulcers a quick aspirate of skin tumor shows tons of neoplastic mast cells which are degranulating and releasing histamine causing H+ release from parietal cells, and also releasing heparin, prolonging PT and PTT. what do we do to treat animal? H2 blockers. case 2. 2yr old female russian wolfhound. hx "arthritis", anorexia x 2 days, lethargy, collapse. PE: pale mms, diffuse abdominal pain, shock tx: NSAID - ibuprofen was given at human doses for several days by the owner. got GI hemorrhage and so forth due to severe ulceration. sent animal to ICU - she did recover. owner was an MD - he ended up with a $5000 bill. pathogenisis here, therefore, is different. this animal had been given a potent NSAID which damaged the gastric mucosal barrier, resulting in GI ulceration and hemorrhage. if this animal needs NSAIDs, consider giving misoprostol (prostaglandin analogue). ----break---- kotlikoff: review of processes leading to inflammation we're going to focus a bit more on specific substances and pathways leading to release of substances. this is preview for lecture on steroids, NSAIDs, and autacoids inflammatory cascade is triggered by a variety of insults: microorganisms, trauma (acute or chronic). can be triggered appropriately or inappropriately - eg, response to pollen is inappropriate. antibodies see it as dangerous and trigger protective response, but really the response is more damaging than the pollen. many of these processes are specific for particular inciting events. first thing we have is some kind of cell damage or recognition of foreign substance which activates system - eg, invading microbe damaging cell walls, a foreign substance like pollen that binds Ab and stimulates mast cell degranulation and then cause cell damage; parasite; trauma like chronic arthritis which directly cause cell damage, etc. the inflammatory process is triggered in response to injury or foreign invasion, and triggers release of lysosomal enzymes from leukocytes and also responses mainly from mast cells and monoytes in tissues. PMNs, mast cells, and monocyte/mphages are initial amplifiers of the cascade, drawing in other inflammatory cells and producing local reactions. what are the processes triggered by this injury or recognition of foreign Ag or microbes? four major systems: complement system in plasma - results in release of chemoattractants and so forth, draws in inflammatory cells coagulation system - leakage of plasma triggers this also. fibrinolytic system - normally we activate fibrin and activate this system kinin system - will hear more about this later; results in release of bradykinin. component w/in plasma that's activated when plasma is released from blood vessels. a common trigger for these systems is to act on membrane phospholipids and trigger what we call the arachadonic acid cascade. this releases a slew of mediators. the manipulation of this pathway is a major target for antiinflammatory drugs. one thing that's triggered is activation of phospholipase A2 within cells to make free arachadonic acid. this is complexed with membrane phospholipids in every cell, sitting there waiting to be released. so phospholipase A2 is a target enzyme, activated by various stimuli eg complement components, a variety of the listed mediator (see below) and present in all cell types. once free, the arachadonic acid can be acted on by lipooxygenase enzymes, which then generate leukotrienes. the lipoxygenases are so termed because they are breaking down a lipid precursor to generate active byproducts - really only this occurs in white cells. all cells make the arachadonic acid and have the cyclooxygenase and can make the prostanoids, though. note that phospholipase A2 in addition to making arachadonic acid can also generate PAF platelet activating factor, which can do a lot of things other than activating platelets. but anyway, the leukotrienes are made in the white cells - mainly mphages, leukocytes, PMNs, etc - and the other main pathway is arachadonic acid is metabolized by cycloxygenases into prostanoids. glucocorticoids (steroids) - make a lipocortin that inhibits phospholipase A2, preventing arachadonic acid formation - blocking generation of leukotrienes and prostanoids. this is why they're such potent antiinflammatory agents. prevent liberation of arachadonic acid. there are two cyclooxygenases. all cells contain this stuff. many prostaglandins aren't inflammatory substances, but normal physiologic regulators. so inhibiting prostanoid formation or prostaglandin formation has effects on normal function. aspirin and other NSAIDs block activity of cyclooxygenase - both COX1 and COX2 - although some have some degree of selectivity. leukotrienes: LTB4 is a chemoattractant substance - brings in more cells, and directly has inflammatory effects. see diagram in handout showing flow of mediators. what are the hallmarks of inflammation? rubor, dolor, calor, tumor rubor: redness/erythema due to local vasodilation - caused by prostanoids, leukotrienes, etc. tumor: swelling - due to increased vascular permeability, extravasation of plasma, edema calor: heat - due to the vasodilation/increased blood flow dolor: pain - due to sensitization of nerve endings resulting from prostanoids and kinins and neuropeptides (mainly prostanoids) also loss of function. the prostaglandins, leukotrienes, etc, are mainly responsible for local inflammation, sensitization of nerve endings, platelet aggregation, increased temperature/fever, anaphylaxis/bronchospasm, diarrhea and intestinal spasm. looking more closely at upstream arachadonic acid cascade - we can trigger arachadonic acid release not only by phospholipase A2 but also we can use phospholipase C and diclycerol lipase - these are common signalling pathways. phospholipase C generates inositoltrisphosphate - many receptors are coupled to this - also generates diacylglycerol - which can then be used to make arachadonic acid. many normal signalling processes then can be used to make arachadonic acid. we're really only going to discuss 5' lipoxygenase products when we discuss lipoxygenase products - other lipoxygenases make other products, but they are poorly understood. go first to prostaglandin pathway. cyclooxyganse - COX1 and COX2 - act on arachidonic acid to form intermediates PGG2 and PGH2 which are then broken down into specific prostanoids depending on what cell they are in. all cells have COX - COX1 is in all cells, constituitively expressed, and COX2 is induced during inflammation. so if we talk about ideal targets for drug therapy, COX2 would be preferred. COX1, the constitutive enzyme, is more important for normal physiological function. thromboxane A2 is needed for platelet aggregation, PGI2 (prostacyclin) is important for integrity of mucosa in GI tract, and a variety of things esp PGE2 are important for regulation of renal blood flow. so the inhibition of the formation of these things will result in inability to clot, GI ulceration, and renal dysfunction. so ideally, we'd target COX2. depending on which tissue we're dealing with, platelets have a lot of thromboxane synthase, so they make mainly thromboxane, and this occurs during platelet activation. kidneys have more PGE synthase, vascular endothelium has more PGI synthase, etc. so product formation is dependent on cell type. cox2 generally causes formation of PGE2, PGF2a, PGD2 (i think that's what he said). thromboxane A2 is very short lived. it is released during inflammation and it causes platelet aggregation, smooth muscle contraction. PGI2/prostacyclin is a vasodilator that inhibits platelet aggregation. these two are the main opposing forces of coagulation. prostacyclin is made by endothelium. PGD2, E2, and F2a are made in kidney to control blood flow, they have specific degratory pathways. also in other organs. PGE2 causes sensitization of nerves underlying some of the pain of inflammation, causes constriction of the airway smooth muscle, and some local relaxation of blood vessels. PGF2a is a potent constrictor, important regulator during pregnancy in myometrium. the other limb - the leukotriene limb - arachadonic acid acted on in white cells by lipoxygenase - produces very active compounds, some of the most potent bronchoconstrictors - LTC4, LTD4, and LTE4 were called slow reacting substance of anaphylaxis before. LTC4 and D4 and E4 are called something special b/c they have amino acids on them. LTB4 is a potent chemoattractant with no amino acid complex. so the white cells make these things that constrict airways, increase capillary permeability, and call in more white cells to amplify process. this is a major target of antiinflammatory drugs. glucocorticoids inhibit this cascade, but NSAIDs do not. this explains the potency of steroids relative to NSAIDs. steroids will block this whole set of mediators that NSAIDs do not. LTC4 and D4 also produce mucous in the airways and receptor antagonists for these compounds are used clinically now or are being studied another point re: inflammation - in addition to the immediate process of inflammation whereby we have some insult, trigger inflammation, clean it up, and everyone goes home; many processes relate to chronic inflammation - that which is triggered over and over again, due to recognition of self as nonself, or something - chronic exposure to foreign antigen, food allergy, flea allergy whatever. could be something like rheumatoid arthritis, or whatever. in addition to immediate effects, then, there are chronic effects, which also relate to the fact that there is cell death, fibrosis -so normally, when tissue architecture is disturbed, tissue may respond by dividing and replacing itself, or may respond with fibrosis (or both) - eg, when cartilage in joints is destroyed,a fibrous replacement takes over, and there are chronic sequelae. alsoo in vasculature or lungs - asthmatics have thick airways, increased smooth muscle - part of chronic inflammation results in hyperplasia, hypertrophy of existing tissue. so chronic effects often need to be considered and treated as part of your treatment regime. this comes up in a variety of diseases like arthritis, asthma, etc. pharmacologic manipulation of arachadonic acid cascade. several key targets: one is the phospholipase A2 which we target with glucocorticoids (which also have a variety of other effects in the body besides targetting phospholipase A2) another is cyclooxygenase which we target with NSAIDs like aspirin, ibuprofen. we are working on COX2 selective ones. lipoxygenase inhibitor- used mainly in asthma also, receptors for leukotrienes are looked at - we're working on receptor antagonists. prostaglandins are used clinically somewhat also in addition to this cascade there are other cascades that can be important depending on specific situation. the mediators: histamine - from mast cells. receptor antagonists are used - H1/H2 antag. role of histamine in inflammation is initial and not critical PAF - platelet activating factor from nomocytes and mphages, basos, eos. PAF antagonists not really used clinically cytokines - ILs, IFNs, made by inflammatory cells. very important in recognition of foreign Ag, Ab response, CMI response. some investigation about IL1 inhibitors and so forth to try to reduce specific inflammation eicosanoids - 20 carbon molecules including prostaglandins and leukotriens kinins - we have bradykinin inhibitors useful for alleviating upper resp signs like rhinitis neuropeptides - released largely by nerves in area of inflammation - substance P et al. these play a minor role, we think. cells: mast cells, monocyte/mphages, basophils, eosinophils, T cells, B cells, platelets, endothelial cells so the main thing, as stated, is to use glucocorticoids or NSAIDs, and to develop antileukotriene drugs. there are other immune modulators which work mainly on inflammatory cells - some of them like high dose glucocorticoids et al are used to prevent tissue rejection in a superphysiologic, aggressive anti-immune/antiinflammatory treatment. ---end----