* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download 753_Module2_GITract
Survey
Document related concepts
Discovery and development of antiandrogens wikipedia , lookup
Zoopharmacognosy wikipedia , lookup
Drug interaction wikipedia , lookup
Discovery and development of angiotensin receptor blockers wikipedia , lookup
5-HT2C receptor agonist wikipedia , lookup
Toxicodynamics wikipedia , lookup
Gastrointestinal tract wikipedia , lookup
Discovery and development of proton pump inhibitors wikipedia , lookup
5-HT3 antagonist wikipedia , lookup
Cannabinoid receptor antagonist wikipedia , lookup
Psychopharmacology wikipedia , lookup
Neuropsychopharmacology wikipedia , lookup
NK1 receptor antagonist wikipedia , lookup
Transcript
Osteoclasts Have proton pumps These pumps are important in facilitating remodeling bone Acidic conditions are important for Ca++ absorption Couple to that, is that there is a potential for high concentrations of drug to interfere w/osteclast proton pumps and bone remodeling These 2 factors may affect bone at very large doses and probably not likely at tx doses Sucralfate Complex of sucrose, Al and sulfate When put in to pH<4, forms a gel and likes to bind to protonated surfaces which gives preference for exposed proteins…..like ulcerations The gel creates a barrier that lasts for 6 hours Is typically taken before eating/peak acidic conditions Sucralfate gel is not absorbed systemicallygood SE profile SE Potential concernAl toxicitymyriad of neurologic sx’s Only of importance in pts w/renal impairment Some constipation w/chronic use there is potential for malabsorption of vitamins and minerals give before meals and not w/antacidsneeds acidic environment to become a gel Bismuth pepto bismol interacts w/exposed tissue and forms a barrier over the wound seems to increase production of mucous and HCO3 seems to have antibacterial activity (i.e. against H. Pylori) by itself inadequate to treat gastritis and ulcers common as an adjunct to tx ulcers caused by H. Pylori SE minor potential for bismuth toxicity (renal pts) dark stools black furry tonguerx w/chemicals in oral cavitydiscoloration tongue not clinically important but may help w/dark still differential Antacids not used frequently not very effective, requires a lot of buffer to offset high acidity also have to take w/high frequency to have significant action SE there are DIs that cause chelation of drug by the salts of antacids classic case is tetracycline different salts have different effects Alconstipation Mglaxative CO3/HCO3belching/gas Ca++not as effective Most antacids are w/Ca++for supplementation Sometimes Mg antacids are used for their laxative effects All ions can cause problems for renal pts Antibacterials Helicobacter=campylobacter H. Pylori generates a urease which does 2 things… Its highly immunogenicimmune response Urease generates ammonia which is a basic substance… We get microenvironments where the pH isn’t low enough in stomach This stimulates gastrin rlsmore acid rls Things are out of balance regarding the proper amounts of acid rlsd and amount of protection available H. Pylori latches on to epithelial cells and generates an immunogenic enzyme and causes increase acid production 70% of us have this bug but no problems…what triggers it to be a problem in 1 person vs the other??? Abx for H. Pylori TCN Amoxicillin Metronidazole Clarithromycin Aggressive tx of H. Pylori ulcers include combo tx i.e. Metronidazole w/Amoxicillin and a PPI and maybe some bismuth (sometimes we see 3 or 4 drug combos) Emetic Physiology Emetic Center (EC) ‘The’ place that causes emesis When stimulated, several things happen…….. Get a decrease in gastric motility Get a relaxation of the the upper GI and the sphincter between the GI and esophagus Increase in tone in the SI Get a contraction of abdominal muscles(diaphragm) All of this results in wretching EC receives info from many places EC located in the brain stem and is affected by ‘higher centers’ i.e. limbic system Things that feed into the higher centers affect the EC These things include smell, sight, emotion Vestibular Apparatus (VA) VA also feeds into EC This is the place for motion sickness Nucleus Track Solitarias (NTS) Feeds into EC A lot of info from gut feeds into NTS The gut-to-NTS feeding pathways are called vagal and sympathetic afferents They monitor the stomach for dyspepsia and other disturbances Chemoreceptor Trigger Zone (CTZ) Feeds into EC Auxillary feed from NTSCTZ Regulates emesis or allowing for emesis Most accessible part of the emesis piece that’s in the CNS Located @4th ventricle and has good exposure to body fluids(CSF) more so than the other parts of emesis pie Get exposure to : drugs, toxins in the blood stream, apomorphine, chemotherapeutic agents The Receptors Viscera/Stomach 5HT3 Afferents in gut have Substance Pthe NK1 receptor CTZ 5HT3 D2 Musc.??? Vestibular H1 Musc. NTS H1 Musc. 5HT3 (more important) D2 NK1 EC CB1 Antihistamines H1 Antihistamines and antimuscarinics lumped together b/c antihistamines have antimuscarinic action Moderately effective Tx motion sickness Diphenhydramine an antihistamine w/anticholinergic effects Scopolamine—antimuscarinic SE Sedation Dry mouth To tx things greater than motion sickness leads to unacceptable SEs D2 antagonists Prototype is metoclopramide (best) Prochloperazine (compazine) Promethazine (phenergan) Just about any D2 ant i.e. haldol Work better than Antihistamines Less effective than 5HT3 ants Decent SE profile and commonly use for tx of N+V from chemotherapy Metocloproamide D2 ant (CTZ, NTS) Up the dose5HT3 antagonism Can also be a 5HT4 @ tx dosesprokinetic activity, stimulates peristalsis leading to less nausea SE (D2s) Can induce extrapyramidal sx’s (EPS) Parkinsons like sx Tardive dyskinesia Unlikely in short term but need to monitor and cut back when necessary Olanzapine Dirty b/c it hits a lot of other receptors, perhaps there is less chance of EPS similar mechanism to D2s but w/better SE profile 5HT3 antagonists considered most effective today against N+V prototype is ondansetron 5HT3 are important in activating visceral afferents which feed into NTS NTS have them also Also found in CTZ Superior efficacy in all cases Effective acutely against N+V But don’t have very long lasting effects Not very effective against delayed onset N+V So they are combined w/other agents taking care of the acute phase while the other agents extend their actions SE Good profile HA around 20% of time Constipation10% Corticosteroids Combined often w/5HT3 ants Dexamethasone Not a great explanation available as to why they are good agents More effective against delayed onset Delayed onset = some chemotherapeutic agents don’t immediately induce N+V, but do later Common to see corticosteroid in combo w/5HT3 for chemotherapy induced N+V Cannabinoids CB1 receptor in EC Not super effective but good as adjunct Don’t have to smoke to have an effect….yeah right! Side benefit: chemotx induced N+V pts have trouble w/eating But get the munchies w/some weed NK1 antagonists Aprepitant Receptors in NTS By itself not good, but as adjunct can extend/enhance effects A study of dexamethasone + ondansetron+aprepitant increased the number of people who benefit for the longer time period vs the dexamethasone+ondansetron only combo Benzodiazepine Emetics Helpful w/anticipatory N+V i.e. routine chem. Pt who has had bad N+V during his/her chemo sessions can now pop a BZD before the next appointment and possibly experience less N+V at that session OR bring one to the next test!! vet applicationsuse apomorphine is a dopamine agonist, not for humans for humansSyrup of Ipecac, an irritant stimulates CTZ make sure pt has something to throw up encourage a lot of H2O intake Pro-Kinetics (PK) stimulate contraction of GIT diabetics develop diabetic gastroporesis, muscles not working right in GIT (atony) PK also good for severe constipation not relieved by anything else and need peristalsis i.e. IBS sometimes accompanies severe constipation PK agents can be helpful in GERD therapy or…. Try to reach maximum anti-emetic effect via moving stuff thru GIT as quickly as possible PK agents enhance cholinergic action in the lining of the GIT, so efficacy is reached by….. Increasing ACh availability in localized areas in gut or… Increase sensitivity to ACh PK Goals… Increased contraction in upper GI Get decrease tone in the pyloric sphincter… Both of these things help decrease emptying time Also like to see increase peristalsis….so once out of gut… need to get it moving along So that it gets to colon more quickly To keep stuff in the stomach…we get increased tone of the esophageal sphincter Again Keep stuff in stomach by increasing esophageal sphincter tone Get the stomach contracting but relax the pyloric sphincter??(hard to hear on audio) to get it out Increase peristalsis in intestine to get movin along This is what happens w/5HT4 agonist All this can happen w/o changing gastric secretion and only manipulating muscle contractions Efficacy Related to availability of ACh Or increasing sensitivity to ACh present Bethanecol Musc. Agonist Has some action to increase tone in stomach Not a great PK agent but has some efficacy D2 inhibitory pathway Blocks ACh rls Drugs that block this are Domperidone Metaclopramide Another opportunity: There is a cholinergic pathway that will activate the eventual cholinergic pathway that will cause muscle contraction. We can turn this on by activating 5HT4 receptors Metaclopramide is a D2 antagonist and a 5HT4 agonist and can turn this PK action Togaserod 5HT4 partial agonist Cisapride Also a 5HT4 agonist Not used much Formerly used for severe constipation/IBS Lengthens QT interval Now used under special conditions PK actions Bethanechol does a little in blocking D2 pathway, okay not super Best is metaclopramide (dual action D2 ant, 5HT4 agonist) Metaclopramide is high on list for anti nauseants for its anti nausea effects and PK effects All these agents have their actions above the colon They are not very good below the colon. Cisapride was good below the colon Good at enhancing colonic tone. Motilin Endogenous Works almost only in upper GIT to increase motility Macrolide Abx can mimic this action Best known one is Erythromycin Ie someone w/advanced diabetes (gastroparesis) may be on erythromycin for motility and not infections