Download 753_Module2_GITract

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 systemicallygood SE profile
SE
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Potential concernAl toxicitymyriad 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/antacidsneeds 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
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minor
potential for bismuth toxicity (renal pts)
dark stools
black furry tonguerx w/chemicals in oral cavitydiscoloration
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
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there are DIs that cause chelation of drug by the salts of antacids
classic case is tetracycline
different salts have different effects
Alconstipation
Mglaxative
CO3/HCO3belching/gas
Ca++not as effective
Most antacids are w/Ca++for supplementation
Sometimes Mg antacids are used for their laxative effects
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All ions can cause problems for renal pts
Antibacterials
 Helicobacter=campylobacter
 H. Pylori generates a urease which does 2 things…
 Its highly immunogenicimmune response
 Urease generates ammonia which is a basic substance…
 We get microenvironments where the pH isn’t low enough in stomach
 This stimulates gastrin rlsmore 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 NTSCTZ
 Regulates emesis or allowing for emesis
 Most accessible part of the emesis piece that’s in the CNS
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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 Pthe NK1 receptor
CTZ
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5HT3
D2
Musc.???
Vestibular
 H1
 Musc.
NTS
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H1
Musc.
5HT3 (more important)
D2
NK1
EC
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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
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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 dose5HT3 antagonism
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Can also be a 5HT4 @ tx dosesprokinetic 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
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Good profile
HA around 20% of time
Constipation10%
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
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Emetics
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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 applicationsuse apomorphine
is a dopamine agonist, not for humans
for humansSyrup 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
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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
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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