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pharm
2/13/98
washabau

pharmacology of the small animal GI 
tract

pharmacology of gastric acid secretion:

we'll also discuss 
therapy for gastric acid secretory disorders.
quick review of physiology:


slide: gastric lumen via endoscope. this is a dog stomach. we see rugal 
folds in the fundus which disappear when you get into distal stomach. in 
these folds, we have some important cell types.

gastric pits: the major 
cells we're discussing today are the parietal or oxyntic cells. these are 
the ones that are destined for acid secretion. they line the pits, 
secrete some acid at a basal rate, and a lot of it in response to various 
stimuli. other cells to consider include the chief cell, committed to 
secreting proteases - pepsinogens, mainly. these get cleaved by H+ into 
pepsins which digest proteins to a limited degree. there are a number of 
endocrine cells throughout the GI tract, we won't discuss them all. just 
know that some of them are in there, they secrete stuff like gastrin and 
so forth. in the antrum the antral G cells secrete gastrin which 
circulates as a hormone to distant sites where there are gastrin 
receptors to promote acid secretion. there's also a somatostatin cell, 
and somatostatin can directly inhibit H+ secretion by parietal cell. 
somatostatin can also be released in a paracrine fashion - it can diffuse 
into the interstitial matrix and act as a paracrine substance. there are 
also neurons innervating these cells, some of which secrete somatostatin 
across their synaptic space. there are endocrine, paracrine, and 
neurocrine releases of somatostatin.

so we have all these cell types. we 
also have the mucous cells - mucous neck cells which eventually migrate 
up and become surface mucous cells. these all secrete mucous, which is a 
complex of sulfated glycoproteins which lie over the mucosa and prevent 
back diffusion of H+ into the mucosa and submucosa. major part of gastric 
mucosal barrier. it's there to prevent autodigestion of the stomach. 
these are the major cell types.

physiologic regulation:
there are as 
outlined in the handout several mechanisms for physiologic regulation of 
H+ - these can occur during unregulated states. can occur during cephalic 
phase - seeing or smelling food - as shown by pavlov. there's a gastric 
phase - things that happen in stomach that stimulate or inhibit H+ 
secretion. also intestinal phase. basal phase = unstimulated phase = more 
important in humans than in our pets. we're continuous acid secretors - 
that's why we get stress ulcers. the horse is to some extent also, but 
dog and cat secrete much less under basal circumstances. mostly during 
cephalic and gastric phase, some during intestinal.

cephalic: smelling 
or tasting food - this stimulates H+ secretion mostly mediated through 
vagal nerve, vagotomy stops it. vagus innervates parietal cells, releases 
ACH, binds M2 cholinergic receptor, leading to number of events 
culminating in release of H+ into lumen in exchange for K+. this is one 
of the events of cephalic phase. also other neurons innervate the antral 
G cells - again cholinergic, but also GRP (gastrin releasing peptide) is 
involved. but ACH binds receptor, gastrin cell releases gastrin which 
circulates to distant sites to bind receptors - can bind one on parietal 
cell, which releases H+. 
so we have these two neural mechanisms and an 
endocrine mechanism. animals with gastritis, or erosions or ulcers - we 
d/c feeding, prevent animal from seeing or smelling food - because these 
things contribute to H+ secretion. 

what about gastric phase? most 
important for H+ secretion. two stimuli - things already chewed and 
swallowed and in stomach. distention of stomach activates 
mechanoreceptors, through long vagal-vagal pathways and short enteric 
neuronal synapses, and evokes cholinergic stimulation of H+ secretion 
from parietal cells. this is another reason why animals with secretory 
disorders have to have small meals once we start feeding them again. 
also, the amino acid/peptide content of diet is important for acid 
secretion - when an animal is recovering from a disorder, the small meals 
should be low in protein. this will diminish H+ secretion.

other 
indirect effects - stimulation of gastrin release from antral G cell also 
occurs during the gastric phase.

function of gastric acid:
protein 
digestion - H+ carries out acid hydrolysis of pepsinogens to pepsins to 
start protein digestion in gastric lumen. but, if there were no H+ 
secretion at all, there would still be some level of protein digestion, 
b/c most of it occurs in small intestine due to proteases. so this isn't 
an absolutely vital function.
inactivation of bacteria, viruses, and 
parasites - H+ suppresses proliferation of these organisms. in the 
setting of what we call achlorhydria, humans and animals are at increased 
risk for overgrowth of bacteria in stomach and SI, and infection 
w/viruses and parasites. this doesn't always happen, but it can.
iron 
absorption - H+ plays a limited role

pharmacology: what do we need to 
know? what are the receptors, pathways, etc?
how can we use this 
information clinically?

diagram in handout - parietal cell - this cell 
has polarity - a lumenal side and a basal side. it secretes into the 
lumen - H+ into the lumen - in exchange for K+ via the H-K-ATPase. this 
accounts for the dramatic ability of the cell to secrete H+. many 
receptors exist on the cell which may lead to stimulation or inhibition 
of H+ secretion. the story is pretty complicated, and we don't have time 
for it all. major receptors involved in stimulation are the histamine 
receptor, which responds to histamine from mast cells, enterochromaffin 
cells. this receptor is of the H2 conformation. it's a histamine H2 
receptor subtype (there are 3 histamine receptors that are well 
characterized, and probably 4 or 5 others). about 25 yrs ago, scientists 
went into labs and developed antagonist drugs selective for this H2 
subtype. this revolutionized tx of gastric acid secretory disorders. 
there is a paracrine mechanism for the stimulation of acid secretion - 
secretion of histamine from mast or enterochromaffin cells which goes to 
the parietal cell and stimulates this receptor. the signal transduction 
involves G proteins, activation of adenylate cyclase, leading to 
increased cAMP. there are some phosphorylation events that occur, 
involving the final common pathway - the proton pump. the phosphorylation 
activates the H-K-ATPase transporting enzyme causing increased H+ 
secretion. not only is there a paracrine mechanism, but ther'es  also a 
mechanism of neurocrine type - vagal postganglionic cholinergic neurons 
release ACH which binds to M2 cholinergic receptor, leading to activation 
of the cell. the M2 receptor is coupled to influx of Ca++ from ECF and 
Ca++ release from intracellular stores. G proteins involved. final common 
pathway - phosphorylation of regulatory proteins and proton pumping 
enzyme leading to H+ translocation and K+ uptake. also, there's an 
endocrine mechanism involving gastrin. gastrin's release is stimulated by 
ACH and GRP neurons. antral G cells secrete gastrin which circulates to 
distant sites - stimulates some muscle contraction, some pancreatic 
acinar cells, and also binds to a gastrin receptor on the parietal cell, 
through endocrine mechanism, stimulating H+ secretion. it's coupled to 
Ca++ influx and so forth. IP3 is involved, phosphorylation is involved, 
and finally the proton pump final common pathway is stimulated. so there 
are neurocrine, paracrine, and endocrine mechanisms for stimulating H+ 
secretion. 

pharmacologists have antagonists for each of these 
receptors, thinking they might be useful for reducing H+ secretion. there 
are also irreversible inhibitors of the proton transporting enzyme pump 
on the lumenal surface - like omeprazole and other similar compounds. 


mucosal defense mechanisms - remember the mucous neck cells which secrete 
mucous as they go up the pits to the mucosal surface...the mucous will 
contribute to gastric mucosal barrier. the sulfated glycoproteins 
interfere with back diffusion of all the H+ in the lumen. this prevents 
autodigestion of mucosa. also, there are other factors. in addition to 
secreting mucous, there are cells in the overlying epithelium that 
continuously secrete bicarbonate. the bicarb will serve to neutralize 
some of the H+ that back diffuses into the unstirred mucous layer. so 
there's a mucous component, a bicarb component - there's the contribution 
of mucosal cell renewal - there are constantly new cells repopulating the 
mucosa during health. during disease, this process may be less effective 
or less efficient - also some medications interfere with mucosal cell 
renewal and lead to damage to gastric mucosal barrier. there is also 
endogenous prostaglandin production by epi cells in the gastric mucosa. 
we know prostaglandins are involved in inflammatory processes - eg 
arthritis, inflammatory bowel disease, etc - but here in the gastric 
mucosa, they are beneficial. we know that prostaglandins directly inhibit 
H+ secretion from the parietal cells, for one thing. further, we know 
that they have what's been called a cytoprotective effect (nebulous term, 
falling out of favor), or tissue protective effect, because they also 
stimulate the mucosal cell renewal, stimulate the bicarb secretion, 
stimulate mucous production, and they stimulate mucosal blood flow. this 
is important b/c if any H+ does diffuse back in, it will be taken up by 
regional circulation and carried away. up til 10 yrs ago, the thinking 
was that all the events that occur in health and disease were explained 
entirely by parietal cells, but now it's clear that the mucosal barrier 
is very very important in preventing the stomach from undergoing 
autodigestion.
how do we build this all into coherent plan for therapy in 
an animal?

pharmacotherapy of gastritis:

1. dietary management
2. 
antacids
3. diffusion barrier
4. anticholinergics
5. histamine receptor 
antagonists
6. gastrin receptor antagonists
7. H+ K+ ATPase antagonists

8. prostaglandins

1. diet can be very important. based on physiologic 
principles, we can reduce gastric secretions and enhance gastric 
emptying. it's largely the protein in the diet that stimulates gastric 
secretion. when an animal has clinical signs of mild gastritis, you may 
suggest witholding food for about 24 hrs, and then feeding a low protein 
diet (high carb). this may take care of mild gastritis without using 
drugs. the other thing we need to do is remember that gastric distension 
also promotes gastric secretion, so enhancing gastric emptying will 
reduce this effect. so we avoid single large meals. we suggest feeding 
small amounts of low protein food several times a day when the animal 
returns to eating. remember there are thing physiologically that will 
feedback inhibit gastric emptying. lipid in the diet inhibits gastric 
emptying. as food with lipid in it gets into the small intestine, you 
experience fullness. lipids feedback inhibit gastric emptying - they call 
it the duodenal brake. it's a braking mechanism related to lipid 
inhibiting gastric emptying. so you also want to keep lipid content low. 
feed small low fat low protein high carb meals several times a day. 
boiled rice is good. studies in dogs show pretty linear relationship b/w 
amount of protein in diet and amount of acid secretion.

2. simple 
chemistry using substances that directly neutralize acid - these are the 
antacids. usually they are sodium bicarb, calcium carbonate, or aluminum 
or magnesium hydroxide. the best are combinations of aluminum and 
magnesium hydroxide. Tums uses the calcium carbonate.  there are huge 
numbers of antacids on the market - AlternaGel. cimethicone is in some of 
them - an antigas agent. Riopan plus 2 - contains magaldrate, whatever 
the hell that is. these things can be used in pets, if the animal has a 
mild gastritis. so this together with nutritional management can work 
well for mild problems.

3. animls with moderate to severe gastritis, or 
erosions or ulcers, need stronger tx. diffusion barriers: sucralfate and 
bismuth compounds like subsalicylate, subnitrate and subcitrate. these 
compounds bind to necrotic tissue proteins in inflamed mucosa or ulcers. 
they have other properties too that we'll hear about later. sucralfate 
has some advantages over the others. it's named because it is based on 
sucrose and it has R groups that are aluminum sulfate substitutions. 
there's a lot of negative charge, which helps it bind to some + charged 
necrotic tissue proteins. when given orally, it diffuses into 
erosive/ulcerative sites and prevents further diffusion of acid, pepsin, 
bile, or other stuff into the site. can think of it as a mucosal band aid 
although that is simplistic. it has a cytoprotective effect. remember 
that after nutrition and antacids, diffusion barriers can be very very 
effective at stopping further acid mediated injury, by binding to 
inflamed sites. they call sucralfate "the Un-H2" in the ad. 

4. 
anticholinergics
5. histamine receptor antagonists
6. gastrin receptor 
antagonists

the paracrine, endocrine, and neurocrine mechanisms all 
stimulate H+ secretion.

muscarinic cholinergic antagonists:

atropine: 
M1, M2
scopalamine: M1, M2
propantheline: M1, M2
pirenzepine: M1 (in 
canada and europe, not here). can inhibit acid secretion even though it's 
M1 antagonist b/c the neuron innervating the parietal cell has an M1 
receptor on it. the parietal cell itself has an M2 receptor. this drug 
probably won't be used in the US.
we won't use this group of drugs, most 
likely

histamine receptor antagonists - we will use these

cimetidine 
(tagamet) - smithkline was the first to make this. it made them a lot of 
money. their patent expired.
ranitidine (xantac)
famotidine (pepcid)

nizatidine (axid) - most recently made

these are all effective histamine 
H2 receptor antagonists
each company thinks their drug is the best, but 
really, clinically, they're pretty similar. the latter three, however, 
can be dosed less frequently, which can be an advantage. they all inhibit 
the same mechanism

histamine receptor distribution:
H1: GI smooth 
muscle, mast cells, vascular smooth muscle, purkinje cells, bronchial 
smooth muscle (contraction), CNS
H2: oxyntic cells (parietal), 
parathyroid epithelia, vascular smooth muscle, atrial myocardium, 
bronchial smooth muscle (relaxation), leydig cells, hematopoeitic stem 
cells, lymphocytes, CNS

so H2 antagonists can lead to reduced PTH, not 
too big a deal, but you can use them to tx secondary hyperparathyroidism 
due to CRF
may see hypotension, due to receptors in vessels
may see 
bradycardia
early H2 receptor antagonists developed pancytopenias due to 
bone marrow effects.

just remember there are H2 receptors in other 
tissues.

gastrin receptor antagonists - the europeans have drugs that 
target this receptor and inhibit it - proclamide is the best example - 
it's a derivative of glutamic acid. it inhibits gastrin receptors. it's 
used a lot in europe but isn't available here and probably won't ever be. 

so mainly we target the histamine receptor.

7. what about the final 
common pathway? can we antagonize it? yes. substituted benzimidazoles - 
the first one is omeprazole, called Prilosec (tm). it inhibits the enzyme 
on the lumenal side of cell, preventing translocation of H+ into the 
lumen. effective, potent, works in our pet species. in the past 9 mos or 
so, there's another drug called lansoprazole which has been developed for 
use in humans, has been tested in rodents, dogs, and primates, and it 
seems to have no advantage over omeprazole in the dog, but it should 
drive the price down. 

8. prostaglandins - note that items 1-7 all focus 
on reducing H+ secretion. now, we know about the gastric mucosal barrier, 
and how important the prostaglandins are in propping it up. the 
prostaglandins also inhibit H+ secretion, increase bicarb and mucous 
secretion and cell renewal and blood flow. the one that's most clinically 
useful right now is misoprostal aka Cytotec. this is a synthetic 
prostaglandin E1 analog that's been modified by adding some methyl 
groups. if given orally, this drug will have all the effects of the 
endogenous prostaglandins. this is a useful adjunct to NSAID therapy 
which tends to have a deleterious effect on the mucosal barrier by 
inhibiting prostaglandin synthesis (which is what helps the arthritis). 
this is a popular and useful drug that can be used to prevent aspirin 
induced ulcers in dogs. 

Gastritis, erosion, ulceration - all lead to 
signs like anorexia, loss of body condition, some vomiting - and perhaps 
serious GI hemorrhage.
hematemesis, melena, etc. very serious 
presentation of these animals to ES.
we have to treat the hemorrhage - 
remember all the things we just discussed - they all have a role in 
therapy.

GI hemorrhage - nonspecific therapy:
ongoing hemorrhage
anemia, 
hypoproteinemia, thrombocytopenia
fluid, electrolyte, acid-base 
disturbances
GI ulcers
bacterial translocation
GI perforamtion	
two 
things: one, we have two cases to go over on monday. two - ten minute 
break.

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medical management of refractory vomiting

we'll 
discuss anti-emetic therapy - physiology, pharmacology, why we use these 
drugs, why we inhibit vomiting. it's important to diagnose disease and 
develop specific therapies. fi the vomiting is due to IBD, dx and tx 
appropriately. if it's due to pancreatitis, dx it, treat it. too often, 
people use antiemetics w/o treating the underlying cause. you should 
always dx the primary dz entity.

the therapies we'll discuss now are 
largely nonspecific - they're not going to tackle the primary disease 
entities. however. owners come in and say "vomiting" but they may be 
wrong. it may be gagging, retching, or regurgitation.

that 
yellow/translucent stuff on the slide obviously came from the inside of 
the animal, but did it come from the stomach/SI or above the lower 
esophageal sphincter? regurgitation is when animal just opens mouth and 
spills out stuff without any preceeding events. vomiting is often 
preceeding by retching and salivation. it's difficult to define, but you 
know when you see it. like pornography

take home points:
two major 
mechanisms for vomiting or emesis. one is neurally mediated and involves 
the emetic center; one is humoral, blood borne, and involves the CRTZ. 

receptors: A2, D2 (dopamine), M1 (cholinergic), 5HT3 (serotonin), 
ENKmu,delta (enkephalin),<--- those are all central, emetic center or 
CRTZ. these are peripheral---> 5HT4 (GI serotonin recp?), Mot (motilin 
receptor)
vomiting disorders:
motion sickness: H1 histaminergic 
antagonists
uremia: D2 dopaminergic antagonists
cancer chemo: 5-HT3 
serotonergic antagonists 
delayed gastric emptying: 5-HT4 agonists, 
motilin agonists

chronic vomiting: he's showing a slide from which we 
will not be asked any questions. when you have an animal that comes in 
with vomiting, you should go through logical, detailed medical exam, 
culminating in dx and specific therapy. that's the bottom line. 


etiologies in dogs:

IBD 32%
recurrent pancreatitis 30%
GI malignancy

hepatobiliary dz
GI obstruction
other

often we can't establish a 
definitive dx because we can't, or owners don't want us to pay or to do 
specific tests, and where does that leave us? with these notes. what do 
we need to know?

scheme of neuroanatomic pathways:

irritation or dz of 
GI tract, heart, liver, peritoneum, genitourinary tract can stimulate the 
vomiting center in the brain stem (aka emetic center), which also gets 
input from higher brain centers

drugs, toxins, uremia, infections, 
motion sickness, and input from the semicircular canals (in dog) can 
stimulate the CRTZ in the brain stem

neural and humoral pathway for 
vomiting. 
neural: you get gastritis, or parvo or whatever. inflammation 
of GI tract ensues. this stimulates the visceral afferent fibers (vagal 
and sympathetic) which stmulate the emetic center and cause vomiting. 
there's an efferent pathway leading back to the stomach causing 
retrograde peristalsis, etc.
also efferent stuff leading to closure of 
airway
we know this is the neural pathway b/c if you feed the dog copper 
sulfate, it will do the same thing as parvo - activates visceral 
afferent, goes to emetic center, and so forth. if you transect the 
visceral afferent, you can give copper sulfate, and dog won't vomit. much 
of what we see clinically is neurally mediated emesis. 
another example 
of neurally mediated emesis is a path from higher cerebral centers to the 
emetic center - if you are stressed or anxious, you may feel nauseated 
and vomit - this involves a neuron from cortex stimulating emetic center 
and so forth. this isn't so important in animals, it's more a human 
thing. 
another example is motion sickness - semicircular canals in dog 
have synapses in CRTZ in dog or emetic center in cat. these are all 
examples of neurally mediated emeses

humoral emesis - nausea and 
vomiting mediated by something in the blood which bathes/perfuses the 
CRTZ which is outside the BBB, activating receptors. best example is 
uremia - toxins stimulate CRTZ receptors. also septicemia works the same 
way - systemic infection results in perfusion of CRTZ with toxin. 

note: 
CRTZ neurons synapse with emetic center. that's what ends up leading to 
the vomiting. so after stimulating of the CRTZ, it ends up working the 
same way.

pharmacology of this: note: do not think this is a 
comprehensive guide to receptors of nausea. 

in the emetic center the 
receptors we can work with are the alpha2 and the 5HT1a receptor. in the 
CRTZ there are D2 dopamine receptors, H1 and H2 histamine receps, A2 
norepi receps, 5HT3 serotonin recepts, the ENK mu/delta enkephalin 
recpeotrs, and M1 ACH receptors. we might be able to create antiemetics 
by working with these receptors. also in the past several years, we've 
found a visceral serotonin receptor that is likely activated in pathology 
- eg, serotonin released with inflammation or neoplasia may bind the 5HT3 
receptor there and lead to neurally mediated emesis. if we antagonize 
this receptor,maybe we can diminish this neurally mediated path. this is 
more important in dog, less important in cat. the 5HT3 receptor in CRTZ 
is more important in cat, less in dog. also, there are motility disorders 
which can lead to delayed emptying, gastric distension, megaintestine, 
etc. all of which can lead to nausea. if we can reduce distension, 
promote GI transit, we may be able to help prevent vomiting. there are 
5HT4 receptors, motilin receptors, and D2 and M2 receptors which are all 
important with regard to gastic emptying. the Mot receptor is 
particularly important wrt the migrating motility complex that empties 
the GI tract during periods of fasting. 

if we know the pharmacology, we 
can build a therapy around these principles.

species differences: wrt 
motion sickness, involving semicircular canals - pathway goes to CRTZ in 
dog, to emetic center in cat. also, 5HT serotonin can be involved in 
humoral and neural emesis, but that the 5HT3 receptors are in the viscera 
in the dog, and in the CRTZ in the cat. also, the D2 dopamine receptor 
which is important during uremi, is very important in dogs, but not so 
much in cats. 

anti-emetic classes:

A2 adrenergic antagonists: remember 
there are A2 receptors in emetic center and CRTZ. 

prochlorperazine - a 
phenothiazine - 0.5 mg/kg TID sq, IM
chlorpromazine - a phenothiazine - 
.2-.4 mg/kg TID po/sq
remember phenothiazines have many properties. these 
two will antagonize the A2 receptors in emetic center and CRTZ. however, 
these drugs also have other properties. they can antagonize A1 receptors 
also, as well as ACH receptors, histamine receptors, calmodulin, and so 
forth. many effects. however, these two examples at these doses will work 
as A2 antagonists and inhibit vomiting. we don't need to know the doses, 
however. remember the hypotensive effects of these drugs, also. in an 
otherwise stable adult animal with good fluid and acid/base balance, 
these can be good.
yohimbine - more selective A2 inhibitor and is also 
approved for use in the dog and the cat, which is unusual among the drugs 
we'll be discussing.

D2 dopaminergic antagonists: these receptors are 
seen in the viscera and the CRTZ

metoclopramide aka reglan - useful to 
tx nausea of CRF (more in dog than cat)
trimethobenzamide
domperidone 
(new in US - on a molar basis, 25x more potent than metoclopramide) 

haloperidol - we don't use this much
prochlorperazine - phenothiazine - 
see above
chlorpromazine - phenothiazine - see above

that other species 
difference - a review of mechanisms of vomiting shows us on the Y axis 
the # of vomiting episodes as a function of incremental doses of 
apomorphine on the X axis. apomorphine activates D2 receptors to cause 
vomiting, you may recall. as dose is increased, amount of vomiting 
increases. dogs are very very sensitive. cats are three log orders less 
sensitive to apomorphine than dogs. one way to interpret this would be to 
consider the D2 receptor less important in mediating nausea and vomiting 
in the cat. in cats with CRF, when we use drugs like metoclopramide to 
antagonize D2 receptor, dr washabau says it's much less effective than in 
dogs. pigeons also are not that sensitie to apomorphine. 

H1 
histaminergic antagonists: important in CRTZ in dog, for motion sickness 
in dog.

diphenhydramine - very effective for motion sickness in dog

dimenhydrinate
prochlorperazine
chlorpromazine - also very effective for 
motion sickness in cat

note that for cat, motion sickness is better 
treated by phenothiazines to knock out the A2 receptors.

M1 cholinergic 
antagonists - CRTZ M1 receptors very significant...
these drugs aren't 
specific for those, though, they inhibit M2, M3 also

pirenzepine - 
effective at M1 only, but not available here
scopalamine
prochlorperazine

chlorpromazine

we won't really use these

5HT3 serotonergic antagonists 
- this whole area has recently exploded - there were only 2 serotonin 
receptors when dr washabau was in vet school. now there are 7 or 9 we 
know about. these 5HT3 ones are in afferent fiber of dog, and CRTZ of 
cat.

ondansetron aka zofran
granisetron - this, or zofran, is best 
choice
tropezatron - only in europe
metoclopramide - not as selective - 
mainly D2 antagonist. it's activity at 5HT3 isn't anywhere near as potent


ENKmu,delta enkephalinergic receptor agonists/antagonists:

butorphanol - 
when given at appropriate dose can inhibit nausea/vom without causing too 
much sedation

what can we do in periphery? we're leaving CRTZ and emetic 
center now. 
5HT4 serotenergic receptors are on myenteric neurons. when 
these are activated that neuron depolarizes, releases ACH which binds 
smooth muscle receptors and contracts, and causes peristalsis, gastric 
emptying.

cisapride (propulsis) - will agonize these receptors, 
promoting peristalsis and emptying
metaclopramide - also does this, but 
not its main function.

motilin agonists:
erythromycin - at lower than 
microbicidal doses, acts as motilin like substance, stimulating gastric 
emptying.

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