Welcome to gastrointestinal pharmacology. We'll go over peptic ulcer disease and also
constipation, diarrhea, emesis, and GI I autoimmune disorders, which we'll just kind of lump together.
So let's start with peptic ulcer disease and kind of what it is and what it isn't. And,
first the pathology begins with the stomach. The acidic digestive enzymes have a
pH around two, so it's pretty hostile environment. Ulcerations are lining breaks in the stomach
or the duodenum, so it goes from the stomach to the duodenum, the small intestine. And
then three, the presentation, usually there's burning pain, one to three hours after eating
may get worse after lying down over night. The way to think about it, or one way to think
about it is as peptic ulcer disease, invaders and defenders. So our invaders include our
knight with his hammer and his shield made up of H Pylori, NSAIDs, gastric acid
pepsin, which is an enzyme and smoking. These five invaders are causes of peptic
ulcer disease and can damage the stomach or the duodenum, whereas our defenders are our
protectors include mucus, bicarbonate, blood flow, and prostaglandins. So let's talk
a little bit more about the invaders or causes. First, Helicobacter Pylori is a Gram
negative bacillus. It colonizes in between the epithelium in the mucus layer. And this
is the most common cause 60% to 70% of the time. This is the reason for the ulceration.
Second are the NSAIDs. So, they block prostaglandin synthesis. This results in less
blood flow, protective mucus production and bicarbonate. We have acid and pepsin
when the protective mucous layer is damaged, acid and pepsin can injure
the GI system and then smoking. This will delay healing of ulcers and can increase acidity,
the peptic ulcer disease defenses with the castle include the mucus layer.
So the GI Mucosa secretes mucus forming a protective barrier to acid and pepsin. Bicarbonate
will neutralize the acid from the stomach. Blood flow, slow blood flow
can lead to cell injury. So we want normal blood flow and prostaglandin to stimulate
the mucus and bicarbonate secretion. And these are the protectors. So what do we do to treat
it? Well, it depends on what kind of severity we have. We can start with antacids just
to see if you know, neutralizing the acid will help. So we'll stick with two of them
to start calcium carbonate, which is brand Tums. This neutralizes stomach acid to raise
the pH. It's a chewable tablet, but it can be constipating on the other in comparison
is magnesium hydroxide or Milk of Magnesia neutralizes the stomach acid to raise the
pH, a liquid suspension generally, and it's got a laxative effect. So constipating versus
laxative effect. And then just some notes. Now we want to take one to three hours after
a meal. It's no less effective than histamine two receptor antagonists, which we'll talk
about in a minute or proton pump inhibitors. But it's more inconvenient to take antacids that
many times a day. It's not for preventing dyspepsia, only treating it and both calcium
carbonate and magnesium hydroxide can bind to tetracycline and fluoroquinolone antibiotics
decreasing their effectiveness. Peptic ulcer disease treatment, histamine
two receptor antagonists. Well, histamine two receptors line the stomach helping secrete
gastric acid and the two antagonists we'll talk about are famotidine brand Pepcid
and Ranitidine brand Zantac [Note: famotidine is now both brand Pepcid and Zantac]. And you'll notice that their endings are the same. That's not
coincidental. After a certain year, we started keeping the endings the same for the same
chemical entities and most of the time the same chemical entity will be in the same therapeutic
class. But we'll see as we get to neuro with like oxetine or something like that, you will
see that a, it might have different therapeutic indications with the same chemical structures
or similar chemical structures. But focusing on this right now famotidine will block
H-2 receptors, prevent acid secretion as will ranitidine, we don't want to use
for more than 14 days if we're just taking it over the counter. The physician of
course, or prescriber can make it longer. Some notes, we take it an hour before the
meal to reduce that acid. It's best for nighttime GERD, gastroesophageal reflux disease caused
more by histamine really. Cimetidine or Tagamet, which is the first one that came
out. It's a histamine-2 receptor antagonist causes adverse effects and many drug interactions
and long term use can put patients at pneumonia risk. We want to do is just picture that here
we have this acidic environment that normally destroys bacteria and then we reduce it. So,
we open the body up to this bacteria and pneumonia,
Peptic ulcer disease, Proton pump inhibitors of antacids, H-2 blockers. These are the
newest, but they're certainly not new omeprazole and esomeprazole, we see that they both have
the -prazole ending and this lets us know that it's a proton pump inhibitor and we'll see
that there's a little bit of an issue with something like aripiprazole, with the piprazole
ending which lets us know that drug is for schizophrenia. But right now -prazole
is a PPI. Omeprazole is brand Prilosec and it shuts off the stomach. Proton pumps raises
the gastric pH where esomeprazole (Nexium) also does the same, but it is the S-isomer
of omeprazole. So omeprazole is actually combination of a left and right-handed chemical,
whereas esomeprazole is just the S- or the left-handed side. The S stands for sinister,
which in Latin literally was if you were left handed, you were sinister or that's how they
thought of you. What it's supposed to be is that well,
if there's two sides to it and only one side does anything, well let's just use the one
side and that's why esomeprazole came along. So notes, usually take it 30 minutes before
the first meal of the day. There is going to be one exception to this. One of the Proton
pump inhibitors doesn't require this, but in general, that's the expectation. You can
take up to seven days to work. So, unlike an antacid, which will resolve some of the
acid right away, this can take some time. We want to taper when stopping to avoid rebound
hypersecretion. So let's break that down real quick. Rebound meaning, so we've been
in a position and now we bounce back. So if we've reduced the acid somewhat and we all
of a sudden stop giving these then the body will create a ton of acid because it was trying
to compensate for the loss of acid from these drugs.
So hyper meaning above and then secretion. So rebound hypersecretion means there's a
significant amount of acid that comes out. Longterm we're concerned about osteoporosis
fractures hypomagnesemia but we expect that hopefully, we only have to use in
the short term. So treatment steps. If the ulcer is from H Pylori, we expect to use at
least two antibiotics and an anti-secretory agent like a Proton pump inhibitor. So we're
going to have three different medications all at once and there are other ways to do
it. But this is one of the most common. If however, we have nonsteroidal antiinflammatory
drugs, we try to D/C the NSAID if possible because some patients can't. If you have arthritis
in this arthritis is keeping you from functioning, then the patient has to have the NSAID. But
we try to stop the offending agent and then we'll use histamine two receptor antagonists
or proton pump inhibitors. We want to just create an environment that's best for healing.
So I will not, we're not really healing the ulcer. What we're doing is creating an environment
where the ulcer can repair itself. So non drug treatments that we can use, the best
of them is to eat five or six small meals daily. If you eat a big meal, a lot of acid
goes in the stomach. If you had a little meal, a little acid goes in. So we get less acid
naturally avoiding smoking, which can lead to extra secretion of acid, stopping those
NSAIDs and aspirin, avoiding alcohol and caffeine and reducing stress as much as possible.
But of these really the five to six small meals daily tends to be the one that's the
most effective. Constipation, diarrhea, nausea, vomiting and GI, auto immune disorders. So
when we look at constipation in the pathology, the first point is that we have primary constipation.
This is caused by slowed or delayed transit. Maybe the bowel is obstructed or secondary
constipation. Maybe it's the diet and lack of fiber. Maybe it's a lifestyle, maybe it's
medications, maybe it's underlying conditions. So those are the two different constipations
we'll talk about in terms of treatment, what's due, look at a generally. Then we'll look
at specific drugs themselves. We can use bulk-forming laxatives. We can use surfactant
osmotic or stimulant. The big difference is some of them just bring water into the bowel
to get more of a mush and the others are really propelling things out and it's more of a push.
So let's look at some of the names. Okay.
Bulk forming. We have psyllium, which is brand Metamucil, which is very much like fiber that
would come in the Diet. Docusate sodium is Colace. Often we see this with opioids, polyethylene
glycol too, very different forms. MiraLAX is a powder that comes over the counter that's
relatively safe and then Go-Lytely is a bowel prep. So a completely different intention
with both of them, but it's the same medication. And then the stimulant Senna this is
something that if things are not going well, you can more push than create this mush.
So if you want to think about mush versus push as bulk-forming and surfactants make
it easier to go making everything mushier. But stimulants, osmotic push about movement
forward, which is a little bit different. So let's start with the laxatives. Bulk forming
mush a, the psyllium or Metamucil, it acts like fiber in the Diet. It swells with water
to increase fecal mass and softness. It's the preferred temporary constipation treatment,
minimal side effects. Notes: You will want to talk with the patients about dietary
fiber. Maybe you can change their diet and they don't have to take this. You do want
to mix well with liquids before taking and it can take up to three days to produce a
bowel movement. So often patients are expecting something to happen relatively quickly. Want
to make sure to let them know that that's not how it works. Another one is the surfactant,
Docusate Sodium or Colace. And this lowers the stool surface tension. Water enters the
feces. And the issue we want to worry about is making sure that they're hydrated. So you
take with water to prevent dehydration. As water leaves the body with a stool, it produces
a bowel movement in one to three days. So a little bit faster than the psyllium and
it should be given to everyone taking an opioid medication.
Okay. Another medication that's on the stimulant
side is senna and we use stimulants after fiber and stool softeners fail. But unfortunately
these are often used. And abused. Expect a bowel movement within 12 hours or overnight
and tablets and suppositories are available. And this is a bit of impatience. Obviously
the patients uncomfortable, they may have waited too long and they want something to
happen right away. The osmotic, again, there's two different sides to it. The polyethylene
glycol, which is the MiraLAX, it's gentle over the counter. Okay for children versus
the bowel prep before colonoscopy. So two very different uses of the same medication.
The polyethylene glycol produces a bowel movement within 72 hours for the MiraLAX,
but with the polyethylene glycol, [GoLytely] it happens very quickly. Need to be near a toilet, but
make sure the patients are drinking fluids. There is a risk of dehydration. Diarrhea
pathology is a change in the normal bowel movements characterized by unusually soft
or liquid stools, three or more times in 24 hours and but lasting less than two weeks.
So some of the common causes, maybe it's viral bacterial parasite, maybe it's another drug,
maybe it's food allergies, maybe it's GI conditions. Most important to know that a diarrhea issue
is not a disease. It's simply a symptom of something else going on.
Okay. So loperamide is brand Imodium. This is a
week over the counter opioid. It's for diarrhea, not of infectious origin, and reduces the
volume of discharge from ileostomies. Diphenoxylate with atropine, that's Lomotil.
It's a controlled substance. The atropine discourages abuse. Someone would be able to
crush the diphenoxylate and inject it. A high dose can bring on a morphine-like
response. So, want to be careful not to give too much of this, but again, this is
a step up from the loperamide if that's not working. Some kind of, if we had some
kind of overdose, we would treat it with naloxone.
Bismuth subsalicylate or Pepto-Bismol. So the OTC is available as liquid or chewable
tablets. It causes this harmless black stool and black tongue, but that might surprise
the patient if they're not familiar with it. And then children's Pepto is not bismuth.
subsalicylate. You can't give a salicylate to a child. So instead it's calcium carbonate,
which is basically Tums, but the manufacturer wanted to keep the Pepto name because it's recognizable.
So again, avoid in children due the risk of Reye's syndrome because of that salicylate component.
If it's infectious, like E. Coli, t's usually self-limiting, but
you may see ciprofloxacin or Cipro. There are new FDA guidelines regarding the
use for minor urinary tract infections and respiratory infections. But this is something
you might see. So again, if there's an infection, then we're going to give some kind of antibiotic
Emesis or vomiting. And usually, it's caused by the activation
of the vomiting center in the brain. So the indirect activation happens when the chemo
receptor trigger zone is first activated. And then this goes on to activate the vomiting
center. We're going to talk about three types of emesis. So the first is anticipatory before
the drug is given. So it's triggered by the memory of severe nausea from a previous dose
acute, which is minutes after giving it resolves within hours or then delayed and may take
more than a day after. And it appears 48 to 72 hours after chemotherapy. The first we'll
look at is a dopamine antagonist or an antiemetic. So it blocks dopamine, two receptors in the
CTZ or the chemo receptor trigger zone. It prevents activation and it's useful for emesis
caused by surgery or cancer, chemotherapy and toxins. Promethazine or Phenergan is
the brand and its contraindicated for children under two, but it is available as a suppository
if they're actively vomiting and they can't take something orally, but it can cause extra
pyramidal effects because of the lack of dopamine. Another drug, the 5HT3 serotonin
receptor antagonists are ondansetron, which is brand Zofran. This was first approved
for chemotherapy and it was really a breakthrough when it came out because we didn't have something
for chemotherapy-induced nausea and vomiting or CINV for regular emesis, and CINV
and it's available as a tablet orally disintegrating tablet that just dissolves on the tongue.
And then IV, it can cause prolonged QT interval and potentially Torsade de Pointes with
V-Tach, but generally the common side effects are just headache, dizziness, a little
diarrhea which are much less severe than nausea or vomiting that someone would
have. And then we'll just look at the auto immune disorders, just comparing ulcerative
colitis and Crohn's. So this GI, autoimmune pathology or irritable bowel disease,
inflammatory bowel disease, can be caused by an exaggerated immune response to the normal
bowel flora. So ulcertative colitis, it's an inflammation
of the mucosa and submucosa. The colon and rectum, can cause rectal bleeding and may require
hospitalization. Crohn's disease is characterized by transmural inflammation and it usually
affects the terminal Ilium, but it can affect all parts of the GI tract. We don't have a cure
for it, but we do have some treatments, the five treatments not curative,
so only relieve symptoms, the five amino salicylates like sulfasalazine and mesalamine.
So there's a salicylate component there. Glucocorticoids, steroids, hydrocortisone, dexamethasone, immunosuppressants.
So trying to suppress the immune system and the immune response. Azathioprine, cyclosporine
and methotrexate, antibiotics like metronidazole or ciprofloxacin and then immunomodulators
like infliximab, which affects the immune system. And let's look at that one. So infliximab
or Remicade, this is a monoclonal antibody, and we can see the ending -mab, a designed
to neutralize tumor necrosis factor Alpha TNF, a key immuno inflammatory modulator,
it's for moderate or severe Crohn's, and it has to be given by IV infusion leading
to some infusion reactions. And then we have an increased risk of lymphoma. And that makes
sense. When you're messing with the immune system, you're reducing the immune response.
Note, we have to screen patients for tuberculosis and other infections before starting the infusion,
because of that immune suppression. And then infusion reactions happen every time.
So you can prevent it hopefully after the first infusion.