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pharmacologyGI
Peptic ulcer
• discontinuity of the mucosa of the GIT that is usually deep penetrate muscularis mucosa
• This is one of the features to differentiate ulcers from erosions.
• Remember that mucosa is made up of 3 parts :• 1. The epithelial lining → which varies as you go
through the duct• 2. The lamina propria → loose areolar
connective tissue.• 3. Muscularis mucosa →the small layer which
made from inner circular, outer longitudinal.for secretion.
jejunum, and ileum ??
• Jejunum used to be affected in the past because the treatment of peptic ulcer was mainly surgical.
• particularly after complications (when there is fibrosis of duodenal ulcer or closure of pyloric antrum), and therefore one of the usual operations that was done is the gastro-jejunustomy; when we connect the jejunum to the stomach, so this was the cause of the jejunual ulceration
stromal ulcer (ulcer that occur at the site of the anastomosis).
Acute ulcer shows no evidence of fibrosis.
Due to NSAID Repeated use of high doses of corticosteroids
Chronic renal failure , hypercalcemia:there’ll be more (H) ions secretions toreplace the calcium lead to higher acidity
psychological stress
prostaglandins
• the mucosa is protected by the layer of mucus. You can see that the PH in the lumen is 1-2, while at the level of the mucosa is almost 7 which means that it is almost protected whenever there is mucus and bicarbonate (this is done by prostaglandins).
- extend from muscularis mucosa all the way to lamina propria
- In each pit > you will see 5-7 gastric gland open there
Regenerative (adult stem cell):
- distinguished usingelectron microscope.- quiescent.- heterochromatic(coiled)ncleus, but they are very rich in RER.
Parietal (Oxyntic):- Pyramidal in shape.- approximately half of the size of this cell is mitochondria (eosinophilic)
Chief (Zymogenic):-Produce zymogen>proenzyme (pepsinogen & g. lipase).-Columnar cells with basophilic (RER)-Mostly in the lower part of the gland
small pits in the cardia >>>>>> go to the body >> pits will grow larger >>in Pyloric region >> the pits are the longest.
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Surface epithelial lining cells
central rounded nucleus.
DNES Cells (diffuse neuro-endocrine system cells )
- Diffuse : along the gut : from the esophagus , more in the stomach, more in the small intestine, even in the large intestine>>so diffuse ).- Or APUD cell ) عبود amine precursor)<<<<) خاليا
uptake and decarboxylation) “old name”.- the only unicellular endocrine gland - They secrete products into the blood.- 13 different types along the GIT.- * Most common is G cells.- Since they are endocrine, they are Located in the
base of the gland( most basal part).
• H.pylori (-) is the main cause or the etiologic factor .
• most of the patients who are having duodenal ulcer in 95% of them H.pylori is present, while those of gastric ulcer only about 70% do have H.pylori and the other 30% are usually explains the NSAID uses.
Peptic ulcer
• non–spore forming bacilli, Microaerobic.
• the flagella will help H.pylori to dig deep in the mucosa to have a more alkaline media in order to resist the acid distraction .
H.pylori has certain enzymes and cytotoxins that affect the mucosa which result in distraction
The urease enzyme of H.pylori is quite useful clinically, because it will help us to diagnose or to detect the presence of H.pylori by radioactive carbon
produce phospholipases that destroy the bicarbonate
-fastidious slow-growing organism.
• patient has received a radiolabeled urea then he will expire radioactive carbon which means that the patient has H.pylori.
• the ammonia will help H.pylori to survive the acidic environment of the gastric mucosa.
(urease Will increase the PH this allows the bacteria to colonize the mucosa). only colonize stomach “especially in antrum”.
• Also endoscopy test.
Both have high sensiti
vity and specificity.
• Breath test is more likely to be used in hospitals as a follow up treatment.
• to diagnose the patient we use endoscope, if the ulcer is duodenal or gastric, f it is gastric; a biopsy should be taken because of the possibility of malignant ulcer.
• Also fecal antigen test can be used because it is cheap as well as serology tests: Poor in children, in elderly, for epidemiologic or surveillance tool.
• Blood culture has no role in diagnosis because it’s not invasive.
Also it has
• VacA (vaculating toxin):destructing mucosal barrier.
• Cag A (cytotoxin Antigen A)
History about H.pylori
• (they discovered it in 1979, in 1982 it was approved and until 1995 to make people accept the idea of infection).
• This is a picture to show you how H.pylori can result in excess acid secretion,
• you can see the disruption of somatostatin secreting cell, this will lead to reduction of somatostatin hormone, then this will lead to increase in gastrin secretion which eventually increase acid production that will reach the duodenum to cause ulcerations.
(-) inhibit gastrin secretion
• H.pylori infection is more common in industrialized countries than developed countries, due to oral hygiene or the type of food.
histologically identical to the fundus
pepsinogen I
mucus secreting cells.Intrinsic factors
more
Pathology and Clinical features
• This disease is characterized by lymphocytic & plasma cell infiltrate in lamina propria.
• cryptitis when the lymphocytic infiltrate is in the crypt wall
• crypt abscess when the lymphocytic infiltrate is inside the crypt (more sever).
Many lymphoid tissues in the mucosa of the stomach, there is some sort ofdestruction in the crypts. The overall architecture of the mucosa is disrupted.
Treatment
• Relief symptoms (pain & dyspepsia): Some patients have H.pylori without peptic
ulcer disease or some patients have no H.pylori but they suffer from peptic ulcer symptoms (dyspepsia, heartburn….), so these patient have non-ulcer dyspepsia usually occurs in obese people and people who eat a lot.
• Heal ulcer. • Prevent recurrence In the past the recurrence was very great
because the only treatment was H2-blockers but nowadays the recurrence rate has been reduced
recurrence may occur especially in patients who have very severe form of excessive acid secretion as in Zollinger–Ellison syndrome.
Treatment Cont.
• Prevent complications (hemorrhage and perforation).
Nowadays there is no surgery for peptic ulcer, unless there is hemorrhage or perforation.
due to the presence of effective treatment for peptic ulcer, therefore the patient will not develop any complications.
• Eradicating H. pylori and Restoring balance
Treatment Cont.
• 2 antimicrobial agents + acid suppressor (proton pump inhibitor)
clarithromycin + Amoxicillin or metronidazole
This treatment usually takes 7-10 days some patients may take it for 2 weeks to eradicate the infection .not healing the ulcer.
• we should take another course of proton pump for one month or one month and a half to heal the ulcer
SIDE-EFFECTS OF H. PYLORI ERADICATION THERAPY
• 1- Diarrhea followed by the use of antibacterial agent specially
this might progress to pseudomembranous colitis.
(The treatment of pseudomembranous colitis is
penicillin(amoxicillin
Cl.difficile
vancomycin or metronidazole
• 2-Metallic taste :by Metronidazole Also the patients how take alcohol with
metronidazole they will have Flushing and vomiting (disulfiram-like reaction).
If chronic gastritis isn't treated well, it will progress to peptic ulcer disease; but if it's left untreated, there will be an expansion of the lymphoid cells and it will progress to gastric lymphoma.(it's the only type of lymphoma that can be treated by antibiotics)but in late stages, it will be resistant.
chronic gastritis• we look for five histologic features; chronicity,
activity” intra-epithelial lymphocytic infiltrate”, atrophy, intestinal metaplasia (presence of goblet cells in the stomach )and dysplasia.
• Dysplasia: we look whether it's present or not.
Why gastric atrophy, intestinal metaplasia?When there is an atrophy The intestinalmetaplasia will take place Try to compensatefor the loss of glandular epithelium.
Drugs Affecting Gastric Acid Secretion
by dissociation of carbonic acid (H2CO3)
• For those that stimulate acid secretion, when they are activated they will activate protein kinase which initiate the action or the function of the proton pump (which is the main pump that secrets acid into the lumen), this is why the proton pump inhibitors are the best suppressor of acid secretion.
• there is some sort of interaction between these receptors (they can stimulate each other).
Weak base
• They are effective in neutralizing the acidity, but clinically we prefer Magnesium hydroxide [Mg(OH)2].and Aluminum hydroxide, because their neutralization is acceptable.
• unlike Sodium bicarbonate[NaHCO3] with HCl to form CO2, it neutralizes the acid to a very high PH very rapidly, and usually this result in CO2 production and therefore gases will occur in the abdomen, as well as Na will be absorbed into the body causing water to be absorbed, and this may lead to problems in patients with heart failure, kidney problems or hypertension.
Simethicone
• Generally, these drugs are used in combinations.
because Aluminum compound lead to Constipation(Air Condition), while Magnesium compound may lead to Diarrhea (Must go to toilet)and therefore to overcome this effect either constipation or diarrhea they are usually given in combination.
• Calcium carbonate is also good but the problem with it is that if it’s taken with excess milk in some individuals, it results in a condition or a syndrome called milk-alkaline syndrome, where the patient feels headache with nausea and abdominal discomfort and vomiting so it is not well-recommended.
The indications
• 1- To relieve pain. • 2- Promote healing of duodenal ulcer. • 3- To prevent stress ulcers. • 4- Prevent hyperphosphatemia in patients
having kidney failure .(aluminum hydroxide, because in the intestine it
will be converted into aluminum phosphate, so it will drain all the phosphate into the stool), so this will lead to hypophosphatemia.
“Nexum”
MOA
• have a short half-life but they have long duration of action, because they irreversibly block the activity of the proton pump enzyme (H/K ATPase). unlike H2 blockers, which are competitive in
their activity.
• The coating is removed in the alkaline duodenum,and the prodrug, a weak base, is absorbed and transported to the parietal cell.
• There, it is converted to the active drug and forms a stable covalent bond with the H+/K+-ATPase enzyme.
by combining with their SH group.
Sulfonamide
• It takes about 18 hours for the enzyme to be resynthesized, and acid secretion is inhibited by more than 90% during this time.
• involving the basal as well as the stimulated (basal stimulation mainly occur at night).
The indications: • 1- Definitely to treat peptic ulcer disease • 2- Stress ulcer whether treatment or prophylaxis. • 3- Gastroesophageal reflux disease (GERD). • 4- Erosive esophagitis. • 5- Prevention of NSAID induced ulcers. • 6- Hyper-secretory states () they are more effective than H2 blockers because the acid
secretion is very high so it need a very effective treatment.
Zollinger-Ellison syndrome
• Proton pump inhibitor is by far better than either of the two so they are preferred to treat GERD and erosive esophagitis.
acid is required for its absorption in a complex with intrinsic factor.
• Omeprazole and Esomeprazole are enzyme inhibitors.• they will interfere with the metabolism of certain drugs,
particularly those which have narrow therapeutic index (e.g. Diazepam, phenytoin and warfarin).
• because they inhibit the enzyme if they are given with clopidogrel (anti-platelet agent) it results in decreasing its effect; because clopidogrel is a prodrug so it has to be converted to its active drug in order to be effective.
• so patients with cardiac problems who receive PPI with clopidogrel are more liable for cardiac attacks or ischemic attacks.
zantac
famoder
• They competitively block histamine (H2) receptors which means that one single dose may not be enough.why?? reversible
• so the duration of action will be shorter than that of PPI; the general protocol of the treatment by these drugs was by giving them 4 times a day.
• Nowadays, they reached a conclusion that the main cause of the ulcer is the secretion that occurs during night and therefore if these drugs are prescribed, they are given usually at supper & bedtime to suppress the basal acid secretion.
• The other difference between PPI and H2 blockers is the incidence of recurrence. In the past, when we were using H2 blockers the incidence was much greater than the incidence nowadays with PPI, probably it is not due to the difference of their mechanism of action, but it is due to the fact that we are eradicating the causative organisms and therefore the recurrence rate has been greatly reduced.
The indication
• Promote healing of duodenal and gastric ulcers. (recurrence is more common)
• Provide long-term treatment of pathological GI hyper secretory conditions.
Some schools think that in cases of hyper secretory conditions, if we would like to use the drug for a very long time, they prefer the H2 blockers over PPI; because the side effects and interactions of H2 blockers were very well known, but PPI when they are introduced, their side effects and interactions were not be known at that time.
• Reduce gastric acid production and prevent stress ulcers. (PPIs are preferred).
The use of these agents has decreased withthe advent of PPIs
• Interaction = same PPI
Patients with NSAID-induced ulcers?? PPI
Adverse reactions:
• Headache, bowel upset, nausea, vomiting (all H2 blockers can cause them).
• CNS effects; restlessness, confusion, convulsions in elderly patients especially If these drugs were given in excess or IV.
• done by cimetidine only : Gynecomastiain male, galactorrhea(continuous
release/discharge of milk)in female, and reduced sperm count (this is due to anti-androgenic effect of cimetidine) so it should not be given to health adult male patients practically if they are newly married or they are going to get married.
Mucosal protective agents
Sucralfate
• It’s a complex of aluminum hydroxide and sulphated sucrose, so because it has aluminum hydroxide, it can prevent the absorption of antimicrobial agents.
بظل , جلي انهو ما زود منالصق
(used in travelers’ diarrhea)“cholera-like illness,”
Misoprostol
M3
M1
