Pharmacology

Gastroesophageal Reflux Disease (GERD)

☆ Overview:-
• Gastroesophageal reflux is the involuntary movement of gastric
contents to the esophagus.

• Gastroesophageal reflux is a normal physiologic phenomenon

experienced intermittently by most people, particularly after a meal.

• Gastroesophageal reflux disease (GERD) occurs when the

amount of gastric juice that refluxes into the esophagus exceeds the
normal limit, causing symptoms with or without complications.

• Patients with GERD can exhibit various symptoms, both typical

and atypical:
1) Typical symptoms include heartburn, regurgitation & belching.
2) Atypical symptoms include non- cardiac chest pain, asthma,
pneumonia, hoarseness and aspiration.

☆ Definition:-
• GERD should be defined as; symptoms or complications resulting
from the reflux of gastric contents into the esophagus, oral cavity
and/or lung.

• GERD can be further classified as

- Non-erosive reflux disease; Symptoms without erosions on
endoscopy.
- Erosive reflux disease; Symptoms with erosions on endoscopy.

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☆ Pathophysiology:-
• Dysfunction of lower esophageal sphincter through various
mechanisms but the most common is transient relaxation of lower
esophageal sphincter .
• Impaired esophageal clearance.
• Delayed gastric emptying (decreased gastric emptying rate).
• Hiatal hernia.
• Obesity.

☆ Causes :
• A functional ( transient LES relaxation) or mechanical (hypotensive
LES) problem of the LES is the most common cause of GERD.
• Transient relaxation of the LES can be caused by:
1- Foods/drinks; Fatty meal, Coffee, Cola, Alcohol, Peppermint
Chocolate, Garlic, Onion.
2- Medications; Nicotine, Nitrates, Calcium Channel Blockers,
Anticholinergics, Tetracycline, Theophylline, and Alpha and
Beta-blockers and Benzodiazepines.
3- Hormones; Dopamine, Estrogen and Progesterone.

☆Notes :
 The most common cause is opening of lower esophageal sphincter
therefore we can use drugs that close LES but this method is
difficult and there are some drugs that are weakly used in and
known as Anti-dopamine such as Metoclopramide which
increases the lower esophageal tone contraction and increases
emptying rate.
 In GERD we have to decrease HCL secretions either 50% or
90% depending on the severity of disease so we use proton pump
inhibitor as we treat peptic ulcer until the time of operation to close
the LES.
 Drugs that increase esophageal clearance acts on serotonin .

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☆ Prokinetic Agents :
• They are drugs that increase GIT motility such as ;
- Cholinergics.
- Drugs that acts on serotonin.
- Anti-dopamine.
• Metoclopramide and Domperidone both are anti-dopamine and
are the best drugs used in the treatment of nausea and vomiting by
acting on chemoreceptor trigger zone (CTZ) on the brain. They
help strengthen the lower esophageal sphincter (LES) and cause the
contents of the stomach to empty faster.
☆ Direct Irritants to the Esophageal Mucosa :
1- Foods;
 Spicy foods, Orange juice, Tomato juice and Coffee.
2- Medications;
 Bisphosphonates; are the commonest drugs in the treatment of
osteoporosis such as Alendronate (Fosamax) which is more
commonly used than tetracycline.
 NSAIDs also cause irritation.
 Iron causes GIT irritation and in high amounts it may cause
perforation resulting in electrolyte leakage and hypovolemia.
 Quinidine is a plant origin drug derived from cinchona plant.
 Potassium chloride.
 The most dangerous drug that cause irritation to esophageal
mucosa is Alendronate.
☆ Diagnosis:-
- Patients symptoms and history: Typical symptoms (heart burn
and regurgitation) is correct in 70% of patients.
- Endoscopy.
- Esophageal manometry which measures the acidity.
- Ambulatory PH monitoring.

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☆ Treatments:
• Goals;
1) Decrease or prevent symptoms.
2) Decrease frequency or recurrence and duration of
gastroesophageal reflux.
3) Promote healing of the injured mucosa.
4) Prevent the development of complications.

• Therapy is directed at;

1- Decreasing the acidity of the reflux.
2- Decreasing the gastric volume.
3- Improving gastric emptying.
4- Increasing LES pressure.
5- Enhancing esophageal clearance.
6- Protecting the esophageal mucosa.

☆ Lifestyle modifications :
1- Avoid foods/drinks may reduce LES pressure.
2- Avoid foods/drinks may cause irritants to the esophageal mucosa.
3- Reduce fat intake (high fat meals slow gastric emptying).
4- Avoid eating 2-3 hours before bedtime.
5- Remain upright after meals.
6- Weight loss if overweight.
7- Reduce or discontinue nicotine use in tobacco products.
8- Elevate head of bed.
9- Avoid tight-fitting clothing (decreases intra-abdominal pressure).
10- Avoid medications that may reduce LES pressure, delay gastric
emptying, or cause direct irritation.

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☆ Pharmacological therapy :
• Patients may benefit from lifestyle modifications but most will
require pharmacological therapy to control symptoms.
• Pharmacological options;
1) Antacids.
2) Acid-Suppression Therapy, such as
a) H receptor blockers ; They block H2 receptors in parietal
cells so decrease acid secretion for 60-70% and used for mild
GERD & peptic ulcer.
b) Proton Pump Inhibitors (PPIs); The most powerful and most
commonly used agents. They decrease acid secretion for
about 90% and used in severe cases.
3) Promotility (Prokinetic) Agents; such as Cisapride,
Metoclopramide and Bethanechol.
4) Anti-reflux surgery is the most dangerous.

Antacids .
Aluminum Hydroxide Magnesium Hydroxide
Calcium carbonate Sodium Bicarbonate
• We have to combine them to get their trade name.
• Antacid are weak bases that react with gastric acid to form water
and a salt to diminish gastric acidity.
• Antacid products are available OTC in a wide variety of
formulations (capsules, tablets, chewable tablets and suspensions).

o Mechanism of action; Antacids reduce pepsin activity ,because

pepsin is inactive at PH greater than 4.
Neutralizing gastric aciddecrease pepsinincrease LES pressure.

o Advantages; Rapid onset of action.

o Disadvantages; Short duration of action.
o Therapeutic uses: Symptomatic relief of peptic ulcer disease and
GERD. (First line in mild symptoms).
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o Side effects :
1) Constipation (Aluminum).
2) Diarrhea (Magnesium).
3) Accumulation of aluminum and magnesium in renal disease
(with repeated dosing).
4) If used for a long time they will increase HCL secretion so
should be used for a short time.
•Aluminum Hydroxide it contains three positive charges therefore
it’s less absorbed and cause constipation. It is dangerous for patients
with renal problems.
•Magnesium Hydroxide it causes watery diarrhea (stoolwatery).
•Maalox® and Mucogel®;
-Combination of Aluminum Hydroxide + Magnesium Hydroxide.
-It’s available as oral tablets or chewable tablets.
•Calcium carbonate; used as calcium supplements for the treatment
of osteoporosis.
•Sodium Bicarbonate it absorbs sodium and not suitable for patients
with hypertension and heart failure.
•The reaction of acids with bases results in the production of CO2 and
other gases that are treated by anti-refluxants.
•Antirefluxants:Simethicone (Maalox plus) or Dimethicone
(Epicogel).
•Gaviscon; it contains alginic acid and sodium which forms a
physical barrier ( increase viscosity of fluids) therefore it decreases
gastric reflux and is not preferred for long term use in patients with
hypertension, heart failure and in pregnancy.
o Drug interactions :These drugs contain two or three positive charges
that interact with other drugs and this interaction is known as chelation
1) Chelation; reduce absorption of Fluoroquinolones and
Tetracyclines.
2) Increases pH (decrease acidity) so reduce absorption of the
following drugs : Ketoconazole, Itraconazole, Iron, Atazanavir,
Delavirdine, Indinavir and Nelfinavir.
3) Increases pH; reduce absorption of, Raltegravir and Saquinavir
(leading to potential toxicity).
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Acid Suppression Therapy .
H2 Receptor Antagonists(H2RAs) .
- The H2 receptor antagonists (HIRAs) reversibly inhibit histamine-
2 receptor stimulatory effect of Histamine on gastric parietal cell,
decreasing the production of gastric acid
(decrease acid secretion for 60-70%).
- Also called antihistamine as Zantac which was withdrawn
recently.
- Four drugs which are rapidly absorbed.
Cimetidine Ranitidine
Nizatidine Famotidine
1- Cimetidine (400 mg twice or 800 mg once) is largely replaced by
other H2 receptor blocker due to it's side effects (increase prolactin
& anti-androgen).
2- Ranitidine 150 mg twice or 300mg once (zantic) works like
cimetidine, but with less side effects, it has been withdrawn from
Yemen.
3- Nizatidine like ranitidine (150mg twice or 300mg once).
4- Famotidine: the most potent. (20mg twice or 40mg once)
 Note: Nizatidine & Famotidine are OTC.
o Mechanism of action:
 Reversible inhibition of histamine receptors in parietal cells
leading to decrease influx of Ca+2 & decrease efflux of HCL
(mainly decrease hydrogen (H+) that interacts with CI).
 Blocking H+ in parietal cells inhibits 50-60-70% of total day
acid secretion.

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o Therapeutic uses :
1- Peptic ulcer disease (duodenal & gastric ulcers):
 If peptic ulcer is painful & intense use PPI.
 If peptic ulcer is moderate use H2RAs.
2- In acidity or ulcer caused by NSAIDS.
3- Sometimes used for Zollinger Elusion syndrome (ZES) which
is a gastrin-secreting tumor of pancreas that stimulate acid
secreting cells of stomach. Most used drugs for ZES are (PPI).
4- For GERD (gastroesophageal reflux disease):
 If GERD is slightly painful (mild) and occur sometimes,
the patient shouldn't use drugs daily.
 If GERD is moderately painful use H2RAs.
 If GERD is severely painful use (PPI).
5- In non-ulcer dyspepsia;
(commonly used for dyspepsia not caused by peptic ulcer).
6- For acute stress ulcer: Because stress plays roll in problems of
GIT either colon or stomach problems.

o Side effects :
 H2 antagonist are extremely safe drugs except cimetidine (which
currently isn't used in many countries).Ranitidine isn't used in
many countries as well but generally, these drugs are safe.
1- Side effects occur in more than 3% of patient are diarrhea,
headache, fatigue.
2- Colonisation by clostridium difficile.
3- Cimetidine inhibits binding of Dihydrotestosterone to
androgen receptors (Anti-androgenic effect) and increase
serum prolactin, long term use may cause:
 Impotence in male (Anti-androgenic effect).
 Gynecomastia in male (Increase prolactin).
 Galactorrhea and amenorrhea in female (Increase prolactin).
 H2RAs are category B in pregnancy.
 NOTE: Antacids are safer than H2 blockers so they are category B
especially Maalox in women with HTN, but in pregnant women we
don't use them unless they are needed.
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Proton Pump Inhibitors .
 These drugs work on the parietal cells in stomach either on pump
itself (direct work on pump) & are called proton pump inhibitors
(proton means hydrogen in cells).
 These pumps have enzyme called Hydrogen Potassium ATPase
which is responsible for K influx and H efflux,
so PPI inhibit this action.
 The most commonly used drugs for GERD and peptic ulcer
diseases are PPI (Hydrogen Potassium ATPase Inhibitors)also
called proton potassium inhibitors or hydrogen (proton)pump
inhibitors.
 When this enzyme is inhibited, it returns to work after 18 hours.
 PPI decrease absorption of vitamin B12.
 PPI decrease secretion of HCL directly.

Omeprazole Esomeprazole Lansoprazole

Dexlansoprazole Pantoprazole Rabeprazole
1- Omeprazole (Lomac) ;liver microsomal enzyme inhibitor ,it is a
common drug (20 mg or 40mg) .
2- Esomeprazole (Nexium)20 mg to 40 mg orally or vial.
3- lansoprazol (Lanzor-original name) 15 mg - 30 mg orally or vial
its very expensive drug, 14 tablets have price of 9000 R.
4- Dexlansoprazol: 50mg-60mg (New drug).
5- Pantoprazol (Pantozal - original name) 20mg- 40mg orally or
Vial.
6- Robeprazol (Pariet-original name) attributed to parietal cells 10
mg-20 mg.
o Mechanism of action :
- Proton pump inhibitors blocks proton pump by forming a stable
covalent bond (irreversible) with the H/K-ATPase enzyme.
- At least 18 hours are required for resynthesized of new H/K-
ATPase enzyme, and acid secretion is inhibited during this time.
• Note : They may decrease the absorption of useful substances as
iron &vitamin B12.
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o Pharmacokinetics :
 All PPI are effective orally.
 All PPI are prodrugs formulated as acid-resistant enteric coated to
protect them from premature degradation by gastric acidity.
 The coating is removed in the alkaline duodenum.
 All PPI should be administrated approximately 30-60min before
meal
 Serum half life is 1.5 hours but acid inhibitions lasts up to 24 hours.
 In standard doses PPIs inhibit 90% of 24hours acid secretions.
 Found as oral tablets that disintegrates (break down to small pieces)
 Metabolized in liver.
 Long duration (18 hours).
 In GERD used before the main meal (usually breakfast) once a day.
 In H.pylori used twice a day (Use PPI & H.pylori drugs).
 I.V in vial.
o Therapeutic uses :
1- GERD (Gold Standard) mostly used.
2- Peptic ulcer.
3- H.pylori associated ulcer ; PPI+ Amoxicillin + clarithromycin.
4- NSAID induced ulcer.
5- Prevention of re-bleeding from peptic ulcer.
6- In non-ulcer dyspepsia.
7- Zollinger Elusion syndrome (ZES).
8- Acute stress ulcer in severe cases.

o Side effects :
1- Diarrhea, headache & abdominal pain are reported only in 1-5%
of patients.
2- Pneumonia respiratory and enteric infections.
3- Clostridium difficile infection.
4- Long term use of PPI (especially omeprazole) have been
associated with several cases of acute interstitial nephritis +
induce cancer.
5- All PPI are pregnancy category B except omeprazole category C.
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o Drug interactions :
1- Drugs with PH dependent absorption.
2- Inhibition of CYP450.
3- Inhibition of CYP2C19:
Clopidogrel ; is a prodrug that requires CYP2C19 so there is a
possible interaction between Clopidogrel and Omeprazole.
4- High dose I.V methotrexate.

Promotility (Prokinetics) .
• Promotility (Prokinetic) agents are a type of drugs which enhance
gastric emptying and enhance intestinal contractions.

Metoclopramide .
• It is a peripherally and centrally acting dopamine antagonist.
o Mechanism of action :
1- Increase LES pressure and accelerates gastric emptying.
2- Antiemetic properties: block stimulation of the medullary
chemoreceptor Trigger Zone (CTZ) by dopamine.
 Note : Dopamine receptors are not only found in CTZ but also in
basal ganglia ,hypothalamus & limbic system so any increase or
decrease in dopamine may lead to various problems.
o Therapeutic uses :
1- Nausea and vomiting.
2- Delayed stomach emptying.
3- Migraine headaches.
o Side effects:
1- Extrapyramidal symptoms.
2- Dizziness. 4- Movement disorders.
3- Fatigue. 5- Hyperprolactinemia.
Cisapride .
- Act as serotonin 5-HT4 receptors agonist (Increase motility).
- It is not common and it causes arrhythmia.

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Bethanechol .
- It is a cholinergic drug.
- It is used in postoperative non-obstructive GIT and urinary
tension.
- Side effects include diarrhea, blurred vision and may increase
gastric acid production.

Important Notes :
1- NSAID induced Ulcer :
 Most NSAIDs that induce Ulcer > ketoprofen, ketrolac.
 Least NSAID that induce Ulcer > ibuprofen.
 Misoprostol is the drugs of choice in NSAID induced Ulcer, but
in Yemen we use H2 blocker or PPI.
 Misoprostol: decrease HCL secretion &mucus production.
2- Acetylcholine works on M1(Type Gs)which releases Ca leading
to efflux of H resulting in increase HCl secretion .Therefore drugs
that inhibit this action are called M1 antagonists such as
Pirenzepine and Telenzepine. These drugs are not common.

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Peptic Ulcer
☆ Overview:-
• Peptic Ulcer Disease (PUD) or Peptic Ulcer,
is a break in the lining of:
 Stomach (gastric ulcer), or
 First part of small intestine (duodenal ulcer), or
 Lower esophagus (esophageal ulcer).

• It can be an ulcer with Helicobacter Pylori or ulcer without

Helicobacter Pylori.

• Ulcer without H.pylori can be treated with the previous three

groups that we studied.

• Ulcer with H.pylori can be treated by :

1- Antimicrobial agents.
2- Antacids.
3- Acid suppression therapy (H2RAs and PPI).
4- Prostaglandin .
5- Mucosal protective agents (Form a physical barrier).
☆ Most common symptoms :
1- Epigastric pain (shortly after meal) is known as gastric pain.
2- Eligastric pain ( 1-3 hours after meal) is known as duodenal
pain.
☆ Complications :
1- GI bleeding .
2- Gastric outlet obstruction (narrowing of pyloric canal).
3- Perforation (Hole in the wall of GIT).
4- Haematemesis (Blood vomiting).
5- Melena (Blood stool).

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☆ Causes :
1- H.pylori.
2- NSAIDS.
- NSAIDs that inhibit COX-1 reduce beneficial effects of PGs in the
GIT, resulting in increased gastric acid secretion and increased
risk for GI bleeding and ulceration.
- NSAIDs that inhibit COX-2 cause less peptic ulcer but more
cardiovascular side effects.
• Relative risk for GI complications of some commonly used
NSAIDs;
- Low-risk drugs; Ibuprofen, Aceclofenac, Diclofenac,
Nabumetone and Celecoxib.
- Moderate-risk drugs; Naproxen and Meloxicam.
- High-risk drugs; Piroxicam, Indomethacin, Ketoprofen and
Ketorolac.
3- Stress ulcer.
4- Lifestyle factors : smoking & caffeine.
5- Hypersecretory states; Zollinger Ellison Syndrome.
6- Others: Genetics, hypercalcemia, infections (cytomegalovirus,
herpes simplex, tuberculosis)

☆ Diagnosis :
Test for H.pylori infection by using endoscopic or non-endoscopic
test.

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☆ Drugs that are used in Peptic Ulcers Disease (PUD):
1- Antacids.
2- Acid-Suppression Therapy;
A) H2-receptor Antagonist.
B) Proton pump inhibitor (PPI).
3- Antimicrobial agents.
4- Prostaglandins:
 Misoprostol (Cytotec) :
- Prevent NSAID-induced gastric ulcer.
- Oxytocic properties.
- Off-label uses:Labor induction, abortion, miscarriage ,
postpartum bleeding.
5- Mucosal Protective Agents:
They form a physical barrier that protects ulcer from gastric
acid.
 Sucralfate:
- Sucrose sulfate-aluminum complex.
- Not used in patients with renal disease.
- Form a physical barrier that protects ulcer from gastric
acid.

o Therapeutic uses :
1- Duodenal ulcer.
2- Prevention of stress ulcers.

o Side effects :
 Doesn't prevent NSAID-induced ulcers.

 Bismuth Subsalicylate:
- Anti-Inflammatory and bacterial action and antidiarrheal.
- Combined with other drugs for the treatment of H.pylori.

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Thank You
Doctor /Sadam Fadeel.
Done by /Hashem Waleed

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