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Lecture 15
Last lecture we said in regard to GERD there are three different
clinical presentations:
1. Classic (Typical ) GERD
2. Extraesophageal (Atypical) GERD
3. Complicated GERD
And we also discussed the signs and symptoms of each one of
them.
- Classic GERD presentations:
1. Substernal burning (heartburn) and/or regurgitation: the
most common symptoms of GERD but alone they are not
specific and not necessarily giving indications for GERD.
2. Postprandial: the symptoms are aggravated by meals, i.e.
patients experience more pain after meals.
3. Aggravated by change in position.
4. Quick or prompt relief by antacids
If these four criteria presented in the patient, we should start
empiric therapy without the need of diagnostic tests to confirm
GERD.
There are indications for the diagnostic tests for GERD but if the
patient already has classic GERD presentations we directly start
the treatment and its nature will depend on the severity of the
condition/symptoms.
Extraesophageal (Atypical) GERD: the symptoms are
exceeding the stomach and esophagus, extending to pulmonary
symptoms, ENT symptoms, chest pain and dental erosion.
Dental erosion: Discoloration of teeth due to the presence of
acid in the dental cavity. (Look at the figure in the slides)
So, even though GERD cannot be confirmed solely based on
clinical symptoms, the guidelines recommend starting clinical
empiric treatment based on the symptoms.
Q: When to perform diagnostic tests?
1.
2.
3.
4.
Uncertain diagnosis
Atypical symptoms
Symptoms associated with complications
Inadequate response to therapy: the symptoms did not
alleviate to the required acceptable level.
5. Recurrent symptoms: patient adhered to his
medications, and the symptoms alleviated, but when he
stopped taking his medications a quick relapse
happened.
 Quick relapse could indicate more advanced phase of
the disease
6. Prior to anti-reflux surgery / Fundoplication
Diagnostic tests for GERD:
1. Barium swallow :
Or called Barium emptying, ideal test if the patient has
structural changes like narrowing in the esophagus.
Barium dye can adequately show structural changes like:
Stricture, Mass, Bird’s beak (narrowing in the esophagus
with curvature) and Hiatal hernia.
Limitations: if there were erosive esophagitis
(inflammation in the esophagus) or change in the type of
cells like in the case of Barrett’s esophagus with NO
structural changes, they cannot be detected by Barium
imaging.
2. Endoscopy: - direct test - allows for visual inspection of
the esophageal mucosa so if there is inflammation
(reddish area) it can be detected easily with endoscopy.
For this reason it is considered the goal standard test and
the most significant test.
Indications for Endoscopy:
1. Alarm symptoms
2. Empiric therapy Failure (any signs or symptoms of GERD
complications).
3. Preoperative evaluation
4. Detection of Barrett’s esophagus
Actually, they are the same indications of the diagnostic tests
mentioned earlier.
Although in practice, unfortunately the patient goes for a
specialized doctor and will be directly advised for endoscopy
which is really not necessary in probably the majority of the
cases.
A student said that in Istishari hospital, they do a test in which
they take sample from saliva and measure the concentration of
Sodium Bicarbonate which is indicative for body reflex
mechanism for excess acid secretion.
But the Doctor said it is not going to be neither sensitive nor
accurate test. Otherwise, it would have been added to the
guidelines for the management of GERD.
 It is indirect test
 Concentration of Sodium bicarbonate in saliva is high
in case of GERD in order to neutralize the acidity.
Inflammation in the esophagus is classified /categorized into
four grades. (Refer to the table 32 -3 in the slides).
Grade 0: Normal esophageal mucosa /no inflammation.
Grade 4: The worst and most severe inflammation, pronounced
structural changes in the patient.
3. Ambulatory pH monitoring: we have to know the concept
only.
A tube on its tip there is small probe which can measure
pH value in the lower esophagus area. Incubation is made
through the nose not the mouth in order to prevent gag
reflux and then it sends signal regarding the pH readings
to the detector which is normally handled at the patient
body. (Look at the figure in the slides). When the acid get up
to the lower esophagus, the pH will become acidic “below
4”. Because the patient can use his mouth during the test,
sometimes it can be done for 48 hours instead of 24
hours. For that reason it is called ambulatory, the patient
is not obligated to sit on the bed all the time during the
test.
The main goal of that test is to determine the period of
time of the day during which the most exposure to acid
happened, because in some severe conditions, the patient
experience pain throughout the whole day, but the actual
contact between the esophageal mucosae and gastric
content is few hours, so it determines the actual time in
which the contact / regurgitation happened regardless of
heartburn and other symptoms.
Can be used in uncertain diagnosis if we are unsure if the acid
reaches the esophagus/acid reflux.
Limitation: doesn’t give visual inspection and examination >>>>
limited / slight use.
Refer to the figure in the slides
In GERD curve, we can see that the time of the day during
which the pH was below 4 is from 11:30 AM to 1:30 AM. This
indicates excess acidity in the lower esophagus resulting from
contact with gastric contents.
Notice in the normal curve there are deep regions during
which the pH is below 4 and this is normal transient condition
and depends on several factors like the the type of meals :fatty
meals, heavy meals , spicy meals etc.
GERD disease differs from normal reflux in the duration and
severity of the condition, pain throughout the day, and as it
gets worse it starts to affect the quality of patient’s life.
So, the pH value remained lower than 4 from 11:30 AM to 1:30
AM and this is not transient regurgitation! It is a persistent
contact which is indicative of GERD, and this would confirm
GERD if it was uncertain diagnosis.
 The condition is more severe and worse for the patient
If the time period during which the pH value below 4 was
longer.
 Ambulatory 24 hour pH monitoring is a sufficient test to
confirm GERD in a particular patient but alone doesn’t
give us sufficient information about the severity of the
case. It is true that the severity depend on the duration
of time during which the pH value was below 4 but if we
have two patients the pH value was below 4 for 2 hours ,
we can’t say that they have the same severity , maybe
one will be more severe than the other . So alone it is
insufficient to evaluate the severity.
4. Esophageal Manometry: The main goal of this test is to
assess the peristaltic movements in the esophagus and to
quantitate the pressure in the LES.
* Pressure in the smooth muscles of the esophagus
changes with food ingestion.
* Problems in the peristaltic movements of the esophagus
can weaken the defensive mechanism regarding GERD
symptoms.
Sometimes there is certain neurological deficit (nerve damage)
causes defects in the peristaltic movements of the esophagus.
So in that case, you can’t guarantee adequate control of GERD
symptoms unless you solve this deficit.
Advantage of Esophageal Manometry test: supply us with
quantitative figures or numbers of LES pressure (not just
released or decreased pressure), as well as information
regarding the severity of the case in the patient.
Refer to table 2 in the slides:
There are other tests or procedures that can be used
sometimes for the diagnosis of GERD:
PPI trial: proton pump inhibitor trial: we give the patient PPI
for 2 weeks, if the symptoms alleviated this favors the diagnosis
of GERD.
Limitation: negative trial does not rule out GERD: which means
if the symptoms in the patient didn’t alleviate, this does not
nessciarily indicate something other than GERD because maybe
it was severe GERD and didn’t respond to PPI dose used in the
test.
An example of procedures is
Esophageal biopsy: used for suspected Barrett’s esophagus
(change in the type of cells) or suspected cancer.
This test is used if there is mass in the esophagus which can be
detected easily during Endoscopy or Barium swallow tests. So
they do biopsy later on to know the type of cells.
Treatment goals for GERD:
1.
2.
3.
4.
Eliminate symptoms
Heal esophagitis
Manage or prevent complications
Maintain remission
Nonpharmacological Treatments of GERD with life style
modifications: not all of them of are applicable at home.
Refer to the table 32-5 in the slides
1. Elevate the head of the bed (increases esophageal
clearance).Use 6- to 8- inch blocks under the head of the
bed. Sleep on a foam of wedge:
What is meant here not to increase the number of pillows. The
bed itself can be elevated * fancy bed*. Most homes don’t
have fancy beds so it is applicable only in hospitals or
specialized clinics. The concept is we use the gravity force to
pull the gastric contents downward and reduce the symptoms
of regurgitation.
2. Dietary changes:
a. Decrease the amounts of food.
b. The time period between the last meal and bedtime
should be at least 3 hours.
3. Weight reduction: The intra-abdominal pressure in
obesity can increase reflux, so in case of GERD patient it
would increase the symptoms. >>>> weight loss would
help
4. Stop smoking: until 2013 it was considered as standard
nonpharmacological treatment for GERD but recently it
was discovered that smoking has nothing to do with
modifying the symptoms. It is true that it increases the
inflammation in the body but if a heavy smoker person
which has already GERD stopped smoking, the same
symptoms will remain.
Conclusion: smoking cessation is no longer considered a
non-pharmacological treatment of GERD.
5. Avoid tight –fitting clothes: they increase the pressure on
the stomach which in turn pushes the gastric contents
upwards.
6. In regard to drugs, if the patient can stop them it would
be better. If not, the last dose should be taken late
afternoon- early evening.
Refer to Table 3 in the slides and notice: Tobacco and alcohol
cessation box.
GERD is classified based on the severity of the symptoms
into three phases:
Phase I: Mild /occasional symptoms. Most patients do not
seek medical help they just rely on OTC medications.
The symptoms (Regurgitation/ Heartburn) will occur more
than in normal condition but they are nor severe neither
annoying for the patient.
Phase IIa: Persistent symptoms, mucosal damage.
Inflammation in the esophagus, symptoms would increase in
duration, heartburn for several hours.
Phase IIb: Severe mucosal damage, heartburn can persist
throughout the day. Psychological problems: in which the
patient may reach a point that he don’t eat anything
because he will be afraid of postprandial symptoms.
Phase III: Refractory disease:
Even with optimum treatments, the symptoms still exist. It is
refractory to standard pharmacological treatment.
Typically, there are two approaches: First choice is: doubling
of the standard doses especially for PPIs and we try it for 1 -2
months. If the Symptoms didn’t alleviate or no acceptable
response was noticed we go for surgery because the
standard treatments would not be effective in this case.
Refer to the Table 32-4: Therapeutic Approach to GERD
PHASE I
A. Life style changes ( for all phases )
 Dietary changes
 Avoid tight-fitting clothes
 Separate between the last meal and bedtime by at least 3
hours
 Decreasing the amounts of food and beverages that can
worsens the symptoms
PLUS
B. Antacids
AND/OR
C. Low-dose OTC H2 blockers
 Famotidine: 10 mg once daily (up to 20 mg still
considered low dose).Maximum daily dose is 80 mg
(40 mg twice daily)
 Ranitidine: 75 mg once to twice daily (150 mg still
considered low dose).Maximum daily dose: 600 mg(
300 mg twice daily or 150 mg four times daily)
 Nizatidine :75 mg
 Cimetidine :200 mg
OR
D. OTC PPI (with doses lower than the standard doses)
If the symptoms are unrelieved with lifestyle changes and OTC
medications after 2 weeks (PPI trial), begin pharmacologic
therapy (phase II therapy) because it is unlikely to be phase I.
it is likely to be more advanced GERD.
Q: Why we start with low doses of H2 blockers? Can we start
with High doses?
A: in case of suspected Phase I GERD, the main reason is to
avoid Tolerance/Tachyphylaxis that develops after the use of
H2 blocker for more than 2-3 weeks. This explain why some
patients experience GERD symptoms after month or month and
a half of treatment on H2 blockers >>>> because of tolerance
development.
So using H2 blockers daily for more than 3 weeks is likely to
result in tolerance.
The solution is to increase the dose until we reach the
maximum daily dose if we are talking about H2 blockers. We
don’t switch from agent to another from the beginning!
If a patient developed tolerance for Ranitidine, can we replace
it with equipotent dose of Famotidine? The answer is NO
because they act on the same binding site of the receptor, so
we should increase the dose of Ranitidine.
 The Duration of the effect of Famotidine doesn’t really
correlate with the half-life. It’s half –life is 24 hours, so it
is supposed to be taken once daily but the clinical
duration is 8 -10 hours which means if a patient wants to
take 40 mg Famotidine, it is better to take 20 mg twice
daily rather than 40 mg once. In case of once daily, at
best its duration will be 10 hours so there is a period of
time not protected.
Q: When is it the best time to take H2 blockers?
A: 30 min to an hour before meals.
 Time of administration/dosing is critical to improve the
response.
If a patient forgot to take them before meals, and he took
it after, efficacy will be very low, maybe one third or
quarter of the efficacy if it was taken before meals.
 Onset of action of H2 blockers: 30 min to an hour.
 Cimetidine is the least commonly used H2 blocker
because of:
1. The large potential for drug –drug interactions because
it is an inhibitor of Cytochrome P450
2. At higher doses can cause Gynecomastia
3. Higher doses required (200 mg...)
 The most two commonly used H2 blockers are:
Famotidine and Ranitidine
 Both of them can be used for children less than 1 year of
age
Ranitidine: from the age of one month
Famotidine: from the age of three months
 Notice that in Phase I, patient is treated for 2 -4 weeks
and after that there is NO need to continue with
maintenance therapy.
 In case of Phase II or III maintenance therapy is a must. If
the treatment was abruptly discontinued, quick relapse
will happen.
PHASE IIa
A. Life style modifications
PLUS
B. Standard doses of H2 blockers for 6 -12 weeks
 Given daily not prn. Either the symptoms exist or
not.
 Cimetidine 400 mg twice daily
 Famotidine 20 mg twice daily
 Nizatidine 150 mg twice daily
 Ranitidine 150 mg twice daily
Nizatidine found in the Jordanian market under the brand
name Axid, its price is more than double the price of Ranitidine
with no advantage in terms of efficacy. So its use is very limited
OR
C. PPI for 4-8 weeks. All are given once daily
PHASE IIb
A. Life style modifications
PLUS
B. PPI for 4 -16 weeks
OR
C. High-dose H2 blockers for 8 -12 weeks
General information:
 The most effective treatment by far is PPI.
 It would be a disaster if we convert from PPI to H2
blocker and vice versa especially in patients with
severe GERD, because the treatment will be
interrupted and this would lead to therapy failure in
patients.
 Clinically, it is not recommended at all to discontinue
PPI treatment and go for H2 blockers taking into
consideration that the course of treatment of PPI is
variable depending on the severity of GERD.
Mild up to 4 weeks - Moderate 8 weeks –Severe 16 weeks
 If the patient stopped PPI before the course of
treatment, there will be no complete healing in the
lower esophagus and this will create refractory GERD
in the patient.
 In Medicinal Chemistry: Famotidine is three times the
potency of Ranitidine. Clinically it is NOT. Because here
in Clinical Pharmacy we look at the efficacy which is
real life data, the information obtained from clinical
practice which is evidence based. So in terms of
efficacy they are similar.
 The body needs 54 hours to synthesize a new proton
pump after irreversible inhibition.
 In case of using PPI, the time decreases to 24 hours and
this time differs from PPI agent to another.
 Fastest with Omeprazole and slowest with
Pantoprazole. The reason is the way of binding to the
proton pumps at the parietal cells.
Done by: Hamza Kiswani