Download H2 Blockers

Lecture 16
Continued GERD classification:
-Phase IIb: Severe mucosal damage.
First –line treatment: maximum daily dose of H2 blockers or
standard dose of PPI for up to 16 weeks. Add-on therapy is optional
*not standard * for example: Metoclopramide (anti–emetic Drug):
can reduce nausea by two mechanisms:
1. It is a Prokinetic agent which means it can reduce nausea by
increasing the gastric emptying so helps to get the stomach empty
faster and consequently reducing the pressure that happens inside
the stomach.
2. due to its antagonistic effects on the Dopamine receptors.
Metoclopramide is given as one tablet 10 mg ac and HS {ac:
before meals, HS: at bed time) so it is taken up to 4 times daily with a
maximum daily dose of 40 mg. If the patient exceeds this dose
Extrapyramidal symptoms EPS will occur (i.e. Parkinson-like
symptoms: Tremor, dyskinesia) since it’s a dopamine antagonist.
Torsade de pointes can also occur.
-Phase III: Refractory phase
PPI can be given in double the standard dose (daily dose)
-Standard doses for PPI:
Omeprazole: 20-40 mg (we say 40 mg in most cases)
Esomeprazole: 40 mg
Lansoprazole: 30 mg
Pantoprazole: 40 mg
Rabeprazole: 20 mg
-PPIs are acid labile, so if they were given as immediate release
non – enteric coated formulation, degradation will happen and
their half - life will be much reduced (in case of omeprazole, it will
become 2 minutes). Here in Jordan, all the formulation of PPI are
enteric coated either enteric coated tablets or capsules with
enteric coated pellets. In the US, There is an immediate release
formulation of PPI called Zegerid which contains omeprazole plus
Sodium Bicarbonate (110mg). Sodium bicarbonate is antacid will
neutralize the acid quickly which would allow immediate
absorption of omeprazole. That’s why its bioavailability is slightly
increased because the absorption starts in the stomach.
In the US, there is a dual release PPI called Dexlansoprazole in
which the release of the drug happens on two phases .Available
doses is 30 and 60 mg, which are doubling the dose of
lansoprazole because the release happens on two phases. It is
more effective than the standard PPI because the dose is doubled
and given regardless of the meals since it’s released on two
phases.
PPIs take several hours up to 24 hours (most of them take 2 – 6
hours) in order to induce its effects, so they are given 30 -60 min
before breakfast. For example if the patient takes it before dinner
it will start working at 4 am or 5 am. So we can figure there is a
gap period in which the patient is not protected and will suffer
from excess acid during it.
In general, half-life of PPIs are short. Ranging from an hour and a
half to two hours and a half.
PPIs are prodrugs, in order to work; they should be activated by
the acid in the stomach. Absorption happens in the duodenum,
when they reach the parietal cells they will be activated by acid
and then they will bind IRREVERSIBLY to the proton pumps on the
cells. So our main concern is on the bioavailable concentration not
on the time it remains in the blood because once the receptor is
occupied, irreversible inhibition will occur. So we tell the patient
to take it 30 -60 min before breakfast and not on empty stomach.
Because as we said, PPI should be activated in the acid and food
stimulate acid secretion. Otherwise, much of the efficacy will be
lost.
If it was taken after the meals, the efficacy will be much reduced
because the absorption will be erratic for 2 reasons:
1. The amount of acid in the stomach is high
2. Gastric emptying time is variable, and this will lead sometimes
to the release of the drug in stomach rather than duodenum
and subsequently PPI will be degraded immediately.
Because the duration of time the drug will remain in the blood is
not important for us, If the patient would take 40 mg of
omeprazole (the standard dose) it is better to take it at once,
because C max will be higher and more inhibition of proton pumps
will occur .We are not concerned if the drug remain in the blood
for longer time, we care for the % inhibition of proton pump.
Because it is irreversible inhibition, Even if the C max increased for
short period of time this would be sufficient to produce more
inhibition of the pumps.
If the patient wants 80 mg omeprazole (which is higher than the
standard dose), it must be given 40 mg twice daily. The reason is:
Proton pumps saturation.
PP on the parietal cells are not all active at the same time , so if I
give a dose higher than the standard dose , proton pumps will be
occupied to a certain level and the excess will be eliminated . For
this reason, it usually takes 5-6 days to reach the maximum effect
for a particular dose.
If a patient took the standard dose and no good response was
noticed, the recommendation is to switch to another PPI, not
doubling the dose .Because the pharmacokinetics of PPIs are
different. So we say similar efficacy but not the same, one agent
could work better than another agent in a particular patient .we
said particular patient because the pharmacokinetics of the drug
will depend in the first place on the host factors not the product
factors. If the patient tried two or three PPIs and still the
symptoms not controlled, he will be diagnosed with Refractory
GERD and requires doubling for the dose. {Assuming that the
diagnoses from the beginning was correct}
Antacids
Typically, they are not given with PPI
An exception: if the PPI and antacid were in the same formulation
with immediate release pattern
If the patient took antacid, he needs to wait at least 2 hours to
take PPI to ensure that the effects of antacids diminished.
Onset of action: within 5 minutes
Duration of action: 20 -30 minutes up to 2 hours, antacids must be
given after meals
Prn only in mild cases, in moderate to severe GERD they are not
effective
H2 Blockers
Onset of action: 30 -60 minutes
Duration of action: 8-10 hours
Combination of H2 blocker and PPI is allowed, in which the H2
blocker is given after the PPI.
Primary treatment is PPI {since they are the most effective than
H2 blockers} 30 -60 minutes before breakfast , H2 blockers are
used for breakthrough heartburn , i.e. prn , not on a daily basis .If
the breakthrough heartburn happens at night , the patient should
take H2 blocker before dinner , If at daytime , H2 blocker should
be given before lunch .
H2 blockers can be used 2 to 3 hours after PPI use, (which is the
time needed for absorption) to ensure gastric emptying and
activation of them in the stomach.
Back to Phase III : first line treatment is doubling the daily dose of
PPI , if not sufficient surgery will be indicated The name of the
intervention is fundoplication , in the Fundus : upper part of the
stomach close to the esophagus , incision and that part is tight
around the lower esophageal sphincter LES , in which we are
making artificial LES , new sphincter , this would minimize the risks of
regurgitation and would allow enough time for the body to heal .
In moderate GERD at the onset of esophageal damage, minimum
duration of treatment of PPI is 4 weeks.
Phase IIa: 4-8 weeks
Phase IIb: up to 16 weeks
This surgery is not considered a final and permanent solution
because turning back can happen and with time, the surgery itself
can fail. Like we said in the case of hemorrhoidectomy, it gives
immediate relief but not permanent solution because if risk factors
still exist, this will give a chance for relapse.
Some patients were obligated to do it several times, with the second
time being more difficult because already there is incision, so the
manipulation is more limited.
Fundoplication is different and much easier than other Bariatric
surgery for weight loss.
Short-term/acute risks of PPI use:
1. Potential drug – drug interactions with drugs requiring acidic
environment for absorption. So their absorption and efficacy will be
affected.
2. Risk of infections: pneumonia in the first place and clostridium
difficile in the second place, because acidic environment of the
stomach is important to prevent these infections.
3. Reduce the absorption of minerals like Calcium.
Long –term / Chronic risks of PPI use:
1. Increase the risks of osteoporosis and fractures
2. Recently there is a controversial about their effects on the renal
function. Until now we cannot link the deterioration in renal function
with the chronic use of PPI.
In regard to Clopidogrel use with PPI : Omeprazole and
Osomeprazole are inhibitors of 2C19 which is the enzyme
responsible for the metabolism or activation of Clopidogrel in the
liver , so it is better to use PPI which isn’t an inhibitor of 2C19 like
pantoprazole and lansoprazole . In the year 2010 , the use of
omeprazole and esomeprazole along with Clopidogrel was
considered a Major drug-drug interaction , but in 2012 , they found
there are different polymorphs of 2C19 that affect the extent on
inhibition done by PPI , so the main focus is on the polymorph of
2C19 not on inhibition of 2C19 which is weak in nature .
*Conclusion: it is better not to use omeprazole/esomeprazole with
Clopidogrel, but in some cases they can be used with patient
monitoring.
Esomeprazole: The S enantiomer of Omeprazole, so we don’t convert
from omeprazole to esomeprazole and vice versa.
Astrazeneca claimed that Esomeprazole is more effective than
Omeprazole. But in fact, clinically they are the same because both
have the same doses 40 mg.
Some examples of Drugs with their corresponding enantiomers and
the differences in doses between them which reflect difference in
efficacy.
Loratidine 10 mg
Cetrizine 10 mg
Desloratidine 5 mg
Levocetrizine 5 mg
The only difference is their pharmacokinetic profile, in which
Esomeprazole has slightly faster onset of action. But the percent
inhibition of proton pump is the same, so it is not a major benefit.
Maximum daily dose of Omeprazole is 360 mg .as we can see there is
really a good safety profile of this agent, although they are
categorized as pregnancy risk category C.
American college of gastroenterology recommends using PPIs if
heartburn in pregnancy is not adequately controlled by H2 blockers.
In pregnancy antacids is the first choice
Not sufficient go for H2 blockers,
Not sufficient go for PPI (even though they are category C)
Omeprazole has the most established safety profile
Omeprazole doses
 20 mg >>>>> OTC
 40 mg >>>>> prescription only
 10 mg >>>>> prescription only :
Target population is children, so it shouldn’t be self-diagnosed
condition and should refer to the doctor for correct diagnosis.
*if the child weight is less than 20 kg, go for 10 mg omeprazole
* 20 kg and higher, go for 20 mg omeprazole
-Nexium (Esomeprazole) can be found in sachet form 10 mg dose
-PPIs have Injectable forms/ parenteral: the first one was
pantoprazole
-Omeprazole also can be found as injection.
-The injectable forms really offer no advantage over the oral one,
except if the patient cannot take oral medication in general.
-IV disadvantage: the elimination is faster so it is really better to get
oral PPI rather than IV.
-A common inappropriate practices in hospitals
1. IV PPI
2. use of PPI in stress ulcers : as a way of prophylaxis they give PPI
and in most of the cases the patients don’t have risk factors for
stress ulcer , so this just increase the risk of infection and drug –drug
interactions as well as the cost . PPI is more expensive than H2
Blockers.
Antacids:
 Antacids are compared by Acid neutralizing capacity ANS:
They take typically 500 mg of the antacid and dissolve it in 15
ml to give a suspension: and then they calculate how many ml
equivalents of H + are needed to neutralize this 500 mg
antacid.
 Sodium Bicarbonate: 8 milliequivalent, fastest acting antacids
and with the shortest duration of action
 Calcium Carbonate: the strongest antacid, 56 milliequivalents,
requires 5 minutes to work, with duration up to 2 hours.
The percentage of elemental calcium in Calcium Carbonate is 40 %.
For example if the elemental calcium should not exceed 2.4 grams in
24 hours, then the maximum daily dose of Calcium Carbonate is 6
grams, not at once, in 24 hours.
 Magnesium Hydroxide : 22 milliequivalent
 Side effects :
Risk of drug-drug interaction: mostly with antacids
containing divalent and trivalent cations (Calcium,
Magnesium, Aluminum).which affects the absorption of
other drugs for example Fluoroquinolones, Tetracycline and
Azithromycin.
# In case of patient taking fluoroquinolones (or other drugs
mentioned above)
If we take the Fluoroquinolones first, we should wait one hour with
we take the antacid.
Or start with Antacid and wait for at least 2 hours then take the
fluoroquinolones.
 Calcium Carbonate in higher doses can cause >>>>constipation
 Magnesium Hydroxide >>>> diarrhea
 Aluminum Hydroxide >>>> constipation
 Maalox: contain Magnesium Hydroxide and Aluminum
Hydroxide. The dose of Magnesium Hydroxide is higher than
Aluminum Hydroxide. So at the end, the NET Gastrointestinal
effect is very mild diarrhea or no diarrhea.
Done by: Hamza Kiswani