Pharmacology of Acid Suppressing Drugs Flashcards
What are antacids?
• what are the two general types?
Antacids:
• Weak Bases that can Buffer Acid
2 types:
•Absorbable and Non-Absorbable
What are the 3 general categories of non-absorbable antacids and what are their side effects?
• what makes them non-absorbable?
3 Categories:
• Aluminum; AE = Constipation
• Calcium; AE = Constipation
• Magnesium; AE = Diarrhea
**These are non-absorbable because they are localized to the GI tract
How do the side effects of absorbable antacids differ from those of non-absorbable antacids?
• what are the absorbable antacids?
Sodium Bicarbonate
• Absorbable Antacid that can leave the GI tract
AEs: Because bicarb can leave GI tract you can get systemic acid-base imbalance and sodium and H2O retention
When are antacids most appropriately used?
When you need FAST relief from heartburn
• Remember that these have a short duration of action
What is the only known physiological function of H2 receptors?
Stimulate HCl secretion from parietal cells
What is the source of histamine that leads to parietal cell stimulation?
• explain how histamine leads to the release of H+ from parietal cells.
Enterochromaffin-like cells secrete histamine (sometimes in response to Ach or Gastrin)
Histamine can bind to the H2 receptor on parietal cells and trigger the cAMP cascade
This increases activity of the H+/K+ ATPase
Why do H2 blockers not lead to a complete reduction in acid production?
Parietal Cells can be directly acted on by Gastrin and Ach
What are the 4 H2RAs (H2 receptor antagonists) approved for use in the US?
Cimetidine
Ranitidine
Famotidine
Nizatidine
If you want an H2RA to be effective, when is the most appropriate time to administer it?
• why is this?
• What happens if you take it at a different time?
• NAME THEM
H2R anatagonists are most effectively used at night because they are really only good at suppressing H+ secretion in the absence of any stimuli
**If patients take them during the day or continue to eat at night after taking the drug the efficacy will be reduced and they’ll end up doing multiple doses
Cimetidine, Ranitidine, Famotidine, Nizatidine
T or F: Tolerance mechanisms can develop against H2RAs
True, H2RAs are antagonists so the cell can respond by upregulating the receptors or modifying other aspects of the cAMP cascade
T or F: H2RAs are your first choice in the treatment of non-H. Pylori related Peptic Ulcer Disease
• name the H2RAs
False, they used to be but now PPIs are the standard of tx in these cases
Cimetidine, Ranitidine, Famotidine, Nizatidine
Why are H2RAs inferior to PPIs in their acid blocking capacity?
They are less effective than PPIs for GERD because they do not elevate intragastric pH sufficiently and do not counteract food stimulated secretion
They lower gastric acid secretion by 90% (pH 1-2 to pH 2-3) but at this pH PEPSINOGEN is still active and can still damage the esophagus
What are the possible Drug interactions with H2RAs?
• Name them all.
Cimetidine inhibits P450’s and can therefore have pretty severe enhancement of effects on drugs like:
• Pheytoin
• Warfarin
• Theophylline
Other H2RAs (Ranitidine, Famotidine, Nizatidine) do not have this problem
What type of patient is most effectively treated with an H2RA?
• how do they compare to antacids?
Someone with mild GERD and relatively infrequent Symptoms
H2RAs have slower onset of action when compared to antacids but have a longer duration of action
Name the PPIs.
the “Prazoles”
Omeprazole Lansoprazole Rabeprazole Pantoprazole Esomeprazole IR-OME/NaHCO3 Dexlansoprazole
What are the purified enantiomers of omeprazole and Lansoprazole?
• are they R or S?
Omeprazole is purified to its S enantiomer Esomeprasole
Lansoprazole is purified to its R enantiomer Dexlansoprazole
Which PPIs are enterically coated?
• which are not?
• Why is enteric coating necessary?
All except Immediate Release - Omeprazole (IR-OME)/NaHCO3 are give as enteric coated capsules
This is necessary because PPIs are ACID LABILE
What are PPIs that are not IR-OME referred to?
These are Delayed Release
Describe the ADME of PPIs.
• how often do they need to be administered?
• How long can levels be detected in blood?
PPIs are absorbed after enteric coating is degraded
PPIs gets absorbed into the blood and concentrated in parietal cells
Metabolism occurs via CYP2C19 and CYP3A4 and then the drugs excreted in kidney
Metabolism leads to elimination of the drug from the blood in 1-2 hours but CONCENTRATION IN PARIETAL CELLS means the EFFECTS PERSIST LONG ENOUGH FOR ONCE-A-DAY DOSING
Do doses of PPI need to be adjusted for renal or Hepatic impairment?
Renal:
• NO - because most biotransformation is hepatic
Hepatic:
• In moderate hepatic dysfunction the dose should be lowered
***Remember PPIs are the “prazoles”
PPIs - the “-Prazoles”
MOA
MOA of PPIs
• PPIs are taken up by parietal cells and get PROTONATED
- Excreted on luminal aspect to become SULFENAMIDES
- -SH bond with CYSTEINE on H/K ATPases
- THIS KNOCKS OUT THE FUNCTION OF THE PUMP AND ACID SECRETING CAPACITY IS ONLY RESTORED BY GENERATION OF A NEW PUMP
T or F: PPIs completely abolish acid secretion
False, they reduce it a lot, but do not completely eliminate it - gastric pH is often below 3 for a fews hour of the day while on these
If PPIs do not completely abolish acid secretion, then how are they so effective?
• does resistance to PPIs develop?
PPIs raise the gastric pH above 4 for a significant fraction of the day
• This is important because PEPSIN CANNOT BE ACTIVATED AT A pH ABOVE 4
• This allows time for healing of the gastric mucosa
**Resistance does not develop to PPIs (they are not competitive antagonists like H2RAs)
T or F: patients who abruptly stop taking PPIs may experience abrupt rebound hypersecretion of acid
True, this effect is mainly the case in patients that are H. Pylori negative (and therefore their gastric disease was caused by hypersecretion of acid)
PPIs
• Potential Adverse Effects
- Headache, Diarrhea, Skin Rash, Abdominal Pain
- Increased risk for Bacterial infections (C. Diff) - due to lack of stomach acidity
- Possible increased risk of BONE fractures
PPIs
• what potential vitamin deficiency theoretically could develop?
Vitamin B12 extraction is somewhat dependent on gastric acid. Reduced gastric acid could cause Macrosidic anemia
**Monitoring of B12 is not necessary in these patients
PPIs
• when is optimal dosing?
PPIs should ideally be given in the morning on an empty stomach around 30-60 minutes BEFORE food
• This timing gives adequate time for the PPI to get into the bloodstream, upon EATING 30-60 minutes later PARIETAL CELLS will uptake a lot of PPI
Note: twice daily dosing is not usually necessary, but if it is implemented it should be given BEFORE dinner. (2x per day is not FDA approved)
What is the relative effectiveness of PPIs when compared to H2RAs when it comes to healing Duodenal and Gastric ulcers?
PPIs heal 2x as fast
How do healing rates of PPI healing compare to H2RA healing in the treatment of GERD and non-erosive esophagitis?
PPIs are better than H2RAs in BOTH GERD and NERD
PPI
• Drug interactions
• Which of the PPIs has the most?
OMEPRAZOLE has the most drug interactions of all the PPIs
PPI potential drug interactions are related to metabolism mediated by CYP3A4 and CYP2C19
Significant interactions with OMEPRAZOLE include:
•Warfarin
• Pheytoin
• Diazepam (essentially inconsequential)
• CLOPIDOGREL
PPIs
• Explain the potential interactions between Clopidogrel and PPIs
• which PPIs is this effect significant with?
• Which PPIs is this effect NOT significant with?
Clopidogrel
• is given as a PROdrug and must be activated by CYP2C19 that is INHIBITED by omeprazole and esomeprazole in vitro
• This could cause pts. on clopidogrel to return to procoagulant state
SAFE PPIs to Use with Clopidogrel:
• Lansoprazole
• Pantoprazole
• Dexlansoprazole
What is the MOA of Clopidogrel?
clopidogrel prevents binding of adenosine diphosphate (ADP) to its platelet receptor, impairing the ADP-mediated activation of the glycoprotein GPIIb/IIIa complex.
glycoprotein GPIIb/IIIa complex is the major receptor for fibrinogen, its impaired activation prevents fibrinogen binding to platelets and inhibits platelet aggregation
A patient is on Clopidogrel and needs to go on a PPI, which can you give them?
SAFE PPIs to Use with Clopidogrel:
• Lansoprazole
• Pantoprazole
• Dexlansoprazole
What are the mains indication for PPI treatment?
- GERD - heals and prevents
- NSAID/Asprin associated ulcers - prevents rebleeding once NSAID/Asprin therapy is restarted
- Prevention of Ulcer rebleeding
T or F: all patients with a history of peptic ulcer disease must be tested for an H. Pylori infection
True
What are the two most commonly used treatments for H. pylori infections?
- Clarithromycin-based triple therapy
• PPI + Clarithromycin + Amoxicillin
• PPI + Clarithromycin + Metronidazole (if patient is penicillin allergic) - Bismuth-based Quadruple Therapy
• PPI (or H2RA) + Bismuth + Metronidazole + Tetracycline
NO SUBSTITUTIONS ALLOWED
T or F: PPI monotherapy is effective in treating H. pylori.
False, but they DO IMPROVE THE EFFICACY OF THE ANTIBIOTICS
How effective are Clarithromycin triple therapy and Bismuth quadruple therapy in clearing H. pylori infections?
only 70-75% effective
Why are failure rates high in the treatment of H. pylori associated infections?
- Antimicrobial Resistance
- Poor Compliance
- Both
T or F: If a patient fails triple therapy, you should prescribe it again and explain the importance of medication compliance.
FALSE, if a patient fails Clarithromycin triple therapy (PPI + Clarithromycin + Amoxicillin/Metronidazole) its because the bacteria is CLARITHROMYCIN RESISTANT
What should you do if a patient fails Triple therapy?
DO NOT represcribe clarithromycin
•Metronidazole is probably okay to represcribe (emergence of resistance is low)
- NO RESISTANCE TO AMOXICILLIN OR TETRACYCLINE SO THESE CAN BE ADDED TO NEW REGIMENS AS NEED
