What are the categories of acid-suppressing drugs?
- Histamine H2-receptor antagonists
- Sucralfate, Misoprostol: not much use for these anymore, but still around
- Tx of H. pylori infection
Antacids MOA and use?
- Weak bases that neutralize gastric acid
1. Acid + base = salt + water
- Most considered non-absorbable: Mg, Al, Ca (often combine 2 or more of these)
1. Side effects restricted to GI tract (other card)
- Avoid absorbable/systemic agents, e.g., NaHCO3, except for short-term use
1. Excessive, long-term use could produce Na + H2O retention, alter systemic acid-base balance
- Mostly used for control of heartburn
1. Rapid onset of action: intraluminal
2. Short duration of action
- NOTE: H2RAs work more slowly than antacids to tx heartburn, but their effect lasts longer; at least one proprietary preparation has combined an H2RA (famotidine) with an antacid
What are the AE's of the antacids?
- Mg-based: diarrhea
- Al- or Ca-based: constipation
- Absorbable: alkalosis (disrupt acid-base balance), Na+ overload if taken excessively
1. Should be avoided long-term
What is the MOA of the H2-receptor antagonists?
- Competitive antagonists of histamine at H2-receptors on parietal cells
- Little or no H1-antagonist activity: H1 receptors are responsible for histamine effects in allergic response
- Only known physiological role of H2-receptors is modulation of gastric acid (HCl) secretion by parietal cells, even though these receptors are found throughout the body
What is the normal role of H2R's?
- Histamine produced/secreted by enterochromaffin-like (ECL) cells close to parietal cells in prox stomach
- Binding leads to INC in IC cAMP -> INC acid secretion from mem-bound molecules of H/K ATPase (protone pump)
- NOTE: parietal cells can be stimulated by other means too, i.e., vagal stimulation leads to a rise in IC Ca, and stimulation of acid secretion w/o involvement of the H2 receptors
What are the 4 H2-receptor antagonists?
- NOTE: chemically dissimilar to e/o, but share same pharma action -> competitive antagonism at H2R
1. Also FDA-approved for OTC use: same, or lower doses than Rx
What are the pharmacodynamics of the H2RA's?
- Modest INH of gastric acid secretion (much less than PPI's)
- More effective on basal/overnight than on food-stimulated acid secretion: when parietal cells are not being otherwise stimulated
1. Best taken before bedtime: patient should not eat afterwards -> relatively disappointing in tx of reflux symptoms b/c these symptoms tend to be associated w/eating
2. H2RA INH effect on acid secretion can be at least partly overcome by the stimulatory effect of food on acid secretion
- Tolerance develops to action within a few days: up-regulation of the receptor
1. Would have to be taken multiple times during day to control daytime acid secretion, leading to more rapid tolerance
- NOTE: main physiologic stimulus to parietal cell secretion is ingestion, sight, smell, etc. of food
What is the difference b/t pharmacodynamics and pharmacokinetics?
- Pharacodynamics = what a drug does to the body
- Pharmacokinetics = what the body does to a drug, in terms of absorption, distribution, metabolism and excretion (ADME)
What is drug tolerance?
- When it becomes necessary to increase the dose of a drug to obtain the same effect that had previously been obtained with a smaller dose
What were the indications for the H2RA's in the past? Why did these change?
- No longer recommended for tx of peptic ulcer -> test and tx for H. pylori; use PPI's in H. pylori (-)
1. PAST: single noctural dose to heal most peptic ulcers (80% DU healed at 4wks, and 80% at 8wks -> GU's always take longer to heal)
a. Single nocturnal dose adequate to maintain healing in most pts, but less effective in smokers
b. Don’t need to get rid of H. pylori to heal an ulcer, but RECURRENCE was common
- Inadequate for tx of GERD in many pts: multiple daily doses in the past -> only suitable for pts with mild/uncomplicated disease
1. Perhaps b/c do not elevate intragastric pH sufficiently and/or b/c relatively ineffective for counteracting food-stimulated acid secretion
What are the drug interactions of the H2RA's?
- CIMETIDINE: non-specific INH of CYP450; multiple clinically irrelevant drug interactions, except some with a narrow therapeutic index:
1. PHENYTOIN: most important; paradoxically, toxicity can even cause seizures
3. THEOPHYLLINE: asthma, emphysema, etc. tx
4. Also interacts with DIAZEPAM (Valium), slightly INC concentration, but NOT CLINICALLY SIGNIFICANT
- NOTE: most of these interactions most likely with Cimetidine (and less likely with the others); the other H2RAs are not associated with any important drug interactions
What are the indications for the H2RA's?
- Healing of DU, GU: now superceded by H. pylori therapy or PPIs
- GERD: not appropriate for erosive esophagitis
1. Inferior to PPIs in endoscopy-negative GERD
2. Useful for mild, intermittent heartburn: if more serious symptoms, give PPI
- GI bleeding/prophylaxis of “stress ulcer:" were widely used IV to prevent/treat this, but very little convincing evidence
1. Still used in seriously ill pts to prevent stress-related UGI bleeding, but efficacy fairly limited and still unclear which pts most appropriate
What are the problems with the H2RA's?
- Relatively ineffective in suppressing food-stimulated gastric acid secretion -> disappointing effect in GERD
1. Can be used for pts w/mild, diet-related heartburn
2. If pt. on PPI, & need to know H. pylori status, can switch pts to this from PPI b/c PPI can affect urease breath test and stool antigen test
- Tolerance devo w/continued dosing: anti-secretory effect on day 1 > than that seen on day 5 or beyond
- Relatively small effect on pH (change from 1-2 to 2-3): pepsin still biologically active in esophagus b/c pepsinogen still converted to pepsin at pH 3
1. Want to get pH >4 to prevent bio activation of pepsin
List the PPI's (chart). Describe their similarities.
- Similarities among PPI’s far exceed differences, so pt should be on the one they have access to, and at lowest effective dose
- Substituted benzimidazoles: most are racemic mixtures of 2 enantiomers – the R- and S- forms
1. Esomeprazole is purified S-enantiomer of omeprazole and Dexlansoprazole is purified R-enantiomer of lansoprazole in a dual delayed-release mechanism
- Each of these drugs has some form of protective enteric coating – except for IR-OME / NaHCO3 (i.e. immediate-release omeprazole with sodium bicarbonate)
1. Enteric coating is necessary because these drugs are acid-labile – and must be protected from the effects of gastric acid. If PPIs are given by mouth without an enteric coating (and without sodium bicarbonate), most of the dose would be destroyed in the stomach and would never be absorbed into the circulation.
What are the pharmacokinetics of the PPI's?
- Denatured by gastric acid, so given as enteric-coated granules (in capsule) or enteric-coated tablets
1. Absorption is erratic
2. Enteric coating designed to break down in proximal small intestines
- One preparation is of pure, non-coated omeprazole in NaHCO3 -> accelerated absorption
- Preferentially taken up by parietal cells
- Metabolized in liver: CYP2C19, 3A4
- Short elimination half-life (1-2 hrs), but pharma effect prolonged due to irreversible binding
Enteric-coated PPIs are also sometimes referred to as delayed-release PPIs. Since the enteric coating has to disintegrate before the PPI can be absorbed, the rate of absorption is unpredictable and erratic. Once absorbed, PPIs are initially widely distributed within the body. However, they are preferentially taken up by parietal cells. They all have a short elimination half-life of 1 – 2 hours. Their effect on acid secretion is much longer, however – so typically these drugs need only be taken once daily.
They are eliminated from the body by hepatic biotransformation and subsequent renal excretion. The cytochrome P450 isoenzymes that are most involved with PPI metabolism are 2C19 and 3A4.
What is the MOA of the PPI's?
- Taken up by parietal cells from the circulation, and protonated (trapped)
- Excreted from luminal aspect of cell, and chemically converted to sulfenamide
- Form covalent -SH bond w/cysteine residues on mem-bound H+/K+-ATPase (the “proton pump”), essentially terminating thier activity
- Recovery of acid secretion by parietal cells depends on synthesis of new molecules of H+/K+-ATPase and their insertion into luminal membrane
What are the pharmacodynamics of the PPI's?
- Marked suppression of gastric acid secretion, both basal AND food-stimulated
1. Proton pump = “final common path”
- Intragastric pH >3 for 16hrs/d, and >4 for 12hrs/d: no substantial peptic activity at these levels of pH
1. pH >4 important to heal erosive esophagitis bc little bio activity of pepsin on esophageal mucosa above this pH
- Do NOT cause achlorhydria: can’t switch off acid production completely bc cell makes more H+ pumps
1. New molecules of H+/K+-ATPase constantly being re-synthesized
- Unlike H2-receptor antagonists, no tolerance devo bc not competitive antagonists
- Inconsistent data on “rebound” acid hypersecretion on withdrawal -> probably not clinically relevant issue
1. Especially likely in H. pylori-negative patients
What are the potential problems with profound suppression of gastric acid secretion?
- Slight INC in enteric infections, incl C. diff and some other bacterial infections bc gastric acid is one of body’s main non-specific defense mechs
1. Someone going to developing world with PPI: need to be extra careful about food hygiene
- No effect on protein absorption, and little effect on Ca, iron absorption (not major)
1. Possible INC risk of some fractures; conflicting evidence, minor effect, if any (mech unknown)
- No INC risk of malignancy
- Possible mild effect on absorption of food-bound Vit. B12: more of a concern with elderly pts, or those with restricted diets, i.e., vegans (true deficiency has not been seen with these drugs)
1. Can give B12 by mouth bc intrinsic factor levels normal
- SIDE-EFFECTS infrequent, relatively mild: headache, diarrhea, skin rash, abdominal pain
How does PPI dosing work?
- Best taken in AM 30-60 minutes before food; most pts ONCE DAILY
1. Food provides gentle stimulus to parietal cell activity, enhancing the uptake of circulating PPI
2. GERD: 10-20% need PPI twice-daily -> 2nd dose before evening meal, NOT at bedtime
- Worst possible time to take a PPI is before bedtime
- Most reflux events occur post-prandial
What is the influence of food intake on the anti-secretory effects of the PPI's?
- Food provides gentle stimulus to parietal cell activity, enhancing the uptake of circulating PPI
- This graph just supports this fact; do NOT memorize
How are PPI's used in peptic ulcer tx?
- Effective in healing DU and GU: Hp+ or Hp-
1. Healing rates at 4 wks > H2RA rates at 8 wks
2. Effective in maintaining healing long-term: only applicable to Hp-/idiopathic ulcers (i.e., ingesting Aspirin or NSAID)
- Do NOT eliminate H. pylori on their own
How are PPI's used in GERD tx?
- Erosive esophagitis healing rates at 4 wks > those seen on H2RAs at 12 weeks
- Control of symptoms far superior to H2RAs
1. Trials also show superiority over H2RAs in endoscopy-negative (non-erosive) GERD
What are the drug interactions for the PPI's?
- Fewer important interactions w/PPIs than w/H2RA's
- OMEPRAZOLE (CYP INH, like Cimetidine) has weak interactions (due to low therapeutic index) with:
1. PHENYTOIN: potentially important
2. WARFARIN: potentially important, but of low clinical significance
3. DIAZEPAM: unimportant
- Others have no known important drug interactions
- Possible interaction with CLOPIDOGREL: FDA advises pts taking this drug to NOT receive Omep or Esomep bc they may slow conversion of Clopidogrel to its active metabolite and reduce its effect on PLT function (as measured IN VITRO)
1. Clinical studies have NOT shown convincing evidence that PPI co-therapy INC the risk of adverse CV outcomes in these pts
What are the indications for the PPI's?
- GERD: DOC for erosive esophagitis, and better than H2RAs in endoscopy-negative GERD; may be used long-term for prevention as well
- Part of H. pylori eradication regimens (NOT bactericidal, but help AB's work by elevating pH):
1. PPI + clarithromycin + amoxicillin
2. PPI + bismuth + metronidazole + tetracycline
3. NO SUBSTITUTIONS ALLOWED
4. 75% effective in Hp eradication: those who fail tx have Clarithro-resistant bug and/or have been non-adherent -> if regimen fails, pt should be re-treated with a different drug combo
- Peptic ulcer: idiopathic/Hp(-) -> related to NSAID use
1. Carry worse prognosis than Hp+ ulcers, and are highly prone to relapse and complications, so tx may have to be given long-term
2. NSAID-related will likely recur if NSAID re-started, so PPI cont'd to prevent recurrence
- Bleeding peptic ulcer: early tx (oral or IV) reduces re-bleeding risk, but PPI's NOT FDA-approved for this
1. Reduces requirement for surgical tx, and may slighty DEC mortallity among those w/most severe bleeding
2. Evidence is actually very strong -> considered STANDARD OF CARE
- Non-ulcer dyspepsia (not FDA-approved), aka, functional dyspepsia
- Prevention of stress-related UGI bleed in critically ill pts: nasogastric/orogastric admin of omeprazole suspension in NaHCO3 (only PPI approved for this, but others may be used IV)
What is the role of PPI's in ulcer bleeding?
- Minor episodes of ulcer bleeding: oral PPI
- Required/received endoscopic tx for ulcer bleeding: IV PPI -> initial IV bolus, then IV infusion up to 72 hrs
1. This is NOT FDA-approved, but is considered STANDARD OF CARE
- NOTE: endoscopy thus determines how to best give PPI after ulcer bleeding
What is the MOA of Sucralfate?
- Sucrose aluminum octosulfate: synthetic salt that adheres to proteins in GI tract and forms insoluble coagulum, or PLUG over the ulcer
1. Aluminum irritates tissue in ulcer, leading to INC endogenous PG production + ulcer healing
2. Prevents further attack from pepsin and acid
- Works best at acidic pH, so should not be used with H2RA or PPI
- Binds bile salts (doubtful relevance for tx effect) and binds o/drugs intraluminally, slowing their absorption
- Rarely used in practice, but was used for GU, DU w/about same efficacy as H2RA's w/o suppressing acid secreton
How is Sucralfate taken? Indications? AE's?
- Taken orally, but hardly any systemic absorption
1. Some aluminum is absorbed, which may be problematic in pts with renal insufficiency
- As effective as H2RA for DU/GU: not used for this
- May be useful for problems (incl. pain and irritation) related to bile reflux into stomach (e.g. after certain types of surgery, like gastrojejunostomy): no clear evidence for this use
- Aluminum effect on GI tract: constipation
- May delay absorption of o/drugs by binding them in GI tract: give 2-3 hrs. away from other drugs it affects absorption of
- NOTE: used to be used to prevent stress-related ulcers and bleeding in UGI in critically ill pts in ICU bc thought to have less risk of nosocomial pneumonia than H2RA's, but now hardly ever used for this
- Synthetic analog of PGE1 taken 2-4x/day: approved for prevention of NSAID-related UGI ulcers
1. Use is limited by need to take multiple daily doses and dose-related adverse events
- AE's: potentially abortifacient bc uterotonic -> must NOT be given to women of childbearing potential
1. Frequently causes abdominal pain and diarrhea (which can be very severe)
- Largely supplanted by PPI's: as effective and much better tolerated w/freq of side effects similar to that of placebo (1x/d and rarely cause diarrhea)
1. PPIs superior for healing NSAID-related DU or GU; Misoprostol may be slightly better for preventing recurrence of GU, and PPI of DU
What is this?
- H. pylori: only exists in GASTRIC MUCOSA; cannot be found on normal duodenum, but can be found on ectopic gastric mucosa anywhere in the GI tract
- G(-) bacterium that lives on gastric-type mucosa in human GI tract -> pediatric infection w/adult consequences
- Single MCC of peptic ulcer and group 1 (“definite”) carcinogen
1. Most pts with H. pylori will never devo gastric cancer (1/100 – 1/1,000)
- When you find it, TREAT IT
- NOTE: H. pylori status at 7th birthday determines status in adulthood (unsure why)
How is H. pylori treated?
- Combo of 3–4 drugs for 10–14 days (preferably 14)
- Once successfully treated in adults, re-infection is very uncommon (can happen in young children, but they can clear it spontaneously)
- Advantages of tx in adults: potential to “cure” peptic ulcer disease (PUD)
1. May reduce risk of subsequent devo of gastric cancer by treating in young adulthood
What are the H. pylori drug combos? Resistance?
- Clarithromycin-based triple therapy (14d):
1. Clarithromycin + PPI + amoxicillin
2. Clarithromycin + PPI + metronidazole if pt allergic to penicillin
- Bismuth-based quadruple therapy:
1. Bismuth + PPI + tetracycline + metronidazole
2. Bismuth (essentially Pepto-bismol: toxic to H. pylori) + H2RA + tetracycline + metronidazole
- NO SUBSTITUTIONS ALLOWED
- RESISTANCE: 14-15% to Clarithromycin -> absolute phenomenon that can't be overcome, so if pt had this in past for Hp (or something else), use other combo
1. Amoxicillin, Tetracycline RES exceptionally uncommon in Hp; can be used again
2. If pt. tx'd w/Metro in the past, but didn’t clear, can tx w/this again, but probably at higher dose
What are the problems with treating H. pylori infection?
- Complexity: poor patient adherence
- Antimicrobial resistance:
1. CLARITHROMYCIN: taste disturbance -> never treat pt for H. pylori w/this twice
1. Metronidazole: avoid alcohol
- Essentially no resistance to: Amoxicillin, Tetracycline
- Diarrhea risk with any AB