Term
protective:
prostaglandins
mucus
bicarbonate
somatostatin
aggressive:
acid
pepsin
NSAIDs
Helicobacter pylori
imbalance between mucosal defense factors and damaging (aggressive) factors lead to acid-peptic disorders |
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Definition
| protective and aggressive mediators of the GI tract |
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Term
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secretion involves a proton pump (P), which is a H+/K+/ATPase
a symport carrier (C) for K+ and Cl-
and an antiport (A) which exchanges Cl- and HCO3-
an additional Na+/H+ antiport situated at the interface with the plasma may also have a role (not shown) |
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Definition
| hydrochloric acid secretion by gastric parietal cells |
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Term
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neurocrine: ACh stimulates M3 -> increased Ca -> acid secretion
endocrine: gastrin secreted into blood -> binds to CCK2 receptor -> increased Ca -> acid secretion
paracrine: histamine secreted by nearby cell -> binds to H2 receptor -> increased cAMP -> acid secretion
H+/K+/ATPase secrets HCl into the lumen |
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Definition
| therapeutic strategies to prevent gastric acid secretion |
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Term
duodenal ulcers
gastric ulcers
NSAID-related ulcers
gastroesophageal reflux disease (GERD)
upper gastrointestinal bleeding
part of the multidrug treatment for eradication of H. pylori |
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Definition
| therapeutic applications of H2-antihistamines and proton pump inhibitors |
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Term
G-protein = Gs (increased cAMP)
distribution: gastric parietal cells, cardiac muscle, mast cells, CNS
receptor agonist: dimaprit
receptor antagonist: cimetidine, ranitidine |
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Definition
histamine receptors
G-protein, distribution, agonist, antagonist |
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Term
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pKa values of 5.8 (imidazole ring) and 9.4 (aliphatic amine)
at physiologic pH > 96% as the monocation, 3% as the dication, and trace free base
as the pH of the environment changes the ionization of histamine will change
exists as a mixture of tautomers:
tau-NH preferred over pi-NH
NH3+ is an electron withdrawing group causing the closest N to become less basic
H prefers to be on the MOST BASIC N (tau-N)
the NH can differ in crossing a membrane or interacting with a receptor, also changes with ring substitution and electron effects |
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Definition
| acid/base properties of histamine |
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Term
the conformation of histamine is important in defining potency and selectivity
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anti: largest groups are 180 degrees apart
gauche: largest groups are 60 degrees apart
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anti conformation of 4-methylhistamine (fully extended) shows bad interaction, thus disfavored, give selective H2 agonist
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A: minimum, no real interactions
B: slight interaction
C: more interactions
D: extended conformation; methyl group and CH2 are touching each other; this form does not exist
need something that looks like A to bind the receptor |
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Definition
| conformational analysis of histamine |
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Term
[image]
alpha and beta methylhistamine exist predominately in gauche conformations - both are very weak at H1 and H2 (suggests anti-conformation is preferred for H1 and H2)
gauche conformation has been suggested at H3 since alpha-methylhistamine and other conformationally restricted analogues are potent H3 agonists
addition of OTHER alkyl substituents onto the imidazole ring generally reduces activity at H2
N-substitution nearly abolishes activity (on ring or alkyl amine) |
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Definition
| histamine structure/selectivity variations: summary of histamine receptor agonists |
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Term
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as basicity of imidazole derivative increases tautomeric equilibration occurs.
less basic histamine favors tau-NH so need to reduce pKa of burimamide
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metiamide:
produced significant increase in healing rate of duodenal ulcers and marked symptomatic relief
a few patients developed granulocytopenia (some kidney toxicity also observed). thiourea was suspected and is regarded as a "toxicophore" to stay away from in medicinal chemistry today
guanidine derivative:
this new guanidine was not a partial agonist (like original lead) but 20x less potent than metiamide
cimetidine:
a potent, selective H2 antihistamine and inhibits gastric acid release |
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Definition
| drug discovery/design strategy of cimetidine |
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Term
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first pass metabolism
hydroxylation of C4 methyl
oxidation of sulfide to sulfoxide, CYP3A4
much of dose is excreted unchanged
cimetidine inhibits CYP1A2, 2C9, 2C19, 2D6, 3A4/4/7 and there for can increase levels of drugs that are substrates for these enzymes including PHENYTOIN, THEOPHYLLINE, BENZODIAZEPINES, WARFARIN, GUINIDINE
the imidazole can coordinate the P450 iron center just as natural histidine
has greatest number of ADRs of class |
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Definition
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cimetidine
metabolism, drug interactions |
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Term
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10x more active than cimetidine with longer half life
isosterically similar to cimetidine
nitroketeneaminal group replaces cyanoguanidine
furan replaces imidazole - most likely a different interaction at the receptor
also interacts with CYPs but with an affinity of only 10% of cimetidine (inhibits CYP2D6) thus only minimally interferes with hepatic metabolism of other drugs
excreted largely unchanged
minor metabolic pathways include N-demethylation; N,S oxidations |
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Definition
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ranitidine
synthesis, CYP inhibition, metabolism |
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Term
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30x more potent than cimetidine
thiazole ring substitution in place of imidazole |
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Definition
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famotidine
synthesis and activity |
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Term
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thiazole ring substitution
last of the H2-antihistamines introduced prior to the advent of PPIs
des-methyl metabolite retains H2-antihistamine activity |
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Definition
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nizatidine
metabolism, synthesis |
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Term
the most potent suppressors of gastric acid secretion are inhibitors of the gastric H/K/ATPase (PROTON PUMP)
member of the P2-type ATPase family and undergoes a cycle of phosphorylation and dephosphorylation coupled to the outward transport of H+ and the inward transport of K+
conformations of the enzyme that bind ions for outward transport are defines as E1
those that bind luminal ions for inward transport are E2
ion binding to E1 activates phosphylation from MgATP to form the intermediate E1-P, which then converts to E2-P in the acid transport step
K+ binding to E2-P stimulates dephosphorylation to give an occluded form followed by conversion to E1-K+ and release of K+ to cytoplasm
PPIs bind to the outer face of the enzyme in the E2 conformation
ALL PPIS BIND TO CYS813 (AT LEAST) RESULTING IN COVALENT INHIBITION OF THE ENZYME VIA THE FORMATION OF A DISULFIDE WHICH STABILIZES THE ENZYME IN THE E2 CONFORMATION |
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Definition
| proton pump inhibitors - biochemistry |
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Term
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1) diffusion into lumen of gut from blood
2) protonization/accumulation
3) cyclization
4) covalent modifications of specific extracytoplasmic cysteine residue |
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Definition
| acid-catalyzed activation of omeprazole |
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Term
little, if any, unchanged drug excreted
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primarily a substrate for CYP2C19; CYP3A4 for a lesser extent
the S atom is a chiral center (omeprazole is racemic)
R(+) enantiomer cleared more rapidly
S(-) enantiomer clearance more dependent upon CYP2C19 form than CYP3A4
but, CYP3A4 mediated sulfone formation favors S(-) enantiomer
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Definition
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omeprazole
metazolism, CYP inhibition |
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Term
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S(-) enantiomer of omeprazole
greater BA in extensive CYP2C19 metabolizers
less variability in slow metabolizing CYP2C19 genotype |
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Definition
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esomeprazole
metazolism, structure |
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Term
metabolized by CYP2C19
fewer drug interactions than omeprazole
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Definition
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lansoprazole
metabolism and drug interactions |
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Term
metabolized by CYP2C19
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Definition
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pantoprazole
metabolism |
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Term
small amount of CYP3A4 oxidation (sulfone)
small amount of CYP2C19 (desmethyl)
extensively to thioether (nonenzymatic reduction)
bactericidal effect on H. pylori
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Definition
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rabeprazole
metabolism |
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Term
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dual delayed release formulation to provide 2 separate releases of medication
dexlansoprazole contains 2 types of enteric coated granules resulting in a concentration/time profile with 2 distinct peaks:
the first peak 1-2 hours after administration, followed by a 2nd peak within 4-5 hours |
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Definition
| special formulation of dexlansoprazole |
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Term
prodrug of omeprazole
designed to provide continued metered absorption: prolongation of plasma residence time |
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Definition
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Term
NOT a benzimidazole - imidazopyridine ring system
raises intragastric pH higher than esomeprazole |
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Definition
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Term
numerous classes under development
may have improved performance in long term use (hypergastrinemia) if successful.
revaprazan has reached clinic currently
these are competitive inhibitors of K/H/ATPase and are referred to as acid pump antagonists (APAs) or competative acid blockers (CABs)
SCH 28080 was used to competitively prevent omprazole from binding to confirm mechanism |
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Definition
MOA of reversible PPIs
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Term
PGE2 and PGI2 are the major prostaglandins synthesized in the gastric mucosa
they bind to the EP3 receptor on parietal cells and stimulate the Gi pathway, thereby decreasing intracellular cAMP and gastric acid secretion
PGE2 also cytoprotective, stimulating mucus and bicarbonate secretion and increasing mucosal blood flow
NSAIDs diminish PG formation by COX inhibition, lead to gastric damage, ulceration
thus synthetic PG analogs are a possible therapeutic strategy |
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Definition
| role of prostaglandins in gastric acid secretion |
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Term
[image]
only available oral prostaglandin in the US
the orally administered methyl ester is rapidly converted to the active acid
synthetic analog of PGE1 with structural modification of moving the alcohol from C-15 to C-16 and the addition of a C-16 methyl to afford a tertiary alcohol, prevents rapid metabolic deactivation (normal paracrine fate)
Primary catabolic pathway of prostaglandins is initiated by the oxidation of the 15S-hydroxyl group catalyzed by NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH).
mixture of diasteromers is used, most activity derived from the 11R, 16S isomer
effectively reduces basal or food-stimulated gastric acid secretion
administered with some NSAIDs to reduce ulcer/bleeding risk
smooth muscle contraction properties
can cause diarrhea, with or without abdominal pain and cramps
abortifacient, contraindicated during pregnancy, can cause uterine contraction
a polymer delivery system of the active isomer of misoprolol may be a solution to the intestinal side effect problem (only has a local action) |
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Definition
| MOA and ADRs of misoprostol |
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Term
[image]
pirenzepine produces the same rate of healing of gastric and duodenal ulcers as cimetidine or ranitidine
telenzepine has a higher potency than pirenepine
ACh receptors on parietal cells are of the M3 subtype.
however, these drugs are believed to suppress neural stimulation of acid production via actions on M1 receptors of intramural ganglia
anticholinergic ADRs: dry mouth, loss of visual accomodation, photophobia, difficulty urinating |
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Definition
| muscarinic antagonists used to prevent acid secretion and MOA |
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Term
The integrity of the bicarbonate buffered mucus layer is compromised in peptic ulcer
Sulfated polysaccharides inhibit pepsin mediated protein hydrolysis; development of a bioadhesive to mimic this effect
White powder, insoluble in water.
When exposed to the acidity of stomach polymerizes to form a sticky gel that adheres to epithelial cells; it adheres very strongly to the damaged crater of an ulcer (up to 6 hours for a single dose)
Antacids and foods do not affect the integrity of the adherent gel. Thus a strong, protective coating, a replacement for missing mucus is formed
above a pH of 2, sucralfate can inhibit pepsin by adsorption and buffering; below a pH of 2 no inhibition but effective gel formation
sucralfate enhances PGE2 production by stimulating PLA2 for arachidonic acid release |
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Definition
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Term
[image]
bismuth subsalicylate is the active ingredient suspended in a mixture of magnesium aluminum silicate clay
in the acidity of the stomach, bismuth subsalicylate forms salicylic acid, which is absorbed, and various bismuth species
bismuth is thought to have antisecretory, anti-inflammatory, and anti-microbial properties
may form polymers (3-10) in aqueous solution in the stomach to coat ulcer craters |
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Definition
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Term
gastric antacid
effective at neutralizing acid
very water soluble
reacts rapidly
rapidly absorbed from stomach (sodium and alkaline load may be risky for patients with cardiac or renal failure) |
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Definition
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Term
gastric antacid
depends upon particle size and crystalline form
rapidly and effectively neutralizes acid
Ca can induce rebound secretion as it activates the calcium sensor receptor, a GPCR which stimulates gastrin secretion from G-cells and duodenum |
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Definition
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Term
hydroxymagnesium aluminum complex
gastric antacid
rapidly converted to Mg(OH)2 and Al(OH)3 in stomach acid
these are often gel-like and absorbed poorly providing sustained effect
Al3+ can relax gastric smooth muscle producing delayed emptying and constipation
Mg2+ contains opposite effect, supposed to balance each other out. |
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Definition
| MOA and ADRs of Al5Mg10(OH)31(SO4)2·xH2O - magaldrate |
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Term
surfactant that reduces surface tension of gas bubbles
often added to antacids |
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Definition
MOA of simethicone
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