B.23 Flashcards
Drugs influencing gastric acid secretion, protective drugs of gastric mucosa
- PPIs: (Es)Omeprazole, Pantoprazole
- H2-R antagonists: Famotidine
- Antacids: Mg(OH)2 (magnesium hydroxide), Al2(OH)3 (aluminum-hydroxide)
when PPIs should be taken?
PPIs Should be taken 1h before meal since the acid secretion in the secretory canaliculi is stimulated by meals, and acidic environment favors the production of active form of PPIs
(es)Omeprazole, Pantoprazole
MOA: PPIs, inhibits H+/K+-ATPase (→Absorbed in the alkaline intestines→ enter parietal cells and the secretory canaliculi → they are concentrated and protonated and form the active compound, thiophillic sulfonamide cation → it forms a disulfide covalent bond with the cystein of H+/K+-ATPase);
Kinetics: Pro-drugs, should be taken 1h before meal, 3-4 days are needed for maximal effects, lipophilic, weak bases, acid sensitive, formulated as
(1)acid resistant enteric coated capsules(→against acid-induced destruction),
(2)delayed release (omeprazole-also as powder with bicarbonate) and
(3)immediate release.
bind plasma proteins, hepatic metabolism (CYP2C19, 3A4), BA p.o order Pantoprazole >Esomeprazole >Omeprazole, T1/2-0.5-2h;
Effects: inhibits both basal and meal-stimulated acid secretion, inhibits acid secretion by 90-98% for 24h; IND: GERD (non-erosive reflux- H2 blocking drugs intermittent with PPI, Erosive esophagitis- PPIs, once daily or twice daily, Extra-esophageal reflux- twice daily), Peptic ulcer disease (80-90% healing of gastric ulcer after 6-8 weeks, or after 4 weeks in duodenal ulcer), NSAID-ASA-induced ulcer (10-20% asymptomatic ulcer, 1-2% bleeding perforation), Inhibition of rebleeding of peptic ulcer (pH should be above 6→high p.o dose or continuos i.v infusion), Stress ulcer (PPI by nasogastric tube or i.v (omeprazole-immediate release), H.pylori associated acute ulcer (combined with abx), Zollinger Ellison syndrome (1st choice!→gastrinoma, neuroendocrine tumor secreting gastrin, located in pancreas/duodenum);
SEs: Hypergastrinemia (hyperplasia of ECL-cells, carcinoid tumor in rats), bacterial overgrowth (→Potential risk), GI disturbances (rare), CNS (→headache, dizziness), skin rash, leukopenia, acute interstitial nephritis. SEs in long term treatment (GERD, NSAID-induces, aspirin induced ulcer)→Problems related to reduced acid secretion (e.g. bacterial colonization in the stomach), Community aquired and nosocomial pneumonia, Bacteria induced diarrhea (e.g. C.difficile, Salmonella etc), Nutrition problems (with impaired absorption of vit B12, iron, Ca2+), Osteoporosis (increased risk of hip, spine, wrist fractures)
Omeprazole interactions
(1)Omeprazole inhibits the formation of the active metabolite of Clopidogrel→the reduced antiaggregation may result in reinfarction. Mechanism: CYP2C19 is responsible for the formation of the active metabolite of clopidogrel and the metabolism of omeprazole.
(2)Inhibition of the absorption of vitamin B12, ampicillin, ketoconazole and iron-salt
Famotidine
Antisecretory agent;
MOA: H2-R antagonist
(competitive reversible antagonism of H2-R - Gs-PCR on parietal cells→↓AC activity→↓cAMP levels→↓PKA activity→↓phosphorylation and activation of H+/K+ ATPase→↓gastric acid secretion);
Effects:
(1)Inhibition of gastric acid secretion- inhibits both basal and stimulated (M-antagonist, gastrin) gastric acid secretion, especially effective in nocturnal (H2-R mediated) and fasting acid secretion, Less effective against meal stimulated acid secretion (gastrin-, ACh-, H2-R mediated).
(2)Other- enhanced immune response (?), Antagonism of certain effects of histamine on heart and vessels (H2-R mediated);
Kinetics: good abs. from the stomach (food, antacids reduce its abs.) Significant First pass metabolism, wide distribution, crosses the placenta, secreted into breast milk, metabolized and excreted by the kidneys (glomerular filtration, tubular excretion)→dose adjustment in renal failure, DOA- 10h (x2/day);
IND: GERD (x2/day, less than 3 heartburn/week→in erosive esophagitis PPIs!!), Peptic ulcer disease (largely replaced by PPIs)→ Duodenal ulcer (85-90% are healed after 8 weeks treatment), Gastric ulcer (50-70% healed after 8 weeks), with NSAID (for prophylaxis! in active ulcer→PPIs!!), Non-ulcer-intermittent dyspepsia- stress ulcer (deacreased bleeding incidence), Perianesthetic medications (in emergency);
SEs: VERY SAFE, headache, dizziness, nausea, diarrhea, constipation, myalgia, skin rashes, pruritus, nosocomial pneumonia (RARE!), CNS disturbances (in elderly), Rare effects (→thrombo-leukocytopenia, hepato-renal toxicity, i.v. inj.-bradycardia via H2-R); Common problems of antisecretory drugs: Hypochlorohydria (favors bacterial survival/respiratory infections/nosocomial pneumonia, atrophic gastritis), Diagnosis of gastric cancer can be retarded in the presence of PPIs/H2-R blockers);
Dose: 40mg at bedtime→ 2x20mg
Mg(OH)2 (magnesium hydroxide)
Antacid;
Chemistry: Mg(OH)2+2HCl=MgCl2+2H2O;
Kinetics: poor solubility, prolonged neutralizing effect, cathartic effect;
SEs: diarrhea, hypermagnesemia (if absorbed)
Al(OH)3 (aluminum-hydroxide)
Antacid;
Chemistry: Al(OH)3+3HCl=AlCl3+H2O;
Kinetics: insoluble, slow action;
SEs: constipation, if absorbed can cause encephalopathy;
Drug-interaction: binds tetracyclines, phosphate
Gastric epithelial damage
Cytotoxin
Ammonia and derivatives (urease)
PLA2 and PLC activity
Leukotriene release
PAF release
Endotoxin-induced endothelial damage
Aggressive factors
- HCl, pepsin
- H.pylori
- NSAIDs
Protective factors
- Mucous-bicarbonate layer
- Surface active phospholipid
- Tight junctions proteins
- Mucosal microcirculation (PG, NO)
Types of ulcers
Ulcer - Type I:
In case of {distal, antral and duodenal ulcers hypersecretion is observed → dominancy of aggressive factors
Ulcer - Type II:
In case of upper gastric ulcer and the acid secretion is normal or decreased (Tends to malignant transformation!→ Decreased defensive mechanisms:
Ulcer disease: Damaging the aggressive factors
Therapy: inhibition of acid secretion, antibacterial agents
Ulcer disease: Damaging the protective factors:
Therapy: Sucralphate
Ulcer therapy
- Inhibition of aggressive factors:
Anti-secretory agents
Neutralizing agents - Enhancement of gastric mucosal defense (=Increased mucosal resistance):
Sucralfate
Bismuth compounds
Rabepramide - Inhibition of aggressive factors+Increase of mucosal resistance:
Prostaglandins - Eradicaiton of H.pylori:
Triple therapy
Modified triple therapy
Alternative triple therapy
“Rescue” therapy
- Inhibition of aggressive factors
Anti-secretory agents:
1. H2-R antagonists
2. PPIs
3. Potassium-competitive acid blockers (PCAB)
4. M1-R antagonists
Neutralizing agents:
1. Antacids (Sodium-bicarbonate, Sodium-citrate, Magnesium-hydroxide, Aluminium-hydroxide, Basic Aluminium-carbonate gel, Aluminium phosphate gel, Calcium-carbonate, Combination-Magaldrate)
