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Flashcards in GI drugs Deck (76)
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How do ulcers occur?

imbalance between defensive (mucous barriers) and aggressive (acid production) factors, leading to tissue damage


Where to peptic vs gastric ulcers form?

peptide = duodenum, stomach
gastric = stomach


What are four protective factors against ulcer formation?

Mucous - continually secreted, protective effect bicarbonate - secreted from endothelial flow
blood flow - maintains mucosal integrity
prostaglandins - stimulate secretion of bicarbonate and mucous, promote blood flow, suppress secretion of gastric acid


What causes ulcers?

- helicobacter pylori infection
- increased gastric acid
- decreased mucosal blood flow
- increased pepsin
- reduced bicarbonate
- reduced thickness of mucous layer
- NSAIDs: decreased constitutive PG's and Cox-1 inhibition
- smoking: nicotine stimulates gastric acid production by acting on ACh receptors


how many people are infected worldwide with helicobacter pylori? How many develop Peptic ulcer disease (PUD) or gastric cancer?

50-80% of world population; 10-20% develop PUD or gastric cancer


Which cell pumps H+ ions out into the stomach? What reaction leads to the production of H+ ions in these cells?

Parietal cells. CO2 and H20 react with carbonic anhydrase to produce carbonic acid. Carbonic acid then dissociates into bicarbonate and hydrogen ions. The hydrogen ions are pumped through an ATP dependent channel into the stomach lumen.


How does Cl- ions get into the stomach lumen?

Cl- ions are pumped from the plasma into the parietal cell. Then are pumped out the luminal side of the parietal cell and forms HCl with H+ ions.


What are the treatment strategies for peptic ulcers?

- non pharmacological
- anti-secretory agents
- cytoprotective agents and mucosal strengtheners
- treating helicobacter pylori


What are the groups of anti-secretory agents?

H2-receptor antagonists, proton pump inhibitors, antimuscarinic drugs


What are the groups of cytoprotective agents and mucosal strengtheners?

sucralfate, prostaglandins, bismuth, antacids


What are some non pharmacological measures to treat peptic ulcers?

- avoid smoking
- avoid alcohol
- weight loss
- avoid hot, spicy and greasy foods
- administer NSAIDs with food or in low dosage
- do not just eat before bedtime


What type of receptors do PGE2, gastrin, ACh and histamine bind to on the parietal cell membrane?

G-protein coupled receptors


What second messenger system is activated upon binding of gastrin, ACh and/or histamine to the parietal cell membrane?

GPCR - increases conversion of ATP to cAMP, increase in [Ca2+]i, increased activated protein kinases, increased H+/K+ ATPase pumps leads to increased H+ in stomach lumen


What happens when PGE2 binds to parietal cell membrane?

binds to GPCR - inhibits conversion of ATP to cAMP; inhibits gastric acid secretion by inhibiting production of H+/K+ ATPases


How does gastrin move around the body?

Hormone released in the bloodstream


What do enterochromaffin-like cells do?

Stimulated by ACh or gastrin, cause the release of histamine, histamine binds to H2 receptors stimulating gastric acid secretion


What is the mechanism of action of H2 receptor antagonists?

reversible competitive inhibitors of H2 receptors, compete against histamine - block the effects of histamine - reduce gastric acid secretion
- inhibit nocturnal acid secretion
- promote healing of duodenal ulcers
- relapse on withdrawal (increased acid secretion)
e.g. ranitidine 'Zantac', 'Ranihexal', 'Ranoxyl'


What are the pharmacokinetics for H2 receptor antagonists like cimetidine, ranitidine, famotidine, nizatidine

- famotidine 30x more potent than cimetidine; ranitidine and nizatidine 5-10 x more potent than cimetidine
- 1/2 life of 1-4 hours
- famotidine longest acting (12 hours)
- all have renal elimination, ranitidine and famotidine have liver or biliary elimination
- cimetidine is a potent inhibitor of cytochrome P450


ADRs of histamine receptor antagonists?

- very low incidence of reversible side effects
- e.g. headache, dizziness, skin rash, nausea, diarrhoea, confusion
- more rarely: impotence and gynaecomastia
- cimetidine may interfere with hepatic metabolism (CYP450) of certain drugs e.g. warfarin, theophylline, phenytoin, ethanol
- absorbed orally: decreased absorption if taken with antacids
- high renal excretion: blood levels rise quickly in patients with renal failure


Mechanism of action of proton pump inhibitors (PPI)?

- first line treatment in peptic ulcer disease
- block acid secretion by irreversibly inactivating the hydrogen-potassium pump (H+/K+) ATPase proton pumps at the parietal cell surface
= prodrugs at neutral pH, activated in acidic environment


Features of PPIs

- weakly basic: they accumulate in the canaliculi of parietal cells
- are activated in canaliculi and bind covalently to extracellular domain of H+/K+ ATPase
- irreversible inhibition of proton pumps, therefore acid secretion resumes only after the synthesis of new molecules
- they are the most effective drugs in anti-ulcer therapy (~90% inhibition)
- 'prazole' e.g esomeprazole


What are the pharmacokinetics of PPIs?

- administered as capsules containing enteric coated granules to ensure they reach site of action
- pantoprazole is given iv
- t1/2 1-1.5 hours and affects acid secretion for 2-3 days
- administered 1 hour before meals
- other acid suppressing agents are not co-administered


ADRs of PPIs?

- extremely safe (some headache, skin rashes, dizziness; rarely gynaecomastia, renal impairment)
- inhibit CYP450 (less metabolism of warfarin, phenytoin, theophylline) but newer drugs like pantoprazole and rabeprazole have no significant interactions


Mechanism of anti-muscarinics?

rarely used due to significant ADRs
- constipation, dry mouth, blurred vision, urinary retention, gastric stasis, *skin rashes* = all ADRs are similar to atropine except skin rashes


Are gastrin antagonists used often? Why/why not

Largely experimental - poor effectiveness (used overseas, not in Australia)


route of administration for somatostatin analogues?



What is sucralfate?

= complex of aluminium hydroxide and sulphated sucrose
- viscous at acid pH and adheres to surface of ulcers, to act as a barrier to the aggressive luminal factors e.g. acid, pepsin, bile salts
- stimulates mucosal protecting mechanisms e.g. mucous, bicarbonate, PG's
- taken on empty stomach 1hr before meals (4/day)
- antacids and meals should not be taken within 30 minutes of sucralfate as they may raise the gastric pH and alter the physicochemical properties of sucralfate


ADRs of sucralfate?

- constipation
- inhibit absorption of some drugs as it coats the lining of GIT


Mechanism of action of prostaglandin analogues?

PGE2 and PGI2 are protective of GIT lining
- inhibit acid secretion, increase mucosal blood flow and mucous, cytoprotective on gastric mucosa
e.g. misoprostol (PGE1 analogue) - produces same effects as prostaglandin E, has comparable ulcer healing efficacy with H2 receptor antagonists
- only used in patients using NSAIDs with high risk of ulcer


What are ADRs and contraindications of prostaglandin analogues?

ADRs: - pain endings are sensitised so pain is often worse initially
- diarrhoea, nausea, headache and dizziness
- contraindicated in pregnancy as prostaglandins stimulate uterine contractions