33 - Drugs and the Gut Flashcards
What 2 types of drugs inhibit gastric secretion?
- H2 (histamine 2) receptor antagonists
- proton pump inhibitors
Who invented the first H2 receptor antagonist?
Sir James Black
- before this they did surgery/resection of vagus nerve
Most common gut disease?
Gastro-oesophageal reflux disease (GORD)
What do I need to know?
- the problems with the delivery of drugs to the appropriate region of the GI tract
- understand the appropriate treatment for gastric acid suppression
Histamine is involved in both … and …
Allergic reaction and gastric acid secretion
What 3 receptors are on parietal cells in the stomach?
- histamine receptors
- ACh/vagus nerve receptor
- Gastrin Receptor
How many histamine receptors are there and what are they?
2
H1 receptor - on smooth muscle and endothelial cells, responsible for allergy
H2 receptor - on parietal cells and responsible for acid secretion
What do anti-histamines work on?
They are H1 receptor antagonists
Anti-acid medications act on
H2 receptor
How do H1/2 medicines work
The drug and histamine COMPETE for the receptor binding site (competitive antagonist)
H2 receptor drugs are
competitive antagonists
What are the consequences of the H2 receptor antagonists being competitive antagonists?
- can be overcome by a strong agonist
- increasing the dose has a less additive dose
- there is a tolerance/trachyphylaxis
- rapid action and can saturate receptors in 6-8 hours
What is tachyphylaxis?
tolerance
Can be receptor saturation and so tolerance to the medicine - first dose response good but subsequent doses are less effective
What are some problems with H2 competitive antagonists?
- not effective for many patients with heartburn
- is unable to heal moderate to severe reflux oesophagitis
- needs multiple doses 4 times a day for severe symptoms
- the maximum acid suppression for H2 antagonists is 50%
- okay for peptic ulcers given as a single night dose BUT they reoccur on stopping the treatment
Are H2 antagonists effective for people with heartburn?
not effective for many
What is the maximum acid suppression for people taking H2 antagonists?
50% - not great
Do H2 antagonists cure peptic ulcers?
Work well when taken once nightly but once you stop taking it they reoccur
How long does the medicine last and what does this mean?
last 4-6 hours means you have to take it several times a day
Why is there only max 50% acid suppression?
gastrin and Ach also stimulate parietal cells
What do you use after H2 antagonists are ineffective?
Proton pump inhibitors
Why are proton pumps so important?
They are the final common pathway before acid secretion
Example of proton pump inhibitor?
Omeprazole
How does omeprazole work?
- absorbed into blood and travels to parietal cell
- in the presence of acid omeprazole is converted to sulphonamide
- sulphonamide reacts with the sulphydryl group of cysteine at the proton pump
- blocks entire pump resulting in 90% acid secretion suppression
Simply, what does omeprazole do?
Irreversible blockage of activated proton pump for a long duration/whole day
Perk of proton pump inhibitors compared to H2 inhibitors
- long lasting
- 90% suppression
- blockage CANT be over-ridden by an increased stimulation by histamine OR gastrin or ACh
What are proton pump inhibitors largely used for and not so much for?
- GORD
- ulcer disease CAUSED by NSAIDs (non-steroidal anti-inflam drugs) like aspirin
- useful in acute ulcer bleeding
- not so much peptic ulcer disease due to the improved treatment of H pylori infection
Why is omeprazole effective for acute ulcer bleeding?
Pepsin usually dissolves fibrin clot trying to form at ulcer - is inactive in higher pH, so blocking proton pumps increases pH and decreases pepsin activity
Who discovered H.pylori?
only treatment was H2 receptor antagonists
Barry Marshal
Proved by drinking H pylori to prove caused peptic ulcer disease (even though no treatment!!)
When should you use H2 receptor antagonists?
- one off heart burn
- good for nocturnal symptoms
- rapid onset and good first dose effect
- not as good for food stimulated acid secretion
When use proton pump inhibitors
- takes 4-6 weeks/10 days to see impact/several days for maximal effect
- good for maintenance treatment
- give empty stomach/30 min before meal as need to stimulate proton pumps
Long term problem with long term acid suppression?
- in ICU population can cause bacterial overgrowth of stomach
> aspirate stomach contents with bacteria causing pneumonia - malabsorption of B12/calcium/iron
- potential formation of carcinogenic compounds
- decreased sterilisation of food
- ECL hyperplasia (see as polyps) to compensate
What are 5 effects of the gut on drug delivery
- Acid can degrade drugs - need to be enteric coated
- Acid can enhance absorption
- Effect of rate of gastric emptying
> matching insulin and meals - Hepatic enzyme function
- Enterohepatic circulation/biliary secretion
Give an example of how gastric emptying can effect drug delivery?
i.e. matching insulin and meals. If you give insulin but have no rush of glucose in blood it will empty blood of the little BG it has > hypoglycemic. Need gastric emptying for food absorption and blood glucose for insulin to act on
> need a meal within 30 min of insulin dose
What are the problems and solutions of supplementing someone with pancreatic enzymes due to pancreatic insufficiency? patient has steatorrhea
- large vol of enzymes needed
- they are degraded by the gastric acid as require a neutral pH as is in the duodenum naturally
- enzymes need to be released/active in the proximal SI as this is where fats are absorbed
Possible solutions to supplementing pancreatic enz?
- enteric coated capsules. Means they are protected from the acid but their release will be delayed
- give proton inhibitor to decrease acid and increase pH to stop degradation
What is enteric coating?
acid resistant coating. Protected in stomach and delayed release in the small intestine
Creon =
pancreatic enzyme supplement
How does creon supplementation work?
Enteric coated minimicrospeheres in gelatin capsules
- the gelatin capsule dissolves in stomach release the 100s of minimicrospheres that are acid resistant
- the enteric coating of the minimicrospheres dissolves in a pH greater than 5.5 i.e. SI to release enzymes for fat digestion
Treatment for ulcerative colitis?
5 - ASA
Problem with 5-ASA?
5-ASA is the drug used to treat IBD BUT is degraded by gastric acid and needs to get to LI and terminal ileum (areas of inflam)
How to solve problem of acid degradable 5-ASA?
- Join 2 5-ASA molecules together with an AZO bond which needs colonic bacteria to BREAK
- Enteric coating to resist gastric breakdown
- Time dependent release
- pH dependent release (neutral/alkaline)
What is sulpasalazine?
5-ASA linked to sulphapyridine
needs colonic bacteria to cleave to be active
What are the limitations of sukpasalazine?
- adverse affects in 20% of people can include hypersensitivity or intolerance due to sulphur
- only successful in colon disease i.e. can’t give to CHRONS patient
- higher doses are more effective BUT cause more side effects
How can you target delivery of 5-ASA for IBD treatment?
- azo bond cleaved only by bacteria in colon
- moisture dependent release
- pH dependent release
- apply topically
= site specific delivery
What is the diagnosis - ibuprofen for 6 weeks > melaena
NSAID > gastric ulcers > omeprazole
NSAIDs cause .. from …
GI bleeding from gastric ulceration
How do NSAIDs work????
- arachidonic acid forms COX-1 (NSAID)
- COX-1 inhibits prostaglandin 2 which is primarily involved in cytoprotection
- results in decreased mucus secretion, HCO3- secretion and mucosal blood flow
- the alkaline mucus layer usually protects the gastric mucosa from acid
- results in injury to epithelium that can’t heal
- peptic ulcers and GI bleeding
- melaena
What 2 functions do prostaglandins have?
Cytoprotection (protects cells)
Inflammatory
What is the main mechanism of NSAIDs?
Inhibition of COX 1
What does COX 1 do usually?
Important in producing prostaglandins - inflam AND cytoprotection via stomach coating
How can you reduce the risk of GI bleeding from NSAIDs?
- stop NSAIDs; are they needed
- alternatives (panadol)
- use lowest dose
- use a protective drug AS well i.e. proton pump inhibitor/omeprazole
- COX2 inhibitor
Why use COX 2 inhibitor rather than COX 1
Cox 2 acts most for inflam while COX 1 is cytoprotective
risk of bleeding is halved
more expensive and ^ risk of myocardial infarction and stroke (work of platelet aggregation)
