20 - GI Pharmacology Flashcards
What defence mechanisms does the stomach have against stomach acid?
- Epithelial integrity
- Cell replication and restitution by stem cells in the crypts
- Alkaline mucous membrane barrier against the acid
- Vascular supply regulated by COX causing vasodilation of the collareral blood supply (can be affected by NSAIDS)
What factors aggrevate gastric muscosa?
- Acid
- Drugs
- Helicobacter pylori
What are the symptoms, complicatons and risk factors for GORD?
What is the stepwise management of treating GORD?
1. Lifestyle: change diet, lose weight, elevate head whilst sleeping, stop NSAIDs as these interfere with prostaglandins helping blood supply to stomach
2. Antacids: Gaviscon is alkaline so buffers for short term relief
3. H2 RA: rantidine which have short half life so need to dose twice a day. cheap and few side effects
3. PPIs: omeprazole, lansoprazole, esomeprazole
4. Fundoplication
How can we treat gastritis?
Erosive Cause: remove irritant (NSAIDs, alcohol, bile) and give PPIs or H2 RA
Non-erosive Cause (H Pylori): triple or quadruple therapy
Autoimmune Cause: Give cyanocobalamin
Need to treat as gastric atrophy predisposes to cancer
How do we treat peptic ulcer disease?
H Pylori Negative:
- Stop NSAIDs, consider Celecoxib as this is COX2 inhibitor so won’t affect COX1 prostaglandin synthesis
- PPI or H2 RA
- If you need to continue NSAIDs (e.g RA) then consider misoprostol (prostaglandin analogue)
H Pylori Positive:
- H Pylori eradiaction scheme followed by C-13 urea breath test or stool antigen test to check eradicated
Why are COX-2 inhibitors like Celecoxib not good long term?
Even though they can be gastric protectants but not good for CVS as unbalanced thromboxanes
How do prostaglandins aid mucosal defence in the GI system?
- Decrease acid secretion
- Stumulate mucus and bicarbonate secretion in stomach
- Reduce permeability of epithelium to acid
- Reduce release of inflammatory mediators (e.g histamine) that may contribute to mucosal injury
- Promote ulcer healing by increasing blood flow to area
What are the stimulatory receptors on the basolateral membrane of a parietal cell?
How do parietal cells transform from a non-secreting state to a secreting state?
- When non-secreting the proton pumps (H+/K+ ATPase) are located in tubulovesicles that lack K+ permability so pumps cannot work
- When secreting the vesicles fuse with the membrane which moves the pump into a position where they can exchange H+ for K+
What is the mechanism of action of PPIs and what are some examples of this drug?
Lansoprazole and Omeprazole
Bind irreversibly to gastric H+/K+ ATPase and block its function suppressing ALL acid secretion as de novo synthesis of pump needed for more acid
Basic prodrugs that accumulate in acidic parietal cell canaliculus to give high concentration
Need enteric coating to prevent premature activation as unstable in acid
How are PPIs metabolised and excreted?
- Metabolised by CYP3A4 and CYP2C19 in the liver so smaller dose in liver failure
- Excreted by kidneys
What are the ADRs and DDIs associated with PPIs?
- Risk of gastric carcinoid tumours as increase levels of gastrins so parietal cell hyperplasia
- Headache, nausea, GI tract issues, abdominal pain, osteoporosis (long term)
- Decrease effectiveness of clopidogrel (antiplatelet) as both use CYP2C19 but clopidogrel needs to activate
- Risk of infection when used in hospital as reduced innate barrier
- Inhibit CYP2C so decrease metabolism of warfarin and phenytoin
What is the mechanism of action of H2 RAs and what are some examples of this drug?
Ranitidine
Reversibly binds to H2 receptors and also indirectly blocks effects of gastrin and Ach on parietal cell. Stops PKA production needed to change shape of parietal cell
Absorbed by SI, excreted by liver and kidney
Not as effective as PPIs as doesn’t target end pathway of stomach acid production
What are the ADRs and DDIs associated with H2 receptor antagonists?
- Diarrhoea, constipation, muscle ache, fatigue, headache
- Reduced ketoconazole absorption as need acidic environment but normall topical antifungal so doesn’t matter
- Cimetidine inhibits CYP450 enzymes so increases lidocain, phenytoin, theophylline and warfarin levels to toxic doses in the blood
What are the mechanism of action of prostaglandin analogues, what are the side effects and the contraindications for this class of drug use?
Misoprostol
Act on similar pathway to H2 RAs
Diarrhoea and abdominal pain which often cause non compliance
Cannot be used in pregnant woman as can cause uterine contractions, abortion drug
What are some of the main antacids and how do they work?
- Aluminium Hydroxide neutralises HCl
- Alginic acid in the presence of saliva can combine with sodium bicarbonate to inhibit reflux as sodium alginate produced
What is the step up step down therapy used in the treatment of GORD?
Step up: start patient on H2 RAs as cheaper and then progress to PPIs if neccessary
Step down: start on PPIs and then see if you can drop to H2 RAs to maintain
If no economic considerations continuous PPIs would be used
How do we eradicate H.pylori?
Triple therapy for a week (10-14 days only increases eradication by small amount)
- PPI and 2 antibiotics
- Need to check for eradication with urea breath test, if there is a failure to eradicate it is often to do with non-adherance as polypharmacy
- SEs include diarrhoea, nausea
How does H pylori lead to the development of peptic disease?
What is a high output stoma?
- When the output of a stoma causes the patient to become water, sodium and magnesium depleted
- Often when the whole large bowel is removed as the large bowel removes a lot of water from the faeces
- Can give patient loperamide before eating, PPIs to stop stomach secretions
