Pharmacology of ulcers and inflammation

What is a peptic ulcer?

Errosion of small parch of stomach lining or duodenal lining leads to stoamch or duodenal ulcers and causes inflmamtion and pain

How can a peptic ulcer be revealed

By a gastric endoscopy

What are the symptoms of peptic ulcers

Malaise, loss of appetite , abdominal pain , gastric irritation, vomiting, perforation, bleeding, inflamed mucosa , submucosa and cell infiltration

What is the pathogensis of peptic ulcers

Overwhelmed mucosal defence

H pylori

Mucosal erosion pain inflammation bleeding

What protective factors are there that protect from ulceration

Protective mucus surface layer

Secrete bicarbonate - increases ph of stomach lining so less likely to be damaged

Cytoprotective prostaglandins eg pge2 pgf2a

Good mucosal blood flow - prevents aggressive factors like stomach avid building up

Epithelial regenerates - able to withstand damage and regeneration

Epithelial tight junctions - hold epithelial cells together - prevent acid diffusion into lamina propria

Explain some mechanism involved in gastric mucosal protection and gastric acid secretion

PGE can stimulate goblet cells to release mucus and bicarbonate in to gastric lumen - ph 7 is maintained

Gastric lumen ph 2

Epithelial cells - ph 7

Parietal cells secrete hydrogen ions - increase gastric acid - H+ K+ atpase pump - increases H+ secretion

Endogenous gastric - activates endocrine receptor, causes release of histamine which acts on h2 receptors initiating EP receptor activity which increase camp activity

Can add prostaglandins - like pge2 can bind to EP receptors on parietal cells - inhibits camp activity so less hydrogen ions secretion and acid secretion

Muscarinic and h2 receptor agonist - increase acid secretion

Muscarinic stimulation can lead to bicarbonate and mucus secretion

PPIs - protect against ulcers

Change in calcium levels - within parietal cells can stimulate acid secretion

What does PGE do

Can stimulate goblet cells to secrete mucous and bicarbonate in to gastric lumen makes the epithelial layer higher ph of 7 whilst acidic gastric lumen is ph2 - protection from that

Why do parietal cells allow for increased gastric secretion

Have H+K+ ATPase which secrete H+ increased hydrogen secretion means more gastric acid

How does gastric increase acid secretion

Gastrin activates endocrine receptors results in release of histamine which acts on h2 receptors causing in created acid secretion

Can result in EP receptor activation resulting in increase CAMP levels so more acid secretion

How can prostaglandins reduce gastric acid secretion

Can bind to EP receptor on parietal cell prevent CAMP increase less camp means less hydrogen ion secretion and acid secretion

What drugs can increase acid secretion, what can reduce and what levels can cause acid secretion

Increase acid secretion : h2 receptor agonists and muscarinic receptor stimulation- increase acid secretion , muscarinic receptor stimulation can result in bicarbonate secretion and mucous so its protective

Calcium - change in calcium levels within parietal cells can stimulate acid secretion

Reduce - prostaglandins - bind to EP prevent camp increase so less acid secretion

And ppi - inhibit h+ k+ ATPase pump so less acid secretion

List some factors that can attack gastric and duodenal mucosae

Acids and Pepsins

Bile reflux and gastric emptying

Lack of prostaglandins - eg NSAIDs can inhibit prostaglandin production

No epithelial regeneration eg due to anti cancer drugs

Stress alcohol aspirin

H pylori

Micro vascular vasoconstriction - reduced blood low to gastric mucosa - can't repair itself

Describe how acid stimulators can cause gastric ulcers, histamines, gastric ach

Have h+ k+ atpase pump - releases h+ in to gastric lumen and k+ inside cell

Gastric - causes increased acid secretion - activates endocrine receptors causes histamine release which acts on h2 receptors - causes increase in camp activity causing increased acid secretion. Can also activate calcium dependent atpases increasing acid secretion

Prostaglandins - can activate EP receptor - inhibit this h2 mechanism and inhibit the camp activity reducing acid secretion

ACH - released by vagus nerves, acts in muscarinic receptors which increases acid secretion, increase risk of ulcers

What does histamine do?

It's the final common mediator

What does histamine, gastric and ach cause

They act on parietal cell , they activate the atp dependent proton pump - exchanges h+ for k+

How does PGE2 work

It inhibits the same pump by reducing CAMP activity within parietal cells

What can you give to relieve pain of ulcers

Antacids they neutralise acids reduce secretion include AL(OH)3 NaHCO3 Mg carbonate

What can you give for ulcers to allow healing

Mucosal strengthens

Anti secretory agents

Give h2 antagonists

How can you prevent relapse of ulcers

Avoid stress alcohol smoking aspirin change lifestyle

What can you give for h pylori

Give antibiotics

Combo therapy of PPi antibiotics

Eg omeprazole clarithryomycin metronidazole or amoxicillin

After a positive urea breath test

What can you give to improve mucosal defence/ strength

Bismuth chelate - covers ulcer area - caused stained stools tongue , lower relapse, can use in combo with clarithroymcin and another antimicrobial if needed

Sucralfate- protects ulcer area

Upsides and downsides of antacids

Pros neutralise acids quickly eg mucogel - and given when think you'll get pain like between meals

Downsides - as ph increases more acid gets secreted so don't use for over 4 weeks

The cations non absorbable eg mg2+ can have a laxative effect and Al3+ can have a constipating effect

Eg gaviscon

Give examples of h2 antagonists that reduce acid secretion and what they do

Ranitidine, cimetidine, famotidine

Block endogenous h2 histamine from increasing camp activity and reduces acid secretion

Reduce acid secretion under fasting, meal induced, sleeping conditions relapse is common, give at bed time to prevent relapse

Give examples of ppis and how they reduce acid secretion

Like omeprazole, lansoprazole

Can inhibit proton dependent atpase pump - h+ k+ atpase pump at ph3

They're prodrugs at ph 7

What does sucraflate do

Makes unstirred layer more robust

Improves mucosal defence

What effect does aspirin have on ulcers

Blocks enzyme that makes PGE2 - has an ulcerative effect

Give an example of anti muscarinic and why they're not used anymore

Pirenzipine

Can have widespread effects, blurred vision, dry mouth, difficulty in mictruition

Reduced gastric motility - so have anti ulcer effect

What do prostaglandin analogous do eg misoprostol

They're antisecretory cytoprorective

They mimic the action of pge2 - which normally allows mucus and bicarbonate release and is a vasodilator

They have affinity ep receptors cause bicarbonate and mucus release

Reduce camp activity and h+ depended atpase activity on parietal cells h+ k+ atpase pump

It's an agonist

Can prevent NSAID associated ulcers

What are the causes of inflammatory diseases

Elevated levels of tnf alpha and inf y

What does ulcerative colitis involve

Large bowel

What does Crohn's disease involve

Small intestinal and it's due to inf y

What's the aim for inflammatory bowel disease

Aim to reduce episodes and prolong remission

Give two examples of anti inflammatory

Corticosteroids aminosalicylates

Give an example of anti cytokine agents

Infliximab

Give examples of corticosteroids for inflammatory bowel disease and what it does

Enema or systemic

Prednisolone, hydrocortisone, budesomide

Inhibits phospholipase A2 activity and AA-PG cascade

What do you give if steroids don't work

Give immunosuppressive likes ciclosporin to reduce T cell number and signalling

What do monoclonal TNFa antibodies be used for

Eg infliximab inhibits tnfa activity

Adalimumab- for severe crohns disease if patient is intolerant to steroids and for maintenance therapy in cd

Give examples of aminosalicylates used

Sulfalazine (prodrug) , mesalazine

Take orally or rectal

Bacterial degradation releases 5 ASA

Olsalazine- 2 molecules of 5 ASA given orally