42- ulcers Flashcards
discuss the timeline of ulcer drugs. what was it like pre 1960’s. how were they treated in the 1960s. what was introduced in 1976. what was introduced in 1989. what was discovered in 1984.
- Before 1960
- Ulcers dangerous and often fatal
- Significant impact on quality of life → painful, needed diet
- 1960’s
- Treat ulcers with antacids and diet
- 1976 H2 antagonists introduced
- Lowers acid production in the stomach → by controlling regulatory processes
- 1989 Proton pump inhibitors
- Prevents acid production in the stomach
why are ulcers fatal and how many deaths per year in north america
- Estimate >20,000 deaths per year North America
- Bleeding is internal, no blood visible
how much was spent on antacids in 2014
1.4 billions
how much was spent on prescription stomach meds in 2014
20 billion
why does acid in the stomach cause ulcers
- Stomach contains acid
- Acid is corrosive
- Therefore excess acid causes corrosion of the stomach (ulcer)
what do antacids treat
- only the symptoms
- base that gets rid of excess acid
what are some of the bases used for antacids
- sodium bicarbonate
- calcium carbonate
- oyster shells
- milk of magnesia Mg(OH)2
- metal hydroxides Al(OH)3
discuss how neutralizing stomach acid treats the symptoms.
- Works only short term
- Does not address the underlying cause → only treating symptoms
- Body produces too much acid
why do metal salts in antacids cause problems
- Body does not metabolize metals well
- Metals often build up in body
- kidney
why is reducing acid production safer
- Can use organic compounds
- Safer than metals
- Body can remove them
- Organics suitable for long term
- Address the underlying cause directly
- Excess stomach acid
discuss the market potential of ulcer drugs
- Chronic condition
- Drugs treat not cure
- Serious condition
- Fatal
- Big impact on quality of life
- Large numbers of patients
- Developed world
- Patients can pay
discuss the development of tagamet. what was it based on and what did it suggest?
- Project started in 1964
- Early example of rational drug design
- Based on animal experiments
- Administering histamine to animals resulted in increased stomach acid production
- Suggested that histamine helped to regulate acid production (hormone)
why was histamine a high risk project but what were they a proof of
- Histamine receptor was not known
- High risk project
- Histamine antagonists were possible (proof of principle)
- Allergy medications available since 1930’s
- first step
what happened when animals were injected with histamine and what did this suggest
- increased stomach acid production
- Increased [histamine] = increased [HCl]
- histamine=messenger=receptor=antagonist=reduced amount
- This suggests that a selective histamine antagonist would result in less acid being produced
how does an antagonist affect histamine. what happens if there is no histamine present
- Histamine still produced, but gives weaker effect
- less of the acid being produced
- don’t know when no histamine is present… you could get inverse agonist or antagonist
why should a histamine antagonist be possible
- Conventional antihistamines existed for allergy, nausea
- BUT These drugs did not affect stomach acid
describe how the project began with histamine agonists. blood vessels and stomach
- Turn an agonist into an antagonist (→ abnormal shape change)
- Change conformation of receptor by changing binding shape
- Histamine agonist in blood vessels available
- H1 receptor
- Agonist causes vasodilation
- Lowers blood pressure because of the vasodilation
- Histamine agonist in stomach
- H2 receptor
- Agonist increases HCl production
what happens to the receptor when an agonist binds to it
- Receptor changes shape
- New receptor shape results in a biological response
what happens to the receptor when an antagonist binds to it
- Receptor changes shape
- New receptor shape is DIFFERENT to what is “supposed” to happen
- No biological response
is it more difficult to go from agonist to antagonist or from antagonist to agonist
antagonist to agonist
how do you measure agonist and antagonist behaviour
- Agonist → measure [HCl], administer drug, measure [HCl]
- Antagonist → measure [HCl], admin drug, measure [HCl] → add admin histamine, measure [HCl]
- shouldn’t see change in HCl if it works as antagonist
