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Omeprazole (Prilosec) is metabolised in and cleared by the liver. This is a well admitted medical fact: there a number of learned papers which warn about possible problems is using Omeprazole with certain liver condition.
To quote a wikipedia article
The central role played by liver in the clearance and transformation of chemicals also makes it susceptible to drug induced injury.
Logic says that clearance of drugs could also easily interfere with other functions of the liver.
To minimise the possibility of damage or interference with normal functioning of the liver it is common sense to keep relevant drug levels in the body to the minimum that will be effective.
Oddly, the pharmaceutical industry, and therefore the medical profession in general, seem to be unaware of the concept of "minimum effective dose"!
A foreign chemical such as a drug (a xenobiotic - see a Wikipedia article) in the body is eliminated, generally by the liver. The rate it is eliminated at is directly dependant on the concentration in the blood plasma. There is an article in Wikipedia on drug metabolism.
So if the dose of a xenobiotic is doubled, the rate of clearance is doubled. This gives rise to a useful measurement: the drug's half-life. This is the time it takes the liver to reduce the concentration in the blood to half the original level.
Drug clearance is a specialist subject called pharmacokinetics.
Omeprazole has a short half-life.
The U.S. Food and Drug Administration Center for Drug Evaluation and Research says
The half-life of omeprazole is short, 0.5-1 hour. There is also a slow pharmacodynamic onset, with acid inhibition only 50% of maximum at 24 hours, and a long-acting pharmacodynamic effect of acid secretion reduction to baseline over 3-5 days. It is these effects that make Prilosec ineffective in acute relief and make it beneficial for 24-hour prevention.
A Wikipedia article says half-life is 1-1.2 hours. That Wikipedia article quotes a number of references.
So Omeprazole is metabolised very quickly in the liver. From this, it is evident that there are two possible approaches:
Method 1 involves giving few tablets at long intervals. Yes, there is initially a very high 'overdose' level where the blood level of the drug is far, far higher than that needed for effective operation of the drug, but if the drug is cheap and has no recognised side-effects, this is the choice. But if there are going to be side effects - these are much more likely to be triggered by the high overdose levels. This is the standard prescribed method!
Method 2 involves taking more frequent, smaller doses. Overall use of the drug will be much diminished and blood levels will not have the high overdose levels of method 1. Possible side effects are much less likely to be triggered. Less of the drug will be metabolised and more used for the intended purpose.
Now, some time after taking a dose, the level in the blood will peak. If the half life is two hours, then two hours after the peak, blood level will halved. 2 hours later again it will be ¼ of the peak, 6 hours after the peak it will have fallen to 1/8th. After 20 hours (which is the time a 40mG dose is said to be effective) the level in the blood will be 1//1024 of the peak (there are ten 2 hours in 20 hours, every 2 hours the level halves, 2^10 is 1024).
If the half life is actually 1 hour - that low level would be 2^20 - or one millionth of the original peak!
It's difficult to know totally accurate figures as the granules are slow release - a Wikipedia article says it is completely absorbed within 3-6 hours. So he peak is flattened and delayed. Also the half life is not well defined. My own experience suggests 2 1/3 hours, but it is still clear from the known facts that even a 10mG dose must be a huge initial overdose, and a 40mG dose ....
It's to Omeprazole's credit that an overdose level of, maybe, 1000 times the minimum efective dose causes so few recognised side effects. But if any side effects are present, the massive overdose will provoke them. Maybe there is here a failure to recognise side effects....
A large number of other side effects have been attributed to Omeprazole and other PPIs. I cannot comment on these as I have not experienced them, but if the drug needs administering little and often because of its very short half life, it seems reasonable to expect to minimise side effects by keeping blood levels low (near the minimum effective dose). Small doses administered frequently.
There is a www site Omeprazole side effects which lists a huge number. I think an over-reaction, but it's an American site - which may explain that! It is also a conmmercial site trying to sell a cure for reflux: that cure essentially seems to be eating a particular brand of apple - a claim I find difficult to believe!
The liver produces bile.
Bile production and release is normally triggered by food, especially fatty food. Bile is released into the duodenum where it mixes with the food. There is a Wikipedia article on bile which explains it all.
I have suffered from bile reflux. The doctor said that it simply showed a lax pyloric sphincter. But to get bile reflux as I did sometimes in the middle of the night when my stomach must have been empty seemed wrong. This niggled me and needed explaining: I read up on the subject. To get bile reflux when the stomach is empty requires bile to be produced and released at the wrong time. So something other than food must be triggering abnormal bile release.
Yes - a lax pyloric valve will allow bile back into the stomach, but that can only happen if bile is being produced when there is no food present to trigger it! I also had a theory that this was all weight related: certainly the laxness of the valve would be affected by visceral fat.
There is lots of anecdotal evidence (if you look hard enough) that bile reflux is apparently not uncommon in people on Omeprazole. It is even said to be one possible reason why PPIs are not always as effective as expected.
I have proven to myself that it is indeed Omeprazole overdose that causes bile reflux. Proven by reducing the Omeprazole dosage when the bile reflux stopped. A trial on one individual is hardly scientific proof but it was arrived at by scientific methods: I had a suspicion that the bile reflux and the tickly cough were both caused by Omeprazole.
I put the theory to my doctor: he said that other PPIs were likely to have the same effects, I should try Ranitidine. That did not adequately control acid production. That may be another story - there may be antagonism between Omeprazole and Ranitidine, and long term effects of Omeprazole may mean the 2 week trial was not a fair test. But the discomfort on Ranitidine was generally greater than on Omeprazole, so I decided to continue experiments with reducing Omeprazole levels.
Some time after writing the above, I have found one mechanism that explains some of the bile reflux. Seethe page PPIs increase gastrin levels
On first endoscopy I was put on 1 x 40 mG dose per day.
At second endoscopy 7 weeks later I was told that was not enough. That dosage lasted about 20 hours so I should double it.
Two things struck me at this point: firstly the correct dosage was a matter of opinion! Secondly that if 40 mG was effective for 20 hours, then 40mG every 16 hours made more sense than 40mG every 12 hours. A 16 hour cycle is quite convenient. First day, first thing in the morning and last thing at night. Next day at 3 p.m. This worked, but I had a tickly cough and occasional bile reflux episodes.
I opened a capsule and found granules - half a capsule would be easy. I was still wondering what the ideal dose was and there were, on the www, lots of hints that bile reflux and Omeprazole were connected - the link is to a Google search.
So I experimented. It's not an easy experiment to do with any real accuracy but these figures are correct give or take an hour or so:
| Dosage (mG) | Time (Hrs) |
|---|---|
| 40 | 20 |
| 20 | 18 |
| 10 | 15 |
| 5 | 10 |
Yet, despite many hours searching the www for information on the minimum effective dose of Omeprazole, I am unable to find any reference to the subject! I have listed some of the more interesting pages I have found on Barrett's oesophagus, Omeprazole dosage and bile reflux. One realises that Omeprazole causes bile reflux. None have investigated MED!
Seems to me that the profession as a whole know it is a safe drug without side effects so nobody has ever thought along the lines of a MED!
My own experiments are pointing to a very low MED - maybe much less than 1mG per hour (if hourly dosage were practical!).
In fact a Google search for Minimum effective dose is informative in how little information it divulges on any drug!
They refer to the acid-suppressing property of the drug. I found, from personal experience, that the effect of the liver and bile release is even longer than that! As related above Omeprazole (and presumably other PPIs) interferes with bile production and release. Eventually when I reduced doses to 5mG the constant bile release ceased immediately. However - some 12 - 15 days after reducing the dosage I had three separate nocturnal bile incidents. It wa as if my liver and bile was finally releasing the stored PPIs.
Since that date (now 4 months ago) the only times bile reflux has occurred are after I have eaten oily food (e.g. at an Indian restaurant) too late at night. The 3 episodes in question do not relate to any such food evens and can only be due to the delayed effects of PPI dosage reduction.
Omeprazole dosage is tricky: As the reference above says, there is a delayed onset and a delayed 'recovery'. It's as if the body learns to live with the drug. Not too surprising - all such bodily functions have a feedback mechanism which, in this case, stabilised the stomach pH at the 'right' level. Omeprazole interferes with this feedback and (as an electronic engineer) I am well aware of the possible instabilities when altering or interfering with a feedback loop! One of the instabilities I noticed was that, as the dosage wore off I first noticed a tickly cough, then I would regularly start to taste bile in the refluxate.
I was taking a 10mG dose every 12 hours. When I tried Ranitidine, I still had a tickly cough and occasional bad bile reflux. I wanted to find out if (as I suspected) a 5mG dose would be better. I changed to a 5mG dose last thing at night to start the routine
Twice I had very bad bile attacks that woke me up in the middle of the night. But I persisted! Third time lucky!
I am now taking a 5mG dose 3 times a day - a not-inconvenient routine, first thing in the morning, 15:00 hours and last thing at night. If I forget a dose, I am gently reminded by the onset of a tickly cough!
Since going on this routine, bile reflux has stopped: as I write this I have been on the regime for 25 days and have not tasted either the slightest trace of bile, nor excess acidity in refluxate. In fact - the worst acidity is after I have had a glass of cider (pH around 3). The tickly cough too has gone - unless I forget to take a 5mG dose on time, so it serves as a useful early warning system!
Addendum to the above.
Now (Tuesday the 12th of April, 2011) I have been on this regime for around 7 months. No change: the regime works fine. However, the tickly cough that I used to have as an 'early warning' seems to have stopped. Can't tell exactly when as I had a cold at the appropriate point! I am now in bwtter health than I have been for years and, at my last endoscopy, islands of normal cells were observed in the Barret's area - this apparently is how Barrett's oesophagus regresses.
You may wonder how I, an electronic engineer, can have any useful input on the theory involved.
As I understand it all glands, body chemicals etc are controlled by biological feedback loops. There is most certainly a feedback loop that controls the pH of stomach acid, and another that controls timing so that acid is released at the correct time and strength. There must also be more that control bile production and release.
There is a well understood maths that applies to every single feedback loop. It will apply as much to a biological loop as to a mechanical or electronic loop. The theory may possibly br thought as not relevant as the input parameters in a biological system are extremely difficult to determine - so you cannot apply maths!
However I suspect that an understanding of some of the basic principles can throw light on some of the effects:
This effect may well be the case of the reports of "rebound acid hypersecretion after PPI discontinuation": in English that means excess acid production when PPIs are stopped. I believe I myself may have experienced this when dropping from 2 x 10mG doses to 3 x 5mG doses of Omeprazole per day. Twice when making the step I had horrendous nocturnal bile reflux. Third time lucky - the transition occurred without a hitch.
It is quite clear that the response time of the loops involving Omeprazole can be very long - tens of days even. One if the feedback loops is that which involves clearance by the liver: there have to be systems in the body which recognise a foreign chemical (a xenobiotic) and cause the liver to eliminate it. I suspect that a low enough blood concentration may not trigger this clearance mechanism - which would explain the long time that seems to be needed to stabilise after PPIs are stopped.
If you know the right keywords to search on the www you can find a lot. Unfortunately there is no way of searching for the correct keywords to start the search. Suspecting that PPIs might be part of the problem and not part of the solution, I stated searching such things as "PPI or Omeprazole cause cancer". Eventually I arrived at a group of researchers at the Norwegian University of Science and Technology. Some of the pages of interest are on the References page.
Stomach acid is secreted in response to an enzyme in the blood called Gastrin. If stomach acid is suppressed - gastrin levels rise as the body tries to secret acid, but cannot. The condition is called hyergastremia and itself can be dangerous.
Wikipedia has an interesting article on gastrin. According to that article, gastrin promotes pancreatic secretions and gall bladder emptying. It also lowers the tone of the lower oesophageal sphincter so reflux is more likely.
Which is how bile reflux is often a problem on PPIs as I have discovered for myself.
However the capsules are two-part gelatine and easily come apart (some need more force than others). They are full of granules - there is a wikipedia article with a section on how these granules are made. It is easy to roughly divide the contents into two: no great accuracy is required, 5mg seems to easily remain effective for about 10 hours.
I simply swallow the granules with a drink of water, so have plenty of spare capsules. I pour the granules into two capsule lids so the levels are about the same. It's a slight fiddle having to divide them like this, but a lot better than suffering bile reflux.
Document URI: www.torrens.org.uk/Med/Ome.html
Page first published: Sunday the 10th of October, 2010
Last modified: Tue, 10 May 2011 08:07:50 BST