Sep 21, 2011
Drug interactions in the Liver 101.
What you need to know.
My clinic has postponed treating any patients with triple therapy until their software is updated to include all of the newest information regarding P450 interactions. Therefore I’m NOT the only person realizing just how crucial and important this all has become. Ergo I’ve decided to regroup my thoughts and explain the basics.
The people most in need of this information are late stage liver patients, and those taking anti-rejection, or HIV drugs, or who are medicating for any other serious medical condition. Especially if these groups plan on treating their Hepatitis, this information could prove invaluable. Actually anyone doing triple therapy really does need to pay attention here.
Many of you have written privately asking me to filter my knowledge base down to it’s essence on my favorite topics. I’m sorry for my long delay, but here is at least a first attempt on one topic.
For further clarity one may reference my 2 past threads on P 450 drug interactions in this forum..
The key words here are cytochromes, P 450, hepatoxicity, inhibitors and inducers
PAUSING TO MARVEL-The liver’s job is to break down drugs, make them usable, soluable, removing their hydrophobia and preparing them for the body, and for excretion as well. The liver is the most phenomenal organ in the human body, performing millions of complex chemical conversions everyday, and replacing tired worker cells 5 times faster than elsewhere in the body. If we had to represent the liver’s daily workload by having chemists standing by to achieve in test tubes what the liver does so effortlessly, we would have to fill several hundred Costco warehouses full of chemists, and they would still be hard pressed to do for you what this little organ does!! And how does it know what to do with each atom, each molecule? Why does it prioritize and try to remove toxins (like alcohol etc.) first? How does it detect what is lifethreatening, and where is it’s database, that each cell can know just what should be done with the thousands of compounds showing up each day?
The amount and complexity of the work done each day by this organ is truly staggering.
Back to work:
Here is a good primer on hepatoxicity.
OK, so now we’ve covered the basics. Did you notice acetaminophen (Tylenol, Paracetamol) is now considered the most hepatoxic of all OTC drugs? That of course, remains a hot topic of debate with some, but I myself am entirely convinced Tylenol and later stage liver disease should be mutually exclusive items. It’s not just the drug itself, it’s the number of other drugs that cause a build up that is the issue, and also it’s a travesty that so many OTC products contain it, but that the public doesn’t always realize that they are double or triple dosing themselves when they add one or two cold/flu remedies to their daily regime. Pain control is a serious issue, and must be addressed, but there are safer ways to control pain or fever that are not as damaging to the liver. However there is a whole generation who grew up with, and were medically trained to believe that tylenol could do no wrong, so I won’t debate the topic, I’ll simply mention that the research and current chemistry is converting more docs to a cautionary stance with every passing day. OK, enough of that, we aren’t here to debate Tylenol, we are here to understand how the liver deals with drugs.
So, let’s begin.
Here is my favorite P 450 Chart. http://medicine.iupui.edu/clinpharm/ddis/table.aspx
Although this chart is not as up to date as some others I have found, this one at least color codes the most dangerous drugs, which I found very helpful.
So what is a P 450 cytochrome and why should we care?
Put simply it’s a protein whose enzymes help break down drug metabolites into forms our bodies can use, and also into forms we can later eliminate from our bodies. A cytochrome is an iron based structure, (cytochrome means cell enzyme, cytochromes are specialist, they have in common, regardless of which substrate they belong to, that they all depend on iron for their function ) …they reside primarily in the liver and help us deal with certain chemicals. Without them, many more substances would be toxic, and few if any would help us.
Think of the substrates as just mechanics in a garage, one guy does your brakes, another guy does tranny, another does engines, Same with substrates, it simple means that certain cells specialize in certain drugs. Sometimes more than one substrate participates. Like one chemical process occurs first and then it gets passed to the next cytochrome for a different process.
Like with your car, maybe you go for brakes and tires, and one guy does his job first, then the other process will follow.
The reason which substrate a drug uses is important is because there are only so many of each cytochrome, so in order not to overwhelm the system the thought occurred to me to switch my other meds away from CYP3a (the one the tx drugs use) as much as possible.
Most of the articles and explanations I’ve read concerning cytochromes and drug (P 450) interactions are highly technical.
This post will attempt to speak to the layman for that reason, to bring some small clarity perhaps.
A good synopsis might be just to say that certain proteins within special cells have been identified as responsible for the metabolism of drugs within the body. Most exist within the liver, but they are found throughout other parts of the body as well. Where ever they are found, they do the same job.
The important thing for a liver patient is to make sure their doctor tailors their treatment to the other conditions for which they must medicate.
This is important at all times, but especially if undergoing chemotherapy for hepatitis or liver cancer, any kind of chemo therapy really.
Especially true in later stages of liver disease, where the amounts of healthy liver tissue have been reduced, it becomes important to create as few conflicts as possible within the drug profile of a patient.
It also becomes important that a patient remain PATIENT with their doctor.
Especially true while on chemotherapy we will sometimes be desirous of instant relief.
Often a patient may have side effects and be tempted to take an EXTRA dose of something to alleviate some of their suffering, or to use OTC products without their doctor’s knowledge.
These actions must be avoided or taken with a goodly dose of trepidation. This is one time when if one is good, two could be deadly, not better.
Increases in dosage of helper drugs should be allowed only if the effects, sides, and the blood work all indicate the patient is tolerating the additional drug without marked elevations of liver enzymes. Additonal to toleration one must bear in mind competition means one drugs uptake will inhibit another drugs uptake. Ergo even well tolerated things can and do reduce the amount of chemotherapy drugs that will be metabolized, and, as plasma builds of the non utilized drug, the toxic metabolites not broken down (since no cell can get to it) are also building. Think of this like the IRS at tax time…there’s only so many folks to shuffle all that paper…and as the paper stacks up, the fire hazard also increases exponentially.
Since some chemo drugs are strong inhibitors and/or inducers (they can increase or effect the strength of other regular meds and drugs). Therefore any new drug must be introduced slowly and watched cautiously. The cautions are for our benefit, because the understandings of all these interactions are still in their infancies this cautionary is needful. Especially where the new Protease Inhibitors are concerned, both those for HCV and those for HIV, some of these new antiviral drugs have marked effects on all other drugs being utilized.
It may help to pause here to explain inducers and inhibitors. They do what the word describes.
1. An inhibitor competes with other drugs. It inhibits them and changes how they perform. It’s sort of a bully trying to take over so to speak.
2. An inhibitor can also increase the plasma levels of other drugs, making them many times more potent, and inhibiting them from clearing the body in a timely manor. This then leads to build ups, toxic levels of one or multiple drugs competing for that cytochrome.
3. An inhibitor can stop another important drug from working because the inhibitor competes for the same few cells to be “metabolized”. Therefore a strong inhibitor can prevent another weaker drug using that same cytochrome from working at all. It’s rather akin to there being just so many seats in the theatre, once the theatre is booked, no more can get in; and, should you let more in, and create a “standing room only situation” then the meds become so tightly packed like sardines that when it comes time to exit, no one can get out!! They are crammed too tightly to move at all. This may be a poor analogy but it’s all that comes to mind just now.
On Dr. Flockhart’s charts (link above) one will observe certain drugs have been marked in red, orange and so forth…this is to alert you to their strengths as an inhibitor or inducer. A red or orange drug needs to be treated with a lot of respect. They are the atom bombs so to speak of the drug world, and can do a lot of good, but a lot of harm as well, when it comes to interactions.
Here they are listed as follows:
A strong inhibitor is one which raises a drugs plasma AUC value > 5-fold or more, or causes an 80% drop in clearance rate. (that means 4/5 of the drug that should leave the body will not leave when it should. This then leads to a potentially deadly hepatoxicity very quickly.
A moderate inhibitor is one that causes a > 2-fold increase in the plasma AUC values or 50-80% decrease in clearance.
A Weak inhibitor is one that causes a > 1.25-fold but < 2-fold increase in the plasma AUC values or 20-50% decrease in clearance.
Even moderate or weak inhibitors need to be respected. If you must be on a medication, you will need to half your dose in order to adjust for the 2 fold increase a moderate inhibitor would cause.
This should not effect your health then, because the lowering will still leave you with the same amount in your body as previous to beginning chemo therapy. Of course, you will still be monitored for signs of build up, and when chemo is over, you will no doubt be returning to your former dose.
Please don’t be scared by all of this, just try to understand that your doctors now have tools to help them navigate through these mine fields, and they and you would be remiss in not using them. For many years the reason that some folks made it through chemo therapies just fine, while for others it proved fatal was not well understood. However not that the chemistry and role of the various cytochromes has come to light, many more positive outcomes will become possible.
Other drugs listed on Dr. Flockhart’s charts are simple inhibitors, and they will not compete for room to be metabolized by the available cytochromes, they will instead enhance or Induce a stronger response and more enzyme activity. Whenever a drug or food stimulates the synthesis of more enzyme protein,9 enhancing the enzyme's metabolizing capacity, it is known as an inducer. It is however difficult to predict the time of any enzyme induction because many factors exist, amongst them are enzyme turnover, drug half-life etc. In other words, it’s extremely difficult to time an inducer to induce, which is why there are no drugs yet for HCV that are prescribed to do it.
With INHIBITORS: The fact that they are not classified as strong, moderate or weak, does not mean they are problem free. Any drug utilizing the same cytochrome will still compete for available space to metabolize. Doses of each drug must therefore be adjusted to compensate for this and/or watched carefully through blood work.
SIDEBAR, the one that STEAMS me was that barbequed items are on the list…it’s going to hard to forego my favorite cooking method, but for what it’s worth we can’t live without a liver….so for a few months I’ll do without it, especially important if I have to go on Cipro again.
With INDUCERS, we have another issue, that the inducer will effect the strength of the other drugs using that cytochrome. Inducers make other things stronger, apart from clearance issues, this can be problematic. Foods can also be inducers. The temptation will always exist to use an inducer to create a stronger presence of a drug not readily absorbed. I’m reminded of some folks who thought they should add a grapefruit derivative to their regime years ago for this purpose. The dangers however far outweighs the benefit.
We only have one body, turning it into a test tube with unproven and potentially unsafe adjuncts is not wisdom.
Make sure whatever you add to your regime is added with your doctor and pharmacists knowledge and approval!!
Whether one speaks of natural substances such a St. John’s Wort, or certain drugs that are known to induce, the fact remains that the predictability of response has not been established and therefore the possible complications are a real and present danger. Since the discovery of inducers much research has been and continues to be done on certain pro-drug transporters in an attempt to find inducers that will benefit other drugs, create a more therapeutic or quicker absorption rate without overshooting and creating hepotoxicity. Here is where a portion of the Hippocratic oath must be observed, “First, do no harm”…and this applies to the patients private attempts especially,( it should be we, not just our doctors who adhere to first, do no harm.).
Of course, no matter how simple one tries to make all of this, it does get complicated. If you take antacids or proton pump inhibitors this will effect the treatment drugs and how absorbable they will be, if you take antidepressants you may have to be switched to a safer one than the one you take. This is because an SSRI using the same substate could result in serotonin overload and poisoning, a serious issue. AGAIN, I share this in the hope that we as patients will take seriously our need for due diligence and for including a good medical team in all our decisions going forward.
Back to inducers, many folks have thought hey, why not take something to make the other things I take stronger..now that we know what the inducers are. You would not be the first to have thought of this. To date however, very few inducers have proven safe, though some are in clinical trials every year….they are known as pro-transporters. Yet to date there has been limited success for obvious reasons. Since time, foods, other drugs, fat content of meals, stomach acids, bile salts, colon bacterium, and dozens of other things factor into drug absorption rates, it is easy to shoot past a goal when trying to create an instant effect with an inducer. Since every patients profile is different, their metabolisms differ, they drugs they take differ….so the complexity of helping vs. killing them is very real. Since some inducers have been observed creating 100 fold increases in plasma levels, it is imperative that the patient NOT attempt to improve the synergy of any drug without the knowledge and approval of his or her physician.
BOOZE_ A common inducer we should mention here is alcohol, it is responsible for more overdoses than all other inducers combined. Alcohol creates sufficient increases in bioavailablity across all substrates of so many substances that it could be classified as the number 1 killer, if we were to reclassify drug overdoses as what they more often really are, alcohol related drug overdoses. Alcohol’s effects are not only due to cytochrome use, but due to it’s solvent nature, rapidly altering myriad drugs on every substrate. It is responsible for a great deal of the aspirin and acetaminophen poisonings since it increases their levels so severely, and with barbiturates and alcohol taken together we see countless deaths.
POT_Tetracannibinol (marijuana) is also an dangerous inducer, and has been shown to cause a 7 fold increase in liver fibrosis comparative to alcohol. Perhaps because the greater the inducing, the greater the toxicity then of other drugs, and hence the greater the inflammation as a result of the toxicity. Inflammation of course, is considered to have the greatest influence on fibrosis and scar formations. In other words the cascading effects of certain substances has been well documented.
I trust that sometime in the near future enough will be known for medicine to gingerly enter the world of pro-transporters, especially for those drugs hard to absorb. To date however, I think the most hopeful research comes rather from a process known as electroporation, currently being tested by Inovio and other firms in regards to HCV treatments. This method allows instant penetration into the cell, if it ever makes it to market it will undoubtedly close the gap by achieving therapeutic levels of all treatment drugs in hours, not weeks, and hence reduce the chance of mutations to zero. Of course prior to this treatment adjustment to current medications would be wisdom to avoid all that has been mentioned here.
CONCLUSIONS: About 30% of all the drugs we take are metabolized by the CYP 3a, and so are the Protease inhibitors. The interferon is an inhibitor also (in fact, the reason many hepatitis patients need stronger doses prior to and during tx, of many meds is because of natural interferon, (any viral infection raises interferon levels,) inhibiting the way all drugs are then metabolized. The Interferon making the system more sluggish as it concerns other activities. However, one study did observe improvements even in the presense of treatment drugs once one month had ensued, http://www.ncbi.nlm.nih.gov/pubmed/1695539?dopt=Abstract), (and assuming a drop in VL no doubt) Finally ribavirin metabolism involves several cytochromes. but primarily 2D6 and 3a. Here I would focus on the cyp 3a, because the telaprevir or boceprevir are also reliant on this cytochrome. Meaning this cytochrome will have plenty to do while you are treating.
My SUGGESTIONS to the patients, and the high risk or late stage patients especially would be
1. to try to find drugs that metabolize on cytochromes that are not being used for the chemo drugs, or better yet,
2. choose drugs or find things that are dealt with chiefly by the kidneys, as some drugs are able to bypass the liver, not dependant on that organ as they do not have to be conjugated, changed into a different metabolite to be useful), so choose these rather than the liver dependant drugs whenever possible (of course this is not always possible, but it doe not hurt to ask, or do a search for example, google “ medcication metabolized by kidneys for ________(your disease). This is of course ONLY good advise if your kidneys are healthy and in good shape.
3. involve your physician and report every item you are taking accurately including vitamins, minerals, herbs, protein drinks, etc etc.
4. involve your pharmacist and give them the same complete list, and make sure they are alerted to your chemotherapy even if you receive your chemo drugs from a specialty pharmacy make sure you have a local pharmacist that is aware you are on the chemo drugs, and who will keep an eye on every new addition.
5. Remember the average pharmacist has had 6 YEARS of training exclusively drugs and chemistry, whereas the average specialist had one year of training…so whom may be more savvy is hard to say…1 year….vs. 6 years….hmmm.
6. get all your meds, as much as possible from ONE primary pharmacy the better to eliminate information loss or half engaged providers. Form a rapport with said pharmacist.If you are undergoing chemotherapy I would strongly advise against using mail order pharmacies simply because with the volume they do, and the distance, there is not as much chance of them catching
7. try to get a CBC within a week of starting any new drug so you can see and head off any build up. Watch Alt/ast and bilurubin especially. Do not settle for a monthly CBC if you are adding helper drugs twice monthly should be a minimum, or weekly would be better when on multiple meds and chemo. If you are a distance from your clinic, arrange for a closer clinic to do the labs and forward them to your hepatologist. Don’t postpone any labs. (at my clinic missed labs is grounds to be removed from treatment…it’s that crucial to your health, so don’t treat this lightly)
8. try natural methods before resorting to drugs wherever possible. Example: before taking an oral anti-itch RX, try tepid showers, olive oil rubs and silk sheets. Then try a toical cream and only lastly resort to a systemic RX, and if you must because the itching is unbearable, then allow your liver doctor to prescribe you one, do NOT use benydryl, it cheap yes, but more hepotoxic than the one they will give you if you ask. But again, try natural methods first…. If you can get by without the additional drugs it will be far better for your liver.
9. try half or quarter doses for side effect helper drugs. (not epo or neupo those you must take full dose), and not your regular meds like heart or BP meds etc…those reduce only with doctor approval…but for the things more minor such as itch or nerves or sleep. You may find that you can get enough relief from a lesser dose (partly due to the inhibitor buildup effect) than what your doctor prescribed. The smaller the dose that you can get by on, the better your chemo drugs will work, remember most will compete for the same few cytochromes that your chemo drugs are trying to use. Get a good pill cutter. Half or quarter non-time-release drugs and experiment with less.
10. If you have iron overload already, or liver cancer, you will want to avoid drugs needing to use Cyp1a2 as this cytochrome is where much oxidative stress occurs. If you can find a drug using a different substrate with these conditions, it might be wisdom in order to lower your oxidative stress.
11. Nevertheless do not discontinue any medicine without doctor approval.
OF COURSE, THESE HINTS won’t work for everyone in every circumstance, but even switching one or two medications to a similar medication that happens to utilize a different cytochrome might help
A. make your chemotherapy more successful, and
B. help it to be less toxic simultaneously.
PS….remember I’ve mentioned all chemicals are drugs so to speak. Even vitamins are a type of drug. Even if natural they are concentrated chemicals and must thought of as chemicals and be used judiciously.
Even though many are friendly and helpful, one needs to do some real research before assuming everything touted as good for really is.
An example would be one I mentioned recently on my PURINE thread….that brewers yeast greatly interferes with ribavirin absorption. Therefore you should not take a multi, or a B vitamin with your riba meal. Anything derived from Yeast will interfere with the treatment drugs. This is a whole other topic, so I’ll stop here.
SIDEBAR: Please note, my clinic, and many others as well, are adding patients slowly to their rosters. This is because the alarm bell about the protese inhibitors being so incredibly interactive has finally gone out. No patient wants to wait in a line to treat this disease, but because of the complexity of the treatment landscape the docs cannot add everyone waiting at once. They need to take the sickest first, and get them well established, and then add more each month as they are able. AIDS patients in particular will need special care and possible changes to their current regimes. We need to recognize that if they can treat ten or 20 a month well, it’ll be a better outcome than if they try to treat 100 at once. In which case either standard of care suffers or docs get zero sleep…both really. So if you’ve been waiting to treat, then you are learning why we are called “patients”.
Since most clinics only have a handful of docs truly familiar with this disease I feel the wait is well justified.
If some of you are stage 2, and are asked to wait an extra few months to begin treatment, be glad. It would be better to wait for the specialists that to go to some GI guy who has never treated with the PI on board and doesn’t have the information, training and staff to really deal with the issues that may emerge. If you want to be safe in treating, wait your turn patiently for a specialist and the reward will be that those professionals will be able to help you more and keep you safe from harm. (just my opinion)
I realize this is a lot of information, and apologize in advance for those not wishing to have to think about any of it.
Let’s just hope that our doctors are all thinking it thoroughly through for us.
Meanwhile, some few of us do wish to be informed, this was for us.
Good luck to us all.