NEw link to the drug interaction Flockhart P450 substrate table/chart or inducers and inhibitors:
http://medicine.iupui.edu/clinpharm/ddis/ClinicalTable.asp
mb
example: OK, believe it or not....my liver guy is pretty smart...top of his class..stanford educated well known in liver circle etc. etc.
and he's the one who warned me not to take the MACROBID......but instead he put me on CIPRO....which it turns out is on the top of the Flockart Chart for RED ZONE,,,most dangerous inhibitors....the ones to AVOID if you have abum liver !!!!!!!
not saying this to put him down.....just as an example of how underknowledgable most docs still are in this relatively new field.
average doc training in pharmacological matter-1 yr.
average pharmacist training-6 years....
it's so sad.
mb
I'm extremely bummed that the Flocart chart is not available online right now, and hope this is only temporary.
I've been going to phamacist forums and getting their take on all my P450 concerns and let me tell you, they are adamant that every patient should be making sure for themselves and with their pharmacist. In fact they claim that everyday something potentially fatal get prescribed by docs who were mostly trained before Flockart and who are still clueless as to the liver and kidney limitations.
ex: http://www.scribd.com/doc/6810480/DrugAssociated-Disease-Cytochrome-P450-Interactions
maryB
50 million american have some degree of hypertension, and with liver disease drug interactions with your HBP medicines can be a big issue.
here's an interesting JAMA article by Flockart who has done much of the research on the various inhibitor/inducer substrates
http://archinte.ama-assn.org/cgi/reprint/162/4/405
mb
hmmm...maybe someday soon there'll be an isoform specialist...
docs will have one on board or consults and not rely on already overtax pill counters...who once had time to keep an eye on their clients...
I know a few pharmacists who would love that job and claim docs prescribe incorrectly every day in their experience.....
in fact, a couple of my stroke patients were in that boat because their docs had no idea about interactions...and they didn't even have bad livers!
mb
here's a interesting part of a study I was reading.
It points out that the protese inhibitors are BIG culprits in inhibitor overdosing....and yet they have both inhibitor and inducer qualities..
like I said above so does caffiene....and judging by the way Riba effects many, it may also do both..
anyway, interesting excerpt:
Illustrative Case 2
A 47-year-old man recently diagnosed with HIV infection visited his physician with flushing, dizziness and swelling of the feet and ankles. He had been taking sustained-release nifedipine for treatment of hypertension for about three years. Approximately two weeks earlier, his physician had prescribed a combination of lamivudine, zidovudine and the protease inhibitor ritonavir.
The HIV-1 protease inhibitors ritonavir, indinavir, saquinavir and nelfinavir all inhibit the CYP3A subfamily of enzymes, thus increasing the serum levels of other drugs that are metabolized by this pathway, including nifedipine. It is likely that the addition of ritonavir to this patient's medical regimen resulted in an increase in the serum level of nifedipine and the subsequent symptoms of flushing and dizziness. Of the currently available protease inhibitors, ritonavir, because of its ability to both inhibit and induce CYP450 enzymes, is associated with the most drug-drug interactions.68
Final Comment
Physicians who become familiar with the role of the various cytochrome P450 enzymes in drug metabolism can often predict the consequences of drug interactions and explain patients' responses to medication regimens. Although tests for isoform expression are not widely available, it is conceivable that such testing may become standard practice in the future, given the clinical importance of isoform deficiencies. In the future, testing may help to identify individuals at risk for drug interactions and adverse events.
mb
thanks be to the mystery person who sent me some answers to these important questions!!
"OK remember in the Rodriguez-Torres study where it talks about the rations of mitochondrial dna dropping from 200-1 down to 30-1 with certains antivirals and PI therapies?? "
>>>>>>>>>>>A decrease in the ratio of mitochondrial to nuclear DNA from its normal 100-to-1 (NOT 200-1) to approximately 30-to-1 leads to clinical mitochondrial toxicity.
(oxidative stress also causes mitochondrial DNA depletion).
"Wouldn't this then mean that since the mitochondrial is "the powerplant that drives the cell" that this would creat a marked drop in ability to metabolize any and all drugs?"
>>>>>>>But the mitochondria is not only in the liver....and drugs are absorbed differently in different tissue and organs.
>>>>>>Mitochondrial toxicity in the liver may promote lactic acidosis. Mitochondrial toxicity in adipose tissue might promote body composition change....lipodystrophy (which of course is associated with IR). Mitochondrial dysfunction in peripheral nerves is suspected to cause neuropathy.
>>>>>>>>Mitochondrial dysfunction caused by Ribavirin, can also be related to development of pancreatitis....which can raise your blood sugar >>>IR : )
"So your explaination of CYP2E1 means that tx componds the whole issue as one is having a tremendous drain of RNA/DNA brought on chiefly by the riba, or telprevir.."
>>>>>>>>Some drugs can cause more mitochondrial toxicity than others. For example, some of the PI's used by HIV patients (or co-infected) can cause mitochondrial damage in the liver, which can cause lactic acidosis....so for them it is riskier to take Metformin which can also cause lactic acidosis.
???????????But for an HCV patient, the risk of lactic acidosis is rare and usually happen as a secondary event caused by things like trauma. So for them, the risk of lactic acidosis is not the same as for co-infected patients.
I just wonder what you think of the metformin in light of this. Would preloading be safest, and continuing as long as stage/grade and enxymes indicated tolerance was good?
>>>>>>>>Tx should be started when you're sensitive to insulin to give you the best chance for SVR. It shouldn't be, let's predose for a month or three months, but when you're sensitive to insulin.
"7 very small meals is better than 3 large ones in terms of how overtaxed the liver gets, especially when disease has reduced its size and function.
So how much of a role would you say this plays in say, for instance whether one should be on any drug therapy in addition to SOC. "
>>>>>>Depends what you're eating. Are you eating charbroiled foods 7 times a day? Because that will induce CYP1A2. Do you skip breakfast? Because fasting induces CYP2E1. Are you drinking grape juice or pomegranate juice? Because they'll inhibit CYP3A.
>>>>>Great questions!
>>>>>>>Trivia:
1. Normal mitochondria react to insulin by boosting production of an energy-carrying molecule, ATP, by 90 %. But the mitochondria from insulin-resistant people only boosts ATP production by 5 %.
2. Aerobic exercise creates more mitochondria.
Thanks for the answers!!! That last thing about the ATP is scary isn't it??!!
mb
here is the other reason why I cut my meds to the bone when I learned this about interferon:
Can J Physiol Pharmacol. 1990 Jun;68(6):777-81.Related Articles, Links
Regulation of hepatic cytochrome P-450 during infectious disease.
Renton KW, Knickle LC.
Department of Pharmacology, Dalhousie University, Halifax, N.S., Canada.
During episodes of infectious disease the mixed function oxidase system is depressed and the capacity of the liver to metabolize drugs can be compromised in both animals and humans. The depression that occurs during viral infections is mediated via the production of interferon. This action of interferon requires the synthesis of an intermediate protein(s) yet to be identified. Using an oligonucleotide probe for a unique sequence in cytochrome P-450LA omega we have now shown that the mRNA for this isozyme is depressed following the administration of interferon inducers. The magnitude in the loss of mRNA corresponds to the magnitude of the loss in the levels of this isozyme. This depression is observed within 6 h of interferon exposure. It is concluded that the decrease in drug metabolism during viral infections is caused by an interferon-mediated loss in mRNA and subsequent cytochrome P-450 synthesis in the liver.
mb
In laymanese it means the interferon itself cuts the livers capacity to handle other drugs way down which IS WHY looking for drugs that don't tax the P450 family makes the most sense.
it was probably my numerous questions re: xanax.
bandman
sorry dude, been trying to rember what you were asking about...trouble is...that would require me to go reread 2 threads with 80 posts each....if it was even there ....still hoping it'll just come back to me..
as to the last post....yeah me too....let's hope the experts will show up and decode that one!!
mb
could you explain the following so all can understand what this means:
Regulation of hepatic cytochrome P-450 during infectious disease.
Renton KW, Knickle LC.
Department of Pharmacology, Dalhousie University, Halifax, N.S., Canada.
During episodes of infectious disease the mixed function oxidase system is depressed and the capacity of the liver to metabolize drugs can be compromised in both animals and humans. The depression that occurs during viral infections is mediated via the production of interferon. This action of interferon requires the synthesis of an intermediate protein(s) yet to be identified. Using an oligonucleotide probe for a unique sequence in cytochrome P-450LA omega we have now shown that the mRNA for this isozyme is depressed following the administration of interferon inducers. The magnitude in the loss of mRNA corresponds to the magnitude of the loss in the levels of this isozyme. This depression is observed within 6 h of interferon exposure. It is concluded that the decrease in drug metabolism during viral infections is caused by an interferon-mediated loss in mRNA and subsequent cytochrome P-450 synthesis in the liver.
here is a great link to find out how much each drug effects your P450
http://medicine.iupui.edu/Flockhart/table.htm
if you scroll to the second chart, you can see which are strong and weak inhibitors
AND if you CLICK on any drug it will pull up more information from pubmed about that drug as it relates to P450.
Knowing this you can make more quality desicions about which drugs may be safer to use especially while treating.
A good liver doctor should know for instance which antibiotics and antidepressants will do the least to inhibit your SOC regime and also to protect your liver.
However as consumers we also owe it to ourselves to check it out.
Taking precautions, especially for older treaters who may be on as many as 10 or fifteen other drugs while doing SOC need to do their homework for the sake of a better chance at SVR.
If you take note of what Cowriter and Jim both said above, the cumulative effects of even two substances together can be entirely different that one taken alone.
Tylenol become toxic with any alcohol, and grapefruit juice cancels out SOC and many other drugs as examples.
Even though I get my SOC drugs from a specialty pharmacy, I told my LOCAL pharmacist I was on SOC, and ask her to research each new med for possible drug interactions. It never hurts to have more eyes on your medication regime.
Pharmacist, BTW have 6 years of drug only training. Therefore their knowledge base of what does what to what (interactions) is vastly superior to most MD's and specialist who have only 1-2 years of drug training...not 6.
Most doctors now have a software program available to them to help them search for interactions and safety issues. They can plug in your regime, and then search.
However they do not always avail themselves of this...whereas my pharmacist always checks.
However, even this system can be flawed since it does no include recent developments.
Example: vioxx was pulled before it got into some databases...avandia this year has been shown to increase heart risk, but this will not be in the data base until it is proven
at which point it may or may not be pulled.
this might be a good reason to google your together your medication and the word "safety" each year. You may find out something isn't safe before becoming a statistic in it's history.
mb
"Am I off here in my reasoning?? I have been cutting and keeping my meds to an absolute minimum to survive mode for some time, but the metformin discussion and a question of bandman's"
Bandman has lots of questions!
Just wondering which one you are refering to?
bandman
After a little research, the rx "phobic" post from the past I was referring to did not originate with you, so forgive the slight sarcasm re tx hepatoxicity.
The best advice I heard re drugs/liver/toxicity came from one of my hepatologists at a point where I was SVR 12 and probably somewhere around stage 2.
He said that all these drugs (statins/antibiotics/tylenol,alcohol, you name it) are hepatoxic to a degree but that there is no reason for me to avoid them any more than if I had a normal liver. In other words he wasn't saying I should not go out and drink and take tylenol because I once had Hep C, he was saying no one should do it, even with a healthy non-HCV liver.
Conversely, each of us has to decide how many of these toxins we want to put into our system by weighing the risks versus rewards. Same with diet I suppose. Sometimes you eat the cookie. Sometimes you pass. Some of us never eat the cookie. And then there are the cookie monsters out there :)
-- Jim
of course I know tx can be hepotoxic Jim....that was my whole point to having thiese discussions.
NOT to make people medication phobic, but to up the awareness of which drugs to take and when.
Since somethings are metabolized in the liver, others are not, it pays to look into the toxicity of each, especially while we have these SIC tx drugs on board it become important. I run every item by my liver doc since he seems the only guy with more than a smattering of interaction and toxicity knowledge in his arsenal.
You mention the "normal safety" of certain drugs, but then point out exactly what Cowr. was referencing regarding the CYP1A2 response.
Of course, this bring us back around to efficacy and safety of many items that may have a positive effect, such as the statins etc.
I guess my question is, with SOC on board, how much else is too much.
that's why I looked for drugs that didn't tax P450 in my med regime, and especially when it came to treating side effects or other conditions looked for those considered most benign to the liver.
then of course you have the interaction issue alwaya, which is why even with the safest meds keeping dosages low, AND alcohol abstinence a constant seems the most reasonable approach.
trying as someone pointed out....to see that the treatment is a success AND that the patient lives...should be the watch phrase.
mb
MB: understand that pregnacy is OUT of the question for treaters, and for some while afterwards due to all the RNA damage, but does this hold equally true for the rest of us as it relates to how much of, and whether to consider a medication.
----------------
The only reason pregnancy is "out of the question" for treaters (or for six months after) is because ribavirin is tetragenic, i.e can cause birth defects. Forgive me if that is what you're implying but I didn't pick that up.
That's why we always tell people that Tylenol by itself is not really a problem but never to take it with alcohol).
---------------
Its not just the alcohol. Tylenol can be a problem if more than "x" pills a day are taken or the equivilant in it's active ingredients. I leave it "x" because I don't want to rely on memory but the safe daily dosage has been posted before.
MB: for instance, my urologist told me to take something that my liver doctor said ABSOLUTELY not to take. Called macrobid
-----------
I'm unfamiliar with this drug so obviously do not take it if your doctor told you not to. That said, there have been previous discussions I believe you have been involved in (apologies if Im confusing you with someone else) where people have been warned about taking a whole list of rx drugs during treatment including a number of antibiotics and statins and even I believe Tylenol. Truth is that most antiboitics, statins and tylenol (proper dosage) are perfectly safe to take during treatment and the rewards outweigh any of the risks. Do you realize that interferon can be hepatoxic to some extent as well but we take it to kill the virus?
I know I asked a lot of remedial questions just now, but it's for everyones benefit.
also, I'm remembering HR's discourse now on meal size, which is not just a big part of diebetic therapy, but gives the liver a real rest. 7 very small meals is better than 3 large ones in terms of how overtaxed the liver gets, especially when disease has reduced its size and function.
So how much of a role would you say this plays in say, for instance whether one should be on any drug therapy in addition to SOC.
would the portion control not benefits ones tolerances and ability to still process the few therepeutic meds essential? Of course the answer is yes, butif you'd care to elaborate.
Also, why do we read so much about one dose shutting peoples liver's down these days.
Like the antifungals do that, some of them. How can people know what's too much for their liver when half the time the docs don't even know.
for instance, my urologist told me to take something that my liver doctor said ABSOLUTELY not to take. Called macrobid, it's listed in the top 100 worst drugs...
commonly shutting down organs in the elderly....
yet 3 of my doctors didn't know this.....
Must apologize now.....it's 6:00 Am and still no bedtime for bozo...I wonder if I accidentally took too much riba....anyway something sure it workin...
I'll shut up now
mb
I know you know but for those who do not...the study I'm referencing
http://www.hcvadvocate.org/hepatitis/About_Hepatitis_pdf/1.1.1_Living_With_HepatitisC/SIDE_EFFECTS.pdf
bottom of page 9 -top of page 10....
mb
OK remember in the Rodriguez-Torres study where it talks about the rations of mitochondrial dna dropping from 200-1 down to 30-1 with certains antivirals and PI therapies??
Wouldn't this then mean that since the mitochondrial is "the powerplant that drives the cell" that this would creat a marked drop in ability to metabolize any and all drugs?
I mean, other studies suggest this when saying marijuana for instance creates 10x the fibrosis and alcohol 7x more. But the why of it is explain partly by what the virons are doing, but partly by the SOC itself it would seem.
So your explaination of CYP2E1 means that tx componds the whole issue as one is having a tremendous drain of RNA/DNA brought on chiefly by the riba, or telprevir..and so more that at any other time one's liver quotient or..."the straw that might break the camels back" would be a real concern.
Am I off here in my reasoning?? I have been cutting and keeping my meds to an absolute minimum to survive mode for some time, but the metformin discussion and a question of bandman's just got me rethinking about all this stuff.
I understand that pregnacy is OUT of the question for treaters, and for some while afterwards due to all the RNA damage, but does this hold equally true for the rest of us as it relates to how much of, and whether to consider a medication.
You know there was one chart posted a while back about what taxed the P450 family the most and the least..and I've been going by that.
I just wonder what you think of the metformin in light of this. Would preloading be safest, and continuing as long as stage/grade and enxymes indicated tolerance was good?
For newbies I mean.
And what do you think of the reduction of 80% in that ratio for Rna...am I the only one who finds that a stunning AND a frightening reduction number?? !! that's true, an awful lot of one's essence is going up in smoke....maybe this is why I feel shrived up inside, and like someone took a cheesegrater to every body part...especially my brain.
mb