Hiya Shoreline, how are you doing? I have been away for a little over a week, was wondering how youre doing? Last I spoke with you, you had a nasty fall coming out of the shower, and was wondering if youre doing better now? I hope so! I even mentioned you in my prayers---I figured any little bit helps, hehehe. I was reading thru some of the posts Ive missed, and see youve been back in your usual top-notch helpful form, so Im assuming you are doing better---something everyone on this board is happy about, Im sure, hehe.
On a side note, I had a curious question about something you said in one of your always-informative posts. Its nothing major, more just something I found fascinating, more than anything. You were talking about an enzyme, and its something Ive never heard of, so Ill paste it here to show you part of what I read:
"If you have several meds using the same route of eliminaton, serum levels can rise to unsafe levels, the Cytochrome P450 Inhibitors like tagament can either reduce or increase the serum level of several drugs including opiates making them dangerous, alcohol and opiate or alcohol and benzo's are dangerous. But if your not overloading the ability of the P450 cytochrome enzyme it can effectvely break down and excreete any amount of opiate unless you using other drugs that take the same route of elimination using the same enzyme. Cold meds, stomache meds and nausea meds can cause problems due to this same enzyme.OxyC uses the P450, Morphine uses the P450, and many otrher drugs use the same cytochrome and if you overload this one enzymes abilty to break down meds down you will have consequences and sometimes lethal consequences. But pure opiates alone, as much as I have researched don't damage the liver. - Shoreline."
I found this fascinating, because I had never even heard of such a problem. I was wondering, can things like the Ibuprofen and Tylenol add to this problem? Im wondering now if part of the problems I was having before might have been caused by some of the medications I was taking at the same time. Is it a certain amount of time before the enzyme gets "refreshed" or something, or taking certain meds hours apart might help? Just wondering exactly how to be cautious about the "same route meds", for those of us who take several different types of medication, since it both surprised and interested me at the same time.
Anyways, thats more of a curious question, so if youre still not quite back up to your old-self after what youve been thru---by all means take your time! I wanted to check on ya more than anything, so if youre time to reply is limited just lemme know how you are holding up! Or if youre glued to the election coverage like alot of us here probably are, I will talk to ya tomorrow, hehe. Take Care Dave!
Hey Phlox, There is usually a warning on the paper work you get about interaction with other meds that use the same liver enzymes to break them down.
West Virginia University School of Pharmacy, Morgantown, West Virginia
Many drug interactions are a result of inhibition or induction of cytochrome P450 enzymes (CYP450). The CYP3A subfamily is involved in many clinically significant drug interactions, including those involving nonsedating antihistamines and cisapride, that may result in cardiac dysrhythmias. CYP3A4 and CYP1A2 enzymes are involved in drug interactions involving theophylline. CYP2D6 is responsible for the metabolism of many psychotherapeutic agents. The protease inhibitors, which are used to treat patients infected with the human immunodeficiency virus, are metabolized by the CYP450 enzymes and consequently interact with a multitude of other medications. By understanding the unique functions and characteristics of these enzymes, physicians may better anticipate and manage drug interactions and may predict or explain an individual's response to a particular therapeutic regimen.
The basic purpose of drug metabolism in the body is to make drugs more water soluble and thus more readily excreted in the urine or bile.1,2 One common way of metabolizing drugs involves the alteration of functional groups on the parent molecule (e.g., oxidation) via the cytochrome P450 enzymes. These enzymes are most predominant in the liver but can also be found in the intestines, lungs and other organs.3-6 These cytochrome P450 enzymes are designated by the letters "CYP" followed by an Arabic numeral, a letter and another Arabic numeral (e.g., CYP2D6).7 Each enzyme is termed an isoform since each derives from a different gene. It should be noted, however, that structural similarity of enzymes cannot be used to predict which isoforms will be responsible for a drug's metabolism.
Drug interactions involving the cytochrome P450 isoforms generally result from one of two processes, enzyme inhibition or enzyme induction. Enzyme inhibition usually involves competition with another drug for the enzyme binding site. This process usually begins with the first dose of the inhibitor,8,9 and onset and offset of inhibition correlate with the half-lives of the drugs involved.9
Until genetic tests for isoform expression become available, a physician can often anticipate drug interactions in a patient by knowing which medications inhibit or induce P450 enzymes.SSRIs and cimetidine inhibit metabolism of tricyclic antidepressants, but the clinical significance of this finding depends on individual genetic variations and concomitant medications.
Enzyme induction occurs when a drug stimulates the synthesis of more enzyme protein,9 enhancing the enzyme's metabolizing capacity. It is somewhat difficult to predict the time course of enzyme induction because several factors, including drug half-lives and enzyme turnover, determine the time course of induction.
If you do a google search for cytochrome p450 you will get tons of info. It's alslso not just drugs that use this enzyme but foods too. Grapefruit juice is a notorious cyp 450 inhibtor.
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I can do a quick search adding Tylenol to the search like Tylenol and the cytochrome p450.
Be right back.
Bye the way, I am feeling better now, It took agood 5 days for things to setle down and I've just been buisy wit my daughter and haloween and yesterday I got to test my standing limits again while waiting to vote. I did manage 90 minutes of alternating from standing, kneeling and sitting on the curb, But was a sweaty mess by the time I got my name checked. I gueess it's good to test your limits from time to time.
Take care, Dave
PS IF I find anything about Apap and p450 I will let you know
Hey phlox , just quickly it loks like you would have to take overdose amounts to create a problem with this enzyme. I did a search using tha phrase
cytochrome p450 Tylenol interactions and did get several more articles about P450 and one particulalry about Tylenol and the history or apap , way more than anyone nees to know unless apearing on Jeopardy. LOL
Metabolism
Acetaminophen is metabolized primarily in the liver, where most of it is converted to inactive compounds by conjugation with sulfate and glucuronide, and then excreted by the kidneys. Only a small portion is metabolized via the hepatic cytochrome P450 enzyme system. The toxic effects of acetaminophen are due to a minor alkylating metabolite (N-acetyl-p-benzo-quinone imine), not acetaminophen itself or any of the major metabolites. This toxic metabolite reacts with sulfhydryl groups. At usual doses, it is quickly detoxified by combining irreversibly with the sulfhydryl group of glutathione to produce a non-toxic conjugate that is eventually excreted by the kidneys.
Toxicity
Overview
Acetaminophen is one of the safest medications available for analgesia. The drug lacks effects on the cyclooxygenase system so does not cause injury to the esophagus, stomach, small intestine or large intestine, in contrast to NSAID's. Additionally, patients with kidney disease are able to take acetaminophen wheras NSAID's can cause acute renal failure in certain patients. Acetaminophen also lacks problems with drug interactions. The analgesic potency is equivalent in non-inflammatory conditions to NSAIDs as long as the dose of acetaminophen is adequate. 1 gram of acetaminophen three times a day is equivalent to analgesia provided by NSAID's in osteoarthritis, for example. When coadministered with amitriptyline 50 mg twice a day, the combination is as effective as acetaminophen with codiene, but does not lose effectivness as an analgesic over time as does chronic administration of narcotics. For children, acetaminophen does not contribute to the risk of Reye's syndrome in patients with viral illnesses. These factors have made acetaminophen the anagesic of choice for mild and moderate pain for patients in hospitals and makes it the leading analgesic for outpatient use.
However, acetaminophen single doses above 10 grams or chronic doses over 5 grams per day in a well nourished non-consumer of alcohol, or above 4 grams per day in a poorly nourished consumer of alcohol, can cause significant injury to the liver. Without timely treatment, acetaminophen overdoses can lead to liver failure and death within days. Because of the wide over-the-counter availability of the drug, it is often used in suicide attempts.
Acetaminophen should not be taken after alcohol consumption, because the liver, when engaged in alcohol breakdown, cannot properly dispose of acetaminophen, thus increasing the risk of hepatotoxicity.
Mechanism of action
As mentioned above, acetaminophen is mostly converted to inactive compounds by conjugation with sulfate and glucuronide, with a small portion being metabolized via the cytochrome P450 enzyme system. The cytochrome P450 system oxidizes acetaminophen to produce a highly reactive intermediary metabolite, N-acetyl-p-benzo-quinone imine (NAPQI). Under normal conditions, NAPQI is detoxified by conjugation with glutathione.
In cases of acetaminophen toxicity, the sulfate and glucuronide pathways become saturated, and more acetaminophen is shunted to the cytochrome P450 system to produce NAPQI. Subsequently, hepatocellular supplies of glutathione become exhausted and NAPQI is free to react with cellular membrane molecules, resulting in widespread hepatocyte damage and death, clinically leading to acute hepatic necrosis. In animal studies, 70% of hepatic glutathione must be depleted before hepatotoxicity occurs.
If you have specific meds your worried about I can check, But generally Antidepressants, cold medications, and some of the benzo's and many other drugs that aren't involved in pain mnagement are metabolized by P450
http://medicine.iupui.edu/flockhart/table.htm
Wow---always a wealth of knowledge Dave, thank you very much! I found that part saying that NSAIDS can have a bad effect on people with Kidney problems very interesting---again, something I didnt know! Why would something like Ibuprofen affect the Kidneys?
Anyways Im glad to hear youre doing better, Im sure your kids were glad to see you up and at-em for Halloween! I know what you mean about standing in line voting--I was behind several elderly people that couldnt read the candidates properly, and kept having to ask for help, hehe.
I think youre right about testing limits, too. Seems it would be good for the body to be reminded occasionally what its supposed to do, even if it cant do it all the time. And testing limits is good for the soul, too, hehe. Glad youre doing better!!
Analgesic Nephropathy (Painkillers and the Kidneys)
An analgesic (AN-ul-JEE-zik) is any medicine intended to relieve pain. Over-the-counter analgesics (medicines bought without a prescription) include aspirin, acetaminophen, ibuprofen, naproxen sodium, and others. These drugs present no danger for most people when taken in the recommended dosage. But some conditions make taking even these common painkillers dangerous for the kidneys. Also, taking one or a combination of these drugs regularly over a long period of time may increase the risk for kidney problems. Most drugs that can cause kidney damage are excreted only through the kidneys.
Analgesic use has been associated with two different forms of kidney damage. Some patient case reports have attributed incidents of sudden-onset acute kidney failure to the use of over-the-counter painkillers, including aspirin, ibuprofen, and naproxen. The patients in these reports had risk factors such as systemic lupus erythematosus, advanced age, chronic kidney disease, or recent heavy alcohol consumption. These cases involved a single dose in some instances and generally short-term analgesic use of not more than 10 days. Acute kidney failure requires emergency dialysis to clean the blood. Kidney damage is frequently reversible, with normal kidney function returning after the emergency is over and the analgesic use is stopped.
A second form of kidney damage, called analgesic nephropathy, can result from taking painkillers every day for several years. Analgesic nephropathy is a chronic kidney disease that over years gradually leads to irreversible kidney failure and the permanent need for dialysis or a kidney transplant to restore renal function.
Longstanding daily use of painkillers composed of two or more analgesics (particularly aspirin and acetaminophen together) with caffeine or codeine are most likely to damage the kidneys. These mixtures are often sold as powders or tablets. Recent studies have suggested that longstanding daily use of single analgesics such as acetaminophen or ibuprofen may also increase the risk of chronic kidney damage, but this evidence is not as clear.
In view of these findings, patients with conditions that put them at risk for acute kidney failure should check with their doctors before taking any analgesic medicine. People who take over-the-counter painkillers on an ongoing and regular basis should check with their doctors to make sure the drugs are not hurting their kidneys. The doctor may be able to recommend a safer alternative.
Here is one from the NIH, but I haven't really found the mechanism of action other than overloading the kidneys ablity to process aspirin , apap and NSAID'S.
Analgesic Nephropathy: Painkillers and the Kidneys
An analgesic (AN-ul-JEE-zik) is any medicine intended to kill pain. Over-the-counter analgesics (medicines bought without a prescription) include aspirin, acetaminophen, ibuprofen, naproxen sodium, and others. These drugs present no danger for most people when taken in the recommended dosage. But some conditions make taking even these common painkillers dangerous for the kidneys. Also, taking one or a combination of these drugs regularly over a long period of time may increase the risk for kidney problems. Most drugs that can cause kidney damage are the ones that are excreted only through the kidneys.
Case reports have attributed incidents of acute kidney failure to the use of painkillers, including aspirin, ibuprofen, and naproxen. The patients in these reports had risk factors such as systemic lupus erythematosus, advanced age, chronic renal conditions, or a recent binge of alcohol consumption. These cases involved a single dose in some instances and never more than 10 days of analgesic use. Acute kidney failure requires emergency dialysis to clean the blood. But normal kidney function often returns after the emergency is over.
A different kind of problem can result from taking painkillers every day for several years. Analgesic nephropathy is a chronic kidney disease that gradually leads to end-stage renal disease and the permanent need for dialysis or a kidney transplant to restore renal function.
The painkillers that combine two or more analgesics (for example, aspirin and acetaminophen together) with caffeine or codeine are most likely to damage the kidneys. These mixtures are often sold as powders. Single analgesics (e.g., aspirin alone) have not been found to cause kidney damage.
Patients with conditions that put them at risk for acute kidney failure should check with their doctors before taking any medicine. People who take painkillers on a regular basis should check with their doctors to make sure they are not hurting their kidneys. The doctor may be able to recommend a safer alternative.
Information provided by the
National Institutes of Health
Definition:
Analgesic nephropathy involves damage to one or both kidneys caused by overexposure to mixtures of medications, especially over-the-counter pain remedies (analgesics).
Alternative Names:
Phenacetin nephritis; Nephropathy - analgesic
Causes, incidence, and risk factors:
Analgesic nephropathy is one type of toxic injury to the kidney. It is usually a result of prolonged or chronic ingestion of analgesics, especially over-the-counter (OTC) medications that contain phenacetin or acetaminophen and nonsteroidal antiinflammatory drugs (NSAIDs) including aspirin or ibuprofen. The ingestion may have been excessive, with as much as 4 to 5 pounds of total medication ingested over a period of years, or about 3 pills per day for 6 years. This frequently occurs as a result of self-medication, often for some type of chronic pain.
Analgesic nephropathy occurs in about 4 out of 100,000 people, mostly women over 30 years old. The incidence has decreased significantly since phenacetin is no longer widely available in OTC preparations. Risk factors include use of OTC analgesics containing more than one active ingredient, chronic headache, chronic backache or musculoskeletal pain, pain with menstrual periods, emotional and/or behavioral changes, and history of dependent behaviors including smoking, alcoholism, and excessive use of tranquilizers. There may also have been a history of the following conditions:
Urinary tract infections (see acute UTI)
Interstitial nephritis
Renal calculi
Prerenal azotemia
Congestive heart failure
Blood volume depletion (such as dehydration).
The damage occurs within the internal structures of the kidney. There is interstitial nephritis and renal papillary necrosis, eventually leading to acute renal failure or chronic renal failure. The tissue of the kidney may slough off into the urine. There may be blood and pus in the urine, with or without positive urine cultures or other signs of infection, and there may be minimal or no loss of protein in the urine.
Symptoms:
Weakness
Fatigue
Increased urinary frequency or urgency
Blood in the urine
Flank pain or back pain, renal colic (occasional)
Decreased urine output
Decreased alertness
Drowsiness
Confusion, delirium
Lethargy
Decreased sensation, numbness (especially of extremities)
Nausea, vomiting
Easy bruising or bleeding
Swelling, generalized
Note: There may be no symptoms.
Signs and tests:
An examination may be unrevealing but may indicate interstitial nephritis or renal failure. The blood pressure may be elevated. There may be signs of fluid overload, including abnormal heart or lung sounds. Premature skin aging may be evident.
A blood toxicology screen may be positive for salicylate.
A urinalysis shows blood and white cells.
A CBC may show anemia, with decreased number of red blood cells.
A histology (examination) of sediment or tissue passed in the urine may show necrotic (dead) papillary tissue.
An IVP (intravenous pyelogram) may show papillary necrosis (tissue death) or sloughed papillae in the renal pelvis or ureter.
Treatment:
The primary goals of treatment are to prevent further damage and to treat any existing kidney failure. The health care provider may advise you to stop taking all suspect analgesics, particularly OTC medications.
Signs of kidney failure should be treated as appropriate to the extent and severity of the kidney failure. This may include dietary changes, fluid restriction, dialysis or kidney transplant, and other treatment.
Counseling, behavioral modification, or similar interventions may assist in developing alternative methods of control of chronic pain.
Expectations (prognosis):
The damage to the kidney may be acute and temporary, or chronic and long term.
Complications:
Acute renal failure
Chronic renal failure
Interstitial nephritis
Renal papillary necrosis (tissue death)
Urinary tract infections, chronic or recurrent
Hypertension
Transitional cell carcinoma of the kidney or ureter
Calling your health care provider:
Call your health care provider if symptoms indicate analgesic nephropathy may be present, especially if there has been a history of use of analgesics.
Call your health care provider if blood or solid material is present in the urine, or if the urine output decreases.
Prevention:
Follow the directions of the health care provider when using medications, including OTC medications. Do not exceed the recommended dose of medications without the supervision of the health care provider.
Shoreline, Feeling Better? Great Posts, btw! 
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