Flush with drugs: a new database for common pharmaceuticals provides insight into surface water contaminantion

A while back I wrote about the “drugs down the drain” program, targeted primarily at those with unused drugs who might decide to tip those bottles of old aspirin, or unused antibiotics. Yes, yes, I know – there should be no such thing since we’re all told to complete the course. But – there have been times when amoxicillin just didn’t cut it. Those times when the kids’ ears still screamed with pain and a visit to the docs office leads to a mid-course correction - a stronger antibiotic– leaving a half-full bottle of the pink stuff in our fridge.

In these cases it’s important to dispose of the stuff properly – so they don’t end up medicating everything downstream. But what about the pain-killers, heart drugs, antidepressants, antibiotics, gastrointestinal aids that we (and here I’m using the royal WE) take daily? What happens to them when we, pardon the expression, pee?

According to a recent review (introducing a new database) by Emily Cooper and others, just published in Science of the Total Environment, “…between 30 and 90% of an administered dose of many pharmaceuticals ingested by humans is excreted in the urine as the active substance…” and “…up to 90% of drug residues may remain in effluent after [sewage] treatment…”

Although the fact that flushed drugs end up in local streams, rivers and estuaries isn’t new to me – these numbers are astounding. Just imagine if we could reclaim all those drugs. Why - in our school district that might just pull us out of the fiscal hell we've been experiencing for the past decade! And aside from all that waste (though it makes you wonder if pharmaceutical companies design them that way,) once they're in the water - they're no longer beneficial, but rather, environmental contaminants.

But wait – the astute reader (perhaps one of my astute students) might say. What about dose? Certainly the stuff gets diluted, certainly the local trout are not exposed to therapeutic doses of valium or Tylenol? Certainly not. But as the authors point out, several studies now show that chronic exposures to low concentrations can adversely impact aquatic organisms. And, don’t forget – that the Tylenol that I might send over to the local treatment plant will mix with my neighbor’s kid’s antibiotics, and the psychotherapeutics of another neighbor and …you get the picture. There’s a little bit of a whole lot of stuff going down all of our drains collectively.

So what to do with a problem so pervasive? Prioritize, prioritize, prioritize. Fortunately Cooper and co-authors introduce a new, fairly user-friendly database called “Pharmaceuticals in the Environment, Information for Assessing Risk” or PEIAR that will allow researchers and others to do just this.

After a quick tour, I found the site easy to navigate, and easy to track back to original sources, and full of useful information. However, since I’ve made a career of avoiding risk assessment I can’t comment on its utility to risk assessors. I’ll leave that to the pros.

Check it out at http://www.chbr.noaa.gov/peiar.

More on grapefruit juice and drugs

A few weeks back, I wrote about drug interactions. On the recommendation of my editor (it was originally for the local paper,) I'd removed the details of how certain drugs are metabolized - the part I found most interesting, and the part he thought would most likely lead to bored and frustrated readers.

At the time I'd agreed with him and cut. But then, over the Thanksgiving Holiday, when I'd jokingly commented on the cranberry juice cocktail my friend was about to finish off, she said,

"...but I only take the Lipitor at night. Drinking a glass of cranberry juice during the day shouldn't matter."

Maybe, maybe not. I don't know much about the combination of Lipitor (atorvastatin calcium) and cranberry juice but the comment reminded me of why I'd written about the details of drug metabolism in the first place.

While the science of drug metabolism is complicated enough, when one adds the potential for drug-drug or drug-food interactions the level of complexity can skyrocket.

First, a quick introduction to drug metabolism. Lipitor is a drug metabolized primarily by enzymes belonging the CYP detoxification or drug metabolizing system. Years ago the CYP system was one of the few recognized detoxification systems in the body. That is, a collection of enzymes working together to metabolize toxic chemicals and send them on their way before they can cause any damage. Back then we knew of only a couple of enzymes, now there are dozens and dozens grouped into "families" of CYP enzymes. In the case of Lipitor, CYP3A4 is key for proper metabolism and eventual excretion of the drug.

For chemicals that require metabolism by CYP enzymes prior to excretion, the CYPs play an important role in determining the half-life of a drug or chemical.

Half-life refers to the length of time required for a drug or chemical to be reduced to one-half the initial concentration. Knowing the half-life is necessary to determing dosage ensuring that 1) there is sufficient levels of drug in the system and 2) concentrations don't get too high that they become toxic.

Anything that screws with the half-life of a chemical is potentially very dangerous. For chemicals that must be metabolized in order to be excreted, an increase in CYP metabolism would reduce half-life, resulting in drug concentrations that may no longer effective. Conversely, a reduction of CYP metabolism, or inhibition of metabolism can increase half-life, causing drugs to accumulate to toxic, possibly even lethal concentrations.

And even asking "what's the half-life" of a drug under normal conditions isn't so simple. Take the example of Lipitor. While the parent compound Lipitor (the actual drug that you ingest) may have a half-life of only fourteen hours, the metabolites of the drug - which in this case are most active - have a much longer half-life of twenty to thirty hours. That means that it can take up to thirty hours for half the initial concentration of active metabolites to exit your body.

Now lets consider the interaction between grapefruit juice (really certain chemicals in grapefruit juice) which act as inhibitors of CYP3A4. In this case, those CYP enzymes responsible for metabolic breakdown of Lipitor would be inhibited, essentially extending the half-life of the drug possibly leading to potentially toxic concentration of the drug.

And, what makes this all really complicated is that depending on how an inhibitor like grapefruit juice does it's dirty-work, the inhibitory effects may either very short-term or can last for days. In the case of grapefruit, according to one article in Pharmacy Times drinking grapefruit juice not only has immediate (within 30 minutes) impacts on metabolism, but, depending on how long and how much one has been drinking, inhibitory effects can last up to three days. This is because the chemicals responsible for inhibition by grapefruit juice, essentially combine irreversibly to CYP3A4, taking them out of action for good, necessitating synthesis of new enzyme.

Phew - maybe my editor was right! Well, you get the point I hope.

When taking new drugs or adding new food and beverages to your diet, it's well worth the little extra effort to inform your doctor or your pharmacist of the changes.

Drug Interactions: more common than you might think

Many years ago, my father suffered a TIA or transient ischemic attack – a sort of mini-stroke. This episode occurred in association with a very common type of cardiac irregularity called atrial fibrillation. And what should have been a relatively short hospital stay turned into an all too real example of the adverse effects resulting from multi-drug interactions.

Following the TIA, thanks to a quick response by the local ambulance company, by the time my father reached the hospital he was relatively symptom free. A fact apparent to all but the admitting doctor who, upon checking for impaired mental capacity, asked him to recite the months backwards, beginning with the current month.

He said, “Enuj.”

It was the month of June, and that was my dad.

But as doctors struggled to find a safe and effective dosage of Coumadin (known generically as warfarin), a common blood thinner used to prevent future and more severe blood clots that can cause TIAs and worse, my dad’s blood levels of Coumadin bounced around, predictably unpredictable, thanks in part to his well developed drug metabolism system. You see, in his early twenties, following a bout of spinal meningitis, my father was diagnosed with epilepsy. For the rest of his life, he relied upon a combination of Meberal and Tegretol, two powerful medications to keep the seizures at bay.

Meberal is a derivative of phenobarbital, a drug that I’d been using in the toxicology laboratory at that time to increase the amounts of specific drug metabolizing enzymes. Tegretol will do the same. These enzymes belong to a system of detoxification enzymes that essentially alter toxic chemicals into more excretable compounds sending them on their way out of the body before they can cause any damage. Most likely, it was those same enzymes, induced by years of Meberal and Tegretol, which wreaked havoc with my father’s early Coumadin levels, measured then as “pro-time”, or anticoagulant activity.

To be fair, Coumadin is one of the most difficult drugs to manage, in part, because it is so susceptible to interactions with other drugs and nutrients (more on that later). Says Ed Tessier Pharm.D, and clinical pharmacist at Baystate Franklin Medical Center in Greenfield, MA, “It’s a life saving drug, but it’s known nationally as one of the most difficult to manage, not only because of drug interactions but genetics as well.” As with most biological systems, there is a strong genetic component of the detoxification system. Some of us are rapid metabolizers, some of us are not.

But here’s the thing. Although many of us don’t think we’re prime candidates for Who Wants to Host a Complex Drug Interaction, many of us do occasionally ingest potentially toxic combinations of drugs and chemicals in our food and drink without a second thought. Sometimes one of these combinations render drugs ineffective, sometimes it turns them toxic.

Take caffeine and Tylenol (or acetaminophen) for example. Acetaminophen is one of those drugs metabolized by the liver enzymes mentioned above and according to an article published online by eMedicine by Dr. Susan Farrell, assistant professor in the Department of Emergency Medicine at Harvard Medical School, “Acetaminophen is the most widely used pharmaceutical analgesic and antipyretic agent in the United States and the world….. As such, acetaminophen is one of the most common pharmaceuticals associated with both intentional and accidental poisoning.”

Most of the time, most of the acetaminophen we ingest is metabolized by specific detoxification enzymes to nontoxic by-products or metabolites, which we excrete without a problem. But sometimes, depending on the amount ingested, or, since we are talking about drug interactions, whatever else we may have ingested prior to, or along with the acetaminophen, some of it takes the toxic route, resulting in highly toxic metabolites. If you’re a cat owner, this may sound familiar. Acetaminophen and cats are a potentially lethal combination because in cats, unlike in humans, most acetaminophen is routinely metabolized via this toxic route.

Since most of this drug metabolizing drama takes place in the liver, it is the liver that is most susceptible to toxic metabolites. Notes Farrell, “In the United States, acetaminophen toxicity has replaced viral hepatitis as the most common cause of acute hepatic failure, and it is the second most common cause of liver failure requiring transplantation in the United States.”

Now say we drink a few too many Starbucks Grandes in addition to ingesting a hefty dose of Tylenol. According to Dr. Sidney Nelson, Professor of Medicinal Chemistry at the University of Washington, and lead author of a recent article in Chemical Research and Toxicology on the interaction between APAP and caffeine, “…very high concentrations of caffeine (the amounts individuals might achieve by drinking approximately 20 cups of coffee) can triple the amount of a liver toxic metabolite of acetaminophen.”

Twenty cups? That seems like an awful lot, although these days between high-test coffee and higher-test energy drinks, it would be wise for those heavy drinkers to take note. Not only that, but if one were to add a night of excessive drinking (this time I mean alcohol), followed by a morning requiring Tylenol and caffeine, it may not take twenty cups before your liver begins to suffer the consequences.

Says Dr. Nelson “…There is a period of 12-36 hours [after acute alcohol consumption] during which more acetaminophen toxic metabolite will be formed because of increased amounts of the metabolizing enzyme.”

You see alcohol, like my dad’s anti-seizure drugs also increases specific enzymes involved in certain detoxification (sometimes toxification) systems. And unfortunately, it’s not just “recreational drugs” like caffeine and alcohol that can interact with other drugs in potentially devastating ways. For a few years following my father’s TIA, after doctors figured out the correct Coumadin dosage, his blood levels of the drug remained relatively stable. He was an extremely attentive patient, interested in tracking levels of the drug as the doctors made them available, well aware of potential interactions of drugs and diet.

Then one day his Coumadin level shot up. This time, his medications weren’t to blame, nor was his overactive liver. Something was inhibiting the metabolism. The culprit, doctors eventually discovered, was his latest favorite beverage, grapefruit juice. Once again, my father’s real-life experience reflected what I had learned in toxicology. To inhibit detoxification enzymes in some of our experiments, we had used quercitin, one of the active substances in grapefruit.

According to Ed Tessier, for most Coumadin patients grapefruit juice may not be as important as other food and drug interactions, however, “grapefruit does affect metabolism of a great number of other drugs, including most of the “statin” drugs to lower cholesterol (such as atorvastatin – Lipitor®) and can lead to rhabdomyolysis - a life threatening condition which results in muscle tissue injury and possible kidney failure.”

As we add new foods to our diet, and new pharmaceuticals and herbal remedies to our medicine cabinets the potential for interaction is never-ending. One more product I am compelled to mention is St. John’s Wort, the herbal remedy commonly used to treat depression, also induces detoxification enzymes.

According to Nelson, “Chronic ingestion of St. John’s Wort….may increase the formation of the toxic metabolite of acetaminophen. If acetaminophen is taken in therapeutic doses, it is very unlikely that there would be any problem. However, if the individual taking these drugs takes larger doses of acetaminophen and drinks large amounts of caffeinated beverages (say 8 cups or more of strong coffee) or takes large amounts of caffeine-containing drugs, they would form significantly more of the toxic metabolite that could put them at risk of liver damage.”

And, among the many medications that may fall prey to enzymes induced by St. John’s Wort are most antidepressants, as well as many migraine medications, HIV medications, and birth control pills. Only in the case of some of these drugs -- including birth control pills -- the result of increased metabolism isn’t increased toxicity, but reduced efficacy.

Should this brief lesson in drug interaction scare you off your meds, fear not. These days, doctors like Kathleen McGraw MD, Medical Director of Hospital Medicine at Baystate Franklin Medical Center are blessed with instant access to reams of information on drug interactions through the web some of which can be downloaded onto hand held computing devices.

Within minutes of my mentioning St. John’s Wort, McGraw was on her PDA running the Epocrates program, scrolling through lists of drugs known to be adversely impacted by St. John’s Wort. Just as quickly she rattled off drugs affected by grapefruit juice.

To avoid problems caused by the potent chemicals in grapefruit juice, says McGraw, “I tell patients they need to give it up totally (same with cranberry juice) unless it is something they can't live without in which case they have to commit to having the same amount every single day. Given that choice, everyone says they'll quit.”

Adds McGraw, “I encourage every patient on Coumadin to remind any physician giving them a prescription for a new medication (especially antibiotics) about the Coumadin and ask if it will be affected.”

Thankfully, since the days of my dad’s TIA, the science and the awareness of drug-drug and drug-food interactions have come a long way. But it’s a two-way proposition. For pharmacists and doctors to do their part, we have to do ours, whether it’s disclosing that we’re on Coumadin, Viagra, birth control pills, herbal medications, Starbucks Grandes or the newest favorite, pomegranate juice.

UPDATE March 2010: it is well known that individual metabolic differences can dramatically impact drug metabolism. Particularly important for drugs like warfarin (coumadin.) A recent study shows that by tailoring doses based on genetic testing may help reduce hospitalizations due to drug imbalance. Read more here: http://www.businessweek.com/lifestyle/content/healthday/637031.html

Reprinted from the Montague Reporter, please feel free to quote using proper attribution.

Drugs Down the Drain

Many years ago a study out of England reported the discovery of mixed-sex fish (primarily male fish with eggs). Although nothing new now, this was one of the first reports of feminized fish. What I remember most about that study, was how we laughed (I was working with some fish physiologists) at some of their possible explanations, which included hormones from the pill or just every-day urine that had been flushed down the toilet.

Years later, the USGS routinely measures drugs, or the remnants of drugs flushed after passing through our bodies, or intentionally flushed by folks wanting to discard old or unused drugs. Scientists are increasingly concerned about the impacts of pharmaceuticals not only on aquatic creatures (imagine swimming in a sea of heart medication, pain killers and birth control pills) but in some cases on drinking water.

Now the American Pharmaceuticals Association (APhA) has teamed up with the U.S. Fish and Wildlife service to educate the public about proper drug disposal through a campaign called SMARxT DISPOSAL.

I don’t have the numbers on how much is estimated to come from intentional disposal and how much is excreted, (although either way – giving drugs a proper burial as described in the disposal guidelines has got to be better than ditching them down the tube – and some, they actually suggest you do flush), but it will be interesting to monitor the impact of this program.

Antimicrobials: Too Much of a Good Thing?

What do my husband’s armpits, my son’s sandals, my mother’s steak knives and my daughter’s hairbrush all have in common? Antibacterials. They are all impregnated with antibacterial chemicals – well maybe not the armpits, but the underarm deodorant. These days, just about anywhere that is suitable for bacteria is apparently also suitable for antibacterial treatment by manufacturers wishing to attract health-conscious shoppers.

But here’s the rub – antibacterial chemicals are now showing up in the environment – in places they were never meant to be. In water flowing into rivers downstream from sewage treatment plants, in fish, and in treated sewage sludge that is applied to agricultural crops.

Additionally, while it’s clear that the use of antibacterials are beneficial in clinical settings, according to a Food and Drug Administration panel on Nonprescription Drugs there is little or no indication that such additives protect the consumer any better than washing with plain soap and water.

As a one-time teacher of microbiology, I’d always prided myself on having the foresight to stay away from purchasing soap products with antimicrobials. Although to my surprise, there they were in other household I’d purchased including the Teva sandals and the Old Spice Classic with triclosan that I’d bought for my husband.

“[The antibacterials] triclocarban (and triclosan) were introduced in the hay-days of chlorine chemistry, when chemicals like DDT and PCBs were considered safe. Relative to the latter, the antimicrobials are less problematic, but now that PCBs and DDT are banned, the focus has shifted to other chlorinated chemicals like triclocarban and triclosan,” says Dr. Rolf Halden, of Johns Hopkins University.

Recently, Dr. Halden’s group reported in the journal Environmental Science and Technology that the majority of triclocarban that is washed down the drain and into sewage treatment plants ends up in sewage sludge, which in turn may end up on agricultural fields.

His research reveals not only the persistent nature of the chemical (not unlike those other chlorinated chemicals now banned.) It also highlights the high volumes of these chemicals that are used by consumers and released into the environment. Halden’s group estimated that in their study area alone, more than one ton of triclocarban ends up in the environment (and on agricultural land – where it can be taken up by crops) each year!

While Halden is concerned about the release of the chemicals into the environment, Dr. Stuart Levy, the director of the Center for Adaptation Genetics and Drug Resistance at Tufts University, is concerned about the potential for antimicrobials to encourage development of antibiotic or drug resistant microbes.

Development of antibiotic resistance is an important survival mechanism for microbes, and soil microbes in particular. Soil is packed with microbes. They are part of what makes healthy soil healthy. Soil is also a fertile hunting ground for new antibiotics. In fact the first mass-produced antibiotic, penicillin was produced by a soil-dwelling microbe. What better way to stake one’s microscopic claim then to poison one’s neighbors? So soil microbes are constantly battling antibiotics produced by neighboring soil microbes. And in order to “keep up with the Jones’” or at the very least survive the Jones’ constant assaults, bacteria have become adept at developing antibiotic resistance.

The same can be said for the millions of bacteria that live on and in our bodies. When they are constantly exposed to antibiotics, it is possible that some will overcome, and develop antibiotic resistance. This is where the antimicrobials come in.

“We produced the original evidence that triclosan [a chemical simlar in structure to triclocarban] can lead to antibiotic resistance,” said Dr. Levy, “but while resistance to antibacterials has been found among bacteria outside the laboratory, they have not been linked to the use of triclosan.”

“Triclocarban is another antibacterial found in soaps. No one has looked at its mechanisms of action. There is clearly concern about the exposure to both of these antibacterials [causing antibiotic resistance], but in particular triclosan. The other antibacterials of concern are those under the heading of quaternary ammonium compounds like benzalkonium chloride. More and more data are linking resistance to this product with antibiotic resistance.”

So, antibacterials which have the potential to cause antibiotic resistance are released into the environment in huge quantities as a result of consumer use, and an FDA panel has concluded that antimicrobial products appear to be no more protective to consumers than soap and water. Who’s in charge of regulating this stuff?

Antimicrobials are regulated by both the FDA and the Environmental Protection Agency, depending upon their use, and claims made by manufacturers. EPA regulates antimicrobials when they are used as pesticides, for example to reduce odors in my son’s stinky Tevas, but FDA regulates them as drugs when used in something like the bottle of soft-soap that graces the bathroom sink at my daughter’s school. In either case – since triclosan and triclocarban were developed and registered at least thirty years ago, back when persistent chemicals weren’t known to be a problem, and antibiotic resistance hadn’t reared its ugly head – one wonders how today’s research has enlightened the regulators.

“Advances in a number of fields have changed the way we examine and interpret the potential risk of synthetic chemicals,” says Halden. “Many studies conducted in the 1970’s would not pass muster today.”

But there’s hope, according to Stuart Levy, who noted that while “there is no evidence of a change in regulation, there certainly seems to be a greater insight and concern by regulatory agencies like the FDA and EPA. They are both looking more closely at this issue, thanks to the advocacy of scientists and others.”

It’s also worth noting that perhaps not all products present the same risks. “It is presumably more likely that triclosan in a water-solubilizable form [soft-soaps for example] would be more risky than that which has been incorporated into something like a mattress or sneakers,” suggests Levy, who notes that even with these products, the fate of antibacterials is unknown.

So where does that leave us? According to Dr. Bernadette Albanese, a public health expert, “If people spent as much time washing their hands, as they do reading the labels of this stuff, we’d all be better off. Putting antibacterial in soap, towelettes, band-aids is mostly useless. The message should be proper and frequent hand washing, use plain (liquid) soap and paper towels. That is the message the public needs to hear.”

Although I’m not sure I’m ready to give up the microban treated Tevas (have you smelled a well-worn pair of Tevas?) I’ll definitely be reading my consumer products labels more carefully.