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how do drugs work in your body?  in many cases, no one really knows


“Adverse drug reactions are common. Identifying true drug allergy, however, can be challenging. Complicating factors of drug reactions include the myriad clinical symptoms and multiple mechanisms of drug-host interaction, many of which are poorly understood.” From the November, 2003 issue of American Family Physician (Adverse Drug Reactions: Types and Treatment Options)

“More than 150 million people around the world take the antidiabetic drug metformin each year. Despite its widespread use, the drug’s mechanism of action is poorly understood and controversial.”  From a 2014 issue of the Journal of Biological Chemistry (Antidiabetic Drug Metformin Suppresses Gluconeogenesis)

“Antidepressants are widely prescribed in the treatment of depression, although the mechanism of how they exert their therapeutic effects is poorly understood.”  From the March 2004 issue of Brain Research (Mechanisms of Action of the Antidepressants Fluoxetine……)

“Diprivan Injectable Emulsion is an intravenous sedative-hypnotic agent for use in the induction and maintenance of anesthesia or sedation.  As with other rapidly acting intravenous anesthetic agents, the mechanism of action, like all general anesthetics, is poorly understood.”  From the Rx List’s header for Diprivan

“Beyond this, its relatively low efficacy, high risk of side effects (especially when taken with alcohol) and lack of knowledge about how it works has given some experts pause. For women who are trying to decide whether the benefits will outweigh the risks, they’ll certainly have their work cut out for them, as they sift through the hype to get to the science.  Sprout and its fans are celebrating a drug with low efficacy, significant side effects, and a poorly understood mechanism of action.”  From an August 2015 issue of Forbes (Why Libido Drug Addyi Is Not The ‘Female Viagra’)

“Malaria is a major health burden in tropical and subtropical countries. The antimalarial drug primaquine is extremely useful for killing the transmissible gametocyte forms of Plasmodium falciparum and the hepatic quiescent forms of P. vivax. Yet its mechanism of action is still poorly understood.”  From April’s issue of Redox Biology (The Antimalarial Drug Primaquine……)

“Combination chemotherapies have been a mainstay in the treatment of disseminated malignancies for almost 60 years, yet even successful regimens fail to cure many patients. Although their single-drug components are well studied, the mechanisms by which drugs work together in clinical combination regimens are poorly understood.”  From the January 2013 issue of the Proceedings of the National Academy of Sciences of the United States of America (Defining Principles of Combination Drug Mechanisms of Action)

“Diuretics are drugs that increase the rate of urine flow. There are several classes of diuretic drugs. These agents are used in the management of edema and hypertension.  Thiazide diuretics….  cause Ca2+ excretion to be decreased via a poorly understood mechanism.”  From the online syllabus for Dr. Piascik’s advanced pharmacology class at the University of Kentucky (The Pharmacology of Diuretic Drugs)

“Pyrazinamide is an important sterilizing drug that shortens tuberculosis (TB) therapy. However, the mechanism of action of pyrazinamide is poorly understood.”   From a 2003 issue of the Journal of Antimicrobial Therapy

“How confident are you that the drugs you take, whether they’re over-the-counter or prescription, are totally understood by the companies who make them?  After all; drug makers know what their products do when they enter your body, right?  You shouldn’t assume that.   Today we are going to talk about everything from Tylenol to fen-phen to Viagra and why you should probably think hard before you take any drug at all.”  Luke Timmerman and Meg Tirrell from STAT’s daily podcast, Signal (Before You Pop that Tylenol, Tune in to this Podcast) — the article we are discussing today

“Not understanding a drug’s mechanism of action sets the table for a vast array of side effects.”  Dr. Russell Schierling

I receive several different daily medical news publications in my inbox.  My two favorite are MedPage Today and STAT.  Make no mistake about it, both are medical publications, meaning they routinely pick on alternative medicine, while spending their time, energies, and money (think advertising dollars here) extolling the virtues of drugs, surgeries, and tests.  So when I saw the title of STAT’s recent podcast, I had to have a listen.

Timmerman & Tirrell start out by talking about ACETAMINOPHEN (Tylenol), revealing that even though it has been around for over six decades, no one really knows how it works.  We shouldn’t be surprised that John Q Public has no idea how it works, but the real surprise is that no one — including the drug companies themselves —- knows what its mechanism of action is.  Furthermore, the authors went on to say that this is not an uncommon phenomenon — not surprising after looking at the quotes above.  In fact, they described the mechanisms of many of the drugs we use as, “mysterious and unpredictable“.  Probably why Tylenol no longer uses their old slogan, ‘Nothing Safer‘.   None of this is new information.

“A jury found Tylenol to be a cause of 5-year-old Lacy Keele’s death, but it let Tylenol’s manufacturer, Johnson & Johnson, off because her parents were adequately informed of the risks. Risks with Tylenol? The product’s advertising slogan, after all, was: “Nothing’s safer.”   In the eight years since Lacy died, there have been hundreds of fatalities and serious liver injuries attributed to acetaminophen, the active ingredient in Tylenol. J&J has paid out millions of dollars in legal settlements. A handful of these cases have drawn coverage in newspaper and television stories. The word is beginning to get out that, safe though it is in proper doses, Tylenol can be very dangerous indeed in doses not much greater.”   From Thomas Easton’s piece in Forbes (Johnson & Johnson’s Dirty Little Secret) written almost two decades ago (Jan of 1998).

Part of the problem is that as I have shown you repeatedly (including just THE OTHER DAY), drug reactions are absurdly under-reported.  In fact, Underreporting has become such a huge problem, that it has actually become it’s own entity known as (drum roll please) UNDERREPORTING.  But this is far from the only reason that drugs aren’t as safe as we’ve been led to believe.  Another reason is that people are just plain different, not only from each other, but from lab animals and test tubes.  Listen to what T&T said on their podcast (I am loosely quoting here)…..    “The sheer unpredictability of biology is the reason so many drugs fail….   The fact is, we don’t know how drugs are going to react in the body until we give them to lots of people.

But 60 years? Think about the sheer numbers of people who have taken Acetaminophen in that time period, not realizing what it’s doing to them.  In the words of the Fox Football crew, “C’mon Man“.  What does all this really mean for you, the consumer?  Plain and simple; you are the GUINEA PIG.   Some of the reasons the authors give for this are some of the same things I talk about regularly on my site — GENETICS, MICROBIOME, DIET, etc, etc.  Viagra was an example they used of this sort of ‘guinea pigging’.

When Viagra was being developed as a vasodilator (blood vessel opener) for people with congestive heart failure back in the early-mid 1990’s, the animal studies were so poor that, “it almost did not make it to human trials“.  But make it it did, and when researchers found out it caused raging erections in the college-aged males who volunteered (they were paid) to test the drug for short-term side-effects, the company got a proverbial “erection” of its own.  Interestingly, it seems that accidents are the norm in this arena — probably why the podcast said, “There’s still a huge amount of luck at work in drug discovery.”  The example I always tend to think of when discussing this all-too-common phenomenon is Rogaine (Minoxidil); a drug that was originally developed to treat ULCERS back in the 1950’s.

Later on (in the 1970’s), it was used to treat high blood pressure.  The doctors who worked on it for this purpose “discovered” that this new BP DRUG had the ability to grow hair (HERE) in a certain percentage of the population.  Oh; and by the way, if you read Wikipedia’s entry on the stuff, it says “The mechanism by which minoxidil promotes hair growth is not fully understood.”  When mechanisms are not understood, according to the authors you are much more likely to end up with drugs like, “Thalidomide, Fen-Phen, or Vioxx“.  Another drug they mentioned by name was Enbrel.

Enbrel is a drug given to suppress one of the markers of inflammation called Tumor Necrosis Factor Alpha or TNF-α.  When Enbrel first hit the market, it was considered a wonder drug.  According to the authors, the side-effect profile was “pristine“.  But as time went on, increasing numbers of serious problems came to light (a common theme in this podcast).  

INFLAMMATION is a vital and necessary part of the healing process.  Certain things, however, cause it to climb to exceedingly high levels.  This is commonly seen in RHEUMATOID ARTHRITIS, as well as other AUTOIMMUNE DISEASES.  However, suppressing TNF-α carries it’s own set of side-effects — one of the chief being CANCER.  If your body can’t kill (necrosis) mutating cells that can become cancer, they tend to become just that.  Thus, it’s not surprising that Enbrel’s side effect profile has gone from “pristine” to something VERY DIFFERENT.


“We tend to assume that anything approved by the FDA is inherently safe, and that’s just not true.”Timmermann and Tirrell from their podcast. All of this begs a couple of simple questions; how can these sorts of things happen if the drug was approved by the FDA, and what does FDA approval really mean?  The authors of this podcast delved into this topic.  Amazingly, the one and only factor that determines whether or not a drug is going to be approved is the risk-to-benefit profile.  In other words, do the perceived benefits outweigh the perceived harms?  Sounds logical on the surface, but there are any number of problems with this approach, considering the way we do things here in America.

The first thing you have to understand is that just like other governmental regulatory agencies, the FDA is prone to all sorts of bribery and cannot be trusted (HERE and HERE).  Related to this is the fact that the drug companies are doing their own research (i.e. the fox is guarding the hen house).  This is how debacles like THIS and THIS can occur.  If you want a picture of how corrupt this system is from top to bottom, simply take a moment and browse the titles of THESE POSTS.

The authors go on to say that, “The evidence evolves over time.  It happens with a lot of drugs.  We could sit here listing them all night.  Lab models are inherently flawed.  A Petri dish is not the same as a cell in a live human being.”  What might this sort of “evolution” lead to?  It often leads to drugs being taken off the market years, or even decades, after they were released to the public.  But just as often, dangerous drugs are never removed from the public.

The authors mentioned that some drugs are almost impossible to pull off the market or even have their safety label changed.  In similar fashion to the way certain substances were approved for human use decades ago (think MSG under GRAS — Generally Regarded As Safe, or MERCURY / ALUMINUM IN VACCINES), doing much of anything about drugs like Acetaminophen is all but impossible.  Ultimately, this means that you cannot trust the drug companies — or the government — to to look after your best interests as far as your health is concerned (or anything else for that matter).  They are too busy figuring out new ways to fleece and control you.


Relative Risk Absolute Risk

  The image above was done by Karl Thienemann in 1842.  It is of a traveling huckster, surrounded by curious onlookers as he challenges all comers to a game of thimblerig, otherwise known as “the shell game”.  A popular online encyclopedia says of the Shell Game……

In the shell game, three or more identical containers are placed face-down on a surface. A small ball is placed beneath one of these containers so that it cannot be seen, and they are then shuffled by the operator in plain view. One or more players are invited to bet on which container holds the ball – typically, the operator offers to double the player’s stake if they guess correctly.  The shell game is notorious for its use by confidence tricksters who will typically rig the game using sleight of hand to move or hide the ball during play and replace it as required.

Shades of the ‘Shell Game’ can be seen in Sharon Begley’s fantastic June 15th article in STAT called What are the Odds that your Medication will Help you get Better?  I’ve frequently written about the difference between absolute risk and relative risk.  If you want to understand this concept better, which will help you understand the potential risks of certain medications, as well as how effective (or ineffective) they might be, you need to read Begley’s article.

One of the things she spends ample time on is the concept of NNT (Number Needed to Treat).  This is the number of people who will have to take a particular medication in order to see a benefit.  Begley says (cherry-picked)…..

“An NNT of 5 or less was probably associated with a meaningful health benefit, while an NNT of 15 or more was quite certain to be associated with at most a small net health benefit.  Yet interventions with NNTs above 15 are common.  Statins, which have become synonymous with heart-attack-and-stroke-preventing have an NNT of 104 for heart attack and 154 for stroke: That’s how many healthy people have to take statins for five years for those respective outcomes to be prevented.  The NNT for aspirin to prevent cardiovascular calamities is even higher. A whopping 1,667 healthy people need to take aspirin every day for a year to prevent one stroke or heart attack.”  

Again, none of this is new information.  If you follow my STATIN POSTS or what I’ve written about ASPIRIN, you have seen this any number of times — a nightmare once you understand the magnitude and seriousness of side effects and their GROSS UNDERREPORTING.  If you are curious about the difference in relative risk and absolute risk for drugs that you or your family are taking, you can take a look at THE NNT SITE.  The more you learn about “EVIDENCE-BASED MEDICINE“, the easier it is to recognize BIG PHARMA’S tricks.  After all, figures never lie but liars figure. 


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