Central  South  Dakota Medical News
The Clinical View
by P.E. Hoffsten, M.D.

HOW MEDICINES WORK – THE LOCK AND KEY MODEL

     In the sophomore year of medical school,  how medications work is taught from the basics up.  Barely half a dozen of the medications that I learned about then are used today.  Most of the modern medications have come on the market in the last twenty years and even some of them are being replaced by newer medications yet.  Be that as it may, the basic concepts of how a medication works remain the same.  Our pharmacology professor taught us using the model of a lock and a key.  He made the point that our cells have receptors on them that are very much like a key hole on a lock.  A drug comes along, attaches to the receptor much as a key goes into a key hole on a lock and then anyone of a number of things can happen.

      Of course, the simplest thing that can happen between a lock and a key is that the key just doesn’t fit.  As an example, fifty years ago many bacteria had  receptors on them which would bind penicillin.  When penicillin attached to the bacterial protein receptor, the ability of the bacteria to make a cell wall was interfered with and the bacteria died.  Today, very few of the important bacteria causing infections in humans will bind penicillin.  Thus, the penicillin doesn’t stick to the bacteria.  The bacterial wall is made normally and penicillin just doesn’t work anymore  because the key doesn’t fit the lock.

       The second thing that might happen between a lock and a key is that the key fits just fine, it turns the lock and the lock opens.  Wonderful!  The lock and key work.  An example of this in medicine would be the use of thyroid hormones.  Thyroid hormone is made by the thyroid gland in the neck and it attaches to cells all over the body to regulate how fast the body will “idle”.  Just like you have a given idle speed when your car is sitting still, your body has an idle speed that is set by the amount of thyroid hormone that you have.  Sometimes, a person’s thyroid gland doesn’t work as well as is needed and extra medication as a thyroid supplement pill is used instead.  This almost always will correct the lack of thyroid hormones because thyroid hormone fits into its receptor just like a key fits into the lock that works.

       But then things get more complicated.  I remember the time that a friend of mine in college had an old car that was kind of hard to start.  He would get very irate with this car, turn the key a little harder thinking that would make it start better and one day he twisted the key right off leaving the shank in the lock and no way to get it out.  Now here was a lock with the key hole blocked and no way to start that car.  The example in medicine is any of the large number of “blocking drugs” that interfere with the function of receptors that are causing disease in the body.  As an example, platelets have receptors (key holes) on them that allow platelets to stick together when that receptor is stimulated.  This is the way that a blood clot can grow and prevent bleeding in an injury.  This is good.  Unlocking this platelet receptor (lock) can also lead to the growth of a blood clot in a blood vessel in your heart or your brain causing a heart attack or a stroke and that is bad.  When a person is past age 40 or 50, severe injuries are relatively unusual and thus forming good blood clots isn’t necessarily very useful.  Instead blood clots that form too easily in the brain or the heart cause heart attacks and strokes and are the leading cause of death in our society.  Thus getting in the way of that platelet receptor, causing the  blood clot to grow, would be useful.  Aspirin does this.  Aspirin attaches to the platelet receptor that allows it to stick to other platelets.  When this platelet receptor is blocked, blood clots can’t grow to  block off blood vessels and heart attacks and strokes are prevented.   Breaking the key off in the lock in a medical sense isn’t necessarily bad, although my friend with a cranky car was bent out of shape for quite awhile.

       As another example of the lock and key model,  I knew an ingenious father who liked to sleep at night.  His kids would turn the television up to outrageous volumes, keeping him awake, then he would have to go downstairs and yell at them and everybody was bent out of shape.  He was an ingenious chap who worked for an electronic firm.  He came up with a key that replaced the volume knob on his TV set and he fixed it so that the key  he gave the kids only turned the volume up so far.  No matter what they did it wouldn’t go any higher.  Then he had a key of his own that he could turn the volume up to any level  he wanted.  I thought that was brilliant.  Never could talk him into making one for me.  Something about that he wanted to patent it.

       The medical example of a key that won’t turn the volume up all the way is with pain medicines.  There are receptors in various parts of our body that tell us that we hurt.  When these receptors are stimulated adequately by hormones in our body called endorphins we don’t hurt. When the endorphin levels are low, we will go do something to seek comfort and stop our pain. As a quirk of nature, morphine or heroine look exactly like our own natural endorphins.  Thus if you are hurting and we can’t find a way to fix it, a person can use morphine which will stimulate the pain receptors (or I should say anti-pain receptors) and let a person be comfortable. Morphine is the best anti-pain medicine that we know and stimulates receptors in our brain and spinal cord to tell us that we are not hurting.

       There are less effective drugs that attach to these same morphine receptors.  Among them are products called propoxyphene (Darvon), and pentazocine (Talacen, Talwin), and Ultram. These three products are very much like my friends children’s key.  They will stimulate the pain receptor but not all of the way and a person’s pain problem is decreased but not nearly as much as can be achieved with morphine.  This is the reason that it doesn’t make any sense to use Darvon or Talacen or Ultram in people that are also taking morphine.  Those lesser products simply get in the way of the morphine keeping it from working as well it can.  I once worked in a research laboratory where I had a key that would open the door to my lab, another key that would open the door to the storeroom down the hall, a third key that would open the front door of the building.  Each of these keys looked more or less alike but each one only worked in the lock for which it was designated.  One of my co-workers made a joke one day and he said that he could see that I was not the boss.  I told him I knew that but I wondered how he knew it too.  He said because I had so many keys.  He said the real boss has only one and it opens all the doors.

       The medical example of this has to do with estrogen, the female hormone.  It turns out that there are estrogen receptors on the female womb, the female breasts, both male and female bones and in the female central nervous system.  There are probably other receptors (locks) for which estrogen (the key) works but for this example the above will do.  If a woman with her womb in place is given estrogen replacement therapy over a prolonged period of time, there is a risk of developing cancer of the uterus.  But there is also the benefit of preserving bone mineral and preventing osteoporosis.  One is a benefit obviously.  The other is a very scary detriment. What if the key hole protecting the bones was different than the key hole on the female womb? Then maybe we could have one key that would act just on the bones and not stimulate the female womb at all.  So the drug companies went to work and came up with a product called Evista (raloxifene).  It is a form of estrogen that only works on the bone to stimulate osteoporosis prevention but has no effect on the womb and therefore does not have the risk of causing cancer of the uterus. Just maybe by getting in the way of estrogen’s effect on the female breasts, it may have some effect in preventing cancer of the breasts too.

       These are just a few examples of how the lock and key model can be applied to a better understanding of how medicines work.  The healthcare providers at your local clinics are aware of these concepts and help in designing medical regimens that work for  each individual while avoiding medication side effects.