August 2009


Michael Jackson

Michael Jackson

by James J. Galligan, Ph.D., Associate Chair,
Department of Pharmacology and Toxicology

Regardless of the final legal outcomes, it is sad that Michael Jackson was killed by inappropriate use of sedative drugs.  The ruling that his death was a homicide is suggestive of negligence and perhaps poor understanding of how drugs work.

It seems that MJ was taking a number of different drugs to help with his sleeping problems.  His doctor was using lorazepam and midazolam in addition to propofol to help MJ sleep but he was finding that each drug alone or in combination was not producing the desired results.  Lorazepan and midazolam are both Valium like drugs that can be used as anti-anxiety and sedative drugs.  They can be taken in pill form so the safety factor in terms of an overdose is reasonably good.  It is difficult to overdose accidentally.  Propofol can only be administered intravenously, so the risk for an accidental overdose is much greater with this drug.

A pharmacology lesson comes from a discussion of how these drugs work on the brain to produce their sedative effect.  All of these drugs act at receptors for the neurotransmitter GABA. GABA, lorazepam, midazolam and propofol all act to turn off or inhibit neuronal activity.  When we are talking about neurons in the parts of the brain that are responsible for anxiety, this is good as that is where these drugs produce their sedative actions.  However, when the neurons that control breathing or the heart beat are affected that is where an overdose becomes an issue.

It looks like drug tolerance may have played a big role in what happened to MJ.  His physician was administering lorazepam, midazolam and propofol but finding that they were not working well.  This is because each drug acts at the same site and the brain adapts to the continued presence of the drug.  The drugs become less effective over time and more and more drug is required to get to the same therapeutic effect.  As higher and higher doses are given, an overdose becomes more and more likely.

A beneficial strategy would be to use a sedative drug or drugs that act through mechanisms that are different from those used by lorazepam, midazolam and propofol.  There would be no tolerance to the new drugs and lower and safer dose could be used.  Knowledge of this basic pharmacological principle might have reduced the overdose risk for the King of Pop.

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by James J. Galligan, Ph.D., Associate Chair,
Department of Pharmacology and Toxicology

Anyone who has fished for walleye and beached their boat on a lakeshore to pan fry the freshly caught fish for lunch, knows – that if there is a heaven – this is it.

However, disturbing news has been provided by the results of a recent United States Geological Survey study revealing a very high incidence of mercury in fish caught in streams and lakes throughout the United States (http://www.doi.gov/news/09_News_Releases/081909.html).  Mercury is a neurotoxin.  More specifically, methylmercury is a neurotoxin.  Mercury gets into lakes and streams from a number of sources but emissions from coal-fired power plants is a major source.  Once mercury is deposited in lakes and streams, it is converted into methylmercury by bacteria living in the water and sediments.  Methylmercury is then passed up the food chain where it can accumulate in predatory fish, like walleye.  This bioaccumulation is potentially hazardous to anything or anyone that consumes predators at the top of the food chain.

Why do we care?  Well, methylmercury has numerous effects on the developing and mature nervous system of mammals, including humans.  Methylmercury disrupts signals between nerve cells in the brain leading to movement disorders, memory loss and perhaps permanent nerve cell damage.  Methylmercury also disrupts the normal development of the nervous system in young animals and children.  Methylmercury is also very fat soluble so it can accumulate in tissues and stay there for a very long time.

The Department of Pharmacology and Toxicology at Michigan State University is home to two of the world’s experts on the effects of methylmercury on the mature and developing nervous system.  Dr. Yukun Yuan has been studying the consequences of early methylmercury exposure on the developing nervous system, while Dr. Bill Atchison has identified many of the major targets for methylmercury poisoning in the adult nervous system.

I am one of those who think that pan fried walleye on the lakeshore is as good as it gets.  However, I may have to begin to revise my ideas of what heaven might look like.

by James J. Galligan, Ph.D., Associate Chair,
Department of Pharmacology and Toxicology

Aspirin is amongst the most commonly used drugs in the world.  It is well know for its pain and fever relieving effects and it is now widely used as a preventative treatment for heart attacks and strokes.  Aspirin is a derivative of salicylic acid which is found in the bark of willow trees.  Salicylic acid is very irritating so chemists at the German pharmaceutical giant Bayer modified the chemistry of salicylic acid to produce aspirin which is far less irritating.  Aspirin produces its beneficial effects by inhibiting two enzymes: cyclo-oxygenase 1 and cyclo-oxygenase 2 (COX-1 and COX-2).   COX-1 is present in the stomach lining and it is responsible for protecting the stomach lining against stomach acid.  This is why aspirin can cause an upset stomach or in more extreme cases, ulcers and bleeding.  COX-2 is responsible for producing inflammation and pain (more on COX-2 in a minute).  COX-2 is the target for drugs such as Celebrex which is claimed to produce the pain relieving effects of aspirin without the risk for an upset stomach or bleeding.

Despite the potential side effects (which in some people can be serious) of aspirin use, a new study published in the Journal of the American Medical Association indicates that aspirin may reduce the risk of death from colorectal cancer in patients previously diagnosed and treated for this disease.  Colorectal cancer is the second leading cause of cancer-related deaths in the United States so this finding has great life-saving potential.  An interesting finding in this study is that aspirin therapy was only beneficial in those patients who had tumors that expressed COX-2; no benefit was found in patients whose tumors did not express COX-2.  This is another example of the potential of “personalized medicine” where drug or other treatments for a disease can be tailored to the specific disease profile in a patient.  Personalized medicine could lead to higher success rates and also lower costs as ineffective treatments would not be used for patients that do not have a medical profile appropriate for that treatment.

While any drug treatments (including over-the-counter drugs) should be started only after consulting with your doctor, it seems that the simple aspirin tablet that can be found in everyone’s medicine cabinet is good for many things that might ail you.

by James J. Galligan, Ph.D., Associate Chair,
Department of Pharmacology and Toxicology

The popular and hyperkinetic TV pitchman Billy Mays recently died of an apparent heart attack.  Autopsy reports indicate that cocaine was present in his system, and this could have contributed to his fatal heart attack.  His family has disputed the toxicology report and the legal process should take its course here. However, this case does highlight the question: “How does cocaine cause heart attacks?”

Cocaine is a highly addictive drug because it acts on brain pathways responsible for the euphoric and rewarding feelings associate with cocaine use (the details of this can be the subject of future posts).  However, cocaine can also act as a local anesthetic drug, much like novacaine that you might received at the dentist’s office.  In fact, modern local anesthetics were developed to mimic the local anesthetic effects of cocaine, without producing the “euphoria” that makes cocaine such an easy drug to abuse.

What is a local anesthetic?  Most local anesthetics paralyze the sensory nerve fibers that supply tissues.  The dentist takes advantage of this with a local injection of novacaine before drilling a defective tooth.  The nerves that convey pain messages from the tooth to your brain are anesthetized by novacaine.  Theses pain messages require the electrical signals carried by sodium channels in the sensory nerve fibers. Novacaine and cocaine block these sodium channels so there is no electrical signal coming from the tooth and you continue to sit comfortably in the dentist chair while the drilling goes on.

What does all of this have to do with the heart?  Well the heart also generates electrical signals that occur in rhythms and these rhythms are required for the continuous and coordinated contractions of the heart muscle that are required for efficient pumping of blood.  The electrical rhythms require activity of sodium channels that can also be blocked by cocaine.  Most cocaine users do not experience heart problems.  However, those who might be predisposed to heart arrhythmias put themselves at much greater risk if they use cocaine.  Examples of people who might be at risk for arrhythmias include those who have high blood pressure or perhaps someone with cardiac hypertrophy.  Cardiac hypertrophy can occur in people with high blood pressure or those have had a previous heart attack.  However cardiac hypertrophy is not uncommon in highly trained athletes.  The enlarged heart is more susceptible to disturbances in heart rhythms and cocaine use in these individuals also puts them at great risk for heart attacks.

The lesson here is two fold.

  • Beware of cocaine, and
  • if you have high blood pressure,  take care of it before you put yourself at risk for a heart attack (with or without cocaine)

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