Drug Tolerance

“I don’t need help because if I can’t help myself I can’t be helped.” --Amy Winehouse

“Amy Winehouse found dead at her London flat…autopsy inconclusive…toxicology results expected in two to four weeks.” 

by Jane Maddox, Ph.D., Assistant Professor
Department of Pharmacology and Toxicology

Why do forensic toxicology results take so long? There are several reasons:

Multiple samples must be tested: blood, stomach contents, and urine are commonly first taken, but other tissues such as liver, brain, kidney, and vitreous humor of the eye may also be sampled.

If there are no obvious signs or symptoms linked to specific drugs or toxins observed at the time of death, testing for many different toxic substances must occur.

The tests must identify and quantify a wide repertoire of both legally prescribed drugs and illicit substances to determine if either any single drug or combination of drugs could have been the cause of death.

The initial tests would likely be immunoassays to screen for a wide variety of drugs suspected as the cause of death. These tests use antibodies to detect known drugs, but they can only measure a predetermined set of substances; therefore, if a new or unknown drug has been taken, it can be missed. Other analyses, such as mass spectrometry (that can identify unknown toxic substances) must also be performed.  Mass spectrometry is very sensitive and specific, but it also takes more time to complete.

Once potentially toxic substances have been detected, the concentrations in the sample must be compared with clinical data to determine if the dose, or combination of doses, was high enough to be lethal. In addition, samples may be retested in the same laboratory or sent to a second laboratory for confirmation. Again, these tests take more time. Confirmatory tests are important for several reasons: 1) to ensure scientific integrity of the data, 2) to defend against potential legal issues involved in cause of death, particularly in the case of a celebrity death.

As for the death of Amy Winehouse, it is complicated.

She was alone at the time of death, so no symptoms were observed, and it was reported that no drugs or paraphernalia were found on the premises. Therefore, important clues to direct the toxicology testing were lacking and the search could take some time to complete.

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.

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

I am lecturing next week in our graduate level Principles of Pharmacology and Toxicology course (PHM 819).  I will be discussing drug tolerance, dependence and withdrawal.  These are topics usually associated with drug addiction but as I will convey to the class, drug tolerance, dependence and withdrawal are associated with many non-addictive drugs.  My lectures will focus on cellular and molecular mechanisms responsible for tolerance, dependence and withdrawal. We will discuss in great (some say nauseating) detail what happens to individual molecules and cells when they are exposed chronically to drugs.

Questions often posed by the students include: So what? Who cares?  What does this really mean?  How is this useful for using drugs to treat illness?  I admit that these are all good questions.

It is a coincidence then that the Food and Drug Administration has just come out with a News Release (http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm172366.htm) that is highly relevant to these questions.  The release is related to a new drug called Onsolis (fentanyl).  Fentanyl is a very strong opioid narcotic that is not easy to use because it is highly potent (only a very little of the drug is needed to produce pain relief or to produce respiratory depression which can be lethal).

The Onsolis preparation of fentanyl is novel in that is contained in a film (like some breath mints) that is placed in the mouth and the drug is absorbed directly from the mouth.  Onsolis is approved for use in chronic pain patients who are taking opiates regularly for pain relief.  Onsolis is for use only for breakthrough pain that is not suppressed by the patient’s normal opiate medication.

Now what does this have to do with PHM 819?  Well because these patients take opiates regularly they are highly tolerant to the effects of opiates.  So a fatal overdose due to respiratory depression is much less likely because these patients are much less sensitive to the respiratory depression caused by opiates.  They also develop tolerance to the pain relieving effects of opiates but because fentanyl is such a strong analgesic, it still provides some relief even in the opiate tolerant patient.

This is a real world application of the principle of drug tolerance and how we can take advantage of this to improve patient health.  This is also a good reason for students to understand drug tolerance, dependence and withdrawal.  Finally, it is a good example of why understanding the mechanisms responsible for drug tolerance is important for drug development and patient care (and not just for passing exams)!

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