July 2009

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)!

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

Propofol Structure

Propofol Structure

Diprivan (propofol) is in the news as being a potential contributor to the death of Michael Jackson. What is propofol?

Propofol is a short acting anesthetic drug that is most commonly used in relatively simple outpatient surgical procedures.For example, if you are over 50 years old and have a routine colon cancer screening colonoscopy, propofol would most likely have been the anesthetic you received. The advantages of this drug is that it has a rapid onset of action (less than 1 minute) and its effects are short lived (20 minutes). This makes it ideal for use for the kind of procedures described above.

Propofol is a relatively safe drug when it is used for appropriate purposes and when it is administered by trained medical personnel. The problems arise when the drug is abused. Propofol acts on the nervous system in ways that are similar to other anesthetic and sedative drugs like diazepam (Valium) and barbiturates. All of these drugs inhibit the function of nerve cells in the brain by interacting with receptors for the neurotransmitter GABA. These drugs can inhibit the nerve cells that make you anxious and that is why they are used to reduce stress. However, they also inhibit the nerve cells that control your heart and breathing. Too much of these drugs can cause a person’s heart to stop beating, or they can stop breathing.

Valium and barbiturates are available in orally administered forms (pills) and this makes it harder to overdose (although overdoses happen all the time). However, propofol can only be administered intravenously; there are no propofol pills. This is where the danger arises. When drugs are administered directly into the blood stream there is little margin for error with the dose. Just a little too much can be fatal and if there are no trained medical personnel nearby (as normally occurs with a drug abuser) there is no one to administer life support procedures.

It is not clear at this time if propofol contributed to Michael Jackson’s death. But if he was using this drug in a setting where trained medical personnel were not involved, he was certainly putting himself at great risk.

Everyone is at least somewhat familiar with anthrax (even if you are not into heavy metal bands).  In 2001, there were 10 cases of lethal anthrax infections transmitted via inhalation of spores contained in powders in letters received  by the victims through the U.S. mail.  Six of the patients survived after intensive antibiotic therapy and supportive care.  An effective antidote might have helped to save the other four victims.  However, a recently published study indicates that further help may be on the way with the development of an effective antibody that might be used to prevent anthrax infections and it also might be useful as an effective treatment after infections have already occurred.

Anthrax infects both animals and humans.  It is not uncommon to find anthrax infections in cattle.  Anthrax can infect the skin (surface infections).  These are usually not deadly but they can turn the infected skin black (anthrax is derived from Greek word for coal).  However, inhalation of anthrax spores causes a systemic infection that is almost always deadly unless heroic treatments are available.  The anthrax bacteria produce a three part toxin that is the killer.  One part of the toxin binds to the surface of cells and acts as a transporter to push the other two parts of the toxin into the cellular victims.  Once inside the cell the other two parts of the toxin hijack the cells chemical machinery causing the cell to malfunction and die.  Ultimately when enough of the victim’s cells have been infected and killed, the patient will die.  Well, a new drug (an antibody actually) has been developed that binds to the part of the toxin that attaches to the cell membrane.  This prevents the toxin from gaining access to the cells and therefore the infected victim is protected from the deadly effects of the other two parts of the toxin.  The new drug is called Raxibacumab and it is underdevelopment by Human Genome Sciences.  The data were published in the July 9, 2009 edition of the New England Journal of Medicine (http://content.nejm.org.proxy2.cl.msu.edu/cgi/content/full/361/2/135#R4).  This article described successful outcomes in laboratory animals infected with anthrax bacteria.  Clinical trials are ongoing to test the safety and tolerability of the antibody in healthy human subjects.

This is an interesting study that has helped to understand the basic biology of how bacterial toxins produce their lethal effects.  However, this study will certainly have a positive impact on efforts to combat bioterrorism.  This is good news for everyone, including heavy metal rock bands!

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