Posted by MB on July 16, 2003, at 23:25:21
Interesting Article
MB
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Medscape Psychopharmacology Today
Side Effects and Therapeutic Effects
Thomas Kramer, MD
Medscape General Medicine 5(1), 2003. © 2003 Medscape
Posted 01/29/2003*Introduction*
There are two broad sets of issues that we deal with in psychopharmacology: pharmacokinetics and pharmacodynamics. Pharmacokinetics could be defined as what the body does to drugs, and encompasses all of the issues of drug interactions and drug clearance metabolism. Pharmacodynamics could be defined as what the drug does to the body. One could argue that it is the most important group of issues, because it encompasses the actual therapeutic effect of the drug.Drugs have effects on the body. That is why we give them to patients. Our goal is to have the effect of the drug be therapeutic. Generally speaking, drugs have two kinds of effects: therapeutic effects and side effects. The ideal drug for any therapeutic indication would have only therapeutic effects and no side effects. We all know that in the real world, there are no such perfect drugs, but the best and most commonly used medications have a very high "therapeutic to side effect ratio."
It is, to a certain extent, a value judgment, however, whether a particular effect of the drug is a side effect or a therapeutic effect. Similar to the rallying cry of the software engineer -- "it's not a bug, it's a feature" -- sometimes things that start out being referred to as side effects end up being a primary therapeutic effect. This happens when drugs that were developed for one particular indication end up getting used for something quite different. One of the best examples of this is minoxidil, which was launched in 1979 as a treatment for hypertension. It was noted that many of the patients taking minoxidil who were bald started to grow hair back. Nine years later, minoxidil cream was marketed as treatment for hair loss, and that has become the primary use of this drug. Sildenafil is an enormously successful treatment for erectile dysfunction but was originally developed as an antiangina drug. On clinical trials, it was not particularly successful for that indication, but many of the subjects in the study reported dramatically improved erections.
*Efficacy Vs Effectiveness*
A major part of the drug development process is to weed out those compounds whose side effects overwhelm their therapeutic effects. This gets to the fundamental issue of efficacy vs effectiveness. A drug's efficacy is a measure of the ability of the drug to treat whatever condition it is indicated for. It is not a statement about the drug's tolerability or ease of use. Effectiveness is a measure of how well the drug works and encompasses all 3 of these issues. A drug may have very good efficacy but is so unpleasant to take that its actual utility is extremely limited. This would be determined in clinical trials, and the development of such a compound would cease.For those drugs that do make it to market, there usually is a qualitative difference between side effects and therapeutic effects. The side effects of most compounds, psychiatric or otherwise, are transient. A drug company is much more likely to market a compound if whatever side effects it has go away in a few weeks. All of us who prescribe medications spend a great deal of our time with our patients reassuring them that the difficulties they may be having with their medication are temporary. This then begs the question: why are some drug effects short-lived and others long-lasting with chronic administration of the compound?
*Half-life and Steady State*
One of the main reasons for this gets back to the issues of pharmacokinetics. To review some of the basics of pharmacology, medications vary in how long it takes to clear them from the body. Some are metabolized fairly quickly, while others can take a long time before they are eliminated. We quantify this with the use of the term "half-life." The half-life of a given medication is how long it takes for the body to get rid of half of the dose. When the patient is taking a medication on a regular basis, there is an ongoing process of drug absorption in the form of each dose of the drug and, concurrently, an ongoing process of drug removal with the drug's metabolism and clearance. Eventually, there comes a point when the amount of drug going in is the same as the amount of drug getting taken out. We call this "steady state." It takes somewhere between 5 and 6 half-lives for a medication to reach steady state. Thus, medications with short half-lives reach steady state relatively quickly, while those with long half-lives take a long time to reach steady state.Many drug effects occur primarily when the blood level of the drug is either going up or going down. When the drug reaches steady state, these effects can be either attenuated or completely absent. For those of you who are familiar with calculus, one way to understand this is that these effects only take place if there is a first derivative other than zero. Unwanted side effects from a particular compound are great deal more acceptable if they only take place on the way to steady state (ie, they are transient). Another way to classify drug effects into 2 groups is to classify them into those effects that take place primarily while the blood level is changing and those effects that take place primarily when the blood level is stable at steady state. Ideally, for any drug, all of the unwanted effects would be in the former category and all of the therapeutic effects would be in the latter category. There are many examples of side effects of psychotropics that are considerably worse during increasing or decreasing blood levels of the medication. Extrapyramidal side effects from antipsychotic medications, gastrointestinal side effects from selective serotonergic reuptake inhibitors, and memory problems from benzodiazepines are some examples of this phenomenon.
*Nonsteady State*
There are some examples, however, of medications whose therapeutic effect takes place solely during a rise in their blood level and are considerably less effective at steady state. The euphoric effects of alcohol, probably the most widely used psychotropic compound, only occur when the blood level of alcohol is rising. Unfortunately, the same cannot be said about alcohol-induced impairment. These are some of the reasons alcohol can be addictive and dangerous. Perhaps the best example of this phenomenon in prescribed psychotropics is the use of methylphenidate in attention deficit/hyperactivity disorder (ADHD). While methylphenidate is very effective in the treatment of ADHD, for many years it was somewhat problematic because in order for it to work, the child needed to take multiple doses during the day, requiring visits to the school nurse or other similar arrangements. This is because the therapeutic effect of methylphenidate only takes place when the blood level is increasing. The initial attempts to make a long-acting preparation of methylphenidate were less than satisfactory to both patients and clinicians because they essentially put the child into steady state rather than simulating the process of giving the child multiple doses. The recent success and widespread use of long-acting methylphenidate preparations is because these preparations are made not to slowly release the drug but to release it in a series of boluses so that with a once-a-day administration they can create pharmacokinetics similar to what was achieved with 3-times-a-day dosing.
*Premature Intervention*
Clinicians can often inadvertently exacerbate problems with side effects by doing multiple dose adjustments. For a medication that is going to be taken for a relatively long period of time, it is important to determine what the side effect burden will be at steady state. Addressing and attempting to intervene with side effect problems before that occurs can cause the problem that the clinician is trying to solve.
Thomas Kramer, MD, Director, Student Counseling and Resource Service, The University of Chicago
poster:MB
thread:242747
URL: http://www.dr-bob.org/babble/20030714/msgs/242747.html