Henry R. Black, MD; Domenic A. Sica, MD


July 05, 2012

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Henry R. Black, MD: Hi. I'm Dr. Henry Black. I'm Clinical Professor of Internal Medicine at the New York University School of Medicine, past President of the American Society of Hypertension, and a member of the Center for the Prevention of Cardiovascular Disease at New York University. I'm here today with my friend and colleague, Dr. Domenic Sica. Dom?

Domenic A. Sica, MD: I'm Dr. Domenic Sica, Professor of Medicine and Pharmacology and Eminent Scholar at Virginia Commonwealth University Health System, and President-Elect of the American Society of Hypertension.

Dr. Black: You gave a very nice talk at our recent American Society of Hypertension meeting about the differences in pharmacodynamics and pharmacokinetics between men and women. It is a very intriguing idea that made me wonder whether we should have different doses for women than we do for men. Should we do it on a per kilogram basis? Should we do it on the basis of waist-to-hip ratio? What do you think about that?

Dr. Sica: It's a complex topic that you need to always break down to the fundamentals. When you look at a female, the general belief is that body stature is smaller, thus the volume of distribution for a drug would be less. The metabolic capacity in the liver is finite, based on body size, so you would have less capacity.

Many women have normal renal function, but a caveat of interpreting that phrase would be that normal renal function still has a range. If a man had a glomerular filtration rate (GFR) of 120 mL/min/1.73 m2 and a woman had a GFR of 90 ml/min/1.73 m2, both would be in the normal population range. However, the female would have a value that is 25% less than the male within the normal range. It is as if there is a lesser component of all the mechanisms by which a drug has cleared from the body and a smaller space where the drug, which was taken by mouth, distributes itself into. As a result, you typically see higher blood concentrations.

The devil is in interpreting that, because for most of the drugs we use, when they are given at a 15%-20% higher dose, they are unlikely to cause a significant change in response. If you give a patient a medicine each day for a desired pharmacologic effect to treat a disease, there is wide inter- and intrapatient variability that occurs that is natural in how we respond to a medicine, which dwarfs the inherent change you might see from the kinetic difference.

Dr. Black: In children, we do it per kilogram. We stop doing that in adolescence, when we start dosing them like adults. Are you saying that even though there are clear differences in the blood levels potentially achieved, what really matters is whether the therapeutic effect is there? It isn't worth the time and expense of measuring blood levels and adjusting doses in men vs women?

Dr. Sica: Yes. Therapeutic drug monitoring is of little help. Empirically, if you are a good clinician and your patient weighs 90 lb and another patient weighs 180 lb, the dose given is going to be less. The concentration-dependent side effects, which reflect the prevailing blood level, will be higher in the 90-lb person than the 180-lb person. That's natural.

When we talk about gender, unfortunately, we have to talk about body weight because there are women who weigh 90 lb and some who weigh 180 lb. Each would require different dosing considerations.

Here is a teaching point. If you pick a dose of a drug at the low end of the dose range, then you will give it to someone who is 90 lb; when you give that to them, they may achieve a therapeutic level at a low dose.

Dr. Black: It's not just the level, but the response, that you are looking for, right?

Dr. Sica: The response, which relates to the dose -- the blood levels that are seen. With a smaller body size, a smaller dose may get the desired effect. With a smaller body size, if you give a high-normal dose as you titrate up, you may reach toxic concentrations more readily. You almost have to position yourself to see where the drug apportions itself when it enters the body when there are smaller spaces for it to distribute into. I agree that maybe dosing should be curtailed or cut back for people with very low body weight.

The converse is of equal importance. If you have a 300-lb individual and you give him a conventional dose, you may not get the desired effect because you have not filled up all the compartments in the body necessary to get the drug action. It's a very complex algorithm. Male vs female, there is little difference. It's body size and the GFR issue that I spoke of that become important.

Here is another teaching point. If we treat someone for methicillin-resistant Staphylococcus aureus (MRSA) with vancomycin or if we use gentamicin for a gram-negative infection in a pregnant patient, we must remember that pregnancy is accompanied by a 30% increase in GFR. The patient hyperfilters throughout pregnancy, so if you give a drug that is mainly renally cleared, it is going to be filtered out in abundance, and you will reach subtherapeutic levels clinically very quickly. You have to be mindful of normal range in the high-normal GFRs in interpreting dosing considerations.

Dr. Black: It seems to me that in the end, it's whether you get the therapeutic effect that you are looking for, not so much where you go to do that. You're not going to look for a blood level as much as to cure the infection, reduce the blood pressure, or fix the lipids.

Dr. Sica: If you don't get the desired therapeutic effect, which happens in probably 1 in 4 patients, you have to step back and ask whether you are achieving adequate blood levels. The other 3 out of 4 patients are probably using enough of the drug, and lack of effect is related to patient compliance and adherence. But for 1 in 4 patients, it is an absorption issue (rate and extent of absorption), a body size issue, or a GFR issue. You have to be able to understand and break those down in nonresponders, because it is not always about them not taking the medicine; it's us not delivering the medicine correctly to them.

Dr. Black: We shouldn't blame the patient, as we always seem to do?

Dr. Sica: Sometimes, interestingly, patients blame themselves, because they are put off by the fact that we are accusatory with our body language, and we're not really doing that as clinicians. We don't send the right signals when we don't get the desired response as a doctor.

Dr. Black: Thank you very much, Dom.

Dr. Sica: You're welcome.


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