Drug Dosages Often Incorrect for Obese Patients

As if severely overweight people didn’t already have enough health concerns, experts are raising another red flag – the possibility that some of their prescription medications, especially antibiotics, may not be prescribed at the appropriate dosage and could be ineffective.

Because most adult antibiotics are produced in a “one size fits all” dosage and some doctors are not attuned to this issue, the societal trend towards severe obesity is resulting in more individuals who get inappropriate drug therapies for infectious disease, a new study in the journal Pharmacotherapy suggests.

“The number of individuals with the highest body mass index, very obese people, is up 600 percent between 1986 and 2000,” says David Bearden, a clinical associate professor in the College of Pharmacy at Oregon State University.

“Very obese individuals in some cases, even those with severe infections, may be getting only half the necessary dose of a prescription drug such as an antibiotic,” Bearden said. “That’s a problem. It could lead not only to antibiotic failure but also an increase in antibiotic resistance, another serious issue.”

The problem is somewhat less of a concern with dosages of medications that patients take for extended periods, such as blood pressure or cholesterol medications, because the results of taking those medications are more routinely monitored and dosages can be increased as necessary. It’s a particular concern with antibiotics, Bearden says, because they are often used to treat severe or even life-threatening infections, and “bad things can happen quickly if the drug is ineffective.”

Drug companies are just now becoming more aware of this issue and beginning to test and recommend dosages more appropriate for adults of varying weights, Bearden says. But with older drugs that are commonly used, there often is very little or no data for adjusting dosages. In actual practice the issue is often ignored outright, or “educated guesses” are made with whatever data is available.

Without more attention, the issue may only get worse, and it’s not just a U.S. phenomenon. The World Health Organization estimates that 400 million people were obese in 2005 and that the total will increase to 700 million by 2015. It considers these numbers a “global pandemic” that is affecting low, middle and high-income nations around the world. Obesity is also considered an independent risk factor for surgical site infections and is associated with higher mortality rates in critically ill patients.

Even if the problem is carefully considered, Bearden says, it’s not simple.

“It would be nice if we could just use a simple multiplier to adjust drug dosages for overweight people,” Bearden says. “But it’s not that easy. There are a lot of factors that affect drug distribution in the body, including age, weight, kidney function, other disease problems and the type of antibiotic or other drug.”

Adipose tissue, or body fat, affects how the human body interacts with drugs. With some drugs it absorbs large amounts of a prescription medication, but with others, it doesn’t. And sometimes there is a very fine line between a drug being effective at one dose, ineffective if the dose is too low, and toxic if it’s too high. All of these issues affect appropriate dosages, and in many situations, the data needed to evaluate the problem simply doesn’t exist.

The issue of adjusted drug dosages has been known and addressed in children for decades, experts say, because of the obvious distinction between a 30-pound toddler and a 120-pound youngster. But with adults, far less attention has been given the problem. The medical and pharmaceutical industries often just assume that everyone weighs about 150-170 pounds.

“This is enough of an issue that if I were a very obese person being given an antibiotic, I would discuss it with my doctor,” Bearden says. “Hopefully the doctor will already have considered it and will be able to address your concerns. If not, then it’s a conversation you need to have, and more medical specialists, including pharmacists, may need to be consulted.”

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Faster-acting Antidepressants Closer to Becoming Reality

A new study has revealed more about how the medication ketamine, when used experimentally for depression, relieves symptoms of the disorder in hours instead of the weeks or months it takes for current antidepressants to work. While ketamine itself probably won’t come into use as an antidepressant because of its side effects, the new finding moves scientists considerably closer to understanding how to develop faster-acting antidepressant medications – among the priorities of the National Institute of Mental Health (NIMH), part of the National Institutes of Health.

Ketamine blocks a receptor called NMDA on brain cells, an earlier NIMH study in humans had shown, but the new study in mice shows that this is an intermediate step. It turns out that blocking NMDA increases the activity of another receptor, AMPA, and that this boost in AMPA is crucial for ketamine’s rapid antidepressant actions. The study was reported online in Biological Psychiatry on July 23, by NIMH researchers Husseini K. Manji, MD, Guang Chen, MD, PhD, Carlos Zarate, MD, and colleagues.

“Our research is showing us how to develop medications that get at the biological roots of depression. This new finding is a major step toward learning how to improve treatment for the millions of Americans with this debilitating disorder; toward eliminating the weeks of suffering and uncertainty they have to endure while they wait for their medications to work,” says NIH Director Elias Zerhouni, M.D.

Almost 15 million American adults have a depressive disorder. During the long wait to begin feeling the effects of conventional medications, patients may worsen, raising the risk of suicide for some. Depressive disorders also affect children and adolescents.

By aiming new medications at more direct molecular targets, such as NMDA or AMPA, scientists may be able to bypass some of the steps through which current antidepressants indirectly exert their effects – a roundabout route that accounts for the long time it takes for patients to begin feeling better with the conventional medications.

While ketamine appears to achieve this, it is an unlikely candidate to become a new treatment for depression, because of the side effects it can cause in humans, including hallucinations. It is approved as an anesthetic by the Food and Drug Administration at much higher doses than those given in the study, but its use is limited because it may cause hallucinations during recovery from anesthesia.

Both NMDA and AMPA are receptors for the neurotransmitter glutamate, one of the chemical messengers that enable brain cells to communicate with each other. The glutamate system has been implicated in depression recently, leading to efforts to unravel its molecular machinery in search of abnormalities and of better targets for antidepressant medications.

This focus on the glutamate system is a departure from the thinking that led to currently available antidepressants, which are thought to relieve depression through a lengthy trickle-down process of biochemical reactions that affect the circuitry underlying depression.

The fact that NMDA and AMPA receptors are part of the glutamate system and that targeting them directly led to such rapid, sustained relief of depression-like behaviors in this study – and that a single dose of ketamine did the same in humans in the earlier study – suggests that they are probably the key targets for antidepressant medications.

“In any other illness of depression’s magnitude, patients aren’t expected to just accept that their treatments won’t start helping them for weeks or months. The value of our research on compounds like ketamine is that it tells us where to look for more precise targets for new kinds of medications that can close the gap,” says NIMH Director Thomas Insel, MD. “We’re making tremendous progress.”

To conduct the new study, researchers induced depression-like behaviors in mice; for example, the mice gave up after being forced to engage in hopeless tasks, such as prolonged swimming. A dose of ketamine reversed the depression-like behaviors for at least two weeks.

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