Features September 2004 Issue

Dosage: Too Much...Or Too Little?

Underdosing or overdosing on a medication depends as much on you as it does on the person prescribing or preparing the drug.

The old adage, "Pop two aspirin and call me in the morning," may sound like good advice, but how well any drug actually works depends on you. Your health, your age, even your gender have a profound impact on the effectiveness and safety of many medications.

A new brand of science called pharmacogenomics has revealed many variations in how patients respond to drugs. Scientists working in the field are now researching ways to better match drug doses to individual needs. “For the most part, medications are not one-size-fits-all. Genetic differences cause us all to metabolize drugs differently,” says Mandy Leonard, Pharm. D., manager of the Drug Information Service at The Cleveland Clinic. “Some people break down a drug too fast, others too slow, and some do it at the right rate.”

Slow/fast metabolizers
Drugs are broken down (metabolized) by enzymes in the liver. Your genes determine how well that task is performed. Patients who are slow metabolizers don’t break down a drug fast enough. So a standard dose of medicine hangs around too long. When you take your next dose, it overlaps the last, creating high levels of the drug in your blood. This can provoke potentially dangerous side effects. For example, if you do not metabolize blood thinners, such as warfarin (Coumadin), correctly, bleeding risks can occur. Dosing adjustments can help avert this problem.

On the other hand, “If you’re a fast metabolizer, you may feel the drug isn't working for you. But you're probably just not getting enough,” says Leonard.

Effect of aging
Your age significantly affects how your body absorbs, distributes, metabolizes, and excretes a drug. Both liver and kidney function slow down as you get older. Decreased liver function may result in slower metabolism.

The kidneys eliminate some drugs from the body. Standard drug dosages are typically prescribed for patients with normal kidney function. Those with reduced function may retain a drug for longer periods of time, increasing blood drug levels. For example, overdosing on the pain-killer acetaminophen (Tylenol), which is primarily processed through the liver, can rapidly occur in older patients with liver and kidney disease. Seniors may also break down arthritis medications, such as certain nonsteroidal anti-inflammatory drugs NSAIDs), more slowly, so dosing modifications are often required to prevent side effects. A baseline renal function test, called a serum creatinine test, may be performed before starting a new drug therapy.

Because of body composition changes, such as decreases in body weight, body mass, and body-water content, older people also experience wider variations in the response to a drug than younger people. This is why the elderly are often excluded from clinical trials designed to establish a drug’s standard dose. For example, allergy medications containing diphenhydramine (Benadryl) or cough and cold preparations containing the ingredient dextromethorphan are generally well tolerated by young patients, but can cause drowsiness or dizziness in older adults. Age-related changes in cardiovascular function can also make the elderly more prone to the side effects of certain heart medications.

Inequality of the sexes
Whether you’re male or female also dictates how you respond to a certain drug. Women have naturally lower levels of the brain chemical serotonin than men, so it can take a woman a little while longer to feel the effects of certain antidepressant medications. Female hormones make women more sensitive to narcotic pain relievers than men. Studies also suggest that women with arthritis metabolize corticosteroid drugs, such as prednisolone, faster than men, so the benefit wears off more rapidly. On the other hand, the enzyme responsible for the metabolism of acetaminophen (Tylenol) is more active in men, so they break it down faster, with the result that the pain-relieving benefit declines more quickly.

Personalized medicine
For the most part, medications are safe as prescribed. But when medicines don’t work due to metabolism, age, or other issues, a patient may not feel any better—or worse, dangerous side effects may occur. Underdosing, overdosing, and misdosing remain a leading cause of medication-related adverse effects in this country.

Leonard believes that one day patients may be genetically tested for adverse drug reactions and to predict a drug’s effectiveness. “Pharmacogenomics is an up-and-coming advancement,” she says, “where you could be tested, based on your genes, to see what drugs would work best.”