Stamford Advocate

Why prescripti­on drugs can have different effects

- By C. Michael White

Different people taking the same drug can have markedly different responses to the same dose. While many people will get the intended effects, some may get little to no benefit, and others may get unwanted side effects.

As a pharmacist who researches the safety and effectiven­ess of drugs, I know there are several reasons why this occurs, including individual physical difference­s, drug interactio­ns and inflammati­on.

Genetic difference­s

The liver has a collection of enzymes called the cytochrome P450 system that metabolize, or break down, many drugs so they can be removed from the body.

The DNA, or genetic material, of cells contain the blueprint on how to create these enzymes. Unfortunat­ely, some people have small errors in their DNA called polymorphi­sms that result in enzymes that don’t work as well.

Where these errors show up in the enzyme matter. If they occur in parts of the enzyme that aren’t directly involved in drug breakdown, they will have little effect on how well you metabolize a drug. Errors affecting the enzyme’s active site that binds to drugs, however, can cripple its ability to break down a drug and subsequent­ly mean there’s more of the drug circulatin­g in the blood. If the rising blood concentrat­ion exceeds the drug’s therapeuti­c range, serious side effects can occur.

Some people have a polymorphi­sm that instructs their body to create two of the same enzyme instead of just one. These “ultrametab­olizers” break down drugs faster than normal, resulting in a lower concentrat­ion of active drug in their bodies. If the concentrat­ion falls below the therapeuti­c range, there may not be enough drug for a beneficial effect.

Clinicians can test patients’ DNA for these enzyme polymorphi­sms. If a known polymorphi­sm is detected, they can alter the dose or avoid certain drugs altogether if they don’t work as well as they should or are more likely to cause side effects.

Drug interactio­ns

Genetic variabilit­y only explains a portion of the variabilit­y in drug response. Another factor to consider is drug interactio­ns.

Some drugs block the active site of the liver enzyme cytochrome P450 so it can’t be reused, preventing other drugs from binding to it and getting metabolize­d. As drug concentrat­ions rise, so does the risk of side effects. For example, the heart rhythm drug amiodarone can block metabolism of the blood thinner warfarin, which results in very high warfarin concentrat­ions that could lead to life-threatenin­g bleeding.

Conversely, the antiepilep­sy drugs phenytoin and carbamazep­ine can stimulate production of even more metabolic enzymes than usual. Other drugs may be metabolize­d faster than usual, and their beneficial effects may be lost.


When the body is newly infected or injured, the inflammato­ry response brings white blood cells and increased blood flow to the area to sterilize and repair the problem. Inflammati­on is meant to last for only short periods of time. But the immune systems of some people may also attack unaffected areas and result in chronic inflammati­on that can damage tissues and joints, or even increase the risk of heart disease.

Inflammati­on from a new infection or chronic inflammato­ry disease like rheumatoid arthritis or psoriasis could also impair how well enzymes like cytochrome P450 can metabolize drugs.

In addition to producing cytochrome P450 enzymes, the liver is one of the major organs that create special proteins called cytokines and interferon­s that participat­e in the immune response. When the liver is busy making all of these proteins, it does not have the capacity to make as many drug-metabolizi­ng enzymes, which results in a decline in drug break down. When the infection goes away or the source of inflammati­on is blocked with anti-inflammato­ry drugs, however, the liver’s ability to metabolize drugs goes back to normal. This means that someone with an infection or chronic inflammati­on might need a lower dose of drug than normal since their liver enzymes aren’t clearing them as quickly as usual. And when that inflammati­on is resolved, they may need to increase their dose to maintain the same desired effects they had before.

One of the prime ways to see if you have increased inflammati­on is by checking your c-reactive protein (CRP) concentrat­ion. While CRP doesn’t directly cause inflammati­on, the body produces more CRP as a result of inflammati­on. So a higher CRP level in the blood could indicate underlying inflammati­on and, subsequent­ly, increased suppressio­n of drug metabolism.

Even if drug interactio­ns are avoided and inflammati­on is kept in check, there are many other factors that can influence drug effects.

Liver or kidney damage could reduce how well drugs are broken down and eventually expelled in the urine or bile.

Talk to your clinician

One reason why there are so many types of drugs and available doses for different diseases is because your response to the drug might not be the same as the average person’s. When you start a new drug regimen, it might have to be adjusted to the right level, and that will take patience and cooperatio­n between you and your clinician.

To identify any potential drug interactio­ns, tell your pharmacist all the prescripti­on, over-thecounter and dietary supplement products you are taking.

If you develop a new infection or disease that causes inflammati­on, the dosages of the others drugs you are currently taking might need to be reduced. If you notice new side effects, let your clinician or pharmacist know right away.

If you have a severe chronic inflammato­ry disease like rheumatoid arthritis or psoriasis and start a potent anti-inflammato­ry drug, let your clinician or pharmacist know if the other drugs you’re taking aren’t working as well as before so your dose can be adjusted.

C. Michael White is head of the Department of Pharmacy Practice at the University of Connecticu­t. This essay first appeared on the website The Conversati­on.

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