Different people taking the same drug can havemarkedly different responsesto 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 apharmacistwhoresearches the safety and effectiveness of drugs, I know there are several reasons why this occurs, including individual physical differences, drug interactions andinflammation.
Genetic Differences
The liver has a collection of enzymes called thecytochrome P450system 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 calledpolymorphismsthat result in enzymes that don’t work as well.
Where these errorsshow 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’sactive sitethat binds to drugs, however, can cripple its ability to break down a drug and subsequently mean there’smore of the drug circulating in the blood. If the rising blood concentrationexceeds 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 canalter the doseor 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 isdrug 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 blockmetabolism 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 canstimulate production of even more metabolic enzymesthan usual. Other drugs may be metabolized faster than usual, and their beneficial effects may be lost.
Inflammation
When the body is newly infected or injured, theinflammatory responsebrings white blood cells and increased blood flow to the area to sterilize and repair the problem. Inflammation is meant tolast 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 therisk of heart disease.
Inflammationfrom anew infection or chronic inflammatory diseaselike 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 calledcytokines and interferonsthat participate in theimmune 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 drugsgoes back to normal. This means that someone with aninfection or chronic inflammationmight need a lower dose of drug than normal since their liver enzymes aren’t clearing them as quickly as usual. And when thatinflammation 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 yourc-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 suppressionof drug metabolism.
Other Factors Affecting 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 damagecould reduce how well drugs are broken down and eventually expelled in the urine or bile.
Body size also affects drug response. Drug concentration in the body is determined by both the dose given and the volume of an individual’s body fluids. Giving the same drug dose to asmaller-sized personcould cause a higher blood concentration than when given to a larger person. This is why many drugs are given in lower doses to children than adults.
And finally, some people either don’thave many receptorsin their body for the drug to bind to and produce its effects, or the receptors that they do have don’t work well. This could be due to genetic mutations or underlying disease. An average dose of a drug would only produce a limited response in these patients.
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 pharmacistall the prescription, over-the-counter 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 takingmight 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 takingaren’t working as well as beforeso your dose can be adjusted.
Originally published in The Conversation.
