Many patients express concern about
being on long term medications. In my view, their concerns are
well-founded. At times the treatment can
be worse than the disease. According to CDC statistics 82
percent of adults are on one or more medications, and 29 percent are on five or
more. Polypharmacy (the use of many
drugs together, or excessive medications) is a significant problem of the
elderly, and of those with chronic illness.
These populations are at increased risk for drug-related adverse
reactions. How can a patient assure the
safety of his or her medication? Many turn to alternative medicine, under the
false impression that these substances are somehow safer than those that are
brought to market by the pharmaceutical industry. Others rely on medical professionals—doctors,
nurses, and pharmacists-- to warn them about the possibility of drug
interactions and toxicity. Electronic prescribing has improved drug safety by
automating cross-checking and alerting prescribers when two drugs
interact. However, in my experience
electronic systems can establish such low filters for reporting drug
interactions that virtually every drug prescribed may cause an alert to pop up.
Which of these interactions is clinically relevant? Often clinicians must use
their best guess as to whether two or more drugs in combination will be safe
for a particular patient.
The cytochrome P450 enzymatic
system is involved in the metabolism of many drugs. Although there are more
than 50 of these enzymes, only
six of them are responsible for the metabolism of 90 percent of drugs. Many
significant adverse drug events result from issues that involve this pathway.
Ingested substances, whether it’s grapefruit juice, a cup of coffee, an herbal
product, or a prescribed medication, can alter metabolism by inducing or
inhibiting the activity of the P450 enzymes. Moreover, research has revealed
that there is significant genetic variation in their activity from one
individual to the next. I’ve had many a
patient tell me of his or her unique sensitivity to drugs. These circumstantial observations may well be
founded in science, and pharmacogenetics
is an emerging field that describes the genetic variation in responses to
medication while one patient may have particularly efficacious P450 enzymes,
another may have P450s that are slower to operate. Two or more drugs that are
metabolized by the same P450 may compete and one drug may reduce the metabolism
of another, causing high levels of the “substrate” drug to accumulate, and
potentially cause toxicity. Other drugs
may up-regulate the digestive enzyme and cause a drug to be cleared more
rapidly than normal, reducing its concentration and therapeutic efficacy.
Take the popular cholesterol
lowering medication simvastatin (Zocor).
Simvastatin is used to lower cholesterol and has been associated with
important clinical outcomes in patients who are treated with it-- including a
reduction in cardiovascular death. However, its use has also been linked with
an adverse drug reaction--myopathy, or muscle damage. At its extreme myopathy is known as
“rhabdomyolysis,” a process that can lead to kidney failure and even
death. Rhabdomyolysis occurs at a rate
of 4.4 cases per 100,000 patients exposed to a “statin”-type medication (also
including atorvastatin, rosuvastatin, pravastatin). The risk of myopathy is
dose related and recently the FDA
has warned against using the 80 mg dose of simvastatin for treatment of
elevated cholesterol.
Simavastatin’s metabolism occurs in
the liver with the P450 enzyme CYP3A4.
Numerous other medications affect the activity of this enzyme. The calcium channel blocker amlodipine
(Norvasc) is processed by the same enzyme. Patients who take amlodipine and
simvastatin simultaneously may have reduced clearance of simvastatin, and may
be more prone to muscle damage from the drug.
Consequently the FDA advises limiting simvastatin
dosing in this population to the 20 mg dose. However, enzymatic activity of
CYP3A4 is genetically determined. Within
the population certain individuals may be rapid or poor metabolizers of the
drug, impacting the generalizability of the FDA recommendations from one person
to the next.
Genetic testing for cytochrome P450
enzyme polymorphisms is not yet recommended. Yet, we are moving in that
direction, and no doubt the genetic polymorphisms may prove to provide valuable
insight into why particular patients may not respond to standard
treatments. For example the drug Plavix
(clopidogrel) is an important blood thinner that effects platelet activity and
is indicated in patients who have had a stroke, or who have had stents placed
for coronary artery disease. Clopidogrel
is a pro-drug-- it must be converted in the liver to its active form and
CYP2C19 is the predominate enzyme responsible for this conversion. Patients who are poor metabolizers of Plavix do not effectively
convert the drug to its active form. In these
patients, the drug is less effective at preventing heart attacks, strokes, and
cardiovascular death. It is estimated
that 2 to 14% of the population are poor metabolizers of Plavix; the rate
varies based on racial background. With
this finding, some have advocated genetic testing of all patients who need
Plavix for its important indication.
Another P450 issue has emerged with
Clopidogrel. The popular, and now over
the counter, proton pump inhibitor (PPI) omeprazole is metabolized by the same
hepatic enzyme and is an inhibitor of the enzyme, blocking the conversion of clopidogrel to its active form. However, not all PPIs
have the same degree of inhibitory effect on the enzyme (CYP 2C19). The drug
pantoprozole (Protonix) may be a less strong inhibitors, and therefore safer
for concomitant use with Plavix.
These two
examples demonstrate the complex determinants of drug metabolism—genetic and
environmental—and highlight the importance of using individualized treatment
plans in order to optimize therapy and reduce the risk of
medication related toxicity.
*The FDA website offers a drug Index
of Postmarket Safety Information for Patients and Providers.
I found the website useful for specific drug information.
