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The topic of drug–drug interactions has received a great deal of recent attention from the regulatory, scientific, and health care communities worldwide. Nonsteroidal anti-inflammatory drugs, antibiotics and, in particular, rifampin are common precipitant drugs prescribed in primary care practice. Drugs with a narrow therapeutic range or low therapeutic index are more likely to be the objects for serious drug interactions. Object drugs in common use include warfarin, fluoroquinolones, antiepileptic drugs, oral contraceptives, cisapride, and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. The pharmacist, along with the prescriber has a duty to ensure that patients are aware of the risk of side effects and a suitable course of action should they occur. With their detailed knowledge of medicine, pharmacists have the ability to relate unexpected symptoms experienced by patients to possible adverse effects of their drug therapy.
The topic of drug–drug interactions (DDIs) has received a great deal of recent attention from the regulatory, scientific, and health care communities worldwide. A large number of drugs are introduced every year, and new interactions between medications are increasingly reported. Consequently, it is no longer practical for physicians to rely on memory alone to avoid potential drug interactions. Precipitant drugs modify the object drug’s absorption, distribution, metabolism, excretion, or actual clinical effect. Nonsteroidal anti-inflammatory drugs, antibiotics and, in particular, rifampin are common precipitant drugs prescribed in primary care practice. Drugs with a narrow therapeutic range or low therapeutic index are more likely to be the objects for serious drug interactions. Object drugs in common use include warfarin, fluoroquinolones, antiepileptic drugs, oral contraceptives, cisapride, and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Serotonin syndrome is a potentially life-threatening disorder of excessive serotoninergic activity often due to drug interactions. Many other drugs act as precipitants or objects, and a number of drugs act as both. An overview of selected serious drug interactions is given in Table 1.
The American Food and Drug Administration define a serious adverse event as one when the patient outcome is one of the following:
Severity is a point on an arbitrary scale of intensity of the adverse event in question. The terms “severe” and “serious” when applied to adverse events are technically very different. They are easily confused but cannot be used interchangeably, require care in usage. A headache is severe, if it causes intense pain. There are scales such as “Visual Analog Scale” that helps us assess the severity. On the other hand, a headache can hardly ever be serious, unless it also satisfies the criteria for seriousness listed above.
As research better explains the biochemistry of drug use, fewer ADRs (adverse drug reactions) are Type B and more are Type A. Common mechanisms are:
Abnormal pharmacokinetics due to
Synergistic effects between either
Various diseases, especially those that cause renal or hepatic insufficiency, may alter drug metabolism. Resources are available that report changes in a drug’s metabolism due to disease states.
Inheriting abnormal butyrylcholinesterase (pseudocholinesterase) may affect metabolism of drugs such as succinylcholine.
Inheriting abnormal N-acetyltransferase which conjugated some drugs to facilitate excretion may affect the metabolism of drugs such as isoniazid, hydralazine, and procainamide.[9,10] Inheriting abnormal thiopurine S-methyltransferase may affect the metabolism of the thiopurine drugs mercaptopurine and azathioprine.
The risk of drug interactions is increased with polypharmacy.
These interactions are usually transient and mild until a new steady state is achieved. These are mainly for drugs without much first-pass liver metabolism. The principal plasma proteins for drug binding are:
Some drug interactions with warfarin are due to changes in protein binding.
Patients have abnormal metabolism by cytochrome P450 due to either inheriting abnormal alleles or drug interactions. Tables are available to check for drug interactions due to P450 interactions.
An example of synergism is two drugs that both prolong the QT interval.
An individual’s genetic makeup can alter their response to a drug. Genetics affect pharmacokinetics and pharmacodynamics. Unrecognized mutations can be associated with ADRs or can affect the magnitude of a drug interaction. A common example is the metabolism of ethanol. There are ethnic differences in the metabolism of ethanol by alcohol dehydrogenase. People of Chinese descent have a higher incidence of atypical alcohol dehydrogenase and therefore become flushed and dizzy when they consume alcohol. Their capacity for consuming alcohol is lower than that for other populations.
To apply pharmacogenetics and pharmacogenomics to the management of drug interactions, it is important to know the difference between the two terms. Pharmacogenetics applies to inherited traits and genetic polymorphisms. Polymorphism refers to stable allelic variations found in the population (occurring at a frequency >1%) that result in altered protein activity. Pharmacogenomics applies to the entire spectrum of genes. With pharmacogenetics, the focus is on metabolizing enzymes and transporters, whereas with pharmacogenomics, the focus is on individualized drug and dosage for a specific disease.
The pharmacist, along with the prescriber has a duty to ensure that patients are aware of the risk of side effects and a suitable course of action should they occur. With their detailed knowledge of medicine, pharmacists have the ability to relate unexpected symptoms experienced by patients to possible adverse effects of their drug therapy. The practice in clinical pharmacy also ensures that ADRs are minimized by avoiding drugs with potential side effects in susceptible patients. Thus, pharmacist has a major role to play in relation to prevention, detection, and reporting ADRs.
Avoiding the combination entirely: For some drug interactions, the risk always outweighs the risk, and the combination should be avoided. Because drug classes are usually heterogeneous with regard to drug interactions (as described above), one can often select a no interacting alternative for either the object drug or the precipitant drug.
Adjusting the dose of the object drug: Sometimes, it is possible to give the two interacting drugs safely as long as the dose of the object drug is adjusted.
Spacing dosing times to avoid the interaction: For some drug interactions involving binding in the gastrointestinal tract, to avoid the interaction one can give the object drug at least 2 h before or 4 h after the precipitant drug. In this way, the object drug can be absorbed into the circulation before the precipitant drug appears.
Monitoring for early detection: In some cases, when it is necessary to administer interacting drug combinations, the interaction can be managed through close laboratory or clinical monitoring for the evidence of the interaction. In this way, the appropriate dosage changes can be made, or the drugs discontinued if necessary.
Provide information on patient risk factors that increases the chance of an adverse outcome: It is clear from the clinical experience of physicians and pharmacists as well as published studies that most patients who take interacting drug combinations do not manifest adverse consequences. Substantial evidence from both the clinical experience of physicians and pharmacists as well as published studies suggest that the risk of statin-induced myopathy increases with increasing serum concentrations of the statin. Accordingly, it has been recommended that simvastatin should not exceed 20 mg daily in patients receiving verapamil concurrently.
Excessive number of drug interactions on the systems: Many pharmacists find that computerized drug interaction screening systems detect a large number of DDIs of questionable clinical significance.
Drug class differences not handled correctly: Almost all drug classes interact heterogeneously, because individual members of a drug class are often not metabolized by the same cytochrome P450 isozymes or ABC (ATP-binding cassette) transporters as other members of the class. The statins are a good example, because simvastatin and lovastatin are extensively metabolized by CYP3A4, atorvastatin is moderately metabolized by CYP3A4, fluvastatin is metabolized by CYP2C9, and pravastatin and rosuvastatin are not metabolized by cytochrome P450 isozymes. Thus, combining all members of this drug class together is rarely justified when considering drug interactions. Nonetheless, it is common for reviews and computer systems to include all statins together as interacting with CYP3A4 inhibitors, even though the risk is primarily limited to lovastatin, simvastatin, and to a lesser extent, atorvastatin.
The prescribing information for most drugs contains a list of potential drug interactions. Many of the listed interactions may be rare, minor, or only occur under specific conditions and may not be important. Drug interactions that cause important changes in the action of a drug are of the greatest concern.
Drug interactions are complex and chiefly unpredictable. A known interaction may not occur in every individual. This can be explained because there are several factors that affect the likelihood that a known interaction will occur. These factors include differences among individuals in their;[20,21]
Nevertheless, important drug interactions occur frequently and they add millions of dollars to the cost of health care. Moreover, many drugs have been withdrawn from the market because of their potential to interact with other drugs and cause serious health care problems.
This brief overview of drug interactions does not cover every possible scenario. Individuals should not be afraid to use their drugs because of the potential for drug interactions. Rather, they should use the information that is available to them to minimize the risk of such interactions and to improve the success of their therapy.
Performing or obtaining necessary assessments of the patient’s health status is as follows:
The past several years have seen major advances in our understanding of DDIs, particularly in the area of the molecular mechanisms by which drug interact. However, our ability to appropriately apply this information to specific patients has lagged far behind. Pharmacists must take responsibility for monitoring for drug interactions and notifying the physician and patient about potential problems.
Source of Support: Nil
Conflict of Interest: None declared.