This definition applies to interactions of drugs with other drugs (drug-drug interactions), as well as drugs with food (drug-food interactions) and other substances. Use WebMD's Drug Interaction Checker tool to find and identify potentially of an appropriately qualified and licensed physician or other health care provider. Alcohol is a drug that when taken in combination with other drugs – including medicines or illicit drugs These occur because the two drugs interact in the body.
drugs Interaction with other
If combination therapy is necessary, monitor the patient for toxicity. Monitor for anticholinergic excess and consider lower dosage of tricyclic antidepressant. SSRI plus selegiline Eldepryl or nonselective monoamine oxidase inhibitor. If combination therapy is necessary, monitor the patient for signs and symptoms of serotonin syndrome. Because of new clinical recommendations, the use of warfarin Coumadin has increased in recent years.
Almost all antibiotics can potentiate the effects of warfarin by inhibiting intestinal flora that produce vitamin K. Inhibition of the hepatic metabolism of warfarin is another possible mechanism for increased bleeding.
Clinical trials evaluating warfarin-antibiotic combinations have had mixed outcomes. However, case reports have described potentiation of anticoagulation in patients treated with warfarin and antibiotics. The disparity between the findings of clinical trials and case reports has led investigators to conclude that multiple factors may alter the clearance of warfarin in patients with infections.
Unless the prothrombin International Normalized Ratio INR can be monitored every other day, ciprofloxacin, macrolide antibiotics, metronidazole and trimethoprim-sulfamethoxazole generally should not be prescribed to patients who are taking warfarin.
Alternative antimicrobial therapy is recommended for these patients. Some investigators advise that the hypothrombinemic response to warfarin can increase when acetaminophen is taken in a dosage of more than 2 g per day for longer than one week.
One case-control study identified acetaminophen as a cause of 30 percent of INR values greater than 6. The proposed mechanism is a reduced capacity of cytochrome P enzymes caused by acetaminophen and resulting in decreased metabolism of warfarin. Because acetaminophen is the most frequently ingested medication in the United States, physicians should counsel warfarin-treated patients about the potential risks of a warfarin-acetaminophen interaction.
If acetaminophen therapy is needed, the dosage should be as low as possible, and the drug should be taken for only a short period. In addition, the INR should be monitored closely. Coadministration of acetylsalicylic acid aspirin and warfarin increases the risk of bleeding. The mechanisms of this adverse interaction are antiplatelet effects, gastric mucosal damage and a hypothrombinemic response to warfarin with an aspirin dosage of 2 to 4 g per day.
Although concomitant use of warfarin and aspirin generally should be avoided, certain patients may benefit from this therapy. One study of patients at high risk for thromboembolic events i. Coadministration of nonsteroidal anti-inflammatory drugs NSAIDs and warfarin increases the risk of bleeding. The mechanisms of this interaction are antiplatelet effect and gastric mucosal damage, because most NSAIDs do not produce a hypothrombinemic response. When given to or withdrawn from patients maintained on warfarin, NSAIDs may actually alter anticoagulant control as a result of changes in the amount of circulating warfarin released from plasma albumin binding sites.
One retrospective study found that the risk of hemorrhagic peptic ulcers was 13 times greater in patients older than 65 years who were taking NSAIDs and warfarin than in patients of the same age who were taking neither drug. Patients also should be informed about the risk of bleeding associated with combined warfarin and NSAID therapy.
Fluoroquinolone antibiotics are useful in the management of infections caused by a variety of pathogens. Several agents can substantially reduce the absorption of fluoroquinolones, thereby causing treatment failure. Divalent cations calcium and magnesium and trivalent cations aluminum and ferrous sulfate can form insoluble complexes in the gut if they are taken concurrently with fluoroquinolones.
Common products containing divalent or trivalent cations are listed in Table 2. Studies have shown that the absorption of fluoroqinolones is reduced by 60 to 75 percent when these antibiotics are administered concomitantly with divalent or trivalent cations. If withholding therapy is not feasible, the fluoroquinolone and cation product should be administered at least two hours apart preferably four hours apart.
Carbamazepine Tegretol , phenobarbital and phenytoin Dilantin are commonly prescribed for the management of epilepsy and other disorders. These agents are eliminated through hepatic metabolism. Thus, their effects may be potentiated by drugs that inhibit cytochrome P hepatic metabolism, such as macrolide antibiotics, cimetidine Tagamet and fluconazole Diflucan. Combining a cytochrome P inhibitor with a substrate can potentiate the pharmacologic effects of the substrate. Specific data support interactions between the following drugs: Serum antiepileptic drug levels should be monitored in patients who receive any of these combinations.
Lithium therapy is useful for indications ranging from bipolar disorder to migraine headaches, but several interactions must be considered. As a result, serum lithium levels increase secondary to enhanced reabsorption. If coadministration is necessary, the dosage of lithium should be reduced by 50 percent when a diuretic or an NSAID is added.
Signs or symptoms of lithium toxicity involve the central nervous system drowsiness, confusion, hand tremor, blurred vision, vertigo and seizures , gastrointestinal tract nausea and vomiting and cardiovascular system arrhythmias and widening of the QRS complex.
Rifampin can increase the activity of hepatic enzymes involved in the metabolism of exogenous estrogens. Concomitant use of rifampin and oral contraceptive pills can lead to breakthrough bleeding and an increased risk of pregnancy. The interaction between oral contraceptives and other antibiotics is controversial in that no definitive studies have demonstrated contraceptive failure from such combinations. A recent retrospective study of patients who were taking an oral contraceptive and an antibiotic showed a small but insignificant increase in the risk of pregnancy.
One proposed mechanism is interruption of the enterohepatic circulation of estrogen as a result of reduced bacterial hydrolysis in the gastrointestinal tract. A variety of antibiotics have been implicated. The failure of oral contraception may be suggested by breakthrough bleeding. A reasonable recommendation is to remind patients that the baseline failure rate for oral contraceptives is approximately one pregnancy per woman years i.
Although insufficient evidence is available to make a firm conclusion, it appears possible that oral contraception may fail while patients are taking an antibiotic. Thus, patients should be encouraged to consider using an alternative method of contraception for the duration of the cycle. Troglitazone Rezulin has been reported to reduce the plasma concentrations of oral contraceptives by 30 percent through an unknown mechanism.
Potentially fatal interactions can occur with coadministration of cisapride Propulsid and other drugs. Cisapride has been associated with prolongation of the QT interval, torsades de pointes, syncope, cardiac arrest and sudden death. The primary agents contraindicated for use with cisapride are certain macrolide antibiotics erythromycin and clarithromycin , certain antifungal agents fluconazole, itraconazole [Sporanox] and ketoconazole [Nizoral] , one antidepressant drug nefazodone [Serzone] and certain protease inhibitors indinavir [Crixivan] and ritonavir [Norvir].
Most data on cisapride interactions are derived from case reports. However, current prescribing information warns against the coadministration of cisapride and any medications known to prolong the QT interval, such as class IA or III antiarrhythmic drugs, tricyclic antidepressants, erythromycin, clarithromycin and phenothiazines.
Sildenafil Viagra is the first oral medication labeled by the U. Food and Drug Administration for the treatment of erectile dysfunction. Through inhibition of phosphodiesterase type 5, sildenafil enhances the effects of nitric oxide, potentiating penile erection after sexual arousal. Therefore, patients with erectile dysfunction are often taking other medications. Sildenafil therapy is absolutely contraindicated in patients who are taking any form of nitrates, because of the potentiation of nitrate hypotensive effects.
Sildenafil is primarily metabolized in the liver by cytochrome P 3A4. Drugs that inhibit this enzyme, including erythromycin, cimetidine, ketoconazole and itraconazole, may increase plasma sildenafil concentrations. Sildenafil therapy should be initiated in the lowest dosage 25 mg in patients who are also taking a cytochrome P 3A4 inhibitor. The benefits of lowering cholesterol levels for the primary and secondary prevention of coronary artery disease have been well established.
Most evidence supports using drugs that inhibit 3-hydroxymethylglutaryl—coenzyme A HMG-CoA reductase in the liver, which is the main site of cholesterol synthesis. These drugs are metabolized through the cytochrome P pathway. Concomitant use of statins and erythromycin, itraconazole, niacin or gemfibrozil Lopid can cause toxicity that manifests as elevated serum transaminase levels, myopathy, rhabdomyolysis and acute renal failure.
However, the risk of toxicity increases when statins are coadministered with certain drugs. Because this risk may be dose-dependent, the dosage should be limited to the equivalent of 20 mg of lovastatin per day when any statin is given in combination with an interacting drug. In many patients, HMG-CoA reductase inhibitors fail to lower triglyceride cholesterol levels to a desirable range.
Although concomitant use of gemfibrozil or niacin with an HMG-CoA reductase inhibitor may appear clinically appropriate, these combinations have been associated with a 2 to 5 percent increase in the risk of myopathy. If either combination is used, patients should be alert for muscle pain, tenderness or weakness. Creatine kinase levels should be measured if these symptoms occur. Lovastatin may potentiate the effects of warfarin by displacing the drug from plasma protein binding sites or inhibiting hepatic metabolism of the drug.
Although potentiation of warfarin by lovastatin has been reported in at least 10 patients, controlled trials in large numbers of patients are needed to discern the clinical importance of this effect. Over the past 15 years, selective serotonin reuptake inhibitors SSRIs have become the most commonly used antidepressant drugs.
These agents are generally well tolerated and have a more favorable side effect profile than tricyclic antidepressants.
Concurrent use of SSRIs with agents metabolized by this pathway can result in increased serum concentrations of these agents. Patients already being treated with a tricyclic antidepressant may experience significant increases in plasma antidepressant concentrations and possibly antidepressant toxicity when fluoxetine Prozac is added. When concomitant use of an SSRI and a tricyclic antidepressant is required, the patient should be monitored for anticholinergic excess.
Conservative dosing of the tricyclic antidepressant should also be considered. Isolated case reports suggest that coadministration of fluoxetine and selegiline Eldepryl may result in mania and hypertension. The causal mechanism has not been established. However, selegiline is thought to produce additive serotoninergic effects, because serotonin is metabolized by MAO-A. The prescribing information for selegiline recommends that the drug not be used with SSRIs.
The concomitant use of fluoxetine and non-selective MAO inhibitors has resulted in the serotonin syndrome, which is characterized by anxiety, agitation, confusion, hyperreflexia, myoclonus, diaphoresis and hyperthermia. Several cases of serious or fatal reactions have occurred when tranylcypromine Parnate was used with fluoxetine.
Tramadol Ultram is a centrally acting analgesic with two modes of action: Reports of serotonin syndrome in association with tramadol and SSRI coadministration appear in the literature. At least one case report has described incoherence attributable to the combination of an SSRI and St. John's wort extract of the Hypericum perforatum plant. John's wort is mediated through inhibition of serotonin uptake or MAO antagonism.
As use of this over-the-counter product increases, more data supporting clinically significant drug interactions should become available. Given the popularity of St. John's wort, its availability and the public's propensity for self-medication, it is important to caution patients taking MAO inhibitors and SSRIs against the concomitant use of this herbal remedy.
A recent report documented six cases of serotonin syndrome in patients taking fluoxetine and sumatriptan Imitrex. Another report found that the balance of documented clinical experience pertaining to the concomitant use of sumatriptan and SSRIs suggested that most patients tolerate the combination without adverse effect.
Yet another report on 14 patients discovered no significant interaction between SSRIs and sumatriptan. At least one source recommends that different triptans e. No single method is available to enable physicians to easily avoid drug interactions in clinical practice.
It can be helpful for physicians to keep files on prescribing information for new agents, maintain frequent contact with local pharmacists and have drug interaction resources readily available in the office.
Several sources of information on drug interactions are described in Table 4. Complete database for drug interactions as well as clinically useful drug information; updated quarterly. Easy-to-use index that categorizes a drug interaction by clinical significance, along with a concise reference monograph discussing the interaction; updated quarterly.
Software searches for interactions between two and up to 25 drugs. The Medical Letter on Drugs and Therapeutics. New Rochelle, NY Drug Interactions Analysis and Management loose-leaf or bound manual ; Drug Interaction Facts loose-leaf or bound manual with software. Information about drug-drug and drug-food interactions in a quick reference format, along with descriptive monographs of drug interactions selected on the basis of their potential to alter patient outcomes; updated quarterly.
Already a member or subscriber? Ament earned his doctor of pharmacy degree at Duquesne University School of Pharmacy, Pittsburgh, and completed a residency in hospital pharmacy at Mercy Hospital of Pittsburgh. He is also associate professor of family medicine at Jefferson Medical College, where he earned his medical degree. Bertolino completed a residency in family medicine at Latrobe Area Hospital and a fellowship in academic family medicine at the University of Missouri—Columbia School of Medicine.
Liszewski received his medical degree from the University of Maryland School of Medicine, Baltimore, and completed a residency in family medicine at Latrobe Area Hospital.
Address correspondence to Paul W. Reprints are not available from the authors. Effect of erythromycin in patients receiving long-term warfarin therapy. Interactions of warfarin with drugs and food. For example, when the synergy occurs at a cellular receptor level this is termed agonism , and the substances involved are termed agonists.
On the other hand, in the case of antagonism the substances involved are known as inverse agonists. The different responses of a receptor to the action of a drug has resulted in a number of classifications, which use terms such as "partial agonist", "competitive agonist" etc. These concepts have fundamental applications in the pharmacodynamics of these interactions.
The proliferation of existing classifications at this level, along with the fact that the exact reaction mechanisms for many drugs are not well understood means that it is almost impossible to offer a clear classification for these concepts. It is even likely that many authors would misapply any given classification.
It is possible to take advantage of positive drug interactions. However, the negative interactions are usually of more interest because of their pathological significance and also because they are often unexpected and may even go undiagnosed. By studying the conditions that favour the appearance of interactions it should be possible to prevent them or at least diagnose them in time.
The factors or conditions that predispose or favor the appearance of interactions include: The detection of laboratory parameters is based on physicochemical reactions between the substance being measured and reagents designed for this purpose.
These reactions can be altered by the presence of drugs giving rise to an over estimation or an underestimation of the real results. Levels of cholesterol and other blood lipids can be overestimated as a consequence of the presence in the blood of some psychotropic drugs. These overestimates should not be confused with the action of other drugs that actually increase blood cholesterol levels due to an interaction with its metabolism. Most experts consider that these are not true interactions, so they will not be dealt with further in this discussion.
These chemical reactions are also known as pharmacological incompatibilities. The reactions occur when two or more drugs are mixed outside the body of the organism for the purpose of joint administration.
Examples of these types of interactions include the mixing of penicillins and aminoglycosides in the same serum bottle, which causes the formation of an insoluble precipitate , or the mixing of ciprofloxacin with furosemide. The interaction of some drugs with the transport medium can also be included here. This means that certain drugs cannot be administered in plastic bottles because they bind with the bottle's walls, reducing the drug's concentration in solution.
Many authors do not consider them to be interactions in the strictest sense of the word. The change in an organism's response on administration of a drug is an important factor in pharmacodynamic interactions. These changes are extraordinarily difficult to classify given the wide variety of modes of action that exist and the fact that many drugs can cause their effect through a number of different mechanisms.
This wide diversity also means that, in all but the most obvious cases, it is important to investigate and understand these mechanisms. The well-founded suspicion exists that there are more unknown interactions than known ones. Modifications in the effect of a drug are caused by differences in the absorption, transport, distribution, metabolization or excretion of one or both of the drugs compared with the expected behaviour of each drug when taken individually.
These changes are basically modifications in the concentration of the drugs. In this respect two drugs can be homergic if they have the same effect in the organism and heterergic if their effects are different.
Some drugs, such as the prokinetic agents increase the speed with which a substance passes through the intestines. If a drug is present in the digestive tract's absorption zone for less time its blood concentration will decrease.
The opposite will occur with drugs that decrease intestinal motility. Certain drugs require an acid stomach pH for absorption. Others require the basic pH of the intestines.
Any modification in the pH could change this absorption. However, this occurs less often than an increase in pH causes an increase in absorption. Such as occurs when cimetidine is taken with didanosine. In this case a gap of two to four hours between taking the two drugs is usually sufficient to avoid the interaction. The main interaction mechanism is competition for plasma protein transport. In these cases the drug that arrives first binds with the plasma protein, leaving the other drug dissolved in the plasma, which modifies its concentration.
The organism has mechanisms to counteract these situations by, for example, increasing plasma clearance , which means that they are not usually clinically relevant. However, these situations should be taken into account if other associated problems are present such as when the method of excretion is affected. Many drug interactions are due to alterations in drug metabolism. Cytochrome P is a very large family of haemoproteins hemoproteins that are characterized by their enzymatic activity and their role in the metabolism of a large number of drugs.
As a result of these interactions the function of the enzymes can either be stimulated enzyme induction or inhibited enzyme inhibition.
If drug A is metabolized by a cytochrome P enzyme and drug B inhibits or decreases the enzyme's activity, then drug A will remain with high levels in the plasma for longer as its inactivation is slower.
As a result, enzymatic inhibition will cause an increase in the drug's effect. This can cause a wide range of adverse reactions.
It is possible that this can occasionally lead to a paradoxical situation, where the enzymatic inhibition causes a decrease in the drug's effect: If the metabolism of drug A is inhibited by drug B the concentration of A 2 that is present in the blood will decrease, as will the final effect of the drug.
If drug A is metabolized by a cytochrome P enzyme and drug B induces or increases the enzyme's activity, then blood plasma concentrations of drug A will quickly fall as its inactivation will take place more rapidly. As a result, enzymatic induction will cause a decrease in the drug's effect.
As in the previous case it is possible to find paradoxical situations where an active metabolite causes the drug's effect.
In this case the increase in active metabolite A 2 following the previous example produces an increase in the drug's effect. It can often occur that a patient is taking two drugs that are enzymatic inductors, one inductor and the other inhibitor or both inhibitors, which greatly complicates the control of an individual's medication and the avoidance of possible adverse reactions.
An example of this is shown in the following table for the CYP1A2 enzyme, which is the most common enzyme found in the human liver. The table shows the substrates drugs metabolized by this enzyme and the inductors and inhibitors of its activity: Enzyme CYP3A4 is the enzyme that the greatest number of drugs use as a substrate. Over drugs depend on its metabolism for their activity and many others act on the enzyme as inductors or inhibitors.
Some foods also act as inductors or inhibitors of enzymatic activity. The following table shows the most common:. Any study of pharmacological interactions between particular medicines should also discuss the likely interactions of some medicinal plants.
The effects caused by medicinal plants should be considered in the same way as those of medicines as their interaction with the organism gives rise to a pharmacological response. Other drugs can modify this response and also the plants can give rise to changes in the effects of other active ingredients.
There is little data available regarding interactions involving medicinal plants for the following reasons:. They are usually included in the category of foods as they are usually taken as a tea or food supplement. However, medicinal plants are increasingly being taken in a manner more often associated with conventional medicines: Only the free fraction of a drug that is dissolved in the blood plasma can be removed through the kidney.
Therefore, drugs that are tightly bound to proteins are not available for renal excretion, as long as they are not metabolized when they may be eliminated as metabolites. The excretion of drugs from the kidney's nephrons has the same properties as that of any other organic solute: In the latter phase the secretion of drugs is an active process that is subject to conditions relating to the saturability of the transported molecule and competition between substrates. Therefore, these are key sites where interactions between drugs could occur.
Filtration depends on a number of factors including the pH of the urine, it having been shown that the drugs that act as weak bases are increasingly excreted as the pH of the urine becomes more acidic, and the inverse is true for weak acids.
This mechanism is of great use when treating intoxications by making the urine more acidic or more alkali and it is also used by some drugs and herbal products to produce their interactive effect. Bile excretion is different from kidney excretion as it is always involves energy expenditure in active transport across the epithelium of the bile duct against a concentration gradient.
This transport system can also be saturated if the plasma concentrations of the drug are high. Bile excretion of drugs mainly takes place where their molecular weight is greater than and they contain both polar and lipophilic groups.
The glucuronidation of the drug in the kidney also facilitates bile excretion.
Interactions with other drugs
Prescription drugs that interact with alcohol include benzodiazepines, when mixed with other sedating drugs, or counteract the effect of stimulant drugs. Analyze prescription and OTC drug interactions to determine which drug combinations your patients should avoid. Includes food, alcohol, and herbal. The more medications you take, the greater the chance for your drug interacting with another medicine. Drug-drug interactions can decrease how well your.