At a glance......
- 1 Types of Drug Interactions
- 2 Underlying factors for Drug Interactions
- 3 Pharmacodynamic interactions for Drug Interactions
- 4 Signal transduction mechanisms for Drug Interactions
Drug interactions is a situation in which a substance (usually another drug) affects the activity of a drug when both are administered together. This action can be synergistic (when the drug’s effect is increased) or antagonistic (when the drug’s effect is decreased) or a new effect can be produced that neither produces on its own. Typically, interactions between drugs come to mind (drug-drug interaction). However, interactions may also exist between drugs and foods (drug-food interactions), as well as drugs and medicinal plants or herbs (drug-plant interactions). People taking antidepressant drugs such as monoamine oxidase inhibitors should not take food containing tyramine as the hypertensive crisis may occur (an example of a drug-food interaction). These interactions may occur out of accidental misuse or due to lack of knowledge about the active ingredients involved in the relevant substances.
Types of Drug Interactions
You can reduce the risk of potentially harmful drug interactions and side effects with a little bit of knowledge and common sense. Drug interactions fall into three broad categories:
- Drug-drug interactions – occur when two or more drugs react with each other. This drug-drug interaction may cause you to experience an unexpected side effect. For example, mixing a drug you take to help you sleep (a sedative) and a drug you take for allergies (an antihistamine) can slow your reactions and make driving a car or operating machinery dangerous.
- Drug-food/beverage interactions – result from drugs reacting with foods or beverages. For example, mixing alcohol with some drugs may cause you to feel tired or slow your reactions.
- Drug-condition interactions – may occur when an existing medical condition makes certain drugs potentially harmful. For example, if you have high blood pressure you could experience an unwanted reaction if you take a nasal decongestant.
- Drug-alcohol – Certain medications that should not be taken with alcohol. Often, combining the two can cause tiredness and delayed reactions, and can also increase your risk for negative side effects.
- Drug-disease – The use of a drug that alters or worsens a condition or disease the person has. For example, certain decongestants people take for colds can increase blood pressure. This is a potentially dangerous interaction for people with high blood pressure (hypertension).
- Drug-laboratory – When a medication interferes with a laboratory test. This can result in inaccurate test results. For instance, certain antidepressants (tricyclic antidepressants) have been shown to interfere with skin prick tests used to determine allergies someone may have.
Examples of drug interactions include
- salt substitutes interacting with potassium-sparing diuretics (agents that promote urine secretion) to increase blood potassium levels and cause nausea, vomiting, diarrhea, muscle weakness, and possibly cardiac arrest
- decongestants interacting with diuretics to increase blood pressure
- antacids interacting with anticoagulants (blood thinning drugs) to slow down the absorption of the prescribed drug or interacting with the absorption of other drugs—such as the antibiotic tetracycline—and thus prolonging an infection
- aspirin increasing the effect of blood thinning drugs
- antihistamines increasing the sedative effects of barbiturates (sleeping pills), tranquilizers, and some pain relievers
- iron supplements binding with antibiotics in the stomach, preventing absorption of the antibiotic into the bloodstream
- antihypertensive medications mixed with digitalis (Lanoxin) resulting in abnormal heart rhythms
- anticoagulants mixed with sleeping pills resulting in decreased effectiveness of the anticoagulant
- antibiotics are taken by women on the low-dose birth control pill causing decreased effectiveness of the pill
- nonsteroidal anti-inflammatory drugs (NSAIDs) causing the body to retain salt and fluid that can oppose or antagonize the effectiveness of a diuretic
- beta-blockers, such as propranolol, counteracting certain drugs taken for asthma
Underlying factors for Drug Interactions
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 favor 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
- Old age – factors relating to how human physiology changes with age may affect the interaction of drugs. For example, liver metabolism, kidney function, nerve transmission or the functioning of bone marrow all decrease with age. In addition, in old age, there is a sensory decrease that increases the chances of errors being made in the administration of drugs.
- Polypharmacy – The more drugs a patient takes the more likely it will be that some of them will interact.
- Genetic factors – Genes synthesize enzymes that metabolize drugs. Some races have genotypic variations that could decrease or increase the activity of these enzymes. The consequence of this would, on occasions, be a greater predisposition towards drug interactions and therefore a greater predisposition for adverse effects to occur. This is seen in genotype variations in the isozymes of cytochrome P450.
- Hepatic or renal diseases – The blood concentrations of drugs that are metabolized in the liver and/or eliminated by the kidneys may be altered if either of these organs is not functioning correctly. If this is the case an increase in blood concentration is normally seen.
- Serious diseases that could worsen if the dose of the medicine is reduced.
- Narrow therapeutic index – Where the difference between the effective dose and the toxic dose is small. The drug digoxin is an example of this type of drug.
- Steep dose-response curve – Small changes in the dosage of a drug produce large changes in the drug’s concentration in the patient’s blood plasma.
- Saturable hepatic metabolism – In addition to dose effects the capacity to metabolize the drug is greatly decreased
Pharmacodynamic interactions for Drug Interactions
The change in an organism’s response to the 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.
Pharmacodynamic interactions can occur on
Pharmacological receptors – Receptor interactions are the most easily defined, but they are also the most common. From a pharmacodynamic perspective, two drugs can be considered to be:
Homodynamic, if they act on the same receptor. They, in turn, can be:
Pure agonists, if they bind to the main focus of the receptor, causing a similar effect to that of the main drug.
- Partial agonists if, on binding to one of the receptor’s secondary loci, they have the same effect as the main drag, but with a lower intensity.
- Competitive antagonists, if they compete with the main drug to bind with the receptor. The amount of antagonist or main drug that binds with the receptor will depend on the concentrations of each one in the plasma
- Antagonists, if they bind directly to the receptor’s main locus but their effect is opposite to that of the main drug. These include
Uncompetitive antagonists, when the antagonist binds to the receptor irreversibly and is not released until the receptor is saturated. In principle, the quantity of antagonist and agonist that binds to the receptor will depend on their concentrations. However, the presence of the antagonist will cause the main drug to be released from the receptor regardless of the main drug’s concentration, therefore all the receptors will eventually become occupied by the antagonist. Fetal growth restriction.
Heterodynamic competitors, if they act on distinct receptors.
Signal transduction mechanisms for Drug Interactions
These are molecular processes that commence after the interaction of the drug with the receptor. For example, it is known that hypoglycemia (low blood glucose) in an organism produces a release of catecholamines, which trigger compensation mechanisms thereby increasing blood glucose levels. The release of catecholamines also triggers a series of symptoms, which allows the organism to recognize what is happening and which act as a stimulant for preventative action (eating sugars). Should a patient be taking a drug such as insulin, which reduces glycemia, and also is taking another drug such as certain beta-blockers for heart disease, then the beta-blockers will act to block the adrenaline receptors. This will block the reaction triggered by the catecholamines should a hypoglycemic episode occur. Therefore, the body will not adopt corrective mechanisms and there will be an increased risk of a serious reaction resulting from the ingestion of both drugs at the same time.
Antagonist physiological systems
Imagine a drug A that acts on a certain organ. This effect will increase with increasing concentrations of physiological substance S in the organism. Now imagine a drug B that acts on another organ, which increases the amount of substance S. If both drugs are taken simultaneously it is possible that drug Acould cause an adverse reaction in the organism as its effect will be indirectly increased by the action of drug B. An actual example of this interaction is found in the concomitant use of digoxin and furosemide. The former acts on cardiac fibers and its effect are increased if there are low levels of potassium (K) in blood plasma. Furosemide is a diuretic that lowers arterial tension but favors the loss of K+. This could lead to hypokalemia (low levels of potassium in the blood), which could increase the toxicity of digoxin.
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 behavior of each drug when taken individually. These changes are basically modifications in the concentration of the drugs. In this respect, two drugs can be homers if they have the same effect in the organism and heterergic if their effects are different.
Changes in motility
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.
- pH – Drugs can be present in either ionized or non-ionised form, depending on their pKa (pH at which the drug reaches equilibrium between its ionized and non-ionised form).The non-ionized forms of drugs are usually easier to absorb, because they will not be repelled by the lipidic bilayer of the cell, most of them can be absorbed by passive diffusion, unless they are too big or too polarized (like glucose or vancomycin), in which case they may have or not specific and non specific transporters distributed on the entire intestine internal surface, that carry drugs inside the body. Obviously increasing the absorption of a drug will increase its bioavailability, so, changing the drug’s state between ionized or not, can be useful or not for certain drugs.
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. In the case of the antacids, an increase in pH can inhibit the absorption of other drugs such as zalcitabine (absorption can be decreased by 25%), tipranavir (25%) and amprenavir (up to 35%). 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
Drug solubility – The absorption of some drugs can be drastically reduced if they are administered together with food with a high-fat content. This is the case for oral anticoagulants and avocado.
Formation of non-absorbable complexes
- Chelation – The presence of di- or trivalent cations can cause the chelation of certain drugs, making them harder to absorb. This interaction frequently occurs between drugs such as tetracycline or the fluoroquinolones and dairy products (due to the presence of Ca++).
- Binding with proteins – Some drugs such as sucralfate binds to proteins, especially if they have a high bioavailability. For this reason, its administration is contraindicated in enteral feeding.
- Finally, another possibility is that the drug is retained in the intestinal lumen forming large complexes that impede its absorption. This can occur with cholestyramine if it is associated with sulfamethoxazole, thyroxine, warfarin or digoxin.
- This appears to be one of the mechanisms promoted by the consumption of grapefruit juice in increasing the bioavailability of various drugs, regardless of its demonstrated inhibitory activity on first pass metabolism.
If drug A is metabolized by a cytochrome P450 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 gives rise to product A2, which actually produces the effect of the drug. If the metabolism of drug A is inhibited by drug B the concentration of A2 that is present in the blood will decrease, as will the final effect of the drug.
If drug A is metabolized by a cytochrome P450 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 A2 (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
|Drugs related to CYP1A2|
Enzyme CYP3A4 is the enzyme that the greatest number of drugs used as a substrate. Over 100 drugs depend on its metabolism for their actions 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:
|Foods and their influence on drug metabolism|
|Enzymatic inductor||Acenocoumarol, warfarin|
|Grapefruit juice||Enzymatic inhibition|
|Soya||Enzymatic inhibition||Clozapine, haloperidol, olanzapine, caffeine, NSAIDs, phenytoin, zafirlukast, warfarin|
|Garlic||Increases antiplatelet activity|
|Ginseng||To be determined||by Warfarin, heparin, aspirin and NSAIDs|
|Ginkgo biloba||Strong inhibitor of platelet aggregation factor||Warfarin, aspirin and NSAIDs|
|Hypericum perforatum (St John’s wort)||Enzymatic inductor (CYP450)||Warfarin, digoxin, theophylline, cyclosporine, phenytoin and antiretrovirals|
|Ephedra||Receptor level agonist||MAOI, central nervous system stimulants, alkaloids ergotamines, and xanthines|
|Kava (Piper methysticum)||Unknown||Levodopa|
|Ginger||Inhibits thromboxane synthetase (in vitro)||Anticoagulants|
|Chamomile||Unknown||Benzodiazepines, barbiturates and opioids|
|Hawthorn||Unknown||Beta-adrenergic antagonists, cisapride, digoxin, quinidine|
Drug Interactions Table
Possible effect Additive
|Substance I||Substance II|
|NSAIDs||SSRI, phenprocoumon||Increased risk of bleeding|
|NSAIDs||Glucocorticoids||Increased risk of gastric bleeding|
|ACE inhibitors||Spironolactone, amiloride||Hyperkalemia|
|Tricyclic antidepressants||Low-potency neuroleptics||Increased anticholinergic effects|
|Quinolones||Macrolides, citalopram||QT-interval prolongation, torsade de pointes|
|Acetylsalicylic acid||Ibuprofen||Reduced effects|
|ACE inhibitors||NSAIDs||Reduced effects|
|Levodopa||Classical neuroleptics||Reduced effects|
|Phenprocoumon||Vitamin K||Reduced effects|
SSRI, selective serotonin reuptake inhibitor; NSAID, nonsteroidal anti-inflammatory drug
|Immunosuppressants||Ciclosporin, tacrolimus, sirolimus|
|Protease inhibitors||Indinavir, saquinavir|
|Statins||Atorvastatin, lovastatin, simvastatin|
|Antineoplastic agents||Paclitaxel, anthracyclines, vinca alkaloids, etoposide, imatinib|
|Anticonvulsants||Carbamazepine (oxcarbazepine less so), phenytoin, phenobarbital, primidone|
|St. John’s wort extract||Hyperforin|
|Calcium channel blockers||Diltiazem; felodipine; nicardipine; nifedipine; verapamil especially|
|Macrolide antibiotics||Erythromycin, clarithromycin, not azithromycin|
|HIV protease inhibitors||Indinavir; nelfinavir; ritonavir especially; saquinavir|
|Antiarrhythmic drugs||Amiodarone, quinidine, propafenone|
|Clozapine||NSAIDs||Proton pump||Beta-blockers||Macrolide antibiotics||Statins|
|Miscellaneous||HIV protease inhibitors|
|Fluoroquinolones||Amiodarone +||SSRIs||SSRIs||HIV protease inhibitors|
|Ciprofloxacin ++||Fluconazole ++||Fluoxetine||Duloxetin +||Indinavir ++|
|Ofloxacin||Isoniazide||Fluvoxamine||Fluoxetine ++||Nelfinavir ++|
|Levofloxacin||Paroxetine ++||Ritonavir ++|
|Amiodarone||Omeprazole +||Amiodarone||Clarithromycin ++|
|Cimetidine +||Buproprion||Erythromycin +|
|++ Ticlopidine||Ketoconazole||Quinidine ++||Azole antimycotics|
|Aprepitant +, Amiodarone|
|Naringin + (in citrus fruits)|
|Omeprazole||(oxcarbazepine less so)|
|Hyperforin (in St. John’s wort)|
|Antibiotic Class||Interacting Drug||Comment|
|Penicillin||Methotrexate||Increased risk of toxicity with methotrexate: careful monitoring for signs and symptoms of methotrexate toxicity (i.e. hematological and gastrointestinal toxicity) particularly in patients with renal impairment and the elderly.|
|Consult product SmPC (section 4.5) for an extensive list of interacting medicines.||Many drug interactions due to enzyme inhibition. Check for interactions against the patient’s medication before prescribing.|
|Statins||Risk of myopathy. Avoid concomitant use (hold statin for the duration of the antibiotic course and for 7 days after last antibiotic dose).|
|Warfarin*||Risk of bleeding. Monitor INR closely.|
|NOACs* – Dabigatran,|
Rivaroxaban, Apixaban, Edoxaban
|Monitor; increased risk of bleeding.|
|Drugs that prolong QT interval||Consider risk vs. benefit for each individual patient. Consult the currently approved SmPC for individual agents for further details.|
|Colchicine||Clarithromycin, erythromycin and azithromycin possibly increase the risk of colchicine toxicity—hold or reduce the dose of colchicine (avoid concomitant use in hepatic or renal impairment) (BNF)|
|Antiepileptic drugs||Increased plasma concentrations of carbamazepine with clarithromycin and erythromycin, phenytoin with clarithromycin and possibly valproate with erythromycin.|
|Metronidazole||Warfarin||Enhances the anticoagulant effect of warfarin. Risk of bleeding. – Monitor INR closely.|
|Alcohol||A disulfiram-like reaction can occur between metronidazole and alcohol. The reaction is generally more unpleasant than serious. Warn all patients of the potential effects (flushing and tachycardia). A reaction can occur up to 72 hours after stopping metronidazole.|
|Antacids||Risk of reduced bioavailability and efficacy.|
Separate the doses by 2 to 3 hours or more to avoid interaction.
|Iron, Zinc, Calcium||Risk of reduced bioavailability and efficacy.|
Separate the doses by 2 to 3 hours or more to avoid interaction.
|Warfarin*||Risk of bleeding – monitor INR closely.|
|Methotrexate||Doxycycline, tetracycline increase risk of methotrexate toxicity|
|Trimethoprim and Co-Trimoxazole||Warfarin*||May increase the anticoagulant effect of warfarin with an increased risk of bleeding – monitor INR closely|
|Methotrexate||Risk of severe bone marrow depression and other hematological toxicities – avoid if possible|
|Amiodarone||Possible increased risk of ventricular arrhythmias: avoid concomitant use of co-trimoxazole due to increased risk of arrhythmias.|
|Warfarin||Risk of bleeding. Monitor INR closely.|
|Drugs that prolong QT interval||Consider risk vs. benefit for each individual patient. (Moxifloxacin – contraindicated). See list below|
|Avoid concomitant use due to increased risk of ventricular arrhythmias|
|Epilepsy||Can reduce seizure threshold. Use with caution.|
|Theophylline||Ciprofloxacin can raise theophylline levels by more than 100%. Avoid combination or monitor theophylline levels on day 2 and adjust the dose|
|Antacids||reduce absorption of quinolones, the risk of reduced bioavailability and efficacy|
Ciprofloxacin, levofloxacin: Give at least two hours before or four hours after the antibiotic dose to avoid interaction. Moxifloxacin: give at least 6 hours apart.
|Iron / Calcium / phosphate binders||Give at least two hours before or four hours after the antibiotic dose to avoid interaction.|
|Dairy products||Absorption of ciprofloxacin reduced by dairy products (give doses at least 2 hours apart)|
|Statins||Increased risk of myopathy. Recommended holding the statin for the duration of and 7 days after completing antifungal treatment.|
rivaroxaban, apixaban, edoxaban
|Not recommended – Increased plasma concentration of NOACs, increased the risk of bleeding. (see individual SmPC)|
|Warfarin||Increased anticoagulant effect of warfarin, increased risk of bleeding. Monitor INR closely.|
|Drugs that prolong QT interval**||Consider risk vs. benefit for each individual patient.|
|(NOTE: Ketoconazole oral tablets are no longer recommended in routine practice)||The benefit of oral ketoconazole does not outweigh the risk of liver injury in fungal infections. Topical ketoconazole formulations have very low systemic absorption and may continue to be used as currently approved.|
European Medicines Agency recommends suspension of marketing authorizations for oral ketoconazole
|Voriconazole||Extensive range of contraindications, precautions warnings, and interactions. Refer to SmPC for details|
|Rifampicin||Warfarin||Accelerates metabolism of warfarin resulting in reduced anticoagulant effect – monitor INR closely.|
|NOACs: dabigatran, rivaroxaban, apixaban, edoxaban||Reduced plasma concentrations of NOACs resulting in reduced anticoagulant effect – avoid concomitant use|
|Consult product SPC for an extensive list.||Causes many drug interactions due to potent enzyme induction primarily to enzyme inhibition. Check for interactions against the patient’s medication before prescribing. May require dose adjustment or additional monitoring.|
|Oral Contraceptive Pill (OCP)||Increased metabolism of OCP – the patient should be advised to change to non-hormonal methods of birth control during rifampicin therapy and to continue using this form of contraception for two weeks after completing the course of treatment. Consult individual SmPCs for OCP as recommendations may vary regarding the duration of cover required.|
|Fusidic Acid||Statins||Risk of myopathy and rhabdomyolysis. Avoid concomitant use. Hold statin for the duration of the antibiotic course and for 7 days after last fusidic acid dose.|
|Linezolid||Serotonergic Drugs||Caution, the risk of serotonin syndrome.|
|Tyramine-rich foods||Note: Linezolid is a reversible, non-selective monoamine oxidase inhibitor (MAOI) and patients should avoid large amounts of tyramine-rich foods|
|Other MAOIs||Not to be given with another MAOI or within 2 weeks of stopping another MAOI (e.g. moclobemide, selegiline)|
|Rifampicin||Possible therapeutic failure, rifampicin reduces the plasma concentration of linezolid|
|Sodium Valproate||Contraindicated – Carbapenems reduce the plasma concentration of sodium valproate: potential for inadequate seizure control.|
|Statins||Risk of myopathy. Hold statin for the duration of and 7 days after the last dose of daptomycin.|