 | This articleneeds additional citations forverification. Please helpimprove this article byadding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Drug interaction" – news ·newspapers ·books ·scholar ·JSTOR(November 2023) (Learn how and when to remove this message) |
_white_bg.jpg)
Inpharmaceutical sciences,drug interactions occur when a drug'smechanism of action is affected by theconcomitant administration of substances such as foods, beverages, or other drugs. A popular example of drug–food interaction is theeffect of grapefruit on the metabolism of drugs.
Interactions may occur by simultaneous targeting ofreceptors, directly or indirectly. For example, bothZolpidem and alcohol affectGABAA receptors, and their simultaneous consumption results in the overstimulation of the receptor, which can lead to loss of consciousness. When two drugs affect each other, it is adrug–drug interaction (DDI). The risk of a DDI increases with the number of drugs used.[1]
A large share ofelderly people regularly use five or more medications or supplements, with a significant risk of side-effects from drug–drug interactions.[2]
Drug interactions can be of three kinds:
It may be difficult to distinguish between synergistic or additive interactions, as individual effects of drugs may vary.
Direct interactions between drugs are also possible and may occur when two drugs are mixed beforeintravenous injection. For example, mixingthiopentone andsuxamethonium can lead to theprecipitation of thiopentone.[4]
Pharmacodynamic interactions are the drug–drug interactions that occur at abiochemical level and depend mainly on the biological processes of organisms. These interactions occur due to action on the same targets; for example, the same receptor orsignaling pathway.
Pharmacodynamic interactions can occur on proteinreceptors.[5] Two drugs can be considered to behomodynamic, if they act on the same receptor. Homodynamic effects include drugs that act as (1) pureagonists, if they bind to the mainlocus of thereceptor, causing a similar effect to that of the main drug, (2) partialagonists if, on binding to a secondary site, they have the same effect as the main drug, but with a lower intensity and (3)antagonists, if they bind directly to the receptor's main locus but their effect is opposite to that of the main drug. These may be competitive antagonists, if they compete with the main drug to bind with the receptor. or uncompetitive antagonists, when the antagonist binds to the receptor irreversibly. The drugs can be consideredheterodynamic competitors, if they act on distinct receptor with similardownstream pathways.
The interaction my also occur via signal transduction mechanisms.[6] For example,low blood glucose leads to a release ofcatecholamines, triggeringsymptoms that hint the organism to take action, like consuming sugary foods. If a patient is oninsulin, which reduces blood sugar, and alsobeta-blockers, the body is less able to cope with an insulin overdose.
Pharmacokinetics is the field of research studying the chemical and biochemical factors that directly affectdosage and thehalf-life of drugs in an organism, including absorption, transport, distribution, metabolism and excretion. Compounds may affect any of those process, ultimately interfering with the flux of drugs in thehuman body, increasing or reducing drug availability.
Drugs that change intestinal motility may impact the level of other drugs taken. For example,prokinetic agents increase theintestinal motility, which may cause drugs to go through the digestive system too fast, reducing absorption.[citation needed]
The pharmacological modification ofpH can affect other compounds. Drugs can be present in ionized ornon-ionized forms depending onpKa, and neutral compounds are usually better absorbed by membranes.[7] Medication likeantacids can increase pH and inhibit the absorption of other drugs such aszalcitabine,tipranavir andamprenavir. The opposite is more common, with, for example, the antacidcimetidinestimulating the absorption ofdidanosine. Some resources describe that a gap of two to four hours between taking the two drugs is needed to avoid the interaction.[8]
Factors such as food withhigh-fat content may also alter the solubility of drugs and impact its absorption. This is the case for oralanticoagulants andavocado.[citation needed] The formation of non-absorbable complexes may occur also viachelation, whencations can make certain drugs harder to absorb, for example betweentetracycline or thefluoroquinolones and dairy products, due to the presence ofcalcium ions.[citation needed] . Other drugs bind to proteins. Some drugs such assucralfate bind to proteins, especially if they have a highbioavailability. For this reason its administration iscontraindicated inenteral feeding.[9]
Some drugs also alter absorption by acting on theP-glycoprotein of theenterocytes. This appears to be one of the mechanisms by whichgrapefruit juice increases thebioavailability of various drugs beyond its inhibitory activity onfirst pass metabolism.[10]
Drugs also may affect each other by competing for transport proteins inplasma, such asalbumin. In these cases the drug that arrives first binds with the plasma protein, leaving the other drug dissolved in the plasma, modifying its expected concentration. The organism has mechanisms to counteract these situations (by, for example, increasingplasma clearance), and thus they are not usually clinically relevant. They may become relevant if other problems are present, such as issues with drug excretion.[11]
Many drug interactions are due to alterations indrug metabolism.[12] Further, human drug-metabolizing enzymes are typically activated through the engagement ofnuclear receptors.[12] One notable system involved in metabolic drug interactions is the enzyme system comprising thecytochrome P450 oxidases.
Cytochrome P450 is a very large family ofhaemoproteins (hemoproteins) that are characterized by theirenzymatic activity and their role in the metabolism of a large number of drugs.[13] Of the various families that are present in humans, the most interesting in this respect are the 1, 2 and 3, and the most important enzymes areCYP1A2,CYP2C9,CYP2C19,CYP2D6,CYP2E1 andCYP3A4.[14]The majority of the enzymes are also involved in the metabolism ofendogenous substances, such assteroids orsex hormones, which is also important should there be interference with these substances. The function of the enzymes can either be stimulated (enzyme induction) or inhibited (enzyme inhibition).
If a drug is metabolized by a CYP450 enzyme and drug B blocks the activity of these enzymes, it can lead to pharmacokinetic alterations. A. This alteration results in drug A remaining in the bloodstream for an extended duration, and eventually increase in concentration.[citation needed]
In some instances, the inhibition may reduce the therapeutic effect, if instead the metabolites of the drug is responsible for the effect.[citation needed]
Compounds that increase the efficiency of the enzymes, on the other hand, may have the opposite effect and increase the rate of metabolism.
An example of this is shown in the following table for theCYP1A2 enzyme, showing the substrates (drugs metabolized by this enzyme) and some inductors and inhibitors of its activity:[14]
| Drugs related to CYP1A2 | ||
| Substrates | Inhibitors | Inductors |
|---|---|---|
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[15][9][16] | ||
| Food | Mechanism | Drugs affected |
|---|---|---|
| Enzymatic inductor | Acenocoumarol,warfarin | |
| Grapefruit juice | Enzymatic inhibition |
Main article:Grapefruit drug interactions |
| Soya | Enzymatic inhibition | Clozapine,haloperidol,olanzapine,caffeine,NSAIDs,phenytoin,zafirlukast,warfarin |
| Garlic | Increases antiplatelet activity | |
| Ginseng | To be determined | Warfarin,heparin,aspirin andNSAIDs |
| Ginkgo biloba | Strong inhibitor of platelet aggregation factor | Warfarin,aspirin andNSAIDs |
| 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, alkaloidsergotamines andxanthines |
| Kava (Piper methysticum) | Unknown | Levodopa |
| Ginger | Inhibits thromboxane synthetase (in vitro) | Anticoagulants |
| Chamomile | Unknown | Benzodiazepines,barbiturates andopioids |
| Hawthorn | Unknown | Beta-adrenergic antagonists,cisapride, digoxin,quinidine |
Drugs tightly bound to proteins (i.e. not in thefree fraction) are not available forrenal excretion.[17]Filtration depends on a number of factors including thepH of the urine. Drug interactions may affect those points.[citation needed]
Herb-drug interactions are drug interactions that occur betweenherbal medicines and conventional drugs.[18] These types of interactions may be more common than drug-drug interactions because herbal medicines often contain multiple pharmacologically active ingredients, while conventional drugs typically contain only one.[18] Some such interactions areclinically significant,[19] although most herbal remedies are not associated with drug interactions causing serious consequences.[20] Most catalogued herb-drug interactions are moderate in severity.[21] The most commonly implicated conventional drugs in herb-drug interactions arewarfarin,insulin,aspirin,digoxin, andticlopidine, due to their narrowtherapeutic indices.[21][22] The most commonly implicated herbs involved in such interactions are those containingSt. John’s Wort, magnesium, calcium, iron, orginkgo.[21]
Examples of herb-drug interactions include, but are not limited to:
The mechanisms underlying most herb-drug interactions are not fully understood.[25] Interactions between herbal medicines and anticancer drugs typically involve enzymes that metabolizecytochrome P450.[23] For example, St. John's Wort has been shown to induceCYP3A4 andP-glycoprotein in vitro and in vivo.[23]
The factors or conditions that predispose the appearance of interactions include factors such asold age.[26] This is where human physiology changing 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.[27] The elderly are also more vulnerable topolypharmacy, and the more drugs a patient takes, the higher is the chance of an interaction.[28]
Genetic factors may also affect the enzymes and receptors, thus altering the possibilities of interactions.[citation needed]
Patients withhepatic orrenal diseases already may have difficulties metabolizing and excreting drugs, which may exacerbate the effect of interactions.[28]
Some drugs present an intrinsic increased risk for a harmful interaction, including drugs with a narrowtherapeutic index, where the difference between theeffective dose and thetoxic dose is small.[n. 1] The drugdigoxin is an example of this type of drug.[29]
Risks are also increased when the drug presents a steepdose-response curve, and small changes in the dosage produce large changes in the drug's concentration in the blood plasma.[29]
As of 2008, among adults in theUnited States of America older than 56, 4% were taking medication and/ or supplements that put them at risk of a major drug interaction.[30] Potential drug-drug interactions have increased over time[31] and are more common in the less-educatedelderly even after controlling for age, sex, place of residence, andcomorbidity.[32]
{{cite web}}: CS1 maint: archived copy as title (link) Revised 25 September 2008(subtitle) Researchers explore a number of strategies to better predict drug responses in the clinic
