In pharmaceutical sciences, drug interactions occur when a drug's

mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical Drug interaction, interaction through which a Medication, drug substance produces its pharmacological effect. A mechanism of action usually includes mention o ...

is affected by the concomitant administration of substances such as foods, beverages, or other drugs. A popular example of drug–food interaction is the effect of grapefruit on the metabolism of drugs. Interactions may occur by simultaneous targeting of receptors, directly or indirectly. For example, both Zolpidem and alcohol affect GABA_A 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 a drug–drug interaction (DDI). The risk of a DDI increases with the number of drugs used. A large share of

elderly Old age is the range of ages for people nearing and surpassing life expectancy. People who are of old age are also referred to as: old people, elderly, elders, senior citizens, seniors or older adults. Old age is not a definite biological sta ...

people regularly use five or more medications or supplements, with a significant risk of side-effects from drug–drug interactions. Drug interactions can be of three kinds: * additive (the result is what you expect when you add together the effect of each drug taken independently), *

synergistic Synergy is an interaction or cooperation giving rise to a whole that is greater than the simple sum of its parts (i.e., a non-linear addition of force, energy, or effect). The term ''synergy'' comes from the Attic Greek word συνεργία ' f ...

(combining the drugs leads to a larger effect than expected), or * antagonistic (combining the drugs leads to a smaller effect than expected). 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 before intravenous injection. For example, mixing thiopentone and suxamethonium can lead to the

precipitation In meteorology, precipitation is any product of the condensation of atmospheric water vapor that falls from clouds due to gravitational pull. The main forms of precipitation include drizzle, rain, rain and snow mixed ("sleet" in Commonwe ...

of thiopentone.

Interactions based on pharmacodynamics

Pharmacodynamic interactions are the drug–drug interactions that occur at a

biochemical Biochemistry, or biological chemistry, is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology, ...

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 or signaling pathway. Agonist Antagonist

Pharmacodynamic interactions can occur on protein receptors. Two drugs can be considered to be ''homodynamic'', if they act on the same receptor. Homodynamic effects include drugs that act as (1) pure agonists, if they bind to the main locus of the receptor, causing a similar effect to that of the main drug, (2) partial agonists if, on binding to a secondary site, they have the same effect as the main drug, but with a lower intensity and (3)

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.downstream pathways. The interaction my also occur via signal transduction mechanisms.''Curso de Farmacología Clínica Aplicada'', in El Médico Interactivo
For example, low blood glucose leads to a release of catecholamines, triggering

symptom Signs and symptoms are diagnostic indications of an illness, injury, or condition. Signs are objective and externally observable; symptoms are a person's reported subjective experiences. A sign for example may be a higher or lower temperature ...

s that hint the organism to take action, like consuming sugary foods. If a patient is on

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...

, which reduces blood sugar, and also beta-blockers, the body is less able to cope with an insulin overdose.

Interactions based on pharmacokinetics

Pharmacokinetics is the field of research studying the chemical and biochemical factors that directly affect dosage and the

half-life Half-life is a mathematical and scientific description of exponential or gradual decay. Half-life, half life or halflife may also refer to: Film * Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang * ''Half 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 the

human body The human body is the entire structure of a Human, human being. It is composed of many different types of Cell (biology), cells that together create Tissue (biology), tissues and subsequently Organ (biology), organs and then Organ system, org ...

, increasing or reducing drug availability.

Based on absorption

Drugs that change intestinal motility may impact the level of other drugs taken. For example, prokinetic agents increase the intestinal motility, which may cause drugs to go through the digestive system too fast, reducing absorption. The pharmacological modification of pH can affect other compounds. Drugs can be present in ionized or non-ionized forms depending on pKa, and neutral compounds are usually better absorbed by membranes.Malgor — Valsecia, ''Farmacología general: Farmacocinética.''Cap. 2. en Revised 25 September 2008 Medication like

antacid An antacid is a substance which neutralization (chemistry), neutralizes gastric acid, stomach acidity and is used to relieve heartburn, indigestion, or an upset stomach. Some antacids have been used in the treatment of constipation and diarrhe ...

s can increase pH and inhibit the absorption of other drugs such as zalcitabine, tipranavir and amprenavir. The opposite is more common, with, for example, the antacid cimetidine ''stimulating'' the absorption of didanosine. Some resources describe that a gap of two to four hours between taking the two drugs is needed to avoid the interaction. Factors such as food with high-fat content may also alter the solubility of drugs and impact its absorption. This is the case for oral

anticoagulant An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces the coagulation of blood, prolonging the clotting time. Some occur naturally in blood-eating animals, such as leeches and mosquitoes, which ...

s and avocado. The formation of non-absorbable complexes may occur also via chelation, when

cation An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...

s can make certain drugs harder to absorb, for example between tetracycline or the fluoroquinolones and dairy products, due to the presence of calcium ions. . Other drugs bind to proteins. Some drugs such as sucralfate bind to proteins, especially if they have a high bioavailability. For this reason its administration is contraindicated in

enteral feeding A feeding tube is a medical device used to provide nutrition to people who cannot obtain nutrition by mouth, are unable to swallow safely, or need nutritional supplementation. The state of being fed by a feeding tube is called gavage, enteral fee ...

.Marduga Sanz, Mariano. ''Interacciones de los alimentos con los medicamentos''. o

Some drugs also alter absorption by acting on the P-glycoprotein of the enterocytes. This appears to be one of the mechanisms by which grapefruit juice increases the bioavailability of various drugs beyond its inhibitory activity on first pass metabolism.

Based on transport and distribution

Drugs also may affect each other by competing for transport proteins in plasma, such as albumin. 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, increasing plasma clearance), and thus they are not usually clinically relevant. They may become relevant if other problems are present, such as issues with drug excretion.

Based on metabolism

Many drug interactions are due to alterations in drug metabolism. Further, human drug-metabolizing enzymes are typically activated through the engagement of nuclear receptors. One notable system involved in metabolic drug interactions is the enzyme system comprising the cytochrome P450 oxidases.

CYP450

Cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

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. 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 are CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

.Nelson D (2003)
Cytochrome P450s in humans
. Consulted 9 May 2005. The majority of the enzymes are also involved in the metabolism of endogenous substances, such as

steroid A steroid is an organic compound with four fused compound, fused rings (designated A, B, C, and D) arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes t ...

s or sex 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).

Through enzymatic inhibition and induction

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. In some instances, the inhibition may reduce the therapeutic effect, if instead the metabolites of the drug is responsible for the effect. Compounds that increase the efficiency of the enzymes, on the other hand, may have the opposite effect and increase the rate of metabolism.

Examples of metabolism-based interactions

An example of this is shown in the following table for the CYP1A2 enzyme, showing the substrates (drugs metabolized by this enzyme) and some inductors and inhibitors of its activity: Some foods also act as inductors or inhibitors of enzymatic activity. The following table shows the most common:

Based on excretion

Renal and biliary excretion

Drugs tightly bound to proteins (i.e. not in the free fraction) are not available for renal excretion.Gago Bádenas, F. ''Curso de Farmacología General. Tema 6.- Excreción de los fármacos''. e

Filtration depends on a number of factors including the pH of the urine. Drug interactions may affect those points.

With herbal medicines

Herb-drug interactions are drug interactions that occur between herbal medicines and conventional drugs. 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. Some such interactions are clinically significant, although most herbal remedies are not associated with drug interactions causing serious consequences. Most catalogued herb-drug interactions are moderate in severity. The most commonly implicated conventional drugs in herb-drug interactions are

warfarin Warfarin, sold under the brand name Coumadin among others. It is used as an anticoagulant, anticoagulant medication. It is commonly used to prevent deep vein thrombosis and pulmonary embolism, and to protect against stroke in people who ha ...

, aspirin,

digoxin Digoxin (better known as digitalis), sold under the brand name Lanoxin among others, is a medication used to treat various heart disease, heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. ...

, and ticlopidine, due to their narrow therapeutic indices. The most commonly implicated herbs involved in such interactions are those containing St. John’s Wort, magnesium, calcium, iron, or

ginkgo ''Ginkgo'' is a genus of non-flowering seed plants, assigned to the gymnosperms. The scientific name is also used as the English common name. The order to which the genus belongs, Ginkgoales, first appeared in the Permian, , and ''Ginkgo'' is n ...

Examples

Examples of herb-drug interactions include, but are not limited to: * St. John's wort affects the clearance of numerous drugs, including cyclosporin,

SSRI Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs primarily work by ...

antidepressants,

, indinavir, and

phenprocoumon Phenprocoumon (marketed under the brand names Marcoumar, Marcumar and Falithrom) is a long-acting anticoagulant to be taken by mouth, and a coumarin derivative. It acts as a vitamin K antagonist and inhibits blood clotting (coagulation) by blocki ...

. It may also interact with the anti-cancer drugs irinotecan and imatinib. * Salvia miltiorrhiza may enhance anticoagulation and bleeding among people taking warfarin. *

Allium sativum Garlic (''Allium sativum'') is a species of bulbous flowering plants in the genus ''Allium''. Its close relatives include the onion, shallot, leek, chives, Allium fistulosum, Welsh onion, and Allium chinense, Chinese onion. Garlic is native to ...

has been found to decrease the plasma concentration of saquinavir, and may cause

hypoglycemia Hypoglycemia (American English), also spelled hypoglycaemia or hypoglycæmia (British English), sometimes called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's tria ...

when taken with chlorpropamide. * Ginkgo biloba can cause bleeding when combined with warfarin or aspirin. * Concomitant Ephedra and

caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine chemical classification, class and is the most commonly consumed Psychoactive drug, psychoactive substance globally. It is mainly used for its eugeroic (wakefulness pr ...

use has been reported to, in rare cases, cause fatalities.

Mechanisms

The mechanisms underlying most herb-drug interactions are not fully understood. Interactions between herbal medicines and anticancer drugs typically involve enzymes that metabolize

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

. For example, St. John's Wort has been shown to induce

and P-glycoprotein in vitro and in vivo.

Underlying factors

The factors or conditions that predispose the appearance of interactions include factors such as

old age Old age is the range of ages for people nearing and surpassing life expectancy. People who are of old age are also referred to as: old people, elderly, elders, senior citizens, seniors or older adults. Old age is not a definite biological sta ...

. 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. The elderly are also more vulnerable to polypharmacy, and the more drugs a patient takes, the higher is the chance of an interaction.García Morillo, J.S. ''Optimización del tratamiento de enfermos pluripatológicos en atención primaria'' UCAMI HHUU Virgen del Rocio. Sevilla. Spain. Available for members of SEMI at
ponencias de la II Reunión de Paciente Pluripatológico y Edad Avanzada
Genetic factors may also affect the enzymes and receptors, thus altering the possibilities of interactions. Patients with hepatic or renal diseases already may have difficulties metabolizing and excreting drugs, which may exacerbate the effect of interactions. Some drugs present an intrinsic increased risk for a harmful interaction, including drugs with a narrow therapeutic index, where the difference between the effective dose and the toxic dose is small.The term effective dose is generally understood to mean the minimum amount of a drug that is needed to produce the required effect. The toxic dose is the minimum amount of a drug that will produce a damaging effect. The drug

is an example of this type of drug.Castells Molina, S.; Castells, S. y Hernández Pérez, M. ''Farmacología en enfermería'' Published by Elsevier Spain, 2007 , 9788481749939 Available fro

/ref> Risks are also increased when the drug presents a steep Dose-response relationship, dose-response curve, and small changes in the dosage produce large changes in the drug's concentration in the blood plasma.

Epidemiology

As of 2008, among adults in the

United States of America The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 states and a federal capital district, Washington, D.C. The 48 contiguo ...

older than 56, 4% were taking medication and/ or supplements that put them at risk of a major drug interaction. Potential drug-drug interactions have increased over time and are more common in the less-educated

even after controlling for age, sex, place of residence, and comorbidity.

Notes

References

Bibliography

* MA Cos. ''Interacciones de fármacos y sus implicancias clínicas.'' In: ''Farmacología Humana.'' Chap. 10, pp. 165–176. (J. Flórez y col. Eds). Masson SA, Barcelona. 1997.

External links

Drug Interactions: What You Should Know
U.S. Food and Drug Administration, Center for Drug Evaluation and Research, September 2013
COVID 19 Drug interaction check tool
University of Liverpool {{Authority control Clinical pharmacology Pharmacokinetics Prescription of drugs Drug safety