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{{short description|Change in the action or side effects of a drug caused}}{{More citations needed|date=November 2023}}[[File:Citrus paradisi (Grapefruit, pink) white bg.jpg|thumb|250px|[[Grapefruit]] juice can act as an enzyme inhibitor, [[Grapefruit–drug interactions|affecting the metabolism of drugs]].]]In [[pharmaceutical sciences]], '''drug interactions''' occur when a drug's [[mechanism of action]] is affected by the [[Concomitant drug|concomitant]] administration of substances such as foods, beverages, or other drugs. A popular example of drug–food interaction is the effect of [[Grapefruit–drug interactions|grapefruit on the metabolism of drugs]].
{{short description|Change in the action or side effects of a drug caused}}
{{cleanup rewrite|date=February 2019}}
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Interactions may occur by simultaneous targeting of [[Drug receptors|receptors]], directly or indirectly. For example, both [[Zolpidem]] and alcohol affect [[GABAA receptor|GABA<sub>A</sub> 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.<ref name="pmid24745854">{{cite journal |vauthors=Tannenbaum C, Sheehan NL |date=July 2014 |title=Understanding and preventing drug–drug and drug–gene interactions |journal=Expert Review of Clinical Pharmacology |volume=7 |issue=4 |pages=533–44 |doi=10.1586/17512433.2014.910111 |pmc=4894065 |pmid=24745854}}</ref>
'''Drug interactions''' occur when a drug's [[mechanism of action]] is affected by the [[Concomitant drug|concomitant]] administration of substances such as foods, beverages, or other drugs. The cause is often inhibition of, or less effective action, of the specific [[Drug receptors|receptors]] available to the drug. This influences drug molecules to bind to secondary targets, which may result in an array of unwanted [[Side effect|side-effects]].


A large share of [[Old age|elderly]] people regularly use five or more medications or supplements, with a significant risk of side-effects from drug–drug interactions.<ref>{{cite journal |vauthors=Qato DM, Wilder J, Schumm LP, Gillet V, Alexander GC |date=April 2016 |title=Changes in Prescription and Over-the-Counter Medication and Dietary Supplement Use Among Older Adults in the United States, 2005 vs 2011 |journal=JAMA Internal Medicine |volume=176 |issue=4 |pages=473–82 |doi=10.1001/jamainternmed.2015.8581 |pmc=5024734 |pmid=26998708}}</ref>
The term [[Functional selectivity|selectivity]] describes a drug’s ability to target a single receptor, rendering a predictable physiological response. For example, the binding of [[acetylcholine]] to [[Muscarinic acetylcholine receptor|muscarinic tracheal smooth-muscle receptors]] (M<sub>3</sub>) results in smooth muscle contractions.


Drug interactions can be of three kinds:
When freely binding receptors interact with [[agonist]]- chemicals that activate receptors - and [[Receptor antagonist|antagonists]]- that inhibit/ block activation - the opportunity for selective drugs to bind with the intended receptor cells decreases as most receptors are already accounted for. Therefore, the drugs are more likely to bind to other receptors relative to the intended receptor, causing different effects.


* additive (the result is what you expect when you add together the effect of each drug taken independently),
For example, consuming both [[Zolpidem]] (i.e., Ambien) and alcohol together, both which affect the [[GABAA receptor|GABA<sub>A</sub> receptors]], results in the overstimulation of this receptor, which can lead to loss of consciousness. The risk of a drug-drug interaction (DDI) increases with the number of drugs used.<ref name="pmid24745854">{{cite journal |vauthors=Tannenbaum C, Sheehan NL |date=July 2014 |title=Understanding and preventing drug-drug and drug-gene interactions |journal=Expert Review of Clinical Pharmacology |volume=7 |issue=4 |pages=533–44 |doi=10.1586/17512433.2014.910111 |pmc=4894065 |pmid=24745854}}</ref> Over a third (36%) of the elderly in the U.S. regularly use five or more medications or supplements, and 15% are at risk of a significant drug-drug interaction.<ref>{{cite journal |vauthors=Qato DM, Wilder J, Schumm LP, Gillet V, Alexander GC |date=April 2016 |title=Changes in Prescription and Over-the-Counter Medication and Dietary Supplement Use Among Older Adults in the United States, 2005 vs 2011 |journal=JAMA Internal Medicine |volume=176 |issue=4 |pages=473–82 |doi=10.1001/jamainternmed.2015.8581 |pmc=5024734 |pmid=26998708}}</ref>
* [[Synergy#Drug synergy|synergistic]] (combining the drugs leads to a larger effect than expected), or
* [[antagonism (chemistry)|antagonistic]] (combining the drugs leads to a smaller effect than expected).<ref>{{Cite journal |last1=Greco |first1=W. R. |last2=Bravo |first2=G. |last3=Parsons |first3=J. C. |date=1995 |title=The search for synergy: a critical review from a response surface perspective |journal=Pharmacological Reviews |volume=47 |issue=2 |pages=331–385 |issn=0031-6997 |pmid=7568331}}</ref>


It may be difficult to distinguish between synergistic or additive interactions, as individual effects of drugs may vary.
== Based on pharmacodynamics ==


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 (chemistry)|precipitation]] of thiopentone.<ref>{{Cite journal |last1=Khan |first1=Shahab |last2=Stannard |first2=Naina |last3=Greijn |first3=Jeff |date=2011-07-12 |title=Precipitation of thiopental with muscle relaxants: a potential hazard |journal=JRSM Short Reports |volume=2 |issue=7 |pages=58 |doi=10.1258/shorts.2011.011031 |issn=2042-5333 |pmc=3147238 |pmid=21847440}}</ref>
Drug interactions can be additive (the result is what you expect when you add together the effect of each drug taken independently), [[Synergy#Drug synergy|synergistic]] (combining the drugs leads to a larger effect than expected), or [[antagonism (chemistry)|antagonistic]] (combining the drugs leads to a smaller effect than expected).<ref>{{Cite journal|last1=Greco|first1=W. R.|last2=Bravo|first2=G.|last3=Parsons|first3=J. C.|date=1995|title=The search for synergy: a critical review from a response surface perspective|journal=Pharmacological Reviews|volume=47|issue=2|pages=331–385|issn=0031-6997|pmid=7568331}}</ref> On some occasions, it is difficult to distinguish between synergistic or additive interactions, since the individual effects of each drug may vary from patient to patient.<ref>{{Cite journal|last1=Palmer|first1=Adam C.|last2=Sorger|first2=Peter K.|date=2017-12-14|title=Combination Cancer Therapy Can Confer Benefit via Patient-to-Patient Variability without Drug Additivity or Synergy|journal=Cell|volume=171|issue=7|pages=1678–1691.e13|doi=10.1016/j.cell.2017.11.009|issn=1097-4172|pmc=5741091|pmid=29245013}}</ref> A synergistic interaction may be beneficial for patients, but may also increase the risk of overdose. Drug interaction predictors enable risk assessment of multiple drugs simultaneously with visualizations of risk per therapeutic class, to indicate a spectrum from no risk to high risk.<ref>{{cite web |url=https://www.elsevier.com/solutions/pharmapendium-clinical-data/dmpk |title = PharmaPendium's DMPK Solution - PharmaPendium {{!}} Elsevier}}</ref>


== Interactions based on pharmacodynamics ==
Drug-drug interaction depends on several factors, including the [[network topology|topology]] of cellular reaction networks they target, as well as the desired levels of change in the network output. A pair of drugs may thus interact in a synergistic manner under one condition, and additive or even antagonistic in a different setting<ref>Mehrad Babaei et al., Biochemical reaction network topology defines dose-dependent Drug–Drug interactions. Comput Biol Med 155:106584 (2023) doi: 10.1016/j.compbiomed.2023.106584</ref>.


[[Pharmacodynamic]] interactions are the drug–drug interactions that occur at a [[Biochemistry|biochemical]] 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 [[Cell signaling|signaling pathway]].
Both synergy and antagonism can occur during different phases of the interaction between a drug and an organism. The different responses of a drug receptor have resulted in several classifications, such as partial agonist, competitive agonist, an inverse agonist. These concepts have fundamental applications in the [[pharmacodynamics]] of these interactions. The proliferation of existing classifications at this level and lack of knowledge around drug mechanisms means that it is difficult to offer a clear classification for these concepts. It is possible that authors would misapply any given classification.<ref name="Baños">{{cite book|url=https://books.google.com/books?id=gsb6J2sYdisC|title=Farmacología ocular|author=Baños Díez, J. E.|author2=March Pujol, M|publisher=Edicions UPC|year=2002|isbn=978-8483016473|edition=2da|pages=87|language=es|access-date=23 May 2009}}</ref>


[[File:Agonist Antagonist.svg|300px|thumb|Effects of the competitive inhibition of an agonist by increases in the concentration of an antagonist. A drug's potency can be affected (the response curve shifted to the right) by the presence of an antagonistic interaction.]]
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 (chemistry)|precipitation]] of thiopentone.<ref>{{Cite journal|last1=Khan|first1=Shahab|last2=Stannard|first2=Naina|last3=Greijn|first3=Jeff|date=2011-07-12|title=Precipitation of thiopental with muscle relaxants: a potential hazard|journal=JRSM Short Reports|volume=2|issue=7|pages=58|doi=10.1258/shorts.2011.011031|issn=2042-5333|pmc=3147238|pmid=21847440}}</ref>
Pharmacodynamic interactions can occur on protein [[Receptor (biochemistry)|receptors]].<ref>{{cite web

The change in an organism's response upon 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 several different mechanisms. This wide diversity also means that in all but the most obvious cases, it is important to investigate and understand these mechanisms. A well-founded suspicion exists that there are more unknown interactions than known ones.

[[File:Agonist Antagonist.svg|300px|thumb|Effects of the competitive inhibition of an agonist by increases in the concentration of an antagonist. A drug's potency can be affected (the response curve shifted to the right) by the presence of an antagonistic interaction.pA<sub>2</sub> known as the Schild representation, a mathematical model of the agonist:antagonist relationship or vice versa. NB: the x-axis is incorrectly labeled and should reflect the ''agonist'' concentration, not antagonist concentration.]]
Pharmacodynamic interactions can occur on:
#Pharmacological receptors:<ref>{{cite web
|url = http://canal-h.net/webs/sgonzalez002/Farmaco/INTERACCIONES.htm
|url = http://canal-h.net/webs/sgonzalez002/Farmaco/INTERACCIONES.htm
|title = Interacciones Farmacológicas
|title = Interacciones Farmacológicas
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|archive-date = 2009-01-22
|archive-date = 2009-01-22
|url-status = dead
|url-status = dead
}}</ref> 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 (genetics)|locus]] of the [[Receptor (biochemistry)|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]]s, if they bind directly to the receptor's main locus but their effect is opposite to that of the main drug. These may be c''ompetitive antagonists'', if they compete with the main drug to bind with the receptor. or u''ncompetitive antagonists,'' when the antagonist binds to the receptor irreversibly. The drugs can be considered ''heterodynamic'' competitors, if they act on distinct receptor with similar [[Signaling pathway|downstream pathways]].
}}</ref> [[Receptor (biochemistry)|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:
The interaction my also occur via signal transduction mechanisms.<ref name="Medico">[http://www.elmedicointeractivo.com/farmacia/temas/tema1-2/farmaa3.htm ''Curso de Farmacología Clínica Aplicada'', in El Médico Interactivo] {{webarchive|url=https://web.archive.org/web/20090831065941/http://www.elmedicointeractivo.com/farmacia/temas/tema1-2/farmaa3.htm |date=2009-08-31 }}</ref> For example, [[Hypoglycemia|low blood glucose]] leads to a release of [[catecholamine]]s, triggering [[symptom]]s that hint the organism to take action, like consuming sugary foods. If a patient is on [[insulin]], which reduces blood sugar, and also [[Beta blocker|beta-blockers]], the body is less able to cope with an insulin overdose.
###Pure [[agonists]], if they bind to the main [[locus (genetics)|locus]] of the [[Receptor (biochemistry)|receptor]], causing a similar effect to that of the main drug.
### Partial [[agonists]] if, on binding to one of the receptor's secondary sites, they have the same effect as the main drug, but with a lower intensity.
### [[Antagonist]]s, if they bind directly to the receptor's main locus but their effect is opposite to that of the main drug. These include:
#### 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.
#### 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.
## ''Heterodynamic'' competitors, if they act on distinct receptors.
# Signal transduction mechanisms: these are molecular processes that commence after the interaction of the drug with the receptor.<ref name="Medico">[http://www.elmedicointeractivo.com/farmacia/temas/tema1-2/farmaa3.htm ''Curso de Farmacología Clínica Aplicada'', in El Médico Interactivo] {{webarchive|url=https://web.archive.org/web/20090831065941/http://www.elmedicointeractivo.com/farmacia/temas/tema1-2/farmaa3.htm |date=2009-08-31 }}</ref> For example, it is known that [[hypoglycaemia]] (low blood glucose) in an organism produces a release of [[catecholamine]]s, which trigger compensation mechanisms thereby increasing blood glucose levels. The release of catecholamines also triggers a series of [[symptom]]s, 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 be taking another drug such as certain [[Beta blocker|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 hypoglycaemic 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.
# Antagonistic physiological systems:<ref name="Medico" /> where drugs taken together cause adverse reactions because the effect of one substance is indirectly increased in the presence of another. This can occur when a certain drug, which increases the presence of a physiological substance, is introduced into a system with another drug that is amplified by the same substance. An actual example of this interaction is found in the concomitant use of [[digoxin]] and [[furosemide]]. The former acts on cardiac fibers and its effects 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<sup>+</sup>. This could lead to [[hypokalemia]] (low levels of potassium in the blood), which could increase the toxicity of digoxin.


== Based on pharmacokinetics ==
== Interactions based on pharmacokinetics ==
[[Pharmacokinetics]] is the field of research studying the chemical and biochemical factors that directly affect [[Dosage form|dosage]] and the [[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]], increasing or reducing drug availability.
Modifications in the effect of a drug are caused by differences in the absorption, transport, distribution, metabolism, or excretion of one or both of the drugs compared with the expected behaviour of each drug when taken individually. These changes are modifications in the concentration of the drugs. In this respect, two drugs can be homergic if they have the same effect on the organism and heterergic if their effects are different.


=== Absorption ===
=== Based on absorption ===
Drugs that change intestinal motility may impact the level of other drugs taken. For example, [[Prokinetic agent|prokinetic agents]] increase the [[intestinal motility]], which may cause drugs to go through the digestive system too fast, reducing absorption. {{Citation needed|date=November 2023}}


The pharmacological modification of [[pH]] can affect other compounds. Drugs can be present in ionized or [[Electrically neutral|non-ionized]] forms depending on [[pKa]], and neutral compounds are usually better absorbed by membranes.<ref name="Malgor - Valsecia">Malgor — Valsecia, ''Farmacología general: Farmacocinética.''Cap. 2. en {{cite web |url=http://med.unne.edu.ar/catedras/farmacologia/temas_farma/volumen1/cap2_farmacocinet.pdf |title=Archived copy |access-date=2012-03-20 |url-status=dead |archive-url=https://web.archive.org/web/20120907035648/http://med.unne.edu.ar/catedras/farmacologia/temas_farma/volumen1/cap2_farmacocinet.pdf |archive-date=2012-09-07 }} Revised 25 September 2008</ref> Medication like [[antacid]]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.<ref>Alicia Gutierrez Valanvia y Luis F. López-Cortés ''Interacciones farmacológicas entre fármacos antirretrovirales y fármacos usados para ciertos transtornos gastrointestinales.'' on [http://artigos.tol.pro.br/portal/linguagem-es/interacción%20farmacológica] accessed 24 September 2008</ref>
==== Changes in motility ====
Some drugs, such as 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 a short amount of time, its blood concentration will decrease. The opposite will occur with drugs that decrease intestinal [[motility]].


Factors such as food with [[Fat|high-fat content]] may also alter the solubility of drugs and impact its absorption. This is the case for oral [[anticoagulant]]s and [[avocado]].{{Citation needed|date=November 2023}} The formation of non-absorbable complexes may occur also via [[chelation]], when [[Ion|cation]]s can make certain drugs harder to absorb, for example between [[tetracycline]] or the [[Quinolone antibiotic|fluoroquinolone]]s and dairy products, due to the presence of [[calcium ions]].{{Citation needed|date=November 2023}} . 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 [[Feeding tube|enteral feeding]].<ref name="Marduga">Marduga Sanz, Mariano. ''Interacciones de los alimentos con los medicamentos''. on [http://www.auladelafarmacia.org/docs/AULA%20delafarmacia%20N6%20-%20Medicamentos%20y%20Servicios%20Profesionales%201.pdf] {{Webarchive|url=https://web.archive.org/web/20140707212321/http://www.auladelafarmacia.org/docs/AULA%20delafarmacia%20N6%20-%20Medicamentos%20y%20Servicios%20Profesionales%201.pdf|date=2014-07-07}}</ref>
* [[pH]]: Drugs can be present in either ionized or non-ionized form, depending on their [[pKa]] (pH at which the drug reaches equilibrium between its ionized and non-ionized form).<ref name="Malgor - Valsecia">Malgor — Valsecia, ''Farmacología general: Farmacocinética.''Cap. 2. en {{cite web |url=http://med.unne.edu.ar/catedras/farmacologia/temas_farma/volumen1/cap2_farmacocinet.pdf |title=Archived copy |access-date=2012-03-20 |url-status=dead |archive-url=https://web.archive.org/web/20120907035648/http://med.unne.edu.ar/catedras/farmacologia/temas_farma/volumen1/cap2_farmacocinet.pdf |archive-date=2012-09-07 }} Revised 25 September 2008</ref> 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 large or polarized (like glucose or vancomycin), in which case they may or may not have specific and non-specific transporters distributed on the entire intestine internal surface, that carries 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 for certain drugs.


Some drugs also alter absorption by acting on the [[P-glycoprotein]] of the [[enterocyte]]s. 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 effect|first pass metabolism]].<ref>Tatro, DS. ''Update: Drug interaction with grapefruit juice.'' Druglink, 2004. 8 (5), page 35ss</ref>
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 [[antacid]]s, 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 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.<ref>Alicia Gutierrez Valanvia y Luis F. López-Cortés ''Interacciones farmacológicas entre fármacos antirretrovirales y fármacos usados para ciertos transtornos gastrointestinales.'' on [http://artigos.tol.pro.br/portal/linguagem-es/interacción%20farmacológica] accessed 24 September 2008</ref>
* Drug solubility: The absorption of some drugs can be drastically reduced if they are administered together with food with high-fat content. This is the case for oral [[anticoagulant]]s and [[avocado]].
* Formation of non-absorbable complexes:
**[[Chelation]]: The presence of di- or trivalent [[Ion|cation]]s can cause the [[chelation]] of certain drugs, making them harder to absorb. This interaction frequently occurs between drugs such as [[tetracycline]] or the [[Quinolone antibiotic|fluoroquinolone]]s and dairy products (due to the presence of Ca<sup>++</sup>).
** 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 [[Feeding tube|enteral feeding]].<ref name="Marduga">Marduga Sanz, Mariano. ''Interacciones de los alimentos con los medicamentos''. on [http://www.auladelafarmacia.org/docs/AULA%20delafarmacia%20N6%20-%20Medicamentos%20y%20Servicios%20Profesionales%201.pdf] {{Webarchive|url=https://web.archive.org/web/20140707212321/http://www.auladelafarmacia.org/docs/AULA%20delafarmacia%20N6%20-%20Medicamentos%20y%20Servicios%20Profesionales%201.pdf|date=2014-07-07}}</ref>
** Finally, another possibility is that the drug is retained in the intestinal [[Lumen (anatomy)|lumen]] forming large complexes that impede its absorption. This can occur with [[cholestyramine]] if it is associated with [[sulfamethoxazol]], [[thyroxine]], [[warfarin]] or [[digoxin]].
* Acting on the [[P-glycoprotein]] of the [[enterocyte]]s: 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 effect|first pass metabolism]].<ref>Tatro, DS. ''Update: Drug interaction with grapefruit juice.'' Druglink, 2004. 8 (5), page 35ss</ref>


=== Based on transport and distribution===
=== Based on transport and distribution===
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 [[Clearance (medicine)|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.<ref>[https://web.archive.org/web/20040619231334/http://www.biologia.edu.ar/farmacologia/clas2do%5Cinteraccion_03.pdf Valsecia, Mabel en]</ref>
Drugs also may affect each other by competing for transport proteins in [[Blood plasma|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 [[Clearance (medicine)|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.<ref>[https://web.archive.org/web/20040619231334/http://www.biologia.edu.ar/farmacologia/clas2do%5Cinteraccion_03.pdf Valsecia, Mabel en]</ref>


=== Based on metabolism ===
=== Based on metabolism ===
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The majority of the enzymes are also involved in the metabolism of [[endogenous]] substances, such as [[steroid]]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]]).
The majority of the enzymes are also involved in the metabolism of [[endogenous]] substances, such as [[steroid]]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 ====
==== Through enzymatic inhibition and induction ====
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.
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|date=November 2023}}


In some instances, the inhibition may reduce the therapeutic effect, if instead the metabolites of the drug is responsible for the effect.{{Citation needed|date=November 2023}}
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 A<sub>2</sub>, which actually produces the effect of the drug. If the metabolism of drug A is inhibited by drug B, the plasma concentration of A<sub>2</sub> will decrease and so will the final effect of the drug.


Compounds that increase the efficiency of the enzymes, on the other hand, may have the opposite effect and increase the rate of metabolism.
==== Through enzymatic induction ====
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.


==== Examples of metabolism-based interactions ====
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<sub>2</sub> (following the previous example) produces an increase in the drug's effect.
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:<ref name="Nelson" />


{| class="wikitable" style="margin:1em auto;" width="100%"
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:<ref name="Nelson"/>

{| class="wikitable" style="margin:1em auto;" width=100%
|-
|-
|colspan=3 style="text-align:center;" | Drugs related to CYP1A2
| colspan="3" style="text-align:center;" | '''Drugs related to CYP1A2'''
|-
|-
! Substrates !! Inhibitors !! Inductors
! Substrates !! Inhibitors !! Inductors
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* [[Venlafaxine]]
* [[Venlafaxine]]
* [[Ticlopidine]]
* [[Ticlopidine]]
|-
|}
|}

Enzyme [[CYP3A4]] is the most commonly used substrate in a great number of drugs. Over a hundred 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:
Some foods also act as inductors or inhibitors of enzymatic activity. The following table shows the most common:
{| class="wikitable" style="margin:1em auto;" width=100%
{| class="wikitable" style="margin:1em auto;" width=100%
|-
|-
|colspan="3" style="text-align:center;"| Foods and their influence on drug metabolism<ref>{{cite journal | vauthors = Bailey DG, Malcolm J, Arnold O, Spence JD | title = Grapefruit juice-drug interactions | journal = British Journal of Clinical Pharmacology | volume = 46 | issue = 2 | pages = 101–10 | date = August 1998 | pmid = 9723817 | pmc = 1873672 | doi = 10.1046/j.1365-2125.1998.00764.x }}<br/>Comment in: {{cite journal | vauthors = Mouly S, Paine MF | title = Effect of grapefruit juice on the disposition of omeprazole | journal = British Journal of Clinical Pharmacology | volume = 52 | issue = 2 | pages = 216–7 | date = August 2001 | pmid = 11488783 | pmc = 2014525 | doi = 10.1111/j.1365-2125.1978.00999.pp.x }}{{Dead link|date=January 2019 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><sup>,</sup><ref name="Marduga" /><sup>,</sup><ref>{{cite journal |author=Covarrubias-Gómez, A. |title=¿Qué se auto-administra su paciente?: Interacciones farmacológicas de la medicina herbal |journal=Revista Mexicana de Anestesiología |volume=28 |issue=1 |pages=32–42 |date=January–March 2005 |url=http://www.medigraphic.com/espanol/e-htms/e-rma/e-cma2005/e-cma05-1/em-cma051f.htm |archive-url=https://archive.today/20120629232743/http://www.medigraphic.com/espanol/e-htms/e-rma/e-cma2005/e-cma05-1/em-cma051f.htm |url-status=dead |archive-date=2012-06-29 |display-authors=etal }}</ref>
|colspan="3" style="text-align:center;"| Foods and their influence on drug metabolism<ref>{{cite journal | vauthors = Bailey DG, Malcolm J, Arnold O, Spence JD | title = Grapefruit juice-drug interactions | journal = British Journal of Clinical Pharmacology | volume = 46 | issue = 2 | pages = 101–10 | date = August 1998 | pmid = 9723817 | pmc = 1873672 | doi = 10.1046/j.1365-2125.1998.00764.x }}<br/>Comment in: {{cite journal | vauthors = Mouly S, Paine MF | title = Effect of grapefruit juice on the disposition of omeprazole | journal = British Journal of Clinical Pharmacology | volume = 52 | issue = 2 | pages = 216–7 | date = August 2001 | pmid = 11488783 | pmc = 2014525 | doi = 10.1111/j.1365-2125.1978.00999.pp.x }}{{Dead link|date=January 2019 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><sup></sup><ref name="Marduga" /><sup></sup><ref>{{cite journal |author=Covarrubias-Gómez, A. |title=¿Qué se auto-administra su paciente?: Interacciones farmacológicas de la medicina herbal |journal=Revista Mexicana de Anestesiología |volume=28 |issue=1 |pages=32–42 |date=January–March 2005 |url=http://www.medigraphic.com/espanol/e-htms/e-rma/e-cma2005/e-cma05-1/em-cma051f.htm |archive-url=https://archive.today/20120629232743/http://www.medigraphic.com/espanol/e-htms/e-rma/e-cma2005/e-cma05-1/em-cma051f.htm |url-status=dead |archive-date=2012-06-29 |display-authors=etal }}</ref>
|-
|-
! Food !! Mechanism !! Drugs affected
! Food !! Mechanism !! Drugs affected
Line 186: Line 161:
|Beta-adrenergic antagonists, [[cisapride]], digoxin, [[quinidine]]
|Beta-adrenergic antagonists, [[cisapride]], digoxin, [[quinidine]]
|}
|}

[[File:Citrus paradisi (Grapefruit, pink) white bg.jpg|thumb|250px|Grapefruit juice can act as an enzyme inhibitor.]]
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:
[[File:Hypericum moserianum0.jpg|thumb|left|250px|[[Hypericum perforatum|St John's wort]] can act as an enzyme inductor.]]
# False sense of security regarding medicinal plants. The interaction between a medicinal plant and a drug is usually overlooked due to a belief in the "safety of medicinal plants."
# Variability of composition, both qualitative and quantitative. The composition of a plant-based drug is often subject to wide variations due to a number of factors such as seasonal differences in concentrations, soil type, climatic changes, or the existence of different varieties of chemical races within the same plant species that have variable compositions of the active ingredient. On occasion, an interaction can be due to just one [[active ingredient]], but this can be absent in some chemical varieties or it can be present in low concentrations, which will not cause an interaction. Counter interactions can even occur. This occurs, for instance, with ginseng, the ''[[Panax ginseng]]'' variety increases the [[Prothrombin time]], while the ''[[Panax quinquefolius]]'' variety decreases it.<ref>[http://www.cfnavarra.es/salud/anales/textos/vol29/n2/revis3a.html J. C. Tres ''Interacción entre fármacos y plantas medicinales''. on] {{webarchive |url=https://web.archive.org/web/20120415230850/http://www.cfnavarra.es/salud/anales/textos/vol29/n2/revis3a.html |date=April 15, 2012 }}</ref>
# Absence of use in at-risk groups, such as hospitalized and polypharmacy patients, who tend to have the majority of drug interactions.
# Limited consumption of medicinal plants has given rise to a lack of interest in this area.<ref>Zaragozá F, Ladero M, Rabasco AM et al. ''Plantas Medicinales (Fitoterapia Práctica)''. Second Edition, 2001.</ref>

They are usually included in the category of foods as they are usually taken as tea or [[food supplement]]. However, medicinal plants are increasingly being taken in a manner more often associated with conventional medicines: [[Pill (pharmacy)|pill]]s, [[Tablet (pharmacy)|tablet]]s, [[Capsule (pharmacy)|capsules]], etc.


=== Based on excretion ===
=== Based on excretion ===


==== Renal excretion ====
==== Renal and biliary excretion ====
Drugs tightly bound to proteins (i.e. not in the [[free fraction]]) are not available for [[renal excretion]].<ref name="Gago6">Gago Bádenas, F. ''Curso de Farmacología General. Tema 6.- Excreción de los fármacos''. en [http://www2.uah.es/farmamol/Public/PDF_files/Farma_3M_tema6.pdf] {{Webarchive|url=https://web.archive.org/web/20110916225410/http://www2.uah.es/farmamol/Public/PDF_files/Farma_3M_tema6.pdf|date=2011-09-16}}</ref>
[[File:Gray1128.png|350px|thumb|right|Human kidney [[nephron]].]]
Filtration depends on a number of factors including the [[pH]] of the urine. Drug interactions may affect those points. {{Citation needed|date=November 2023}}
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.<ref name="Gago6">Gago Bádenas, F. ''Curso de Farmacología General. Tema 6.- Excreción de los fármacos''. en [http://www2.uah.es/farmamol/Public/PDF_files/Farma_3M_tema6.pdf]</ref>
[[Creatinine clearance]] is used as a measure of kidney functioning but it is only useful in cases where the drug is excreted in an unaltered form in the urine. The excretion of drugs from the kidney's nephrons has the same properties as that of any other organic solute: passive filtration, reabsorption, and active secretion. 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 [[base (chemistry)|weak bases]] are increasingly excreted as the pH of the urine becomes more acidic, and the inverse is true for [[weak acid]]s. 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.

{| class="wikitable" style="margin:1em auto;" width=100%
|-
|colspan=2 style="text-align:center;" | Drugs that act as weak acids or bases
|-
! Weak acids !! Weak bases
|- style="vertical-align: top;" top;"
|
* [[Acetylsalicylic acid]]
* [[Furosemide]]
* [[Ibuprofen]]
* [[Levodopa]]
* [[Acetazolamide]]
* [[Sulfadiazine]]
* [[Ampicillin]]
* [[Chlorothiazide]]
* [[Paracetamol]]
* [[Chloropropamide]]
* [[Cromoglicic acid]]
* [[Ethacrynic acid]]
* [[alpha-Methyldopamine]]
* [[Phenobarbital]]
* [[Warfarin]]
* [[Theophylline]]
* [[Phenytoin]]
||
* [[Reserpine]]
* [[Amphetamine]]
* [[Procaine]]
* [[Ephedrine]]
* [[Atropine]]
* [[Diazepam]]
* [[Hydralazine]]
* [[Pindolol]]
* [[Propranolol]]
* [[Salbutamol]]
* [[Alprenolol]]
* [[Terbutaline]]
* [[Amiloride]]
* [[Chlorpheniramine]]<ref name=repetida_1>, ''Farmacología general: Farmacocinética.''Cap. 2. en {{cite web |url=http://med.unne.edu.ar/catedras/farmacologia/temas_farma/volumen1/cap2_farmacocinet.pdf |title=Archived copy |access-date=2012-03-20 |url-status=dead |archive-url=https://web.archive.org/web/20120907035648/http://med.unne.edu.ar/catedras/farmacologia/temas_farma/volumen1/cap2_farmacocinet.pdf |archive-date=2012-09-07 }} Revised 25 September 2008</ref>
|-
|}

==== Bile excretion ====
[[Bile]] excretion is different from kidney excretion as it 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 300 and they contain both polar and lipophilic groups. The [[Glucuronic acid|glucuronidation]] of the drug in the kidney also facilitates bile excretion. Substances with similar physicochemical properties can block the receptor, which is important in assessing interactions. A drug excreted in the bile duct can occasionally be reabsorbed by the intestines (in the enterohepatic circuit), which can also lead to interactions with other drugs.


== With herbal medicines ==
== With herbal medicines ==
Herb-drug interactions are drug interactions that occur between [[herbal medicines]] and conventional drugs.<ref name="bjcp2">{{cite journal|last1=Fugh-Berman|first1=Adriane|last2=Ernst|first2=E.|date=20 December 2001|title=Herb-drug interactions: Review and assessment of report reliability|journal=British Journal of Clinical Pharmacology|volume=52|issue=5|pages=587–595|doi=10.1046/j.0306-5251.2001.01469.x|pmc=2014604|pmid=11736868}}</ref> 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.<ref name="bjcp2" /> Some such interactions are [[clinically significant]],<ref name="drugs2">{{cite journal|last1=Hu|first1=Z|last2=Yang|first2=X|last3=Ho|first3=PC|last4=Chan|first4=SY|last5=Heng|first5=PW|last6=Chan|first6=E|last7=Duan|first7=W|last8=Koh|first8=HL|last9=Zhou|first9=S|date=2005|title=Herb-drug interactions: a literature review.|journal=Drugs|volume=65|issue=9|pages=1239–82|doi=10.2165/00003495-200565090-00005|pmid=15916450|s2cid=46963549}}</ref> although most herbal remedies are not associated with drug interactions causing serious consequences.<ref>{{cite journal|last1=Posadzki|first1=Paul|last2=Watson|first2=Leala|last3=Ernst|first3=Edzard|date=May 2012|title=Herb-drug interactions: an overview of systematic reviews|journal=British Journal of Clinical Pharmacology|volume=75|issue=3|pages=603–618|doi=10.1111/j.1365-2125.2012.04350.x|pmc=3575928|pmid=22670731}}</ref> Most herb-drug interactions are moderate in severity.<ref name="ijcp2">{{cite journal|last1=Tsai|first1=HH|last2=Lin|first2=HW|last3=Simon Pickard|first3=A|last4=Tsai|first4=HY|last5=Mahady|first5=GB|date=November 2012|title=Evaluation of documented drug interactions and contraindications associated with herbs and dietary supplements: a systematic literature review.|journal=International Journal of Clinical Practice|volume=66|issue=11|pages=1056–78|doi=10.1111/j.1742-1241.2012.03008.x|pmid=23067030|s2cid=11837548|doi-access=free}}</ref> The most commonly implicated conventional drugs in herb-drug interactions are [[warfarin]], [[insulin]], [[aspirin]], [[digoxin]], and [[ticlopidine]], due to their narrow [[Therapeutic index|therapeutic indices]].<ref name="ijcp2" /><ref>{{cite journal|last1=Na|first1=Dong Hee|last2=Ji|first2=Hye Young|last3=Park|first3=Eun Ji|last4=Kim|first4=Myung Sun|last5=Liu|first5=Kwang-Hyeon|last6=Lee|first6=Hye Suk|date=3 December 2011|title=Evaluation of metabolism-mediated herb-drug interactions|journal=Archives of Pharmacal Research|volume=34|issue=11|pages=1829–1842|doi=10.1007/s12272-011-1105-0|pmid=22139684|s2cid=38820964}}</ref> The most commonly implicated herbs involved in such interactions are those containing [[St. John’s Wort]], magnesium, calcium, iron, or ginkgo.<ref name="ijcp2" />
Herb-drug interactions are drug interactions that occur between [[herbal medicines]] and conventional drugs.<ref name="bjcp2">{{cite journal|last1=Fugh-Berman|first1=Adriane|last2=Ernst|first2=E.|date=20 December 2001|title=Herb-drug interactions: Review and assessment of report reliability|journal=British Journal of Clinical Pharmacology|volume=52|issue=5|pages=587–595|doi=10.1046/j.0306-5251.2001.01469.x|pmc=2014604|pmid=11736868}}</ref> 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.<ref name="bjcp2" /> Some such interactions are [[clinically significant]],<ref name="drugs2">{{cite journal|last1=Hu|first1=Z|last2=Yang|first2=X|last3=Ho|first3=PC|last4=Chan|first4=SY|last5=Heng|first5=PW|last6=Chan|first6=E|last7=Duan|first7=W|last8=Koh|first8=HL|last9=Zhou|first9=S|date=2005|title=Herb-drug interactions: a literature review.|journal=Drugs|volume=65|issue=9|pages=1239–82|doi=10.2165/00003495-200565090-00005|pmid=15916450|s2cid=46963549}}</ref> although most herbal remedies are not associated with drug interactions causing serious consequences.<ref>{{cite journal|last1=Posadzki|first1=Paul|last2=Watson|first2=Leala|last3=Ernst|first3=Edzard|date=May 2012|title=Herb-drug interactions: an overview of systematic reviews|journal=British Journal of Clinical Pharmacology|volume=75|issue=3|pages=603–618|doi=10.1111/j.1365-2125.2012.04350.x|pmc=3575928|pmid=22670731}}</ref> Most catalogued herb-drug interactions are moderate in severity.<ref name="ijcp2">{{cite journal|last1=Tsai|first1=HH|last2=Lin|first2=HW|last3=Simon Pickard|first3=A|last4=Tsai|first4=HY|last5=Mahady|first5=GB|date=November 2012|title=Evaluation of documented drug interactions and contraindications associated with herbs and dietary supplements: a systematic literature review.|journal=International Journal of Clinical Practice|volume=66|issue=11|pages=1056–78|doi=10.1111/j.1742-1241.2012.03008.x|pmid=23067030|s2cid=11837548|doi-access=free}}</ref> The most commonly implicated conventional drugs in herb-drug interactions are [[warfarin]], [[insulin]], [[aspirin]], [[digoxin]], and [[ticlopidine]], due to their narrow [[Therapeutic index|therapeutic indices]].<ref name="ijcp2" /><ref>{{cite journal|last1=Na|first1=Dong Hee|last2=Ji|first2=Hye Young|last3=Park|first3=Eun Ji|last4=Kim|first4=Myung Sun|last5=Liu|first5=Kwang-Hyeon|last6=Lee|first6=Hye Suk|date=3 December 2011|title=Evaluation of metabolism-mediated herb-drug interactions|journal=Archives of Pharmacal Research|volume=34|issue=11|pages=1829–1842|doi=10.1007/s12272-011-1105-0|pmid=22139684|s2cid=38820964}}</ref> The most commonly implicated herbs involved in such interactions are those containing [[St. John’s Wort]], magnesium, calcium, iron, or [[ginkgo]].<ref name="ijcp2" />


=== Examples ===
=== Examples ===
Line 268: Line 184:


== Underlying factors ==
== Underlying factors ==
The factors or conditions that predispose the appearance of interactions include factors such as [[old age]].<ref name="Baños">{{cite book |author=Baños Díez, J. E. |url=https://books.google.com/books?id=gsb6J2sYdisC |title=Farmacología ocular |author2=March Pujol, M |publisher=Edicions UPC |year=2002 |isbn=978-8483016473 |edition=2da |pages=87 |language=es |access-date=23 May 2009}}</ref> 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.<ref>{{cite journal |vauthors=Merle L, Laroche ML, Dantoine T, Charmes JP | year = 2005 | title = Predicting and Preventing Adverse Drug Reactions in the Very Old | journal = Drugs & Aging | volume = 22 | issue = 5| pages = 375–392 | doi=10.2165/00002512-200522050-00003| pmid = 15903351 | s2cid = 26672993 }}</ref> The elderly are also more vulnerable to [[polypharmacy]], and the more drugs a patient takes, the higher is the chance of an interaction.<ref name="Rocío">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: [http://www.fesemi.org/grupos/edad_avanzada/reuniones/ponencias_ii_pppea/view ponencias de la II Reunión de Paciente Pluripatológico y Edad Avanzada] {{webarchive|url=https://archive.today/20130414224619/http://www.fesemi.org/grupos/edad_avanzada/reuniones/ponencias_ii_pppea/view |date=2013-04-14 }}</ref>
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 the appearance of interactions include:<ref name="Baños" />

[[Genotype|Genetic factors]] may also affect the enzymes and receptors, thus altering the possibilities of interactions. {{Citation needed|date=November 2023}}

Patients with [[Hepatic disease|hepatic]] or [[renal disease|renal]] diseases already may have difficulties metabolizing and excreting drugs, which may exacerbate the effect of interactions.<ref name="Rocío" />

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 (pharmacology)|effective dose]] and the [[Lowest published toxic dose|toxic dose]] is small.<ref group="n.">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.</ref> The drug [[digoxin]] is an example of this type of drug.<ref name=":0">Castells Molina, S.; Castells, S. y Hernández Pérez, M. ''Farmacología en enfermería'' Published by Elsevier Spain, 2007 {{ISBN|84-8174-993-1}}, 9788481749939 Available from [https://books.google.com/books?id=FFBjWM-PKzkC]</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.<ref name=":0" />
* [[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.<ref>{{cite journal |vauthors=Merle L, Laroche ML, Dantoine T, Charmes JP | year = 2005 | title = Predicting and Preventing Adverse Drug Reactions in the Very Old | journal = Drugs & Aging | volume = 22 | issue = 5| pages = 375–392 | doi=10.2165/00002512-200522050-00003| pmid = 15903351 | s2cid = 26672993 }}</ref>
* [[Polypharmacy]]: The use of multiple drugs by a single patient, to treat one or more ailments. The more drugs a patient takes the more likely it will be that some of them will interact.<ref name="Rocío">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: [http://www.fesemi.org/grupos/edad_avanzada/reuniones/ponencias_ii_pppea/view ponencias de la II Reunión de Paciente Pluripatológico y Edad Avanzada] {{webarchive|url=https://archive.today/20130414224619/http://www.fesemi.org/grupos/edad_avanzada/reuniones/ponencias_ii_pppea/view |date=2013-04-14 }}</ref>
* [[Genotype|Genetic factors]]: Genes synthesize [[enzyme]]s 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 [[isozyme]]s of [[cytochrome P450]].
* [[Hepatic disease|Hepatic]] or [[renal disease|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.<ref name="Rocío" />
* Serious [[disease]]s that could worsen if the dose of the medicine is reduced.
* Drug dependent factors:<ref>Castells Molina, S.; Castells, S. y Hernández Pérez, M. ''Farmacología en enfermería'' Published by Elsevier Spain, 2007 {{ISBN|84-8174-993-1}}, 9788481749939 Available from [https://books.google.com/books?id=FFBjWM-PKzkC]</ref>
** Narrow [[therapeutic index]]: Where the difference between the [[Effective dose (pharmacology)|effective dose]] and the [[Lowest published toxic dose|toxic dose]] is small.<ref group=n.>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.</ref> The drug [[digoxin]] is an example of this type of drug.
** Steep [[Dose-response relationship|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


==Epidemiology==
==Epidemiology==
As of 2008, among US adults older than 56, 4% were taking medication and or supplements that put them at risk of a major drug interaction.<ref>{{cite journal | vauthors = Qato DM, Alexander GC, Conti RM, Johnson M, Schumm P, Lindau ST | title = Use of prescription and over-the-counter medications and dietary supplements among older adults in the United States | journal = JAMA | volume = 300 | issue = 24 | pages = 2867–78 | date = December 2008 | pmid = 19109115 | pmc = 2702513 | doi = 10.1001/jama.2008.892 }}</ref> Potential drug-drug interactions have increased over time<ref name="pmid18184532">{{cite journal | vauthors = Haider SI, Johnell K, Thorslund M, Fastbom J | title = Trends in polypharmacy and potential drug-drug interactions across educational groups in elderly patients in Sweden for the period 1992 - 2002 | journal = International Journal of Clinical Pharmacology and Therapeutics | volume = 45 | issue = 12 | pages = 643–53 | date = December 2007 | pmid = 18184532 | doi = 10.5414/cpp45643 }}</ref> and are more common in the less-educated elderly even after controlling for age, sex, place of residence, and comorbidity.<ref name="pmid19054196">{{cite journal | vauthors = Haider SI, Johnell K, Weitoft GR, Thorslund M, Fastbom J | title = The influence of educational level on polypharmacy and inappropriate drug use: a register-based study of more than 600,000 older people | journal = Journal of the American Geriatrics Society | volume = 57 | issue = 1 | pages = 62–9 | date = January 2009 | pmid = 19054196 | doi = 10.1111/j.1532-5415.2008.02040.x | s2cid = 205703844 }}</ref>
As of 2008, among adults in the [[United States of America]] older than 56, 4% were taking medication and/ or supplements that put them at risk of a major drug interaction.<ref>{{cite journal | vauthors = Qato DM, Alexander GC, Conti RM, Johnson M, Schumm P, Lindau ST | title = Use of prescription and over-the-counter medications and dietary supplements among older adults in the United States | journal = JAMA | volume = 300 | issue = 24 | pages = 2867–78 | date = December 2008 | pmid = 19109115 | pmc = 2702513 | doi = 10.1001/jama.2008.892 }}</ref> Potential drug-drug interactions have increased over time<ref name="pmid18184532">{{cite journal | vauthors = Haider SI, Johnell K, Thorslund M, Fastbom J | title = Trends in polypharmacy and potential drug-drug interactions across educational groups in elderly patients in Sweden for the period 1992 - 2002 | journal = International Journal of Clinical Pharmacology and Therapeutics | volume = 45 | issue = 12 | pages = 643–53 | date = December 2007 | pmid = 18184532 | doi = 10.5414/cpp45643 }}</ref> and are more common in the less-educated [[elderly]] even after controlling for age, sex, place of residence, and [[comorbidity]].<ref name="pmid19054196">{{cite journal | vauthors = Haider SI, Johnell K, Weitoft GR, Thorslund M, Fastbom J | title = The influence of educational level on polypharmacy and inappropriate drug use: a register-based study of more than 600,000 older people | journal = Journal of the American Geriatrics Society | volume = 57 | issue = 1 | pages = 62–9 | date = January 2009 | pmid = 19054196 | doi = 10.1111/j.1532-5415.2008.02040.x | s2cid = 205703844 }}</ref>


== See also ==
== See also ==
Line 287: Line 201:
* [[Cytochrome P450]]
* [[Cytochrome P450]]
* [[Classification of Pharmaco-Therapeutic Referrals]]
* [[Classification of Pharmaco-Therapeutic Referrals]]
* Drug interactions can be checked for free online with interaction checkers (note that not all drug interaction checkers provide the same results, and only a drug information expert, such as a [[pharmacist]], should interpret results or provide advice on managing drug interactions)
** Multi-Drug Interaction Checker by Medscape [http://reference.medscape.com/drug-interactionchecker]
** Drug Interactions Checker by Drugs.com [https://www.drugs.com/drug_interactions.html]


== Notes ==
== Notes ==

Latest revision as of 18:21, 3 September 2024

Grapefruit juice can act as an enzyme inhibitor, affecting the metabolism of drugs.

In pharmaceutical sciences, drug interactions occur when a drug's mechanism of action 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 GABAA 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.[1]

A large share of elderly 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:

  • additive (the result is what you expect when you add together the effect of each drug taken independently),
  • synergistic (combining the drugs leads to a larger effect than expected), or
  • antagonistic (combining the drugs leads to a smaller effect than expected).[3]

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 of thiopentone.[4]

Interactions based on pharmacodynamics

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

Effects of the competitive inhibition of an agonist by increases in the concentration of an antagonist. A drug's potency can be affected (the response curve shifted to the right) by the presence of an antagonistic interaction.

Pharmacodynamic interactions can occur on protein receptors.[5] 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) 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 considered heterodynamic competitors, if they act on distinct receptor with similar downstream pathways.

The interaction my also occur via signal transduction mechanisms.[6] For example, low blood glucose leads to a release of catecholamines, triggering symptoms that hint the organism to take action, like consuming sugary foods. If a patient is on insulin, which reduces blood sugar, and also beta-blockers, the body is less able to cope with an insulin overdose.

Interactions based on pharmacokinetics

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Pharmacokinetics is the field of research studying the chemical and biochemical factors that directly affect dosage and the 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, increasing or reducing drug availability.

Based on absorption

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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. [citation needed]

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.[7] Medication like antacids 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.[8]

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 anticoagulants and avocado.[citation needed] The formation of non-absorbable complexes may occur also via chelation, when cations can make certain drugs harder to absorb, for example between tetracycline or the fluoroquinolones and dairy products, due to the presence of calcium ions.[citation needed] . 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.[9]

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.[10]

Based on transport and distribution

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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.[11]

Based on metabolism

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Diagram of cytochrome P450 isoenzyme 2C9 with the haem group in the centre of the enzyme.

Many drug interactions are due to alterations in drug metabolism.[12] Further, human drug-metabolizing enzymes are typically activated through the engagement of nuclear receptors.[12] One notable system involved in metabolic drug interactions is the enzyme system comprising the cytochrome P450 oxidases.

CYP450

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Cytochrome P450 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.[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 are CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4.[14] The majority of the enzymes are also involved in the metabolism of endogenous substances, such as steroids 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

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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.

Examples of metabolism-based interactions

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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:[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
Soya Enzymatic inhibition Clozapine, haloperidol, olanzapine, caffeine, NSAIDs, phenytoin, zafirlukast, warfarin
Garlic Increases antiplatelet activity
Ginseng To be determined 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

Based on excretion

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Renal and biliary excretion

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Drugs tightly bound to proteins (i.e. not in the free fraction) are not available for renal excretion.[17] Filtration depends on a number of factors including the pH of the urine. Drug interactions may affect those points. [citation needed]

With herbal medicines

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Herb-drug interactions are drug interactions that occur between herbal 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 are clinically 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 are warfarin, insulin, aspirin, digoxin, and ticlopidine, due to their narrow therapeutic indices.[21][22] The most commonly implicated herbs involved in such interactions are those containing St. John’s Wort, magnesium, calcium, iron, or ginkgo.[21]

Examples

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Examples of herb-drug interactions include, but are not limited to:

Mechanisms

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The mechanisms underlying most herb-drug interactions are not fully understood.[25] Interactions between herbal medicines and anticancer drugs typically involve enzymes that metabolize cytochrome P450.[23] For example, St. John's Wort has been shown to induce CYP3A4 and P-glycoprotein in vitro and in vivo.[23]

Underlying factors

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The factors or conditions that predispose the appearance of interactions include factors such as old 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 to polypharmacy, 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 with hepatic or renal 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 narrow therapeutic index, where the difference between the effective dose and the toxic dose is small.[n. 1] The drug digoxin is an example of this type of drug.[29]

Risks are also increased when the drug presents a steep dose-response curve, and small changes in the dosage produce large changes in the drug's concentration in the blood plasma.[29]

Epidemiology

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As of 2008, among adults in the United 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-educated elderly even after controlling for age, sex, place of residence, and comorbidity.[32]

See also

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Notes

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  1. ^ 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.

References

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  1. ^ Tannenbaum C, Sheehan NL (July 2014). "Understanding and preventing drug–drug and drug–gene interactions". Expert Review of Clinical Pharmacology. 7 (4): 533–44. doi:10.1586/17512433.2014.910111. PMC 4894065. PMID 24745854.
  2. ^ Qato DM, Wilder J, Schumm LP, Gillet V, Alexander GC (April 2016). "Changes in Prescription and Over-the-Counter Medication and Dietary Supplement Use Among Older Adults in the United States, 2005 vs 2011". JAMA Internal Medicine. 176 (4): 473–82. doi:10.1001/jamainternmed.2015.8581. PMC 5024734. PMID 26998708.
  3. ^ Greco, W. R.; Bravo, G.; Parsons, J. C. (1995). "The search for synergy: a critical review from a response surface perspective". Pharmacological Reviews. 47 (2): 331–385. ISSN 0031-6997. PMID 7568331.
  4. ^ Khan, Shahab; Stannard, Naina; Greijn, Jeff (2011-07-12). "Precipitation of thiopental with muscle relaxants: a potential hazard". JRSM Short Reports. 2 (7): 58. doi:10.1258/shorts.2011.011031. ISSN 2042-5333. PMC 3147238. PMID 21847440.
  5. ^ S Gonzalez. "Interacciones Farmacológicas" (in Spanish). Archived from the original on 2009-01-22. Retrieved 1 January 2009.
  6. ^ Curso de Farmacología Clínica Aplicada, in El Médico Interactivo Archived 2009-08-31 at the Wayback Machine
  7. ^ Malgor — Valsecia, Farmacología general: Farmacocinética.Cap. 2. en "Archived copy" (PDF). Archived from the original (PDF) on 2012-09-07. Retrieved 2012-03-20.{{cite web}}: CS1 maint: archived copy as title (link) Revised 25 September 2008
  8. ^ Alicia Gutierrez Valanvia y Luis F. López-Cortés Interacciones farmacológicas entre fármacos antirretrovirales y fármacos usados para ciertos transtornos gastrointestinales. on [1] accessed 24 September 2008
  9. ^ a b Marduga Sanz, Mariano. Interacciones de los alimentos con los medicamentos. on [2] Archived 2014-07-07 at the Wayback Machine
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  11. ^ Valsecia, Mabel en
  12. ^ a b Elizabeth Lipp (2008-06-15). "Tackling Drug-Interaction Issues Early On". Genetic Engineering & Biotechnology News. Mary Ann Liebert, Inc. pp. 14, 16, 18, 20. Retrieved 2008-07-06. (subtitle) Researchers explore a number of strategies to better predict drug responses in the clinic
  13. ^ IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version: (2006–) "cytochrome P450". doi:10.1351/goldbook.CT06821 Danielson PB (December 2002). "The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans". Current Drug Metabolism. 3 (6): 561–97. doi:10.2174/1389200023337054. PMID 12369887.
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    Comment in: Mouly S, Paine MF (August 2001). "Effect of grapefruit juice on the disposition of omeprazole". British Journal of Clinical Pharmacology. 52 (2): 216–7. doi:10.1111/j.1365-2125.1978.00999.pp.x. PMC 2014525. PMID 11488783.[permanent dead link]
  16. ^ Covarrubias-Gómez, A.; et al. (January–March 2005). "¿Qué se auto-administra su paciente?: Interacciones farmacológicas de la medicina herbal". Revista Mexicana de Anestesiología. 28 (1): 32–42. Archived from the original on 2012-06-29.
  17. ^ Gago Bádenas, F. Curso de Farmacología General. Tema 6.- Excreción de los fármacos. en [3] Archived 2011-09-16 at the Wayback Machine
  18. ^ a b c Fugh-Berman, Adriane; Ernst, E. (20 December 2001). "Herb-drug interactions: Review and assessment of report reliability". British Journal of Clinical Pharmacology. 52 (5): 587–595. doi:10.1046/j.0306-5251.2001.01469.x. PMC 2014604. PMID 11736868.
  19. ^ a b c d Hu, Z; Yang, X; Ho, PC; Chan, SY; Heng, PW; Chan, E; Duan, W; Koh, HL; Zhou, S (2005). "Herb-drug interactions: a literature review". Drugs. 65 (9): 1239–82. doi:10.2165/00003495-200565090-00005. PMID 15916450. S2CID 46963549.
  20. ^ Posadzki, Paul; Watson, Leala; Ernst, Edzard (May 2012). "Herb-drug interactions: an overview of systematic reviews". British Journal of Clinical Pharmacology. 75 (3): 603–618. doi:10.1111/j.1365-2125.2012.04350.x. PMC 3575928. PMID 22670731.
  21. ^ a b c Tsai, HH; Lin, HW; Simon Pickard, A; Tsai, HY; Mahady, GB (November 2012). "Evaluation of documented drug interactions and contraindications associated with herbs and dietary supplements: a systematic literature review". International Journal of Clinical Practice. 66 (11): 1056–78. doi:10.1111/j.1742-1241.2012.03008.x. PMID 23067030. S2CID 11837548.
  22. ^ Na, Dong Hee; Ji, Hye Young; Park, Eun Ji; Kim, Myung Sun; Liu, Kwang-Hyeon; Lee, Hye Suk (3 December 2011). "Evaluation of metabolism-mediated herb-drug interactions". Archives of Pharmacal Research. 34 (11): 1829–1842. doi:10.1007/s12272-011-1105-0. PMID 22139684. S2CID 38820964.
  23. ^ a b c Meijerman, I.; Beijnen, J. H.; Schellens, J. H.M. (1 July 2006). "Herb-Drug Interactions in Oncology: Focus on Mechanisms of Induction". The Oncologist. 11 (7): 742–752. doi:10.1634/theoncologist.11-7-742. PMID 16880233.
  24. ^ Ulbricht, C.; Chao, W.; Costa, D.; Rusie-Seamon, E.; Weissner, W.; Woods, J. (1 December 2008). "Clinical Evidence of Herb-Drug Interactions: A Systematic Review by the Natural Standard Research Collaboration". Current Drug Metabolism. 9 (10): 1063–1120. doi:10.2174/138920008786927785. PMID 19075623.
  25. ^ Chen, XW; Sneed, KB; Pan, SY; Cao, C; Kanwar, JR; Chew, H; Zhou, SF (1 June 2012). "Herb-drug interactions and mechanistic and clinical considerations". Current Drug Metabolism. 13 (5): 640–51. doi:10.2174/1389200211209050640. PMID 22292789.
  26. ^ Baños Díez, J. E.; March Pujol, M (2002). Farmacología ocular (in Spanish) (2da ed.). Edicions UPC. p. 87. ISBN 978-8483016473. Retrieved 23 May 2009.
  27. ^ Merle L, Laroche ML, Dantoine T, Charmes JP (2005). "Predicting and Preventing Adverse Drug Reactions in the Very Old". Drugs & Aging. 22 (5): 375–392. doi:10.2165/00002512-200522050-00003. PMID 15903351. S2CID 26672993.
  28. ^ a b 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 Archived 2013-04-14 at archive.today
  29. ^ a b Castells Molina, S.; Castells, S. y Hernández Pérez, M. Farmacología en enfermería Published by Elsevier Spain, 2007 ISBN 84-8174-993-1, 9788481749939 Available from [4]
  30. ^ Qato DM, Alexander GC, Conti RM, Johnson M, Schumm P, Lindau ST (December 2008). "Use of prescription and over-the-counter medications and dietary supplements among older adults in the United States". JAMA. 300 (24): 2867–78. doi:10.1001/jama.2008.892. PMC 2702513. PMID 19109115.
  31. ^ Haider SI, Johnell K, Thorslund M, Fastbom J (December 2007). "Trends in polypharmacy and potential drug-drug interactions across educational groups in elderly patients in Sweden for the period 1992 - 2002". International Journal of Clinical Pharmacology and Therapeutics. 45 (12): 643–53. doi:10.5414/cpp45643. PMID 18184532.
  32. ^ Haider SI, Johnell K, Weitoft GR, Thorslund M, Fastbom J (January 2009). "The influence of educational level on polypharmacy and inappropriate drug use: a register-based study of more than 600,000 older people". Journal of the American Geriatrics Society. 57 (1): 62–9. doi:10.1111/j.1532-5415.2008.02040.x. PMID 19054196. S2CID 205703844.

Bibliography

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  • 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.
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