Editing Drug interaction

{{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]]. 

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> 

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>

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), 
* [[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. 

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>

== Interactions based on pharmacodynamics ==

[[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]].

[[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.]]
Pharmacodynamic interactions can occur on protein [[Receptor (biochemistry)|receptors]].<ref>{{cite web
 |url          = http://canal-h.net/webs/sgonzalez002/Farmaco/INTERACCIONES.htm
 |title        = Interacciones Farmacológicas
 |access-date  = 1 January 2009
 |author       = S Gonzalez
 |language     = es
 |archive-url  = https://web.archive.org/web/20090122214121/http://canal-h.net/webs/sgonzalez002/Farmaco/INTERACCIONES.htm
 |archive-date = 2009-01-22
 |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]].

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.

== 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. 

=== 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>

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>

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>

=== Based on transport and distribution===
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 ===
[[File:CYP2C9 1OG2.png|thumb|200px|Diagram of cytochrome P450 [[CYP2C9|isoenzyme 2C9]] with the [[heme|haem]] group in the centre of the enzyme.]]

Many drug interactions are due to alterations in [[drug metabolism]].<ref name=GENENG15June2008>{{cite news | author=Elizabeth Lipp
 | title=Tackling Drug-Interaction Issues Early On | url=http://www.genengnews.com/articles/chitem.aspx?aid=2509
 | work=[[Genetic Engineering & Biotechnology News]] | publisher=[[Mary Ann Liebert, Inc.]] | pages=14, 16, 18, 20
 | date=2008-06-15 | access-date=2008-07-06
 | quote=(subtitle) Researchers explore a number of strategies to better predict drug responses in the clinic }}</ref> Further, human drug-metabolizing enzymes are typically activated through the engagement of [[nuclear receptor]]s.<ref name=GENENG15June2008/> One notable system involved in metabolic drug interactions is the enzyme system comprising the [[cytochrome P450 oxidase]]s.

==== CYP450 ====
[[Cytochrome P450]] is a very large family of [[hemeprotein|haemoprotein]]s (hemoproteins) that are characterized by their [[enzyme|enzymatic]] activity and their role in the metabolism of a large number of drugs.<ref>{{GoldBookRef|title=cytochrome P450|file=CT06821}} {{cite journal | vauthors = Danielson PB | title = The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans | journal = Current Drug Metabolism | volume = 3 | issue = 6 | pages = 561–97 | date = December 2002 | pmid = 12369887 | doi = 10.2174/1389200023337054 }}</ref> 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]].<ref name="Nelson">Nelson D (2003). [http://drnelson.utmem.edu/P450lect.html Cytochrome P450s in humans] {{webarchive |url=https://web.archive.org/web/20090710050953/http://drnelson.utmem.edu/P450lect.html |date=July 10, 2009 }}. Consulted 9 May 2005.</ref>
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 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.{{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}}

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:<ref name="Nelson" />

{| class="wikitable" style="margin:1em auto;" width="100%"
|-
| colspan="3" style="text-align:center;" | '''Drugs related to CYP1A2'''
|-
! Substrates !! Inhibitors !! Inductors
|- style="vertical-align: top;"
|
* [[Caffeine]]
* [[Theophylline]]
* [[Phenacetin]]
* [[Clomipramine]]
* [[Clozapine]]
* [[Thioridazine]]
||
* [[Omeprazole]]
* [[Nicotine]]
* [[Cimetidine]]
* [[Ciprofloxacin]]
||
* [[Phenobarbital]]
* [[Fluvoxamine]]
* [[Venlafaxine]]
* [[Ticlopidine]]
|}

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%
|-
|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><ref name="Marduga" /><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
|-
|
* [[Avocado]]
* [[Brassicaceae|Brassica]]s (Brussels sprouts, broccoli, cabbage)
|Enzymatic inductor
|[[Acenocoumarol]], [[warfarin]]
|-
|[[Grapefruit]] juice
|Enzymatic inhibition
|
* [[Calcium channel blocker]]s: [[nifedipine]], [[felodipine]], [[nimodipine]], [[amlodipine]]
* [[Cyclosporine]], [[tacrolimus]]
* [[Terfenadine]], [[astemizole]]
* [[Cisapride]], [[pimozide]]
* [[Carbamazepine]], [[saquinavir]], [[midazolam]], [[alprazolam]], [[triazolam]]
{{main|Grapefruit drug interactions}}
|-
|[[Soybean|Soya]]
|Enzymatic inhibition
|[[Clozapine]], [[haloperidol]], [[olanzapine]], [[caffeine]], [[Non-steroidal anti-inflammatory drug|NSAIDs]], [[phenytoin]], [[zafirlukast]], [[warfarin]]
|-
|[[Garlic]]
|Increases antiplatelet activity
|
* [[Anticoagulant]]s
* [[Non-steroidal anti-inflammatory drug|NSAIDs]], [[acetylsalicylic acid]]
|-
|[[Ginseng]]
|To be determined
|[[Warfarin]], [[heparin]], [[aspirin]] and [[Non-steroidal anti-inflammatory drug|NSAIDs]]
|-
|''[[Ginkgo biloba]]''
|Strong inhibitor of platelet aggregation factor
|[[Warfarin]], [[aspirin]] and [[Non-steroidal anti-inflammatory drug|NSAIDs]]
|-
|''[[Hypericum perforatum]]'' (St John's wort)
|Enzymatic inductor (CYP450)
|Warfarin, [[digoxin]], [[theophylline]], cyclosporine, [[phenytoin]] and antiretrovirals
|-
|[[Ephedra (medicine)|Ephedra]]
|Receptor level agonist
|[[MAOI]], central nervous system stimulants, alkaloids [[ergotamine]]s and [[xanthine]]s
|-
|Kava (''Piper methysticum'')
|Unknown
|[[Levodopa]]
|-
|[[Ginger]]
|Inhibits thromboxane synthetase (''in vitro'')
|Anticoagulants
|-
|Chamomile
|Unknown
|[[Benzodiazepine]]s, [[barbiturate]]s and [[opioid]]s
|-
|[[Crataegus|Hawthorn]]
|Unknown
|Beta-adrenergic antagonists, [[cisapride]], digoxin, [[quinidine]]
|}

=== 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]].<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>
Filtration depends on a number of factors including the [[pH]] of the urine. Drug interactions may affect those points. {{Citation needed|date=November 2023}}

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

* St. John's wort affects the clearance of numerous drugs, including [[cyclosporin]], [[SSRI]] antidepressants, [[digoxin]], [[indinavir]], and [[phenprocoumon]].<ref name="bjcp2" /> It may also interact with the anti-cancer drugs [[irinotecan]] and [[imatinib]].<ref name="oncologist2">{{cite journal|last1=Meijerman|first1=I.|last2=Beijnen|first2=J. H.|last3=Schellens|first3=J. H.M.|date=1 July 2006|title=Herb-Drug Interactions in Oncology: Focus on Mechanisms of Induction|journal=The Oncologist|volume=11|issue=7|pages=742–752|doi=10.1634/theoncologist.11-7-742|pmid=16880233}}</ref>
* [[Salvia miltiorrhiza]] may enhance anticoagulation and bleeding among people taking warfarin.<ref name="drugs2" />
* [[Allium sativum]] has been found to decrease the plasma concentration of [[saquinavir]], and may cause [[hypoglycemia]] when taken with [[chlorpropamide]].<ref name="drugs2" />
* [[Ginkgo biloba]] can cause bleeding when combined with warfarin or [[aspirin]].<ref name="drugs2" />
* Concomitant [[Ephedra (medicine)|Ephedra]] and [[caffeine]] use has been reported to, in rare cases, cause fatalities.<ref>{{cite journal|last1=Ulbricht|first1=C.|last2=Chao|first2=W.|last3=Costa|first3=D.|last4=Rusie-Seamon|first4=E.|last5=Weissner|first5=W.|last6=Woods|first6=J.|date=1 December 2008|title=Clinical Evidence of Herb-Drug Interactions: A Systematic Review by the Natural Standard Research Collaboration|journal=Current Drug Metabolism|volume=9|issue=10|pages=1063–1120|doi=10.2174/138920008786927785|pmid=19075623}}</ref>

=== Mechanisms ===
The mechanisms underlying most herb-drug interactions are not fully understood.<ref>{{cite journal|last1=Chen|first1=XW|last2=Sneed|first2=KB|last3=Pan|first3=SY|last4=Cao|first4=C|last5=Kanwar|first5=JR|last6=Chew|first6=H|last7=Zhou|first7=SF|date=1 June 2012|title=Herb-drug interactions and mechanistic and clinical considerations.|journal=Current Drug Metabolism|volume=13|issue=5|pages=640–51|doi=10.2174/1389200211209050640|pmid=22292789}}</ref> Interactions between herbal medicines and anticancer drugs typically involve enzymes that metabolize [[cytochrome P450]].<ref name="oncologist2" /> For example, St. John's Wort has been shown to induce [[CYP3A4]] and [[P-glycoprotein]] in vitro and in vivo.<ref name="oncologist2" />

== 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>

[[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" />

==Epidemiology==
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 ==
* [[Deprescribing]]
* [[Cytochrome P450]]
* [[Classification of Pharmaco-Therapeutic Referrals]]

== Notes ==
{{reflist|group=n.}}

== References ==
{{Reflist|33em}}

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

== External links ==
* [https://web.archive.org/web/20090624065553/http://www.fda.gov/Drugs/ResourcesForYou/ucm163354.htm Drug Interactions: What You Should Know]. U.S. Food and Drug Administration, Center for Drug Evaluation and Research, September 2013
*[https://covid19-druginteractions.org/checker COVID 19 Drug interaction check tool] University of Liverpool

{{Combined substance use and adulteration}}
{{Authority control}}

[[Category:Clinical pharmacology]]
[[Category:Pharmacokinetics]]
[[Category:Prescription of drugs]]
[[Category:Drug safety]]