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 drug 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 Drug receptors, directly or indirectly. For example, both Zolpidem and alcohol affect GABAA receptor, and their simultaneous consumption results in the overstimulation of the receptor, which can lead to loss of consciousness. When two drugs affect each other, it is a drug–drug interaction (DDI). The risk of a DDI increases with the number of drugs used.
A large share of Old age people regularly use five or more medications or supplements, with a significant risk of side-effects from drug–drug interactions.
Drug interactions can be of three kinds:
-
additive (the result is what you expect when you add together the effect of each drug taken independently),
-
synergistic (combining the drugs leads to a larger effect than expected), or
-
antagonistic (combining the drugs leads to a smaller effect than expected).
It may be difficult to distinguish between synergistic or additive interactions, as individual effects of drugs may vary.
Direct interactions between drugs are also possible and may occur when two drugs are mixed before intravenous injection. For example, mixing thiopentone and suxamethonium can lead to the precipitation of thiopentone.
Interactions based on pharmacodynamics
Pharmacodynamic interactions are the drug–drug interactions that occur at a
Biochemistry 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.
Pharmacodynamic interactions can occur on protein receptors.
The interaction my also occur via signal transduction mechanisms.[ Curso de Farmacología Clínica Aplicada, in El Médico Interactivo ] For example, Hypoglycemia leads to a release of , triggering 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, 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 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 increase the intestinal motility, which may cause drugs to go through the digestive system too fast, reducing absorption.
The pharmacological modification of pH can affect other compounds. Drugs can be present in ionized or non-ionized forms depending on pKa, and neutral compounds are usually better absorbed by membranes.[Malgor — Valsecia, Farmacología general: Farmacocinética.Cap. 2. en Revised 25 September 2008] Medication like 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.[Alicia Gutierrez Valanvia y Luis F. López-Cortés Interacciones farmacológicas entre fármacos antirretrovirales y fármacos usados para ciertos transtornos gastrointestinales. on [2] accessed 24 September 2008]
Factors such as food with Fat may also alter the solubility of drugs and impact its absorption. This is the case for oral and avocado. The formation of non-absorbable complexes may occur also via chelation, when Ion can make certain drugs harder to absorb, for example between tetracycline or the fluoroquinolones and dairy products, due to the presence of calcium ions. . Other drugs bind to proteins. Some drugs such as sucralfate bind to proteins, especially if they have a high bioavailability. For this reason its administration is contraindicated in Feeding tube.[Marduga Sanz, Mariano. Interacciones de los alimentos con los medicamentos. on [3] ]
Some drugs also alter absorption by acting on the P-glycoprotein of the . 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.[Tatro, DS. Update: Drug interaction with grapefruit juice. Druglink, 2004. 8 (5), page 35ss]
Based on transport and distribution
Drugs also may affect each other by competing for transport proteins in
Blood 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.
[ Valsecia, Mabel en]
Based on metabolism
Many drug interactions are due to alterations in
drug metabolism.
Further, human drug-metabolizing enzymes are typically activated through the engagement of
.
[ One notable system involved in metabolic drug interactions is the enzyme system comprising the cytochrome P450 oxidases.
]
CYP450
Cytochrome P450 is a very large family of hemeprotein (hemoproteins) that are characterized by their enzyme activity and their role in the metabolism of a large number of drugs.[ ] Of the various families that are present in humans, the most interesting in this respect are the 1, 2 and 3, and the most important enzymes are CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4.[Nelson D (2003). Cytochrome P450s in humans . Consulted 9 May 2005.]
The majority of the enzymes are also involved in the metabolism of endogenous substances, such as or sex hormones, which is also important should there be interference with these substances. The function of the enzymes can either be stimulated (enzyme induction) or inhibited (enzyme inhibition).
Through enzymatic inhibition and induction
If a drug is metabolized by a CYP450 enzyme and drug B blocks the activity of these enzymes, it can lead to pharmacokinetic alterations. A. This alteration results in drug A remaining in the bloodstream for an extended duration, and eventually increase in concentration.
In some instances, the inhibition may reduce the therapeutic effect, if instead the metabolites of the drug is responsible for the effect.
Compounds that increase the efficiency of the enzymes, on the other hand, may have the opposite effect and increase the rate of metabolism.
Examples of metabolism-based interactions
An example of this is shown in the following table for the CYP1A2 enzyme, showing the substrates (drugs metabolized by this enzyme) and some inductors and inhibitors of its activity:
|
| Drugs related to CYP1A2 |
|
| | | | | |
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
Comment in: |
|
| Enzymatic inductor
| Acenocoumarol, warfarin |
| Grapefruit juice | Enzymatic inhibition |
-
Calcium channel blockers: nifedipine, felodipine, nimodipine, amlodipine
-
Cyclosporine, tacrolimus
-
Terfenadine, astemizole
-
Cisapride, pimozide
-
Carbamazepine, saquinavir, midazolam, alprazolam, triazolam
|
| Soybean | Enzymatic inhibition | Clozapine, haloperidol, olanzapine, caffeine, NSAIDs, phenytoin, zafirlukast, warfarin |
| Garlic | Increases antiplatelet activity |
-
-
NSAIDs, acetylsalicylic acid
|
| 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 and |
| Kava ( Piper methysticum) | Unknown | Levodopa |
| Ginger | Inhibits thromboxane synthetase ( in vitro) | Anticoagulants |
| Chamomile | Unknown | , and |
| Crataegus | 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.[Gago Bádenas, F. Curso de Farmacología General. Tema 6.- Excreción de los fármacos. en [6] ]
Filtration depends on a number of factors including the pH of the urine. Drug interactions may affect those points.
With herbal medicines
Herb-drug interactions are drug interactions that occur between herbal medicines and conventional drugs.
Examples
Examples of herb-drug interactions include, but are not limited to:
Mechanisms
The mechanisms underlying most herb-drug interactions are not fully understood.
Underlying factors
The factors or conditions that predispose the appearance of interactions include factors such as old age.[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 ]
Genotype may also affect the enzymes and receptors, thus altering the possibilities of interactions.
Patients with Hepatic disease or renal disease diseases already may have difficulties metabolizing and excreting drugs, which may exacerbate the effect of interactions.
Some drugs present an intrinsic increased risk for a harmful interaction, including drugs with a narrow therapeutic index, where the difference between the effective dose and the toxic dose is small.[The term effective dose is generally understood to mean the minimum amount of a drug that is needed to produce the required effect. The toxic dose is the minimum amount of a drug that will produce a damaging effect.] The drug digoxin is an example of this type of drug.[Castells Molina, S.; Castells, S. y Hernández Pérez, M. Farmacología en enfermería Published by Elsevier Spain, 2007 , 9788481749939 Available from [8]]
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.
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.
See also
-
Deprescribing
-
Cytochrome P450
-
Classification of Pharmaco-Therapeutic Referrals
Notes
Bibliography
-
MA Cos. Interacciones de fármacos y sus implicancias clínicas. In: Farmacología Humana. Chap. 10, pp. 165–176. (J. Flórez y col. Eds). Masson SA, Barcelona. 1997.
External links
