The CAST investigators. Preliminary report. Effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med ; Events in the cardiac arrhythmia suppression trial CAST : mortality in the entire population enrolled. J Am Coll Cardiol ;
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Pablo de Olavide University. These interactions can affect the antiarrhythmic drugs, altering their therapeutic efficacy and adverse effects. The aim of this study was to conduct a review of available data about interactions between antiarrhythmic drugs and food. Methods: The purpose of this review was to report an update of the existing literature data on the main findings with respect to food and antiarrhythmic drugs interactions by means of a search conducted in PubMed, which yielded a total of articles initially.
Results: After excluding different articles which were not focusing on the specific objective, the main results refer to interactions among antiarrhythmic drugs and food in general, grapefruit juice, and others like fibre or medicinal plants. Discussion: Food may affect the bioavailability of antiarrhythmic drugs and in some specific cases dairy products, rich-in-protein diets, grapefruit juice , this should be carefully considered.
The best recommendation seems to advise patients to remove the grapefruit juice from their diet when treatment with these drugs. Fibre should be separated from taking these drugs and regarding medicinal plants and given their increased use, the anamnesis must include information about its use, the reason for that use and what types of plants are used, all in order to give the corresponding recommendations.
Key words: Antiarrhythmic drugs. Food-drugs interactions. Grapefruit juice. Medicinal plants. Interacciones entre alimentos y medicamentos. Zumo de pomelo. Plantas medicinales. Cardiac arrhythmias are one of the leading causes of morbidity and mortality in developed countries with a constant presence in medical practices, often urgently and associated with cases of sudden death. Typically, however, is that patients consult by symptoms resulting from arrhythmia and required therapeutic interventions.
Antiarrhythmic drugs AD are substances capable of interrupting an arrhythmia, preventing its recurrence or mitigating its clinical consequences, through its effects on automaticity and conduction in cardiac tissues. This modifying ability makes AD have a therapeutic window to be considered in order to prevent that AD become producers of arrhythmias. The margin between therapeutic and toxic threshold of the AD is quite narrow, which can lead to serious complications in drug concentrations that only slightly exceed the necessary amount to produce therapeutic effects.
Therefore a proper dosage and the knowledge of its pharmacokinetic characteristics are very important. In relation to the bioavailability of the AD it is necessary to emphasize the importance of cytochrome P CYP , a family of enzymes located in the liver and gastrointestinal tract, which represents the major source of metabolic activity for the phase I reactions. CYP enzyme activity has a Gaussian distribution in the population, with a majority of individuals with intermediate activity and a minority with very low or very high activities.
Besides CYP, P-glycoprotein P-gp , a family of membrane transporters, which is located in the brush border of the enterocytes membrane, should be noted, due to its metabolic importance. In addition to mobilizing endogenous substances, the P-gp mobilizes certain drugs including some AD.
The aim of this study was to conduct a review of available data about interactions between AD and food. The review was conducted through a PubMed search. The initial search term was "Interactions between antiarrhythmic drugs and food," which resulted in a total of articles. Later, a specific search was performed, by entering "Interactions between Thus six additional articles were obtained that were not among those found with the initial search.
As a result, we obtained a total of articles, excluding those that do not make specific reference to the object of the review. Articles without an abstract were also excluded. With respect to case reports and letters, because of the scarcity of articles focusing specifically on a subject, some of them were considered. Among the documented food-AD interactions associated with lidocaine, a group-IB drug, with locking action on the sodium channel, a fast kinetic and which acts without affecting or shortening the action potential duration APD must be noted.
Lidocaine has a high hepatic first pass effect, so its bioavailability is increased when taken with food. Elvin et al. It was also found that the intake did not influence the drug protein transport the free fraction was 0. The authors concluded that increased hepatic clearance was stimulated by the hepatic blood flow after food ingestion. The result was the saturation of the enzymes responsible for this clearance with increased bioavailability of the drug when taken orally with food.
In the case of propafenone, an increased bioavailability related with food intake has been described.
This group-IC AD, with locking action of the sodium channel, slow kinetic and does not affect or lengthens the APD, has a similar structure to propranolol and an important first-pass metabolism. In slow metabolizers the bioavailability was not affected. In the case of slow metabolizers, the slow hepatic metabolism makes the result similar with or without food, most of the drug reaching the circulation without being metabolized in the liver. In this regard, urinary elimination decreases with urine alkalizing diets.
Specifically, the permeability of bidisomide is lower, especially in the ileum, and its absorption appears to be inhibited by the presence of glycine, and glycine-glycine and glycine-proline dipeptydes.
Among beta-blockers group-II , bevantolol bioavailability is not affected when administered with food, 23 whereas the absorption and the maximum concentration Cmax of acebutolol and its major metabolite, diacetolol, are slightly decreased but without clinical significance.
The enzymatic inhibition caused by the amino acids reduction of first-pass metabolism as well as a limitation of co-substrate NADPH or oxygen have been invoked as possible mechanisms involved. Thus, a rich-in-proteins diet substantially increases the bioavailability due to the amino acids inhibitory action on the liver enzymatic system, 28 whereas high-in-carbohydrates diets and poor-in-protein diets do not appear to affect bioavailability.
In studies with artificial membranes, maltooligosaccharides delay the transport of propranolol and pectines produce a similar effect by decreasing its esterification. However, comparing the effect of an experimental oral, intra-arterial or portal thus bridging the intestinal barrier administration of glucose, some interaction glucose-propranolol before the liver step has been observed.
Regarding dronedarone, a multichannel blocker AD benzofuran derivative of amiodarone , it has been noted that strong CYP3A4 inhibitors may increase its Cmax while CYP3A4 inducers reduce its concentration. Felodipine a group-IV AD, calcium channel blocker has a delayed absorption when administered by sustained release forms along with food, which is attributed to increased drug retention in the stomach.
In addition, an absence of bioavailability changes in verapamil has been reported by taking it with rich-in-protein foods. By chance in , Bailey et al. They added that people with higher levels of CYP3A4 with liver failure and with clinical situations that predispose to increase the effects and toxicity of drugs would be more likely to suffer from the interaction of grapefruit juice with administered drugs.
The hepatic CYP3A4 appears to not be inhibited and, on the other hand, the above-mentioned P-gp would be inhibited. Traditionally, drug interactions have been attributed to furanocoumarins. With regard to cardiovascular pharmacology, the fact that inactivation of CYP3A4 is irreversible, it occurs when taking ml, and the effect of increasing the bioavailability of the drugs can occur even after 24 hours of the intake are particularly relevant.
One of the effects of naringenin, another flavonoid of grapefruit juice, seems to be to increase the inhibitory action of the potassium channel blockers AD by an inhibit action at hERG human-ether-a-go-go- related gene level. Considering the AD, grapefruit juice could enhance the toxicity of amiodarone, quinidine, disopyramide and propafenone.
In regard to other components, naringenine causes a more potent inhibition than naringin. The parameters affected are AUC, maximum plasmatic concentration and urinary excretion values. Experimentally, different effects of grapefruit juice on verapamil group-IV AD have been observed depending on the time of intake, thus leading to plasma concentrations changes. With regard to digoxin, the inhibition of P-gp by the grapefruit juice appears to have no significant effect.
Considering orange juice, hesperidin, one of its flavonoids, would be responsible for a lower intestinal absorption of celiprolol. In an experimental study with digoxin, it was found that piperine the main component of black pepper inhibits P-gp and CYP3A4, an enzyme which could affect plasma drug concentrations especially when administered orally. Regarding ramipril, an antihypertensive with antiarrhythmic effect, it has been found experimentally that in combination with felodipine and with a low salt diet or potassium or magnesium alternative salts a greater beneficial cardiovascular effect is achieved.
It is worth mentioning possible interactions with the use of various plants. For example, St. Similarly, licorice Glycyrrhiza glabra , by passing glycyrrhizin to glycyrrhetic acid by hydrolysis and the action of intestinal beta-glucuronidase may increase the effect of digoxin due to an effect of sodium retention and potassium depletion. With regard to caffeine, a study has shown interaction with the use of adenosine used in the detection of coronary artery disease.
Therefore, the use of medications, beverages or foods containing caffeine should be known in advance. Consumption of honey from the genus Rhododendron , with a toxin called grayanotoxin, has resulted in a reported case of complete atrioventricular block alongside taking verapamil. In addition, it appears that the administration of more or less water volume does not affect the drug bioavailability.
In relation to vitamins, there are some controversial results. Thus, the photosensitizing action of amiodarone is well known, and it has been reported that pyridoxine could prevent such effect. Nevertheless, it has also been noted that pyridoxine could aggravate that effect.
Antiarrhythmic drugs are an essential part of medical treatment of cardiovascular disease and the response to them may vary among patients as well as in each individual patient, with potentially serious consequences. This is influenced by the interactions, either drug-drug or drug-food. Taking various and very different drugs is common and it is obvious that food shall be accompanied by the taking thereof. Sometimes that coincidence is required for example, adherence could be improved , but occasionally may cause potentially dangerous interactions.
In any situation where the usual bioavailability is increased by a greater passage of drug into the systemic circulation, the chance of side effects and toxicity will be increased, especially for those drugs with a narrow therapeutic window. In other cases, it is not an increased blood flow which modifies the bioavailability, but an action on the CYP3A4 by means of an irreversible and inhibitory interaction at the intestinal level. On the other hand, some changes in bioavailability will depend on the food action inhibiting P-gp transporter that returns a certain amount of the drug into the intestinal lumen.
The inhibition of this binding protein will cause an increase in the amount of drug absorbed. Finally the action on the transport systems of organic anions and cations OAT, OCT have been involved in some interactions. If the P-gp returns part of the drugs into the intestinal lumen, the above-mentioned transport systems act contrary. Thus a food that selectively inhibits, for example, P-gp and OAT would cause the effect of increasing bioavailability of a drug and, secondly, its decrease.
Regarding the effect of the simultaneous intake of food and AD, while the pharmacokinetics of propafenone is affected only in fast metabolizers, 13 in the case of diprafenone the increase of bioavailability would occur in all cases. Felodipine administered as sustained release forms delays its absorption when given with food. The fact that the reduction of intestinal content of CYP3A4 occurs only some hours after the ingestion may be relevant.
Moreover, the allocation is not due to a simple competition for a substrate, but possibly accelerating the degradation of CYP3A4 by a mechanism of enzymatic inhibition. Therefore, the return of CYP3A4 activity requires a de novo enzymatic synthesis that would explain the prolonged effect of grapefruit juice intake.
Particular care should be taken into account in the elderly, so a proper separation of AD and grapefruit juice should be considered. Other juices, like orange juice, should be taken into account when prescribing AD, especially beta-blockers. With respect to the consumption of medicinal plants, it is noteworthy that Spain has increased the consumption dramatically over its possible therapeutic efficacy sometimes demonstrated and the mistaken belief about its safety.
In the case of drugs used in cardiovascular diseases, digoxin is of particular interest with respect to this type of interactions and the consequent potential adverse effects. Among the consumers, a half use these plants by means of bulk products, which has also been associated with increased potential hazard.
Food may affect the bioavailability of the AD and in some specific cases, such as dairy products and rich-in-protein diets, this should be carefully considered.
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