The effect of drug on a person may be different than expected because that drug interacts with another drug the person is taking (drug-drug interaction), food, beverages, dietary supplements the person is consuming (drug-nutrient/food interaction) or another disease the person has (drug-disease interaction). A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. These interactions may occur out of accidental misuse or due to lack of knowledge about the active ingredients involved in the relevant substances. (1)
Understanding food/drug interactions
There are 4 stages of drug action for medicines:
- the drug dissolves into a useable form in the stomach
- the drug is absorbed into the blood and transported to its site of action
- the body responds to the drug and the drug performs a function
- the drug is excreted from the body either by the kidney, the liver or both
Different groups of Medicines
We know many groups of drugs (2):
A large number of drugs are introduced every year. Food-drug interactions can produce negative effects in safety and efficacy of drug therapy, as well in the nutritional status of the patient. (1)
It is also possible for drugs to interfere with a person’s nutritional status. Some drug interfere with the absorption of a nutrient. Other drugs affect the body’s use and/or excretion of nutrients, especially vitamins and minerals.
If less of a nutrient is available to the body because of these effects, this may lead to a nutrient deficiency. (2)
Drug interactions are to be avoided, due to the possibility of poor or unexpected outcomes.
Like food, drugs taken by mouth must be absorbed through the lining of the stomach or the small intestine. Consequently, the presence of food in the digestive tract may reduce absorption of a drug. Often, such interactions can be avoided by taking the drug 1 hour before or 2 hours after eating.
Like drugs, foods are not tested as comprehensively so they may interact with prescription or over-the-counter drugs. The authors would suggest patients to tell their doctors and pharmacists about their food intake and dietary supplements so that interactions can be avoided.
Among all fruit juices, grape fruit juice (GFJ) possesses high interaction with almost all types of drugs. The juice modifies the body’s way of metabolizing the medication, affecting the liver’s ability to work the drug through a person’s system. Taniguchi in 2007 reported a case of purpura associated with concomitant ingestion of cilostazol, aspirin and grapefruit juice in 79 years old man. His purpura disappeared upon cessation of grapefruit juice, although his medication was not altered. The most probable cause of his purpura is an increase in the blood level of cilostazol because of the inhibition of cilostazol metabolism by components of grapefruit juice.
Numerous reports have documented drug interactions with GFJ that occur via inhibition of CYP3A enzymes. Furanocoumarins present in GFJ inhibit the intestinal CYP 3A4 and have been shown to increase the oral bioavailability of medications that are CYP 3A4 substrates like Felodipine, midazolam, cyclosporine and raise their concentrations above toxic levels.
GFJ is generally contraindicated to patients taking psychotropics and it is advised to inform patients about described interaction
Cholesterol-lowering agent lovastatin should be taken with food to enhance gastrointestinal absorption and bioavailability. The absorption of rosuvastatin, another anti-hyper lipidemic agent, was significantly decreased in the fed state compared with the fasting state, which suggests that rosuvastatin should be administered on an empty stomach.
Simvastatin, Ezetimibe, pravastatin and fluvastatin may be taken without regards to food. However, high fiber diets may lower the efficacy of these drugs. Concomitant administration of statins with food may alter statin pharmacokinetics or pharmacodynamics, increasing the risk of adverse reactions such as myopathy or rhabdomyolysis or reducing their pharmacological action. Consumption of pectin or oat bran together with Lovastatin reduces absorption of the drug.
Warfarin is commonly used to treat or prevent thromboembolic events. Patients taking warfarin are at particular risk of interactions with dietary supplements, yet approximately 30% use herbal or natural product supplements on a regular basis. There is a possible interaction between warfarin and a high-protein diet. The potential for increased dietary protein intake to raise serum albumin levels and/or cytochrome P450 activity has been postulated as mechanisms for the resulting decrease in international normalized ratio (INRs).
Some vegetables (broccoli, Brussels sprouts, kale, parsley, spinach, and others) are high in vitamin K. Eating large quantities or making sudden changes in the amounts eaten of these vegetables, interferes with the effectiveness and safety of warfarin therapy.24
Eating charbroiled food may decrease warfarin activity, while eating cooked onions may increase warfarin activity. Soy foods have been reported both to increase and to decrease warfarin activity. The significance of these last three interactions remains unclear. The combination of warfarin administration and cranberry juice ingestion appeared to be associated with an elevated INR without bleeding in elderly patient.
A number of studies have been documented on the interaction of warfarin and cranberry juice. Cranberry juice is a flavonoid, which has been shown to induce, inhibit, or act as a substrate for the biosynthesis of several cytochrome P-450 (CYP) isoenzymes. Specifically, cranberry juice may inhibit the activity of CYP2C9, the primary isoenzyme involved in the metabolism of S-warfarin. It was suggested that cranberry juice increased the International Normalized Ratio (INR) of patients taking warfarin, but neither clearly identified cranberry juice as the sole cause of INR elevation. If warfarin sodium is ingested with leafy green vegetables, the hypoprothrombinemic effect of warfarin may be decreased and thromboembolic complications may develop.
Antidepressant activity of monoamine oxidase inhibitors (MAOIs) was initially noted in the 1950s. Although older monoamine oxidase inhibitors (MAOIs) are effective in the treatment of depressive disorders, they are under-utilized in clinical practice due to main concerns about interaction with tyramine-containing food (matured cheese, red vine, ripped bananas, yogurt, shrimp paste and salami) or so called cheese reaction, since they are capable of producing hypertensive crisis in patients taking MAOIs.33
The first-generation MAOIs such as phenelzine and isocarboxazid were largely nonselective inhibitors of both subtypes of MAO, MAO (A) and MAO (B). These medications carried with them dietary restrictions.34 Tyramine is an indirectly acting sympathomimetic agent, is degraded by MAO but in the presence of MAOIs, it escapes degradation and reaches the systemic circulation where it is taken up by the adrenergic neuron, leading to a hypertensive crisis.35 However, MAOIs have been well established as an effective intervention for people with treatment-resistant depression, and transdermal formulations may provide a valuable therapeutic option and eliminate the drug-food interaction.36
Patients placed on anti hypertensive drugs will benefit from concomitant moderate sodium restricted diets. Propranolol serum levels may be increased if taken with rich protein food. A change in diet from high carbohydrates/low protein to low carbohydrate/high protein may result in increased oral clearance. Smoking may decrease its plasma levels of by increasing its metabolism. The intestinal absorption of celiprolol (beta-blocker) is inhibited when it is taken with orange juice. Hesperidin, present in orange juice, is responsible for the decreased absorption of celiprolol. The absorption of ACEs inhibitors is increased when taken on an empty stomach. While GFJ increases the bioavailability of felodipine (Ca2 channel blocker).
Licorice extract, a common ingredient of dietary supplement contains glycyrrhizin and glycyrrhetinic acid. It is a potent inhibitor of 11- bet- hydroxyl steroid dehydrogenase, it increases excess of cortisol to mineralocorticoid receptors causing sodium retention and potassium depletion, so it may interfere with various medicines including antihypertensive and antiarrhythmic agents. A high intake of liquorice can cause hypermineralocorticoidism with sodium retention and potassium loss, oedema, increased blood pressure and depression of the renin-angiotensin-aldosterone system. Studies showed that a daily consumption of glycyrrhizic acid of 95 mg or more caused an increase in blood pressure. A practical guideline for an acceptable daily intake of glycyrrhizic acid seems to be 9.5 mg a day. This means no more than 10-30g liquorice and no more than half a cup of liquorice tea a day.
Antibiotics are widely prescribed in medical practice. Many of them induce or are subject to interactions that may diminish their anti-infectious efficiency or elicit toxic effects. Food intake can influence the effectiveness of an antibiotic. Avoid co-administration of antibiotics with milk products which are rich sources of divalent ions, such as calcium and magnesium that complex with some antibiotics and prevent their absorption. The intake of dairy products, however, needs to be monitored and encouraged with appropriate consideration of specific antibiotics involved.
Casein and calcium present in milk decrease the absorption of ciprofloxacin. The effect of interaction of five fruit juices on the dissolution and absorption profiles of ciprofloxacin tablets were determined. It was found that the absorption of ciprofloxacin (500 mg) tablets can be reduced by concomitant ingestion of the GFJ. Therefore, to avoid drug therapeutic failures and subsequent bacterial resistance as a result of sub-therapeutic level of the drug in the systemic circulation, ingestion of the juice with ciprofloxacin should be discouraged. Azithromycin absorption is decreased when taken with food, resulting in a 43% reduction in bioavailability. Tetracycline should be taken one hour before or two hours after meals, and not taken with milk because it binds calcium and iron, forming insoluble chelates, and influencing its bioavailability. The effect of milk added to coffee or black tea on the bioavailability of tetracycline was evaluated in healthy individuals. Results showed that even a little quantity of milk containing extremely small amounts of calcium severely impair the absorption of the drug, so that the presence of this metal ion should be carefully controlled in order to avoid decreasing the available tetracycline.
Food-drug interactions may reduce the bioavailability of drugs taken after meals (negative food effects). However, enteric-coated tablets that start to disintegrate when they reach the middle-to-lower region of the small intestine could reduce negative food effects. Results indicated that food-drug interactions were avoided by separating the main absorption site of drugs from that of food components.52
Analgesics and Antipyretics
Analgesics and antipyretics are used to treat mild to moderate pain and fever. For rapid relief, acetaminophen should be taken in an empty stomach because food may slow the body absorption of acetaminophen. Co-administration of acetaminophen with pectin delays its absorption and onset. NSAIDs like ibuprofen, naproxen, ketoprofen and others can cause stomach irritation and thus they should be taken with food or milk. Avoid or limit the use of alcohol because chronic alcohol use can increase the risk of liver damage or stomach bleeding. The absorption of ibuprofen and oxycodone when given in the combination tablet was affected by the concomitant ingestion of food.
The Cmax and AUC0-alpha of ibuprofen were significantly increased after single and multiple doses of Coca-Cola, thereby indicating increased extent of absorption of ibuprofen. The daily dosage and frequency of ibuprofen must be reduced when administered with Coca-Cola. Food intake did not appear to affect the extent of absorption (ie, total exposure) of oral Diclofenac potassium soft gelatin capsule at doses.
Bronchodilators like theophylline, albuterol, and epinephrine possess different effects with food. The effect of food on theophylline medications can vary widely. High-fat meals may increase the amount of theophylline in the body, while high-carbohydrate meals may decrease it. Avoid alcohol if taking theophylline medications because it can increase the risk of side effects such as nausea, vomiting, headache and irritability. Avoid eating or drinking large amounts of foods and beverages that contain caffeine (e.g., chocolate, colas, coffee, and tea) since theophylline is a xanthine derivative and these substances also contain xanthine. Hence consuming large amounts of these substances while taking theophylline, increases the risk of drug toxicity. Additionally, both oral bronchodilators and caffeine stimulate the central nervous system. Patients may be advised not to consume GFJ when taking theophylline, since it increases the bioavailability, and monitoring of plasma theophylline levels in patients consuming GFJ might be helpful in better management of patient care.
Fexofenadine, loratadine, rupatadine, cimetidine cetirizine, are all antihistamines. It is best to take prescription antihistamines on an empty stomach to increase their effectiveness. Rupatadine is commonly used for the management of diseases with allergic inflammatory conditions. A study indicates that concomitant intake of food with a single 20 mg oral dose of rupatadine exhibits a significant increase in rupatadine bioavailability. Cimetidine is given with food to assist the maintenance of a therapeutic blood concentration. A fraction of cimetidine is absorbed in the presence of food, allowing the remaining drug to be dissolved once the gut is cleared. Thus, therapeutic levels are maintained throughout the dosing interval. A study was conducted on esomeprazole (acid-reducer), and it was observe that its bioavailability was reduced when taken within 15 min before eating a high-fat meal vs. that while fasting.
Anti-tubercular drugs like isoniazid have been associated with tyramine and histamine interactions. Inhibition of monoamine oxidase and histaminase by isoniazid can cause significant drug-food interactions. Food greatly decreases isoniazid bioavailability. Oleanolic acid, a triterpenoid exists widely in food, medicinal herbs and other plants, has antimycobacterial activity against the Mycobacterium tuberculosis, when administered with isoniazid, it exerts synergistic effect.
High fat meals decrease the serum concentration of cycloserine, a bacteriostatic anti-tubercular drug and results in incomplete eradication of bacteria.
Glimepiride is an antidiabetic and a new generation sulfonylurea derivative should be administered with breakfast or the first main meal of the day. It has absolute bioavailability and the absence of food interaction guarantee highly reproducible pharmacokinetics. Immediate release glipizide should be taken 30 minutes before meals. However, extended release tablets should be taken with breakfast. The maximum effectiveness of acarbose, an alpha-glucosidase inhibitor is attained when the drug is taken immediately at the start of each meal (not half an hour before or after), because it delays the carbohydrate absorption by inhibiting the enzyme alpha-glucosidase.
Recent evidence pointed out the role of gastric acid secretion on the subsequent intestinal absorption of thyroxine in relation with the timing of food ingestion as well as with pH impairment associated to frequent gastric disorders like Helicobacter pylori infection and gastric atrophy. Levothyroxine is a derivative of thyroxine. Grapefruit juice may slightly delay the absorption of levothyroxine, but it seems to have only a minor effect on its bioavailability. Accordingly, the clinical relevance of the grapefruit juice-levothyroxine interaction is likely to be small.
Drug interactions may be theoretical or clinically relevant. A summary table is given to highlight some significant food-drug interactions. (1)
Tab.1 (font: www.researchgate.net)
Risk for food/drug and drug/nutrient interactions can be affected by many factors:
- medical history
- body composition
- nutritional status
- number of medication used
Always ask your doctor the better solution for you.