Food and drug Interaction

Introduction:

Drugs are frequently taken with food, and patients often use mealtime to remind them to take their medication. However, food can have a significant effect on the bioavailability of drugs. Food or certain dietary items influence the activity of a drug e. g. Food-Drug interaction. Food may influence drug absorption indirectly, through physiological changes in the GI tract produced by food, and/or directly, through physical or chemical interactions between the drug molecules and food components.

When a food is ingested, stomach emptying is delayed, gastric secretions are increased, stomach pH is altered and splanchnic blood flow may increase. These may all affect bioavailability of drugs. Food may also interact directly with drugs, either chemically (e. g. chelation), or physically, by adsorbing the drug, or acting as a barrier to absorption. In general GI absorption of drug is favoured by an empty stomach. However, some drugs have to be taken with or after a meal in order to avoid gastric irritation or to reduce the side effect. Food often may affect the rate and extant of absorption of drugs from GI tract. For exp. Many antibiotics should be given at least one hr before or two hr after meal to achieve optimal absorption.  

Food will reduce the rate and/or extant of absorption by virtue of reduced gastric emptying time, which particularly important for the drug unstable in gastric fluid and for dosage form designed to release drug slowly. Food provides rather viscous environment which will reduce the rate of drug dissolution and drug diffusion to absorbing membrane. Drug may also bind with to food particles or react with the gastrointestinal fluids secreted in response to the presence of food. The absorption of a few is actually promoted when administered after a meal. For example, the absorption of riboflavin is greater when administered after meal. The absorption of griseofulvin is doubled when administered after a meal containing high fat content. The bioavailability of chlorthiazide is increased when taken immediately following a meal compared to that found in fasting subjects. Exact mechanism of food-drug interaction is complex and unpredictable. Drug absorption may bereduced, delayed, enhanced or unaffected by the presence of food.

Why Food-Drug interaction is important?

          Food may influence drug bioavailability by means of the following mechanisms.

1.   Increased viscosity of GI contents: The presence of food in the GIT will provide a viscous media which may result in reduction in the rate of dissolution in the GI contents. In addition, the rate of diffusion may be reduced by an increased viscosity. Both phenomenons will tend to reduce the absorption of drug and ultimately decrease the bioavailability of drug.

2. Alteration in the rate of gastric emptying: Larger and bulk of meals, longer the gastric emptying time. Liquid meal takes less hr than solid meal to empty. High or low temperature of ingested food (in comparison to body temperature) reduces the gastric imptying rate. Thereby delay the onset of drug action.

3.      Stimulation of GIT secretions: The secretion of GIT is stimulated by food. The gastric secretion includes hydrochloric acid and pepsin where as intestinal secretion includes bail salts, bail acids enzymes etc. They influence the drug stability and the absorption rate. Degradation of drugs takes place in GIT due to chemical hydrolysis and enzymatic metabolism and leads to reduce bioavailability of such sensitive drugs. While bail acid increases the absorption of certain drug by increasing their rate of dissolution in GIT fluids. However bail salt is found to form insoluble, non-absorbable complexes with such drugs as kanamycin, neomycin and nystatin.

4.      Competitive inhibition of drug absorption by food component: There certain specialized absorption mechanism for absorption of certain nutrients. The drugs which have structural similarity with these nutrients are also absorbed by same mechanism. Therefore, there are a competition between drugs and nutrients. Exp. Absorption of levodopa is inhibited by certain amino acid which comes from the breakdown of ingested food containing protein.

5.      Non-absorbable complex formation of drug with food components: In general, reduction in bioavailability due to complexation is observed only when drug forms an irreversible or non-absorbable complexes with food components. For example:

(a)   Tetracycline- metals: Tetracycline can combine with metal ions such as Ca⁺², Mg⁺², Zn⁺², Fe⁺² etc. in GIT to form complex that are absorbed poorly. Thus the simultaneous administration of certain dietary item containing these metal ions (e.g. milk, other product containing Ca⁺²) with tetracycline could result in significant absorption of tetracyclines.

(b)    Fluroquinolons-Metals: Certain dietary items (milk, yogurt), have been reported to reduce markedly the absorption and serum concentration of fluroquinolons, probably as a result of metal ion complexing with fluroquinolons.

(c)    Penicilamine-Metal: Food also will decrease the absorption of penicilamine by chelation and/or adsorption mechanisms.

6.      Blood flow to the liver: Blood flow to the GIT and liver increases shortly after a meal. This increased blood flow to the liver will increase the rate at which drugs are presented to the liver. Thus first-pass metabolism of some drugs (e.g.propranolol, hydralazine, and dextropropoxyphen etc.) is reduced because metabolism of such drugs is sensitive to their rate of presentation to liver, greater the rate of presentation of such drugs to the liver the larger the fraction of the drug that escapes first-pass metabolism. This is due to the enzyme systems responsible for their metabolisms become saturated at that rate of presentation of drugs to the liver.                   

Mechanisms by which absorption of drugs following meal could be increased: Increased drug absorption following a meal could be due to one or more of the under mentioned reasons:

1.      Increased time for dissolution of a poorly soluble drug.

2.      Enhanced solubility due to GIT secretion like bile.

3.      Prolonged residence time and absorption site contact of drug e.g. water soluble vitamins.

4.      Increased lymphatic absorption e.g. acitretin.

Table 1: Effect of Food on Drug Absorption

Reduced	Delayed	Increased	Unaffected
Ethanol Tetracycline Erythromycin Levodopa Captopril Atenolol Aspirin Ampicillin	Aspirin Digoxin Diclofenac Acetaminophen Furosemide Sulfadiazine Sulfixazole Nitrofurantoin	Griseofulvin Diazepam Vitamins Propranolol Metaprolol Chlorthiazide Hydralazine Lebetalol	Mehyldopa Sulfasomidine Propylthiouracil

What should be remembered about food-drug interaction?

• Read the prescription label on the container. If you do not understand something, or think you need more information, ask your physician or pharmacist.

• Read directions, warnings, and interaction precautions printed on all medication labels and package inserts. Even over-the-counter medications can cause problems.

• Take medication with a full glass of water.

• Do not stir medication into your food or take capsules apart (unless directed by your physician). This may change the way the drug works.

• Do not take vitamin pills at the same time you take medication - vitamins and minerals can interact with some drugs.
• Do not mix medication into hot drinks, because the heat from the drink may destroy the effectiveness of the drug.

• Never take medication with alcoholic drinks.

• Be sure to tell your physician and pharmacist about all medications you are taking, both prescription and non-prescription.

What happens during a food- drug interaction?

A food-drug interaction can occur when the food you eat affects the ingredients in a medication you are taking, preventing the medicine from working the way it should. Food-drug interactions can happen with both prescription and over-the-counter medications, including antacids, vitamins, and iron pills.

Some nutrients can affect the way you metabolize certain drugs by binding with drug ingredients, thus reducing their absorption or speeding their elimination. For example, the acidity of fruit juice may decrease the effectiveness of antibiotics such as penicillin. Dairy products may blunt the infection-fighting effects of tetracycline. Antidepressants (called MAO inhibitors) are dangerous when mixed with foods or drinks that contain tyramine (i.e., beer, red wine, and some cheeses).

Not all medications are affected by food, but many can be affected by what you eat and when you eat it. Sometimes, taking medications at the same time you eat may interfere with the way your stomach and intestines absorb medication. Other medications are recommended to be taken with food. Be sure to ask your physician or pharmacist for specific directions on eating prior to or after taking any medication.

Table 2: Medications which should be taken on an empty stomach

Alendronate	Ampicillin	Astemizole	Bethanechol
Bisacodyl	Captopril	Cefibuten	Cilostazol
Demeclocycline	Dicloxacillin	Didanosine	Etidronate
Felodipine	Indinavir	Lansoprazole	Levothyroxine
loratadine	loracarbef	Methotrexate	Moexipril
Mycophenolate	Omeprazole	Oxacillin	Penicillamine
Perindopril	Repaglinide	Rifampin	Rifabutin
Riluzole	Roxithromycin	Sucralfate	Sulfamethoxazole - trimethoprim
Sulfadiazine	Zalcitabine	Tolcapone	Zafirlukast

Table 3: Medications which should be taken with Food

Allopurinol	Atovaquone	Augmentin	Aspirin
Amiodarone	Baclofen	Bromocriptine	clofazimine
Carvedilol	Naproxen	Chloroquine	Cimetidine
Cefpodoxime	Diclofenac	Divalproex	Doxycycline
Felbamate	fenofibrate	Fiorinal	Fludrocortisone
fenoprofen	Griseofulvin	glyburide	Hydrocortisone
Sulindac	Indomethacin	Valproic acid	Itraconazole
Ketorolac	Lithium	Metronidazole	Misoprostol
methanamine	mebendazole	Prednisone	Naltrexone
Ticlopidine	Tolmetin	Trazodone	Troglitazone
Ritonavir	Nelfinavir	Nitrofurantoin	Niacin

The Effect of Food:

Anti-infective agents-Food: The presence of food in GIT will reduce the absorption of many anti-infective agents (e.g. Penicillin and tetracycline derivatives). Erythromycin stearate formulation should be administered at least 1 hr before meal or 2 hr after meal. Although there are many anti-infective agents (e.g. Penicillin V, Amoxicillin, Doxycycline minocycline etc.)  which absorption is not affected by food.

Theophylline-Food: Generally food does not alter the activity of theophylline significantly when the drug is administered in an immediate release formulation. However, variation is seen with the controlled release formulation of theophylline.

Captopril-Food: The presence of food in GIT has been reported to reduce the absorption of captopril by 30% to 40%. It is advisable to administer the drug 1 hr before the meal.

Alendronate & Risedronate-Food: Food and even coffee, orange juice and mineral water may markedly reduce the bioavailability of these drugs. It is recommended that these drugs be administered soon after arising at least half hr before any food, medication, with plan water.

MAOIs-Tyramine: There have been reports of serious hypertensive crisis reactions occurring in people being treated with MAOIs (e.g. Isocarboxazid, Phenelzine etc.) following ingestion of food with a  high content of tyramine (e.g. aged cheese, wine, pickled fish, concentrated yeast extracts, broad-been pods). The interaction can cause a potentially fatal rise in blood pressure.

Grapefruit Juice: Grapefruit juice reduces the activity of cytochrome P-450 enzyme in the gut wall that are involved in the metabolism of certain calcium channel blockers (e.g. Amlodipine, feloidipine, nisoldipine Varapamil etc.), HMG-CoA reductase inhibitors (e.g. Lovastatin) and cyclosporine As a result, larger amounts of unmetabolized drug is absorbed, and serum concentrations are increased.

Orange juice shouldn't be consumed with antacids containing aluminum. 'The juice increases the absorption of the aluminum. Orange Juice and milk should be avoided when taking antibiotics. The juice's acidity decreases the effectiveness of antibiotics, as doe’s milk.

Laxatives-Milk: Milk also doesn't mix with laxatives containing bisacodyl (Correctol and Dulcolax). You might find the laxative works a little "too well" in the morning.

Digoxin-Oatmeal: Large amounts of oatmeal and other high-fiber cereals should not be eaten when taking digoxin. The fiber can interfere with the absorption of the drug, making the act of swallowing the pill a waste of time.

Coumadin-Food: Leafy green Vegetables high in vitamin K should not be taken in great quantities while taking Coumadin. These vegetables could totally negate the affects of the drug and cause blood clotting.

Caffeinated beverages and asthma drugs taken together can cause excessive excitability. Those taking Tagament (Simetidine), quinolone antibiotics (Cipro, Penetrex, Noroxin) and even oral contraceptives should be aware these drugs may cause their cup of coffee to give them more of a Java jolt than they expected.

Theophylline-Grilled meat: Grilled meat can lead to problems for those on asthma medications containing theophyllines. The chemical compounds formed when meat is grilled somehow prevent this type of medication from working effectively, increasing the possibility of an unmanageable asthma attack.

NSAIDs-Food: Regularly consuming a diet high in fat while taking anti-inflammatory, arthritis medications can cause kidney damage and can leave the patient feeling, drowsy and sedated.

Tomato contains small quantities of a toxic substance known as solanine that may trigger headaches in susceptible people. They are also a relatively common cause of allergies. An unidentified substance in tomatoes and tomato-based products can cause acid reflux, leading to indigestion and heartburn. Individuals who often have digestive upsets should try eliminating tomatoes for 2 to 3 weeks to see if there is any improvement

Raspberries: Raspberries contain a natural salicylate that can cause an allergic reaction in aspirin sensitive people.

Horseradish Very high doses of horseradish can cause vomiting or excessive sweating. Avoid if you have hypothyroidism.

Drugs	Effects and Precautions
Antibiotics:
Cephalosporins, penicillin:	Take on an empty stomach to speed absorption of the drugs.
Erythromycin:	Don't take with fruit juice or wine, which decrease the drug's effectiveness.
Tetracycline:	Dairy products reduce the drug's effectiveness. Lowers Vitamin C absorption.
Antidepressants:
Lithium:	A low-salt diet increases the risk of lithium toxicity; excessive salt reduces the drug's efficacy
MAO Inhibitors:	Foods high in tyramine (aged cheeses, processed meats, legumes, wine, beer, among others) can bring on a hypertensive crisis.
Tricyclics:	Many foods, especially legumes, meat, fish, and foods high in Vitamin C, reduce absorption of the drugs.
Antihypertensive, Heart Medications:
Alpha blockers:	Take with liquid or food to avoid excessive drop in blood pressure.
Antiarrhythmic drugs:	Avoid caffeine, which increases the risk of irregular heartbeat.
Beta blockers:	Take on an empty stomach; food, especially meat, increases the drug's effects and can cause dizziness and low blood pressure.
Digitalis:	Avoid taking with milk and high fiber foods, which reduce absorption, increases potassium loss.
Antiasthmatic Drugs:
Pseudoephedrine:	Avoid caffeine, which increase feelings of anxiety and nervousness.
Theophylline:	Charbroiled foods and high protein diet reduce absorption. Caffeine increases the risk of drug toxicity.
Cholesterol Lowering Drugs:
Gemfibrozil:	Avoid fatty foods, which decrease the drug's efficacy in lowering cholesterol.
Antiulcer Medications:
Antacids:	Interfere with the absorption of many minerals; for maximum benefit, take medication 1 hour after eating.
Cimetidine, Fanotidine, Sucralfate:	Avoid high protein foods, caffeine, and other items that increase stomach acidity.
Hormonal Preparations:
Oral contraceptives:	Salty foods increase fluid retention. Drugs reduce the absorption of folate, vitamin B-6, and other nutrients; increase intake of foods high in these nutrients to avoid deficiencies.
Steroids:	Salty foods increase fluid retention. Increase intake of foods high in calcium, vitamin K, potassium, and protein to avoid deficiencies.
Thyroid drugs:	Iodine-rich foods lower the drug’s efficacy.
NSAIDs:
Aspirin and stronger non-steroidal anti-inflammatory drugs:	Always take with food to lower the risk of gastrointestinal irritation; avoid taking with alcohol, which increases the risk of bleeding. Frequent use of these drugs lowers the absorption of folate and vitamin C.
Codeine:	Increase fiber and water intake to avoid constipation.
Sedatives, Tranquilizers:
Benzodiazepines:	Never take with alcohol. Caffeine increases anxiety and reduce drug's effectiveness.