DRUG- NUTRIENT INTERACTIONS
The management of many diseases requires drug therapy frequently involving the use of multiple drugs. Food –drug interactions can change the effects of drugs and the therapeutic effects or side effects of medications can affect the nutritional status . alternatively the diet and the use of supplements or the nutritional status of the patient can decrease a drug’s efficacy or increase its toxicity.
Drug-nutrient interaction can be defined as:
An alteration of pharmacokinetics or pharmacodynamics of a drug or nutritional element or a compromise in nutritional status as the result of addition of a drug.
Pharmacodynamics refers to the quantitative description of drug disposition, which include absorption, distribution, metabolism and excretion of the compound. It refers to the clinical physiologic effects of the drug.
Pharmacokinetics parameters such as halflife-the rate of removal or clearance of the drug administered becomes available in the body, bioavailability-refers to the fraction of drug administered becomes available in the body. It affect the movement of the drug into, around the body.
PHARMACODYNAMICS:
It is the study of biochemical and physiologic effects of a drug. Mechanism of action of drug might include the binding of the drug molecule to a receptor /enzyme or ion channel, resulting in the observable physiologic response. Ultimately this response may be enhanced or attenuated by the addition of other substances with similar or opposite actions.
PHARMACOKINETICS:
It is the study of the time course of a drug in body involving the absorption, distribution, metabolism (bio transformation) and excretion of drugs.
Absorption is the process of the movement of drug from site of administration to blood stream. This process is dependent on the:
· Route of administration
· Chemistry of drug and its ability to cross the biologic membranes
· The rate of gastric emptying(for orally administered drugs) and GI movements
· The quality of the product formulation.
Distribution occurs when the drug leaves the systemic circulation and travels to various regions
of body. Body areas of distribution vary with different drugs depending on drug’s chemistry and ability to cross biologic membranes. The rate and extent of blood flow to an organ or tissue strongly affect amount of drug that reaches the area. Many drugs are increasingly bound to plasma proteins like albumin. The bound fraction of the drug doesn’t produce a pharmacologic effect as it doesn,t leave the vascular system. Only the unbound fraction is able to produce an effect on the target tissue or organ.
Metabolism :
Drug metabolism is the metabolism of drugs, their biochemical modification or degradation, usually through specialized enzymatic systems. This is a form of xenobiotic metabolism.
Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products. Its rate is an important determinant of the duration and intensity of the pharmacological action of drugs.
Drugs are almost all xenobiotics. Other commonly used organic chemicals are also drugs, and are metabolized by the same enzymes as drugs. This provides the opportunity for drug-drug and drug-chemical interactions or reactions.
A xenobiotic is a chemical which is found in an organism but which is not normally produced or expected to be present in it. It can also cover substances which are present in much higher concentrations than are usual. Specifically, drugs such as antibiotics are xenobiotics in humans because the human body does not produce them itself nor would they be expected to be present as part of a normal diet
A drug is eliminated from then body either as unchanged drug or as metabolite or the original compound.
The major organ of metabolism or biotransformation of drug in body is liver although other sites contribute lesser degree.
One of the most important enzyme that facilitate drug metabolism is cytochrome P450 . Substances such as food or dietary supplement which either increase or inhibit the activity of this enzyme system can significantly change the rate or extent of drug metabolism. The general tendency of the process of metabolism is to transform a drug from lipid soluble to a more water soluble compound that can be handled more easily by kidneys and excreted in urine. Let us see in detail :
Biotransformation of Drugs: Phase I vs. Phase II Reactions
Most metabolic biotransformations occur at some point between absorption of the drug into the general circulation and its renal elimination. A few transformations occur in the intestinal lumen (bacterial activity) or intestinal wall (villi). In general, all of these reactions can be assigned to one of 2 major categories:
First-Pass Metabolism
Although every tissue has some ability to metabolize drugs, the liver is the principal organ of drug metabolism. Other tissues that display considerable activity include the gastrointestinal tract, the lungs, the skin, and the kidneys.
Following oral administration, many drugs (e.g., isoproterenol, meperidine, pentazocine, morphine) are absorbed intact from the small intestine and transported first via the portal system to the liver, where they undergo extensive metabolism.
This process has been called a first-pass effect. Some orally administered drugs (e.g., clonazepam, chlorpromazine) are more extensively metabolized in the intestine than in the liver. Thus, intestinal metabolism may contribute to the overall first-pass effect.
First-pass effects may so greatly limit the bioavailability of orally administered drugs that alternative routes of administration must be employed to achieve therapeutically effective blood levels.
Cellular Localization
The lower gut harbors intestinal microorganisms that are capable of many biotransformation reactions. In addition, drugs may be metabolized by gastric acid (e.g., penicillin), digestive enzymes (e.g., polypeptides such as insulin), or by enzymes in the wall of the intestine (e.g., sympathomimetic catecholamines).
Although drug biotransformation in vivo can occur by spontaneous, noncatalyzed chemical reactions, the vast majority are catalyzed by specific cellular enzymes. At the subcellular level, these enzymes may be located in the endoplasmic reticulum, mitochondria, cytosol, lysosomes, or even the nuclear envelope or plasma membrane.
Mixed Function Oxidases
Many drug-metabolizing enzymes are located in the lipophilic membranes of the endoplasmic reticulum of the liver and other tissues. The activity of this enzyme system requires both a reducing agent (NADPH) and molecular oxygen. In a typical reaction, one molecule of oxygen is consumed (reduced) per substrate molecule, with one oxygen atom appearing in the product and the other in the form of water. Two enzymes are important in this process:
- NADPH-cytochrome P-450 reductase. One mole of this enzyme (molecular weight of 80,000) contains one mole each of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). Because cytochrome c can serve as an electron acceptor, the enzyme is often referred to as NADPH-cytochrome c reductase.
- Cytochrome P-450. The name cytochrome P-450 is derived from the spectral properties of this hemoprotein.. Over half of the heme synthesized in the liver is committed to hepatic cytochrome P-450 formation. The relative abundance in liver of cytochrome P-450, as compared to that of the reductase, makes the reductase the rate-limiting step in hepatic drug oxidations.
Microsomal drug oxidations require cytochrome P-450, cytochrome P-450 reductase, NADPH, and molecular oxygen. The cycle involves four steps:
- Oxidized (Fe3+) cytochrome P-450 combines with a drug substrate to form a binary complex.
- NADPH donates an electron to the cytochrome P-450 reductase, which in turn reduces the oxidized cytochrome P-450-drug complex.
- A second electron is introduced from NADPH via the same cytochrome P-450 reductase, which serves to reduce molecular oxygen and form an "activated oxygen"-cytochrome P-450-substrate complex.
- This complex in turn transfers "activated" oxygen to the drug substrate to form the oxidized product. The potent oxidizing properties of this activated oxygen permit oxidation of a large number of substrates.
Substrate specificity is very low for this enzyme complex. High solubility in lipids is the only common structural feature of the wide variety of structurally unrelated drugs and chemicals that serve as substrates in this system.
Enzyme Inhibition
Environmental pollutants are capable of inducing cytochrome P-450. For example, exposure to benzo(a)pyrene, present in tobacco smoke, charcoal-broiled meat, and other organic pyrolysis products, is known to induce cytochrome P-4
Phase II Reactions
Parent drugs or their Phase I metabolites that contain suitable chemical groups often undergo coupling or conjugation reactions with an endogenous substance to yield drug conjugates.
In general, conjugates are polar molecules that are readily excreted and often inactive. Conjugate formation involves high-energy intermediates and specific transfer enzymes. Such enzymes (transferases) may be located in microsomes or in the cytosol. They catalyze the coupling of an activated endogenous substance (such as the uridine 5'-diphosphate [UDP] derivative of glucuronic acid) with a drug (or endogenous compound), or of an activated drug (such as the S-CoA derivative of benzoic acid) with an endogenous substrate. Because the endogenous substrates originate in the diet, nutrition and disease play critical roles in the regulation of drug conjugations.
Sites of Drug Action
Binding and Response
A complete description of a receptor-drug interaction includes an analysis of the binding step and an analysis of the coupling between the binding and the biological response. Both steps of the analysis can be very complicated. In the case of the binding step, the receptor molecule may exist in more than one conformational state each of which exhibit different affinities for the drug. A complete description of the binding mechanism would include a characterization of the affinity of the drug for each conformational state as well as a description of the isomerization between conformational states. The coupling between the binding and the biological response is difficult to discuss in general terms because it is highly dependent upon the tissue under study. Nevertheless, a number of strategies have been developed that are useful in a variety of cases.
Drug Excretion
· Urine
· Bile
· Alveolar
· Milk
Enterohepatic Circulation
Drugs and drug conjugates entering the gut in bile may be reabsorbed and subsequently excreted in urine or returned to the bile. This occurs particularly with small, less polar drugs. Glucuronide conjugates of drugs may also be cleaved by enzymes in the intestinal microflora (e.g., beta-glucuronidase) to liberate the parent lipid-soluble drug, which is then reabsorbed.
Saliva and Gut
Secretions from the saliva and gut play a small part in excretion. Bile is the major source of drugs excreted in the feces
Alveolar
This route is of major importance in the excretion of volatile anesthetics. The large surface area and rich blood supply ensure that equlibration between blood and alveolar air is extremely rapid.
Milk
Excretion in milk is of particular concern in dairy animals.
Sweat and Tears
Excretion in sweat and tears is insignificant.
Diseases and Drug Metabolism
Liver Disease
Acute or chronic diseases that affect liver architecture or function markedly affect hepatic metabolism of some drugs.
Such conditions include fat accumulation, alcoholic hepatitis, active or inactive alcoholic cirrhosis, hemochromatosis, chronic active hepatitis, biliary cirrhosis, and acute viral or drug hepatitis. These conditions may impair hepatic drug-metabolizing enzymes, particularly microsomal oxidases, and thereby markedly affect drug elimination. For example, the half-lives of chlordiazepoxide and diazepam in patients with liver cirrhosis or acute viral hepatitis are greatly increased, with a corresponding prolongation of their effects. Consequently, these drugs may cause coma in patients with liver disease when given in ordinary doses.
Liver cancer has been reported to impair hepatic drug metabolism. For example, aminopyrine metabolism is slower in patients with malignant hepatic tumors than in normal controls.
Impairment of enzyme activity or defective formation of enzymes associated with heavy metal poisoning or porphyria also results in reduction of hepatic drug metabolism.
Cardiac disease, by limiting blood flow to the liver, may impair disposition of those drugs whose metabolism is flow-limited. These drugs are so readily metabolized by the liver that hepatic clearance is essentially equal to liver blood flow.
Pulmonary disease may affect drug metabolism, as indicated by the impaired hydrolysis of procainamide and procaine in patients with chronic respiratory insufficiency and the increased half-life of antipyrine in patients with lung cancer.
Toxic Products
It is becoming increasingly evident that metabolism of drugs and other foreign chemicals may not always be an innocuous biochemical event leading to detoxification and elimination of the compound. Indeed, several compounds have been shown to be metabolically transformed to reactive intermediates that are toxic to various organs.
| 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. |
| Sulfa drugs | Increase the risk of Vitamin B-12 deficiency |
| Tetracycline | Dairy products reduce the drug's effectiveness. Lowers Vitamin C absorption |
| Anticonvulsants | |
| Dilantin, phenobarbital | Increase the risk of anemia and nerve problems due to deficiency of folalte and other B vitamins. |
| Antidepressants | |
| Fluoxetine | Reduce appetite and can lead to excessive weight loss |
| 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. |
| Antihypertensives, Heart Medications | |
| ACE inhibitors | Take on an empty stomach to improve the absorption of the drugs. |
| 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. |
| Diuretics | Increase the risk of potassium deficiency. |
| Potassium sparing diuretics | Unless a doctor advises otherwise, don't take diuretics with potassium supplements or salt substitutes, which can cause potassium overload. |
| Thiazide diuretics | Increase the reaction to MSG. |
| Asthma 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 | |
| Cholestyramine | Increases the excretion of folate and vitamins A, D, E, and K. |
| Gemfibrozil | Avoid fatty foods, which decrease the drug's efficacy in lowering cholesterol. |
| Heartburn and Ulcer 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. |
| Hormone 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. |
| Laxatives | |
| Mineral Oils | Overuse can cause a deficiency of vitamins A, D, E, and K. |
| Painkillers | |
| 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. |
| Sleeping Pills, Tranquilizers | |
| Benzodiazepines | Never take with alcohol. Caffeine increases anxiety and reduce drug's effectiveness. |
RISK FACTORS FOR FOOD AND DRUG INTERACTIONS:
Patient must be assessed individually for the effect of food on drug action and the effect of drugs on nutritional status. Interactions can be caused or complicated by polypharmacy nutritional status , genetics, underlying illness special diets, nutritional supplement, tube feeding, herbal or phytonutrient products, alcohol intake, drug abuse, non-nutrients in food, excipients (excipients – is the substance added to a drug like a buffer, binder, flavouring, dye, preservative, suspending agent or coating also known as the inactive ingredient) in drugs or foods, allergies or intolerances .
Poor patient compliance and physicians prescribing pattern further complicate the risk. Drug induced malnutrition occurs mostly during long term treatment for chronic disease old patients are at a particular increase risk for many reasons.
Existing malnutrition also places patients at greater risk for drug nutrient interactions . protein alterations , specifically lower albumin levels and changes in body composition. Secondary to malnutrition can affect drug disposition by altering protein binding and drug distribution. Patients with active neoplastic disease or active AIDS with significant anorexia and wasting are at special risk because of increased prevelance of malnutrition in these groups .The presence of tumor and resulting illness may lead to reduced intake. Treatment modalities such as chemotherapy and radiation may accelerate nutritional disturbances. Cisplatin and other cytotoxic agents commonly cause nausea,vomiting, diarrhea, anorexia, and decreased food intake.
Drug disposition can be affected by alterations in GI tract such as vomiting , diarrhea, mucosal atropy, and motility changes. Malabsorption caused by intestinal damage from diseases like cancer celiac disease or IBD create greater potential for food drug interaction.
Body composition is an important consideration determining drug response. In obese the proportion of adipose tissue to lean body mass increases .Accumulation of fat soluble drug such as diazepam is more likely to occur. Accumulation of a drug and its metabolites in adipose tissue may result in prolonged clearance and increased toxicity. In older patients this interaction may be complicated buy decreased hepatic clearance of the drug.
The developing fetus, infant and pregnant woman are also at increased risk for nrug nutrient interactions. Many drugs have not been tasted on these populations making it difficult to assess the risk of negative drug effect including food drug interactions.
Food and drug interactions:
Drug can alter food by :
· Altering the appetite(amphetamines suppress the apetite)
· Interfering with tast or smell(methotrexate changes taste sensations)
· Inducing nausea or vomiting(digitalis can do both)
· Changing the oral environment (Phenobarbital can cause dry mouth)
· Irritating the GI tract(cyclophosphamide induces mucosal ulers)
· Causing sores or inflammation of the mouth (methotrexate can cause painful mouth ulcers to form
Drug can alter nutrition absorption by:
· Changing the acidity of the digestive tract(antacids can interfere with iron absorption)
· Aletering motility of the digestive tract(laxatives speed motility causes the malabsorption of many nutrients)
· Altering digestive juices(cimetidine can improve fat absorption)
· Inactivating enzyme systems (neomycins may reduce lipase activity)
· Damaging mucosal cells (chemotherapy can damage mucosal cells)
· Binding to the nutrients(antacids bind phosphorous)
Drug can alter nutrient metabolism by:
· Acting as structural analogs (as anticoagulant and vitamin k)
· Interfering with metabolic enzyme systems (Phenobarbital competes for folate coenzymes)
Drugs can alter nutrient excretion by:
· Altering reabsorption in the kidneys(some diuretics increase the excretion of Na and potassium)
· Displacing nutrients from their plasma protein carriers(aspirin displaces folate)
Foods can alter drug absorption by:
· Changing the acidity of the digestive tract(candy can change the acidity , thus dissolving slow-acting asthma medication too quickly)
· Stimulating secretion of digestive juices (griseofulvin is absorbed better when taken with foods that stimulate the release of digestive enzymes)
· Delaying digestive prcesses(aspisin is absorbed more slowly when taken with food)
· Binding to drugs(tetracycline binds to calcium in dairy foods limiting drug absorption)
· Competing for absorption sites in the intestines(dietary aminoacids interfere with levodopa absorption this way)
Foods can alter drug metabolism by:
· Interfering with a drug’s action (Phenobarbital action is limited by large amounts of folate in the diet)
· Contributing pharmacologically active substances (tyramine from cheese remains active with monoamine oxidase inhibitors)
Food can alter drug excretion by:
· Changing the acidity of the urine(vitamin c can alter urinary pH and limit the excretion of aspirin.
