1 nutrition – drug interactions bmb 505 – advanced nutrition and nutritional biochemistry yearul...

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Nutrition – Drug Interactions

BMB 505 – Advanced Nutrition and Nutritional Biochemistry

Yearul Kabir

(Handout #2)Date: 06.01.2010

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Nutrient Drug Interactions: Introduction

• The impact of the nutritional status on disposition of drugs/ xenobiotics is quite complex and often difficult to predict.

• The drug/xenobiotic disposition in the body depends on several important bioprocesses such as absorption, distribution, metabolism and excretion. The metabolic interactions between dietary constituents and other environmental chemicals and drugs are varied and complex.

• Therefore, to understand drug disposition and its modifications which would ultimately determine the drug responses at any given point of time, it is necessary to be aware of some of these fundamental processes.

• Drugs can act by affecting biochemical or physiological processes in the body.

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Nutrient Drug Interactions: Introduction…

• Most drugs have specific receptors on the membrane of target cells. The action of a drug is governed by two variables:– the magnitude of the response and

– the concentration required to produce the response.

• A selective drug can act on the receptors in a particular tissue at concentrations which produce little effect on the receptors in other organs. Most drugs have multiple actions.

• Drugs are molecules with characteristic physiocochemical properties.

• The physiochemical properties determine the pharmacokinetics or what the body does to the drug. This, in turn, determines the pharmacodynamics or what the drug does to the body and the physiological response.

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Nutrient Drug Interactions: Introduction…

• The special and simultaneously operating processes in pharmacokinetics determine the concentration of the drug in the body and its availability at target tissues in concentrations that yield maximum efficacy with minimum side effects.

• The doses and the doses regime ultimately depend on the physicochemical properties and the disposition of the drug in the body.

• There are no universal rules about the nutrient drug interactions.

• In general, it is important to assess drug nutrient interactions in a particular situation and change the dose depending on the severity of the nutritional status and alterations either in pharmacokinetics or dynamics.

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Pharmacokinetics of Drugs• Absorption

• The drugs administration by oral route have to get absorbed across the mucous membrane of gastrointestinal tract to enter the circulation. The action of drug depends on the rate as well as the extent of absorption.

• The formulation of the drug and its solubility will influence the absorption. Apart from the formulation of the drug, the absorption depends on the degree of ionization and the particle size of the drug.

• Most drugs are absorbed by passive diffusion. Thus the acidic and alkaline environment within the gastrointestinal tract can affect drug absorption.

• Further, the presence of food can either increase or decrease absorption by altering the degree of ionization as well as the interactions of food constituents with drugs.

• The presence of an intact mucous membrane and appropriate metabolism in the gastrointestinal tract and liver will determine the amoun6t of drug entering circulation (first pass clearance).

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Distribution and protein binding

• The rate and the extent of the distribution of drugs in the body depend on the binding of drugs to plasma proteins.

• The interactions between drugs and protein molecules often profoundly influence the biological activity of drug.

• Binding of drugs to plasma and tissue proteins influences its distribution, and duration of pharmacological action and its elimination.

• Plasma is a complex solution of different proteins of which albumin, alpha-1-acid glycoprotein, lipoproteins and globulin are involved in transport of drugs.

• While the acidic drugs bind to albumin, the basic drugs bind to alpha-1-acid glycoproteins and lipoproteins.

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Elimination

• Clearance is a more useful term to denote the elimination of a drug by all routes relative to the concentration of drug in plasma. The clearance has the greatest potential for clinical application and reflects the loss of drug across the body.

• The drug dosage is based on clearance of the drug. Clearances from liver and kidney can also be calculated by using appropriate formula.

• The two principal organs of elimination are the liver and kidneys.

• The liver is the major organ for biotransformation reactions, while the kidneys usually are the primary site of excretion of chemically unaltered drug or water soluble polar metabolites of the parent compound.

• Clearance of a drug is reduced due to disease or pathology in the liver or of the kidney.

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Biotransformation/Detoxification

• The hepatic microsomal and cytosolic drug metabolizing enzymes form an important system of drug metabolism and elimination.

• The enzymes can be induced (increased) or inhibited by several factors including nutrients and non-nutrients.

• The biotransformation of environmental chemicals or xenobiotics (including drugs) involves Phase I (oxidation, reduction and hydroxylation) and Phase II (conjugation processes) reactions mediated by mixed function oxidases and conjugating enzymes located in liver, kidney, lungs, gastrointestinal tract skin, and blood vessels.

• The hepatic microsomal drug metabolizing enzymes are located in the endoplasmic reticulum while the conjugation systems are present in the microsomal and cytosolic functions.

• Most drugs are extensively metabolized in the liver as it is the major organ of drug elimination from the body. 8

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Biotransformation/Detoxification…

• The mixed function oxidases have a broad substrate specificity and can metabolize a wide range of drugs and other xenobiotics, steroids, fatty acids, carcinogens and other environmental chemicals. The most important of the enzyme system is cytochrome P450-dependent, mixed function oxidases.

• The metabolism of drugs and other parent compounds by the Phase I reactions by mixed function oxidases does not necessarily result in loss of pharmacological activity.

• Therefore, the body possesses a second group of enzymes which can metabolize a number of endogenous as well as exogenous molecules by adding sulfates, glucuronic acid and glycine.

• Glucuronidation (UDP glucuronyl transferase) and mercapturate synthesis (glutathione-S-transferase) are the major conjugation systems.

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Drug-Nutrient Interaction• The drug-nutrient interactions that will be considered are those

having direct and/or immediate effects on drug efficacy or safety and those having acute positive or negative effects on nutritional status.

• Drug-nutrient interactions can be classified by:– Location (Table 18-1)

– Mechanism (Table 18-2)

– Pharmacological or nutritional outcomes (Table 18.3)

– Drug group (e.g., antibiotic, antacid, laxative, etc.) (Table 18.4)

– Nutrient(s) involved (e.g., folate, vitamin A, etc.) (Table 18.5)

– Temporal relationship to food or nutrient ingestion (Table 18.6)

– Risk factors (e.g., change to meal time,change to diet from low to high protein, etc.) (Table 18.7)

• For each of these classification systems, examples have been given of the type of interaction that occurs.

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Effects of food on drug pharmacokinetics

• Nutrient-drug interactions occur due to physical, chemical, physiological or pathophysiological interactions between drugs, nutrients and the human body and have a direct bearing on the therapy and its outcomes.

• The nutrient drug interactions can be categorized into:

– the effect of the nutrition status on drug disposition and metabolism

– the effect of the drugs on nutritional status.

• Several pathophysiological changes which occur in protein calorie malnutrition and other nutritional disorders can alter some of the important parameters and result in altered plasma or tissue drug concentrations, leading to altered drug response.

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Food Effects on Drug Disposition

• Until quite lately, we were confident that we could clearly differentiate food effects on drug absorption from food effects on drug metabolism and from food effects on drug excretion. However, increasing knowledge of drug and nutrient disposition and of gastrointestinal physiology has served to blur these distinctions.

• Drug Absorption• Food or food components, can influence drug absorption because of

physical or chemical interactions between:– food and drug or

– nutrient and drug or

– because of physiological changes in the gastrointestinal tract induced by eating or drinking.

Net effect may be:

Drug absorption reduced

Drug absorption slowed

Drug absorption increased by food intake

Table 18.9 and 18.10 list the drugs commonly used for which absorption is significantly altered by food. These same tables also indicate the mechanism whereby effects of food on drug absorption are initiated.

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Drug Absorption…

• When the effect of food on drug absorption is related to interactions between the food and the drug in the gastrointestinal tract, then the practical importance of the effect of food on drug absorption is related to the timing of drug intake in relation to eating time (Table 18-6).

• When the drug is taken at times other than when there is food or food residue in the gastrointestinal tract, interactions will not be observed.

• Food in the stomach can decrease the rate of drug dissolution

• Food can also increase the viscosity of the gastric medium, and thereby decrease the rate of drug diffusion to the mucosal absorption sites, an effect that may slow absorption of Aspirin.

• Fiber components in the diet can absorb drugs, therefore, reducing the amount available for absorption.

• Mineral components in the diet including Ca, Mg, and iron, can form insoluble chelates of drugs, such as the tetracyclines (Table 18-4).

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Drug Absorption…

• The absorption of penicillins and tetracyclines is much more efficient when these drugs are taken in the fasting state (Table 18-7).

• In case of tetracyclines, food can be taken at the time of drug intake, provided the food does not include dairy products containing calcium or food high in magnesium or iron.– It is generally recommended that tetracyclines be taken at least 2 hr

before or after times of intake of milk, other dairy products, or protein foods.

– In order to avoid formation of tetracycline–mineral chelates, it is preferable that the patient abstain from all food at the time of drug intake.

• In hospitals, there was a wide variety of drug administration schedules and that these often coincided with meal serving times. Because drug administration times in hospitals are largely set by the pharmacy or therapeutics committee, and mealtimes are decided by the dietitian, a great cooperation between these groups is required.

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Drug Absorption…

• Drug Formulation influences the rate and extent of drug absorption.– Food may differentially effect the absorption of different formulation

of a single drug.

– When food delays dissolution of solid drug products, drug absorption will also be delayed.

• There has been a rather general belief that suspensions and solutions of drugs are usually less affected by the action of food than other dosage forms.

• However, when phenytoin (an antiapileptic drug) suspension is administered during continuous nasogastric feedings, serum conc. Of the drug are markedly reduced.

• Effect of food on the absorption of enteric-coated aspirin tablets versus enteric coated granules that were encapsulated were compared, the plasma salicylate levels from the two formulation were similar under conditions of fasting.

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Drug Absorption…

• However, food differentially affected the absorption of the two formulations.– Granules: absorption not influence by food intake.

– Tablets: absorption (both) decreased and delayed by food intake.

• Several food related changes in gastrointestinal function that also affect drug absorption include:– Change in stomach emptying time

– Change in intestinal motility

– Change in splanchnic blood flow

– Change in the bile secretion as well as gastric acid secretion and

– Digestive enzyme secretion.

• In the past, it was accepted that slowing of gastric emptying time would delay drug absorption, it is now known – varies with the drug.

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Drug Absorption…

• Drugs that have very low water solubility are better absorbed when they remain longer in the stomach, as they will after a meal, particularly a large meal, a hot meal, or a high fat meal.

• Water-insoluble drugs, such as spironolactone (diuretic drug) and griseofulvin (antifungal drug) are better absorbed when taken directly after a meal.

• However, absorption of these water-insoluble drugs, and also carbamazepine (antiparasitic drug) and nitrofurantoin (antibiotic) is improved when the manufacturer increases the rate of dissolution of tablets by reducing particle size as well as when the product is taken after a meal that allows longer residence of the tablet in the stomach, allowing greater time for dissolution.

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Complex Food Effects on Drug Bioavailability

• There are a number of drugs for which the effects of food on absorption may be complex.

• Spironolactone: food not only promotes disintegration of tablets and improves dissolution of the compound, solubility of the drug also improved by contact with the bile salt released in response to food.

• Spironolactone undergoes rapid first-pass metabolism in the intestinal mucosa and is converted into canrenone, which then absorbed in the body.

• Absorption of canrenone is enhanced when the drug is taken after food.

• It is known that ingestion of food reduces the absorption of isoniazid, due to food-related slowing in gastric emptying so that there is a delay in the entry of the drug into small intestine from which it is optimally absorbed.

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Complex Food Effects on Drug Bioavailability….

• Alternative explanation: drug interacts with a food substance. Isoniazid may form Schiff-bases with vitamin B6.

• Methyldopa (antihypertensive drug), there are also multiple food effects on bioavailability.

• The drug is a modified neutral amino acid, and as such is competitively absorbed with dietary amino acids.

• Protein-rich meal (beef meal) reduced both the rate and extend of the bioavailability of methyldopa.

• May also explain by an increase of “first-pass” metabolism. Methyldopa is extensively sulfoconjugated in the intestinal mucosa, depend on the level of sulfur-containing amino acids in diet.

• Multifactorial effects of food on drug absorption also considered in relation to the beta block drug, propranolol and metaprolol.

• Both of these drugs are better absorbed after food.

• Explained as being due to food-related increase in splanchnic blood flow, together with reduced first-pass metabolism of these drugs either in the intestinal mucosa or in the liver.

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Dietary Effects on Drug Metabolism

• Liver is the main site for drug metabolism.

• There is extensive intestinal drug metabolism, with involvement of mucosal enzymes as well as the intestinal microflora.

• The metabolism of environmental chemicals, including therapeutic drugs, and of endogenous chemicals, such as steroids and indoles, is primarily by the microsomal mixed function oxidase system and also by conjugated system present within the cell cytosol.

• The mixed function oxidase system catalyzes oxidative reactions (Phase I reactions) by electron transfer systems in which cytochrome P450 is the terminal oxidase.

• Phase I metasbolism of drugs

• Drug Oxidation, reduction and/or hydrolysis products.

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Dietary Effects on Drug Metabolism….

• In conjugating system, drugs or other oxidized metabolites are converted to glucuronides, ester sulfates, gluthathione conjugates, or other conjugates (Phase II reactions)

• Phase II metaboism of drugs

• Drug or phase I products ------- synthetic reaction --- Conjugate e.g., glucuronide, sulfate, acetylated derivative.

• Reactions of phase I and II both occur in the liver and in the intestinal mucosa.

• Dietary factors can influence the rate of drug metabolism, as well as the metabolites produced.

• Clinical Observations: Hospitalized children with Asthma.

• Rate of theophylline catabolism is increased, when a high protein diet is fed, as contrast to the rate of catabolism of this drug when a high carbohydrate diet is fed.

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• Clinical important of the study

• It was noted that asthmatic episodes were less frequent when the children were receiving a high carbohydrate, low protein diet. Associated with maintenance of therapeutic levels of theophylline in the plasma.

• Rate of drug (antipyrine or theophylline) elimination (as measured by plasma half-life) was slowest when the high carbohydrate diet was fed and fastest during the high protein period.

• When the high fat diet was fed, there was a small decrease in the rate of antipyrine loss but not with theophylline.

• Natural, non-nutrient components of the diet may exert a profond influence on the rate of drug metabolism, and these effects may occur rapidly after food ingestion.

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• Indolic compounds in vegetables of the brassica family, including cabbage or brussels sprouts, stimulate the rate of human drug metabolism.

• The metabolism of zoxazolamine to 6-hydroxy-zoxazolamine by liver microsomes from neonatal rats can be stimulated 7-fold by the in vitro addition of a flavone. Flavones (bioflavonoids) are naturally occurring compounds present in citrus and other fruits.

• Inhibition of drug metabolism can be brought about by administration of pharmacologic doses of nutrients.

• Anticoagulant activity of drugs such as warfarin, resist by intake of vitamin K in liquid nutrition preparations.

• When mega-doses of vitamin E are ingested by patients receiving moderate doses of warfarin to maintain vitamin K-dependent coagulation factors in a certain range, vitamin E may further depress the levels of these factors, with subsequent hemorrhage.

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• Vitamin E also decrease prothrombin levels in mildly vitamin K-deficient and warfarin treated rats.

• DL-α-tocopherolquinone (a metabolite of DL-α-tocopherol) caused hemmorhage and fetal loss in pregnant mice and inhibits vitamin K-dependent carboxylase in vitro.

• Therefore, there is evidence that vitamin E in pharmacologic doses acts as a vitamin K antagonist.

• These various effects on drug metabolism are summarized in Table 18-11.

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Effects of Drugs and Food Chemicals on Vitamin Absorption

• Promote vitamin absorption

• Vitamin absorption can be the outcome of:– direct interactions or

– changes in gastrointestinal function, including motility and secretion or

– changes in the transport of vitamins across the GI mucosa

• The effects of these factors on absorption of three vitamins (folic acid, riboflavin and vitamin B12) are summarized in Table 18-12.

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Folic Acid

• It is suggested that the effect of glucose is on the passive absorption of folic acid, though the possibility of an enhancement of active transport was not excluded

• The glucose polymer enhances the rate of intestinal uptake of folic acid but does not cause a net increase in folate absorption into blood.

• Several drugs have been shown to reduce folate absorption. These include antacids, sodium bicarbonate.

• Sulfasalazine, which has been extensively used in the treatment of inflammatorty bowel disease, including regional enteritis and ulcerative colitis, cause folate malabsorption.

• Inhibitory effect of sulfasalazine on the intestinal transport of folic acid may be explained by inhibition of intestinal folate enzymes: dihydrofolate reductase, serine transhydroxymethylase, methylene tetrahydrofolate reductase which required to transport of folic acid in intestine.

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Riboflavin

• Factors that influence the absorption of pharmacological doses of riboflavin include:– the form of the vitamin,

– doses,

– the formulation,

– the vehicle used and

– whether or not the vitamin is taken with food or a phosphate-containing beverage.

• Stomach emptying time, gut motility, and gastrointestinal exocrine secretion all influence riboflavin absorption and food or beverage related effects on riboflavin uptake are explain by physiological effects of these on GI functions.

• When encapsulated forms of riboflavin are used, efficiency of absorption is dependent on the diluent used for the vitamin.

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Riboflavin….

• Riboflavin absorption was greater if the diluent in the capsule was lactose rather than koolin.

• Also tablet disintegration time had a marked effect on the availability of the vitamin. Preparations that have a very slow disintegration time are poorly absorbed.

• Factors known to increase the absorption include the form of the vitamin, such as, FMN is better absorbed than free riboflavin, which is better absorbed than FAD.

• FMN > riboflavin > FAD

• Solutions are better absorbed than solid preparations, though this formulation factor mainly affects the rate of absorption, in that solutions are absorbed more rapidly than solid vitamin products.

• Absorption of riboflavin is promoted by concurrent intake of specific drugs.

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Riboflavin….

• A cola type product used for its antiemetic effects and containing sugar and phosphoric acid has been shown to enhance the absorption of pharmacological quantities of riboflavin, as reflected by changes in the urinary excretion of the load dose of this vitamin.

• Absorption of riboflavin as FMN is prolonged and increased by the anticholinergic drug: propantheline bromide, which slows gastric emptying.

• Vitamin absorption also enhanced by a glucose polymer that retards dissolution of riboflavin and also slows gastric emptying.

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Vitamin B12

• Efficient absorption requires normal gastric functioning, including synthesis and release of HCl and pepsin, as well as production of gastric intrinsic factor (GIF), intact pancreatic exocrine function, adequate binding of the B12-GIF complex to the ileal absorption site and synthesis of transcobalamin II, which is necessary for the initial transport of vitamin B12.

• The non-ionic surfactants: polysorbate 80, polysorbate 85 (polyoxyethylene sorbitan trioleate), and G1096 (polyoxyethylene sorbitan hexaoleate) promoted vitamin B12 absorption.

• It was postulated that this was due to the formation of a very viscous mass in the gastric and intestinal lumen that delayed gastric emptying and therefore enhanced the absorption of the vitamin.

• Polyoxyethylene sorbitans are used as food emulsifiers.

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Vitamin B12….

• In theory, vitamin B12 malabsorption could be due to interference with any of the functions necessary for efficient absorption of the vitamin.

• Drug-induced inhibition of gastric secretions or to drug-induced reduction in the binding of the B12-GIF complex to the ileal absorption site.

• Cimetidine reduces the absorption of food-bound (protein-bound) vitamin B12; due to combined inhibitory effects of the drug on secretion of GIF and gastric acid.

• Cholestyramine (the bile acid-adsorbing resin) reduce vitamin B12 absorption. Decrease the uptake of vitamin by binding sites on the intrinsic factor molecule, which normally bind vitamin B12.

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Vitamin B12….

• Vitamin B12 deficiency would only be likely to occur if an individual with depleted vitamin B12 stores were to take cholestyramine on a long-term and regular dosage schedule.

• Biguanides, such as metformin and phenformin, which were once used in the treatment of insulin-independent diabetes, induce vitamin B12 malabsorption.

• Biguanide-induced malabsorption of vitamin B12 could be due to competitive inhibition of vitamin absorption in the distal ileum or to drug inactivation of vitamin B12.

• Vitamin B12 malabsorption can also be chemically induced by drugs such as neomycin and colchicine, which cause ileal mucosal damage and may therefore interfere with binding of the B12-GIF complex.

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Absorption of Drugs: Food Interaction

• Foods may influence the bioavailability of drugs by

– direct binding of drugs to substances in the food

– by altering luminal pH, gastric emptying and intestinal transit time

– through mucosal absorption, chemical interactions, hepatic blood flow.

• Large meals and fluid volumes tend to influence absorption much more than small meals.

• Relative proportions of fat, protein and carbohydrates may have different effects.

• For drugs which are influenced by food intake drug absorption is inversely related to the time gap between eating and dosing, being maximal when the drug is taken immediately after the meals.

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Absorption of Drugs: Food Interaction…

• There is considerable amount of information on the effects of food on drug absorption and bioavailability. Foods can either enhance or decrease the availability of drugs.

• The bioavailability is of clinical significance for drugs with narrow therapeutic index, with well-defined therapeutic levels, for those which have dose-dependent metabolism and those that are likely to have profound clinical consequences.

• For drugs with wider therapeutic index and poor dose-response relationships alterations in absorption are less important.

• Solutions and suspensions are less susceptible to food interactions than other dosage forms because of their diffuse nature and greater mobility in the gastrointestinal tract.

• On the other hand, enteric-coated preparations are more susceptible to food interactions as retention in the stomach delays drug release from these forms.

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Absorption of Drugs: Food Interaction…

• Longer retention in the stomach generally increases drug absorption.

• For drugs with are basic in nature and absorbed by saturable mechanisms, absorption increases by prolonged gastric emptying time; while the acidic compounds are labile and therefore excessive degradation in the stomach may reduce absorption.

• Thus the acidic or basic nature of the drugs, the lypophilicity of the drug formulation and the response of gastric intestinal enzymes to food ingestion will determine the ultimate amount of the drug absorbed.

• The pH of gastric contents and hence the ionization of the drug will tend to alter with food ingestion. In addition, chelation, adsorption and alterations in blood flow induced by food will considerably modify drug concentrations in systemic circulation.

• A list of drugs whose absorption is influence by food is given in Table 3.

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Protein Binding and Distribution

• Drug protein binding in plasma is reduced in the presence of other ligands, amino acids, vitamins, and fatty acids which compete for the same protein binding.

• Many endogenous substrates, such as free fatty acids, steroids, thyroid hormones, tryptophan and uric acid bind to albumin and thus in malnutrition may result in altered binding of other drugs.

• The changes in the protein binding have been shown to contribute to vital parameters such as volume of distribution, half life and drug elimination by hepatic and renal tissues.

• Decrease binding of drugs in plasma can result in elevated free concentrations or formation of reactive substances in the tissues with more toxic properties.

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Protein Binding and Distribution…

• The efficacy of the drug under such circumstances can be enhanced provided the drug metabolizing system in tissue is saturated. Otherwise the free drug will be metabolized and eliminated.

• Alterations in dosage modifications are necessary only in situations where significant changes are observed in highly protein-bound drugs with narrow margin of safety.

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Biotransformation of Drugs in Malnutrition

• In experimental situation nutritional stress has often been shown to alter the activity of several detoxifying enzymes. However, these alterations are dependent on species, stress, age, sex and type, degree and duration of nutritional deprivation and on the substrate being investigated.

• In general, all deficiencies except thiamin deficiency, decrease the enzyme activities whereas general starvation appears to increase the metabolism of certain drugs.

• Toxicities of xenobiotics are enhanced in protein-deficient animals. However, due to variations in species and response to stress, these cannot be extrapolated to human.

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Drug Oxidation and Conjugation in Malnutrition

• Drug oxidations in protein energy malnutrition (PEM) such as Kwashiorkor and Marasmus in children and in famine oedema in adults have been found to be impaired and therefore clearance of drugs from the body is reduced.

• Antipyrine, phenylbutazone and theophylline can accumulate in severe forms of malnutrition.

• On the other hand, in mild and moderate forms of adult malnutrition, metabolism is enhanced in the liver and the steady state levels of drugs are reduced due to faster elimination from the body.

• Drug conjugations in malnourished children are impaired. Clearance of drugs such as chloramphenicol, paracetamol, sulfadiazine and isoniazid is`reduced and therefore the steady state concentrations build up in moderate/severe states of malnutrition. 51

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Drug Oxidation and Conjugation in Malnutrition…

• In adults, however, conjugation including that of steroidal contraceptives is not impaired.

• Thus the drug oxidations and conjugations appear to be related to the severity and the age at which the dietary deficiency occurs.

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Macronutrients and Drug Oxidations

• Several metabolic experiments on varying intakes of energy and protein on the metabolism of drugs such as antipyrine, theophylline and propranolol suggest that very low protein diets which provide not more than 5% of protein energy, reduce the activity of drug metabolizing enzymes and consequently the clearance of drugs from the body.

• When dietary protein contributes more than 20% energy, it induces the enzymes leading to faster metabolism and clearance of the drugs.

• Thus the metabolic experiments and the natural deficiency situations suggest that drug doses in severe states of malnutrition need to be reduced, while in milder forms no alterations are required.

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Elimination of the Drug by the Kidney

• Renal excretion of drugs such as penicillin and cefoxitin is reduced in kwashiorkor.

• Clearance of drugs such as gentamicin, streptomycin and tobramycin is delayed in severe states of malnutrition indicating the need for dosage adjustment.

• On the other hand, in mild and moderate forms of adult malnutrition, drug clearance by the kidney is enhanced.

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Poor Nutrition and Drugs

• Drugs are transported in the blood by binding to specific sites on the protein molecule.

• The effect of administered drugs depends on whether the protein binding site is already utilized or free.

• Drugs that are excreted by the kidneys are eliminated quicker when there is less binding to albumin.

• In severely malnourished subjects the microsomal enzyme activity of the liver is impaired and drugs are not metabolized; this increases the drug blood level.

• The metabolism of chloramphenicol and antipyrine in the malnourished liver is greatly reduced.

• In kwashiorkor, if chloramphenicol and paracetamol are administered together, the half-life of the former is increased from normal 2-3 hours to 18-24 hours, which may prove toxic.

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Poor Nutrition and Drugs...

• Tetracycline absorption and albumin-binding are also decreased. The drug does not undergo any liver metabolism and is readily excreted unchanged through the kidneys; it is therefore administered every four hours.

• However, patients with nutritional edema due to poor kidney excretion tend to retain tetracycline.

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Effects of Foods on Drug: Examples

• Some drugs should be taken half-an-hour to 1 hour before meals because food or gastric acid would compromise their absorption.

• Examples: oral penicillin, ampicillin, tetracycline, rifampicin and isoniazid.

• Penicillins are acid-sensitive, tetracyclines are chelated by calcium in milk and dairy foods.

• Most drugs and medicines, however, are best taken with or just after meals, either for convenience or because they can be gastric irritants.

• Examples: aspirin, metranidazole, phenothiazines, haloperidol, thiazides, theophylline.

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Effects of Food on Drug: Examples …

• A few drugs are absorbed better when taken with meal. The absorption of griseofulvin and etretinate is enhanced by fatty meals.

• The bioavailability of some drugs that are subject to considerable ‘first-phase’ metabolism is increased by simultaneous food ingestion.

• Examples: Alprenolol, metoprolol, labetolol and nitrofurantoin. Cyclosporin and dicoumarol are also better absorbed when taken with food.

• Absorption of iron tablets is enhanced if they are taken with fruit juice, but the tannic acid in tea tends to interfere with iron absorption.

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Effects of Nutrition on Drug: Examples

• The nutritional state or dietary components taken regularly can affect the metabolism of some drugs.

• Drugs and malnutrition: Dosages for malnourished people should at least be adjusted for body weight.

• Many antibiotics are given to children in the form of esters, in syrups. If pancreatic function is insufficient (as occurs in severe PEM) the ester may not be split, or be hydrolyzed only slowly.

• After absorption, if plasma albumin is much reduced, a drug that is mostly protein-bound may be more active because a larger fraction is free in the plasma.

• The plasma level may be higher than expected for the dose if metabolism or excretion are impaired because of dysfunction of the liver or kidneys.

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Effects of Nutrition on Drug: Examples...

• In severe PEM, after oral administration, absorption of chloramphenical, chloroquine, tetracycline and rifampicin is delayed or reduced.

• Serum from kwashiorkor patients has shown reduced protein binding of cloxacillin, digoxin, streptomycin, sulphamethoxazole and thiopentone.

• This is potentially dangerous if the free/bound drug ratio is thus increased for digoxin and thiopentone (pentothal), which should be used very cautiously in severe PEM.

• Malnutrition cause reduced rate of oxidation of drugs in the liver.

• Examples: Antipyrine and phenobarbitone.

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Effects of Nutrition on Drug: Examples ….

• Drugs which are removed mainly by conjugation process (Phase II) show prolonged half-life or high plasma concentration due to malnutrition.

• Examples: Chloramphenicol, paracetamol, isoniazid, sulphadiazine and salicylate.

• Also, penicillin and treptomycin blood levels were higher or lasted longer than expected, presumably due to reduced renal clearance.

• Because the antioxidant carotenoids, vitamins C and E, selenium and glutathionine are usually depleted in severe PEM, drugs are more likely to produce toxic features at high plasma levels.

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Effects of particular dietary components on Drug: Examples

• Extra vitamin B6 reduces the effectiveness of levodopa.

• Patients taking oral anticoagulants (warfarin, dicoumarol) should avoid excessive consumption of leafy vegetables, such as spinach, which is high in vitamin K or similar foods.

• On a strict low-sodium diet, the dosage of most antihypertensive drugs needed to achieve a given blood pressure is lower than in patients taking a more usual diet.

• Consuming 200 g cabbage daily showed significant increased metabolism of antipyrine and phenacetin (by 49%).

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Drug Toxicity

• Nutritional status is a strong determinant of drug toxicities. Hypoalbuminaemia in humans is associated with toxic reactions to several drugs. Apart from PEM, depletion of antioxidants which are protective agents, also increases drug toxicity.

• Hepatocellular toxicity of antitubercular drugs in adults and children and of anthracycline toxicity in children are more often encountered in malnourished individuals.

• Toxicity in malnutrition seems to be determined by a balance of events such as chemical nature of the parent compound and its metabolite, alterations in pharmacokinetic parameters and the adequacy of protective factors in diet.

• Malnutrition can predispose to enhanced chemical carcinogenesis and drug-induced nutritional disorders.

• Hence in malnutrition, greater care is required while using drugs.

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Drug Toxicity….

As the undernourished populations are more susceptible to toxic effects of chemicals, carcinogens and other environmental pollutants --

– It is necessary to alter drug doses depending upon the severity of the nutritional status and the alterations in pharmacokinetics

– Drug monitoring is essential in malnutrition to titrate the dose to get the maximum efficacy with minimum side effects.

– Drugs which are highly protein bound, have a narrow margin of safety and when given over prolonged periods of time have to be carefully administered and plasma concentrations monitored.

– Organ toxicity such as liver and kidney need to be carefully assessed.

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Effects of Drug on Nutrition

• Nutrient-drug interactions as indicated earlier can result in nutritional deficiencies. Hence it is necessary to consider drug effects on nutritional status.

• The risk of drug induced nutritional deficiency varies depending on the chemistry and pharmacological action of the drug concerned.

• Many prescription drugs are known to precipitate nutrient deficiencies and such potential adverse effects are not always noted by the health care providers.

• The modification of the nutritional status by drugs is determined by:– prior nutritional status of the individual

– dose of the drug

– duration of treatment

– the drug combinations used for therapy and

– the genetic variability in drug handling.

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Effects of Drug on Nutrition …

• Although nutrient deficiencies due to use of drugs are documented, a shift in the pattern of use of therapeutic agents on the basis of such adverse effects cannot be recommended.

• However, nutrients can be supplemented along with drugs to overcome the problem of nutrient deficiencies. Dietary intakes may need to be adjusted to compensate for adverse reactions.

• Drugs can precipitate nutrient deficiencies, by:– reduction in nutrient intake

– Decrease in nutrient availability

– Inhibition of nutrient transport across the intestine

– Metabolic antagonism

– Increased nutrient catabolism and

– Increased nutrient losses.

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Effects of Drug on Nutrition …

In developing countries where micronutrient deficiencies are widespread, consumption of drugs can further modify vitamin status (Table below). Children, the aged and patients having chronic debilitating disorders are at greater risk.

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Drugs which Affect Food Intake

Appetite regulation and food intake are affected by several drugs.

–Amphetamines and fenfluramine, are used to reduced appetite and decrease body weight.

–Nalaxone antagonists block the appetite stimulating effect of peptides in the brain and thus reduce food intake in humans.

–Drugs which produce nausea and vomiting decrease appetite, e.g. cancer chemotherapeutic agents (methotrexate).

–Many antibiotics decrease the appetite by precipitating gastrointestinal disturbances.

–Substances such as anti-histamines and contraceptive steroids, medroxy progesterone acetate increase the appetite and body weight.

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Drugs which Decrease Absorption

A variety of commonly used drugs impair digestion and absorption of nutrients like amino acids, vitamins and minerals, through

–changes in intestinal motility

–mucosal changes

–specific inhibition of active transport mechanisms

–suppression of bacterial growth and

–intraluminal interactions.

Malabsorptions both primary and secondary produced by drugs can lead to deficiencies of vitamins A, D, E, K, folate and vitamin B12.

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Effects of Drugs on Nutritional State: Examples

• Appetite may be decreased

• Examples: Anorectic drugs (e.g. dexfenfluramine), phenformin, morphine, indomethacin, levodopa, by drugs used for cancer chemotherapy and alter teste (griseofulvin, penicillamine).

• Appetite may be increased

• Examples: Sulphonylureas, oral contraceptives, chlorpromazine, anabolic steroids, corticosteroids and benzodiazepines.

• Malabsorption for more than one nutrient may be induced

• Examples: neomycin, kanamycin, chlortetracycline, colchicine, cholestyramine, indomethacine and methydopa.

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Effects of Drugs on Nutritional State: Examples …

• Carbohydrates

• Blood glucose may be increased. Examples: glucocorticoids, thiazide diuretics, diazoxide, oral contraceptives and phenytoin.

• Hypoglycemia may be produced. Examples: phonylureas, biguanides, propranolol and by alcohol.

• Lipids

• Plasma total cholesterol may be raised. Examples: thiazides, chlorpromazine and some oral contraceptives.

• Plasma total cholesterol may be lowered. Examples: Specific cholesterol-lowering drugs (statins, cholestyramine), aspirin, colchicine, phenformin and sulphinpyrazone.

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• Plasma HDL-cholesterol may be raised. Examples: phenytoin, ethanol, cimetidine, terbutaline and prazosin.

• Plasma HDL-cholesterol may be lowered. Examples: danazol, propranolol and oxprenalol.

• Plasma triglyceride levels may be raised. Examples: propranolol, ethanol and (oestrogenic) oral contraceptives.

• Plasma triglyceride levels may be lowered. Examples: norethidrone (norethisterone) as well as fish oil supplements.

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• Protein

• Nitrogen balance may be made negative. Examples: corticosteroids, vaccines and tetracyclines.

• Nitrogen balance may be made positive. Examples: insulin or anabolic steroids.

• Plasma amino acid levels may be increased. Examples: tranylcypromine, trimethoprim, methotrexate and aspirin.

• Plasma amino acid levels may be lowered. Oral contraceptives.

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• Vitamins

• Thiamin may antagonized by excess ethanol.

• Riboflavin status be lowered by oral contraceptives and by chlorpromazine.

• Niacin may be antagonized by isoniazid.

• Vitamin B6 may be antagonized by isoniazid, penicillamine, oral contraceptives, hydrocortisone, levodopa and piperazine.

• Folate may be antagonized by ethanol, phenytoin, aspirin, cycloserine and cholestyramine.

• Vitamin B12 absorption may be impaired by cimetidine, ranitidine, metformin, colchicine and methotrexate.

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• Vitamin C plasma concentrations are lowered by oral contraceptives, aspirin and tetracyclines. Ascorbic acid excretion is increased by corticosteroids, barbiturates, phenylbutazone, paraldehyde and chlorcyclizine.

• Vitamin A plasma concentration is increased by estrogens and oral contraceptives. Absorption may be reduced by liquid paraffin and cholestyramine.

• Vitamin D status is lowered by anticonvulsants such as phenytoin, phenobarbitone and glutethimide.

• Vitamin K. Purgatives and intestinal antibiotics (e.g. neomycin, tetracyclines, sulphonamides) may remove the vitamin K contribution from colonic bacteria. Salicylates can reduce prothrombin synthesis. Cholestyramine may reduce absorption.

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• Inorganic nutrients (Minerals)

• Potassium. Drugs are important causes of potassium depletion: purgatives and laxatives increase fecal loss;

• thiazide diuretics and furosemide and ethacrynic acid increase renal loss. Other drugs that may increase urinary potassium are carbenicillin, penicillin and glucocorticoids.

• Drugs that raise plasma potassium include ACE inhibitors, spironolactone, succinylcholine and beta-blocking drugs.

• Calcium. Absorption may be increased by aluminium hydroxide or by cholestyramine and decreased by phosphates and corticosteroids.

• Thiazide diuretics decrease urinary calcium.

• Gentamicin, mithramycin, furosemide, actinomycin D and ethacrynic acid can increase urinary calcium excretion.

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• Iron. Allopurinol, fructose and ascorbic acid increase absorption.

• Antacids, phosphates and tetracycline decrease it.

• Iodine. Sulphonylureas, phenylbutazone, amiodarone and lithium can cause goitre; they interfere with iodine uptake in the gland.

• Serum protein-bound iodine is increased by oral contraceptive & potassium iodide and decreased by phenytoin.

• Magnesium. Depletion from increased urinary loss may be produced by thiazides and furosemide, cisplatin, alcohol, gentamicin, amphotericin and cyclosporin.

• Zinc. Depletion from increased urinary excretion may be produced by thiazides and furosemide, cisplatin, alcohol, penicillamine, phenytoin and valproate.

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Suggested Approaches to Minimize Drug-Nutrient Interaction

• Drugs that are recommended to take with food to maximize absorption.

• Examples: Albendazole, amiodarone, griseofulvin, hydralazine, lithium, lovastatin, rifapentine and saquinavir.

• Drugs that should not be taken with food to allow optimal absorption.

• Examples: Ampicillin, ciprofloxacin, isoniazid, norfloxacin, rifampin, tetracycline and voriconazole.

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Influence of Drugs on Nutritional Status

• Drugs can be classified as follows from the point of view of their action on nutritional status:– Drugs affecting appetite and altering food intake

– Drug influencing absorption of nutrients

– Drug influencing the metabolism of nutrients

– Drug influencing the excretion of nutrients

• Drugs affecting appetite and altering food intake

• The most important groups of drugs which influence appetite and hence food intake are:– Anorectic agents used to depress appetite

– Tranquillizing drugs

– Drugs which affect taste

– Drugs causing vomiting and nausea and

– Appetizers

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Influence of Drugs on Nutritional Status…

• Anorectic Drugs: used to diminish appetite in obese subjects so that they will eat less food. They function by acting on the appetite center. Examples: Cyclophosphamide, digoxin, indomethacin, morphine, fluoxetine.

• Drugs affecting taste sensitivity: Some drugs bring about alteration in taste sensitivity. Radiotherapy given to treat carcinoma of the mouth i.e., tongue, tonsils, or nasopharynx reduces taste sensitivity by damaging the taste buds.

• When taking these drugs or radiotherapy for treating carcinoma of the mouth, the patients should be warned of the possible changes of taste sensation and every effort should be made to make the food acceptable to them by increasing the sweetness or sourness of the food. Examples:

• Grisofulrin, antifungal antibiotic, decreased sensitivity

• D-penicillamine, a copper chelating agent, decreased sensitivity

• Clofibrate, an agent used to bind cholesterol in the gastrointestinal tract, decreased sensitivity

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• 5-fluorouracil, a cancer chemotherapeutic agent, alterations in bitter and sour sensitivity; increased sweet sensitivity

• Cocaine and Eucaine, tranquillizers, decreased sweet and bitter sensitivity.

• Drugs causing nausea and vomiting: Some drugs e.g., Nitrofuradantin used for treatment of urinary infection causes nausea and vomiting.

• Many of the drugs used in the chemotherapy of cancer have this effect. The continued intake of such drugs will reduce appetite and food intake. This should be counteracted by taking anti-vomiting drug e.g., vancomycin, oradexon, methotraxete, etc.

• Appetizers: Several tonics containing gastric stimulants and B-vitamins are prescribed by doctors to improve the appetite of patients suffering from various diseases. Such tonics normally improve the appetite and increase the food intake. Examples: Zinc sulphate, pancreatin, B-complex.

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• Drugs affecting absorption of nutrients from intestine: Drugs such as Podophyllin, Jalap and Colocynth – reduced gastrointestinal transit time. Causes greater losses of proteins, fats and minerals in the feces.

• Drugs: Cholestyramine, clofibrate and colestipol, reduce cholesterol absorption and thus lower blood cholesterol level.

• Neomycin cause histological changes in the intestinal mucosa and diminishes absorption of sucrose and xylose.

• Example of drug which affects intestinal transport mechanisms of the mucosa is Colchicine, an anti-inflammatory drug, used in the treatment of gout.

• Patient taking colchicine have• Reduced serum cholesterol levels

• Increased fecal excretion of bile acids, fat, and protein digestion products

• Reduced absorption of vitamin B12.

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• Drugs affecting excretion of nutrients: Some drugs cause excretion of some vitamins by preventing the bindings of the vitamin with the serum protein which transports the vitamin. The free vitamin is excreted in urine.

• Example: Aspirin prevents the binding of folate with the specific protein present in serum and thus cause the excretion of folate in urine.

• Some drugs which acts as chelating agents, e.g., D-penicillamine and EDTA are used to treat Lead and Copper poisoning. These drugs also chelate with other essential metals such as zinc present in the blood and cause zinc deficiency.

• Some diuretics cause a greater loss of the nutrient by preventing its reabsorption in the kidney.

• Examples: Furosemide and Traimterene prevent the reabsorption of calcium in the kidney and cause increased excretion of calcium in urine.

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Oral Contraceptives

• Oral contraceptives have many affects on the nutritional status of the individual. They cause an increase in plasma levels of triglyceride, blood glucose, vitamin A and E.

• They cause increased nitrogen retention.

• Decreased plasma level of Mg, Zn, riboflavin, folic acid, vitamin C, vitamin B12, vitamin B6.

• Decrease in the serotonin content of brain, causes mental depression (observed often in these subjects). Administration of vitamin B6, increased serotonin to normal and depression relieved.

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Interaction between a Drug and Toxic Compound present in Foods

• Some foods contain amines. Cheese rich source of tyramine. Many fruits, e.g., Banana, contain amines.

• When a monoamino oxidase (MAO) inhibitor is used to treat cases of mental depression, the drug block the oxidation of monoamines present in the body.

• Examples: Clonazepem, Amitryptilline, etc.

• The tyramine absorbed from the cheese and other foods will cause marked increase in blood pressure.

• Such foods should be strictly avoided by patients receiving MAO inhibitors.

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Recommended Books

• Nutritional Biochemistry and Metabolism with Clinical Applications. Edited by Maria C. Linder. Lsevier Science Publishing Company Inc., New York, 1985.

• Textbook of Human Nutrition. Editors: Mahtab S. Bamji, N. Pralhad Rao and Vonodini Reddy. Oxford & IBH Publishing Co. Pvt. Ltd., New Delhi, 1996.

• Advanced Textbook on Food and Nutrition. Volume I, By M. Swaminathan, 1998.