Download Drug Absorption

Nutrition – Drug Interactions
BMB 505 – Advanced Nutrition and Nutritional
Biochemistry
Yearul Kabir
(Handout #2)
Date: 06.01.2010
1
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.
2
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.
3
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.
4
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
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amoun6t of drug entering circulation (first pass clearance).
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.
6
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.
7
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
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major organ of drug elimination from the body.
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.
9
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.
18
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
19
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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21
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
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insoluble chelates of drugs, such as the tetracyclines (Table 18-4).
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
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the dietitian, a great cooperation between these groups is required.
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.
25
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 28in the
intestinal mucosa or in the liver.
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.
29
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.
30
Dietary Effects on Drug Metabolism….
• 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.
31
Dietary Effects on Drug Metabolism….
• 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
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the levels of these factors, with subsequent hemorrhage.
Dietary Effects on Drug Metabolism….
• Vitamin E also decrease prothrombin levels in mildly vitamin Kdeficient and warfarin treated rats.
• DL-α-tocopherolquinone (a metabolite of DL-α-tocopherol) caused
hemmorhage and fetal loss in pregnant mice and inhibits vitamin Kdependent 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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.
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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 phosphatecontaining 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.
40
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
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from these forms.
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.
46
• A list of drugs whose absorption is influence by food is given in Table 3.
47
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.
48
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.
49
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.
50
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.
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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.
52
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.
54
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.
56
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.
57
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.
58
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.
59
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.
61
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%).
62
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
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assessed.
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.
65
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.
66
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.
69
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.
70
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.
71
Effects of Drugs on Nutritional State: Examples …
• 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.
72
Effects of Drugs on Nutritional State: Examples …
• 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.
73
Effects of Drugs on Nutritional State: Examples …
• 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.
74
Effects of Drugs on Nutritional State: Examples …
• 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.
75
Effects of Drugs on Nutritional State: Examples …
• 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.
76
Effects of Drugs on Nutritional State: Examples …
• 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.
77
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.
78
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
79
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
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tract, decreased sensitivity
Influence of Drugs on Nutritional Status…
• 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.
81
Influence of Drugs on Nutritional Status…
• 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.
82
Influence of Drugs on Nutritional Status…
• 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,
Swaminathan, 1998.
By M.
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