Interactions-Readdressing the Issue

8Quality and Accrediations Professional Environmental and Social Governance (ESG) Kolkata Abstract Broadly drugs include all the chemical substances excluding food that affect the bodily processes. The drug is considered to be a medicine if it benefits the body. Whereas, if the drug is injurious to the body, it’s considered as a poison. Therefore, the same chemical can be a boon or curse with respect to the situation, condition of use, dosage and the individual using it. In this contemporary healthcare era, a huge number of medications are formulated each year and new interactions between drugs are reported every now and then. As a result, it is nomore practical for doctors to be dependent on the memory alone to avoid possible drug interactions. Changes in absorption, distribution, metabolism or elimination of drugs are referred to as pharmacokinetic interactions, resulting in alteration in the level of drugs and its metabolites. The effect of drug changes from person to person than expected because it causes different reaction when a drug reacts with the food or dietary supplements they take (drug -food interaction). So, the effect of the drug is altered by means of increasing, decreasing, or producing a new effect which cannot be produced on its own the effect caused by food or dietary supplements. These interactions may occur due to accidental misuse or due to other factors such as lack of knowledge about it. This review provides a comprehensive literature review on various drug interaction. Generally, drug food interactions are neglected and not well defined but it can cause mild to serious effects. However, all clinicians, pharmacists and nurses should be aware of drug interaction to avoid the consequences caused by drug interactions.


INTRODUCTION
B roadly drugs include all the chemical substances excluding food that affect the bodily processes. The drug is considered to be a medicine if it benefits the body. Whereas, if the drug is injurious to the body, it's considered as a poison. Therefore, the same chemical can be a boon or curse with respect to the situation, condition of use, dosage and the individual using it. 1 In this contemporary healthcare era, a huge number of medications are formulated each year and new interactions between drugs are reported every now and then. As a result, it is no more practical for doctors to be dependent on the memory alone to avoid possible drug interactions. 2 The change in efficiency and toxicity of certain drugs in the presence of some other drugs is referred to as drug-drug interactions (DDIs). 3 During a drug-drug interaction, a drug hampers with pharmacodynamics, pharmacokinetic or any pharmaceutical properties of some other drug which subsequently change the net effect of one or both the medication. 4 Apart from the type of drug used, there are certain other factors responsible for an increased incidence rate of DDIs, which includes the number of drugs prescribed, age of the patients and presence of any comorbid conditions in a patient. 5 10-20% of adverse drug reactions is caused as a result of harmful DDIs and requires hospitalization. Especially, the geriatric patients are more susceptible to DDIs with their increasing age, decreased metabolism and the number of medications prescribed. 6 To avoid these DDIs clinical pharmacists contribute significantly to the safety and efficacy of the drug use, and generally they are the first being approached by the patients for medical guidance. Clinical pharmacists are accountable for reviewing the drugs and also, more importantly counselling the patients. Therefore, pharmacist's knowledge of DDIs is important for proper patient's education, improvement in treatment efficiency and avoiding some serious side effects. 7 The possibility of interaction increases, when multiple medications are administered concurrently, such that one drug might affect the other. There might be a positive or negative effect of DDIs on the predictable therapeutic results. A negative effect may deteriorate a patient's state of illness or lead to higher healthcare expenses. 8 DDIs can be classified into: • Pharmacokinetic interactions involving absorption, distribution, metabolism and excretion (ADME), all of which are accompanied to toxicity and management failure.
• Pharmacodynamic interactions are further classifies into: (i) directly effecting the receptor functioning, (ii) interfering with physiological and biological control processes and (iii) additive or opposite pharmacological effect.9

WHAT IS FOOD INTERACTION?
The most common unknown problem observed by a clinical practioner is the interaction between a natural substance and a drug. These interactions are based on similar pharmacokinetic and pharmacodynamics principles as DDIs. Recently numerous fruits and berries have shown to comprise of agents that are known to affect the drug-metabolizing enzymes. An eminent example is grapefruit, sevillian orange, star fruits and polelo, known to have agents inhibiting the most significant enzyme in drug metabolism, that is cytochrome P450 3A4 (CYP3A4). 10 Food interactions are classified into-

• Food-drug interactions • Drug-food interactions
Food interactions that cause delay in absorption is unusual and typically take place with metal ion

Supplementary information
The online version of this article (https://doi.org/10.15520/jcmro.v4i04. 41 4) contains supplementary material, which is available to authorized users.
chelate complex drugs like some cytotoxic agents, oxiquinolones and tetracyclines. On the other hand, another subsequent interaction comprises of circumstances where prolonged management prompts harmful physiological and sometimes pathological changes. Antidiabetic drugs, antipsychotics, corticosteroids and antidepressants can possibly increase appetite which leads to weight gain while drugs like opoids causing nausea have an opposite action. Whereas in some cases the uptake of vitamin K Folic acid absorption is decreased by phenytoin and the mucosal function gets disturbed by antibiotic agents. 11

METHODOLOGY:
Usually drug-drug interactions are well-defined as change in the outcome of one drug after it is being consumed with a different drug. During drug-drug interactions various mechanisms are involved which may cause an increase in the mechanism of any of the drug, an interruption in absorption of either of the drug, reduction in efficiency of drug or an unpredicted adverse drug reaction. The occurrence of interaction escalates when the concurrent use of different drugs become common. 12 There might be positive, lethal or no pharmacological effects between drugs during interaction. Drugdrug interactions can be casually categorized on the basis of physicochemical incompatibility as pharmacokinetic or pharmacodynamics or combination of both. 13

PHARMACOKINETIC DRUG-DRUG INTERACTION
When a drug modifies the absorption, distribution and elimination of another drug (co-administered drug) is referred to as pharmacokinetic drug-drug interactions. Due to these interactions the plasma concentrations may be increased or decreased. These changes can be of variable intensity, but can also results in contraindication of co administration. The several pharmacokinetic interactions include drug transporters, orphan nuclear receptors, drug metabolizing enzyme, controlling the expression of transporters and enzymes at the transcriptional level. When the plasma concentration of drug increases, it is usually related to drug transport inhibition or / and inhibition of enzyme. Similarly, when the plasma concentration of drug decreases, it is as a result of actuation of orphan nuclear receptors with the help of inducers leading to the escalation of drug transporters and enzymes. Induction of drug transport or metabolism takes 7-10 days, whereas the inhibition of drug transport and metabolism is instant, and takes 24-48h. Drugs like rifampin or ritonavir which is both inducers and inhibitors, can cause an increase or decrease in the exposure of co-administered agent (in subject to duration of association). 14 The drug plasma level and its ability to bind to their desired receptors predicts the intensity and duration of drug action. Also, along with the dosage form, the plasma drug concentration is controlled by the rate of absorption, distribution, metabolism and elimination of drugTable 1 . 15

PHARMACODYNAMICS DRUG-DRUG INTERACTION
The formation of a complex is necessary by the drug with its intended receptor or unintended receptor to affect the target or non-target tissues. The effect produced may be intended or unintended. The effect is as a result of the plasma level concentration of a given drug or may be due to the presence of another drug or prolonged usage of one or more drug that led to (a) physiological, (b) pharmacological, or lead to (c) variations in the number of existing receptors or their capability to react, (d) chemical drug interactions, which in turn can be of therapeutic significance. Table 2   When Drug A inhibits the transport of Drug B into hepatocytes and increases its plasma level.
Efflux transporter inhibitors like quinidine with digoxin shows significant clearance changes. 16 When Drug A blocks the transport of Drug B into the intes nal lumen and increases its plasma concentra on.
Verapamil inhibits efflux transporters (P-glycoprotein) increasing plasma concentra on of substrates like cyclosporine and digoxin.

METABOLISM
When Drug A induces a CYP450 isoenzyme which is responsible for the s mula on of metabolism of Drug B.
Phenobarbital increases the rate of metabolism of warfarin resul ng in decrease an coagulant ac vity.
When Drug A induces a CYP450 isoenzyme which is responsible for the inhibi on of metabolism of Drug B.
Erythromycin strongly inhibits CYP3A4, major enzyme responsible for sildenafil metabolism.
When Drug A inhibits CYP450independent oxida on and causes accumula on of toxic intermediary metabolites of Drug B.
Suni nib when concomitantly used with CYP3A4 inhibitors (clarithromycin, erythromycin) results in risk of dermatological toxici es, due to decreased metabolism of suni nib.17 RE-NAL CLEAR-ANCE When Drug A competes for renal transport with Drug B and increases its elimina on half-life.
By causing sodium loss, diure cs can reduce the renal clearance of lithium, and increase lithium reten on, with poten al toxicity.  When Drug A is administered chronically, it reduces the number of its own receptors and/or modifies the adaptability of receptors to physical events.
The decrease in number of insulin receptor during a extended exposure to insulin. The surface receptors for insulin gradually decreases by receptor internaliza on and degrada on brought about by increased hormonal binding.18 When Drug A is administered chronically, it increases the number of its own receptors and/or modifies the adaptability of receptors to physical events.
The increase in number of receptors for nico ne upon chronic exposure to nico ne, despite nico ne being an agonist.18 PHAR-MA-CO-LOG-ICAL When an antagonist (Drug A) and an agonist (Drug B) compete for the similar receptor site and as a result of their respec ve concentra on, they either produce (agonist) or prevent (antagonist) an effect.
Concurrent use of epinephrine and β1-adrenergic receptors: Subsequently the β1-adrenergic receptors are blocked; unopposed α1-adrenergic receptor ac va on by epinephrine possibly can cause hypertensive reac on.

PHYSIOLOGICAL
When Drug A and Drug B interact with different receptors and improve each other's ac ons through different cellular mechanism.
Alcohol enhances analgesic ac vity of aspirin When Drug A and Drug B interact with different receptors and produce opposite effects through different cellular mechanism.
Salicylates decreases the ability of platelets to aggregate thus impairing the Homeostasis if warfarin induced bleeding occurs.

CHEM-ICAL
When Drug A interacts with Drug B and averts Drug B from interac ng with its intended receptor.
When ethanol interacts with seda ves, ethanol averts seda ve from interac ng with its intended receptor.
other new chemical drugs. These products are categorized as dietary supplements with pharmacological properties, yet have potential to cause harmful side effects. The term 'Herbal products' commonly involves preparations obtained from herbs, roots, leaves, spices, stems and other materials of natural source. These include products prescribed therapeutically or OTC (over-the-counter) medications or used as cosmetics or applied topically. 19 It has turned out to be challenging to identify the probability of herb drug interaction, due to the following reasons: Changes in absorption, distribution, metabolism or elimination of drugs are referred to as pharmacokinetic interactions, resulting in alteration in the level of drugs and its metabolites.
• Herb-Drug Interaction at Absorption Level: • Herbs Interactions on Efflux transporters: Efflux of herbal drugs in contrary to a sharp concentration gradient is mediated by ABC (ATP binding cassette) transporters, typically sited in the canalicular membrane of intestinal epithelium, kidney, liver or endothelial cells of blood capillaries of brain.11 These transporters are comparatively easily modified by factors like drugs and herbal medications, foods and drinks.The efflux transporters also play a vital role in restraining the influx of xenobiotics, hence inhibiting the intracellular build-up of their substrates. The interaction of herbs and the activity of efflux transporters may be avoided by competitive and/or non-competitive mechanisms, which eventually leads to potential toxic blood plasma concentration of the substrates. Also, it may lead to treatment failure through induction of efflux transporters by the herbal substrates.23 The examples are-P-Glycoprotein (P-gp): P-glycoprotein play a vital role in oral drug absorption and reduces the bioavailability due to intact drug molecules are driven back to the gastrointestinal tract lumen and are exposed several times to enterocyte metabolism using Adenosine Triphosphate as an energy source.13P-gp plays a significant part in regulation of absorption, distribution, elimination and reabsorption of clinically active therapeutic agents. Therefore, variation in P-gp by herbal products involves direct interaction with one or more binding site on P-gp molecules.25 For example: Grapefruit juice inhibits P-gp rhodamine-123 efflux in-vivo in healthy individuals and in-vitro in Caco-2 cells. It was observed that the bioavailability of nifedipine increases in-vivo in rats and talinolol in-vitro in Caco-2 cells. 26 Multi-Drug Resistance-Associated Protein-2 (MRP2): The expression of MRP2 is relatively high in proximal and very little in distal region of human intestines. It is found in several cancer cells and tumors. It is also responsible for biliary secretion of organic anions like campyothecin and acetaminophen glucuronide.27\Breast Cancer Resistance Protein (BCRP): BCRP is also known as mitoxantrone resistance gene, found in several tumor cells and also in normal human tissues. It causes resistance to few narrow spectrum anticancer drugs.28 For example: Flavonoids such as biochaninA, apigenin, kaempferol from Silybummarianumincreases the buildup of mitoxantrone by inhibiting BCRP. 29 Uptake These interactions involve the pharmacological responses like mechanism of action and altered physiological responses of drugs on body and changes in relation of concentration of drug-to-drug action. Herb-drug pharmacodynamics interactions involve pharmacological changes of drugs through synergistic, antagonistic or additive effects. 40 Any herbal medicine may be a mixture of several ingredients with unknown biological mechanisms, thus an herbal preparation can possibly increase, decrease or mimic the pharmacological effects of co-administered drugs by effecting on similar drug targets. 41 Undesirable effects may cause drug target toxicity, if the drug used concurrently with herbal drug is increased synergistically or additively.
For example: Herbal medicines like ginger, garlic chamomile may increase the anticoagulant activity of warfarin. 42

DRUG FOOD INTERACTION
The effect of drug changes from person to person than expected because it causes different reaction when a drug reacts with the food or dietary supplements they take (drug -food interaction). So, the effect of the drug is altered by means of increasing, decreasing, or producing a new effect which cannot be produced on its own the effect caused by food or dietary supplements. These interactions may occur due to accidental misuse or due to other factors such as lack of knowledge about it. Food-drug interactions occur when drugs or food when taken simultaneously can cause change in the mechanism of the body to metabolize or utilize a food or drug and can cause side effects. Changes in the pharmacodynamic, pharmacokinetic or on pharmaceutical factors are the ones which products clinically significant drug interactions. They can cause benefit or cause adverse drug reactions. 43  sphere of the blood circulation and lymphatic system. The delivery of lipids and the metabolism and tissue uptake of lipoprotein lipids is altered after a meal. Changes in the binding of plasma protein adversely affect those with a small clinical window where clearance is high and hence changes in free plasma concentration.

Plasma Protein Binding
Albumin is the most abundant plasma protein (3.5-5 g/dL concentration) and the most common protein to which plasma drugs bind. While present in far lower amounts than albumin (0.04-0.1 g/dL), alpha-1 acidic glycoprotein (AAG) is the second major plasma protein that binds to narcotics. For some endogenous compounds, some other proteins have particular affinities and can bind to specific drugs. There are two key albumin drug binding sites, site I (also known as the warfarin binding site) and site II (the benzodiazepine binding site). Albumin and AAG concentrations can be affected by changes in diet status. Albumin and AAG concentrations may be decreased by starvation and cachexia, whereas a high protein diet may increase plasma protein concentrations Dietary components and metabolites can also have a possible effect on drug binding to plasma proteins. For starters, fatty acids are strongly bound to albumin, and the binding of drugs to albumin will allosterically modulate changes in fatty acid concentration.

Food effects on metabolism
The effect of drug-metabolising enzymes and drug transporters may be altered by food components. The most well-known example is that grapefruit juice inhibits the metabolism of CYP3A substrates. CYP3A enzyme inducers may also activate essential food intake interactions.

Food effects one elimination
In addition, nutrition will modify the end by modifying urinary pH alkalinization processes due to drain admissions, vegan calories count or due to fermentation caused by a very rich protein diet. The changes in pee pH can contribute to a difference in the pharmacokinetics of medications disposed of by the kidneys when the non-ionized shape is reabsorbed during glomerular filtration or discharge. For example, it is recommended that calorie count should be maintained relentlessly in memantine administration as its pharmacokinetic profile is fundamentally impaired by pH.

Does drug food interaction be considered serious?
Food-drug reactions may have detrimental impacts on the efficacy and effectiveness of drug treatment, as well as on the patient's nutritional status. Generally speaking, medication reactions, owing to the risk of bad or unexpected effects, should be discouraged. Like food, via the lining of the stomach or the small intestine, medicines ingested by mouth must be swallowed. Consequently, absorption of a drug may be decreased by the presence of food in the digestive tract. Sometimes, by taking the medication 1 hour before or 2 hours after feeding, such interactions can be prevented. Like medications, foods are not checked as closely enough that they can compete with prescription or over-the-counter medicines. 49 Drug-food interactions can result in decreased drug effectiveness or increased drug toxicity in hospitalised patients. The increasing complexity of drug therapy regimens has raised the possibility for drugfood reactions to arise, highlighting the need to improve strategies to reduce drug-food interactions of therapeutic importance.
Until choosing the best approach, medications with the potential for clinically relevant reactions with food must be defined in terms of viability of adoption and efficient result. 50

Drug Alcohol Interaction
Ethanol and drugs can influence each other's assimilation, dispersion, digestion system, and excretion. When ingested together, ethanol can increment medicate retention by improving the gastric solvency of drugs and by expanding gastrointestinal blood stream. In any case, tall concentrations of ethanol actuate gastric bothering causing a pyloric fit which in turn may delay medicate retention and/or decrease bioavailability. The 'quality' of the alcoholic refreshment, autonomous of its ethanol substance, can contribute to changed retention of a medicate.
Ethanol is not deeply bound to plasma proteins sufficiently to change the delivery of drugs. Serum albumin levels can, however, be abnormally low in chronic alcoholics, so that certain medications, such as diazepam, have an increased delivery rate.
In addition to the consumed volume, ethanol has an effect on the metabolism of the medication on the duration of its daily intake. Acute ethanol intake prevents the metabolism of many medications, but high-level ethanol intake over the long term (> 200g of pure ethanol per day) will cause liver enzymes to more effectively metabolise drugs. There are actually no reliable methods, with the potential exception of liver biopsy, of scientifically predicting the ability of alcoholics to use metabolic drugs. Several medications can inhibit the metabolism of ethanol at the stage of alcohol dehydrogenase. The magnitude of this drug-ethanol reaction is determined by human predisposition.
Ethanol prevents antidiuretic hormone production during the ingestion process and is also capable of causing accelerated excretion of a drug through the kidneys. However, chronic alcoholics with water accumulation may have decreased opioid excretion through this method.
At the pharmacodynamic stage, ethanol will intensify the deleterious effects on efficiency of sedatives, some anxiolytics, sedative antidepressants and antipsychotics, and anticholinergic agents.
There is a lack of knowledge mechanism of lethal associations between mild and overdose ethanol / opioid / sedation. Any peptides,' unspecific' stimulants, dopaminergic agents and opiate antagonists, on the other hand, can substantially antagonise alcoholinduced intoxication. 51 The acute high dose of rapidly administered alcohol reduces the metabolism of microsomal drugs and thus increases opioid effects. The synthesis of Cytochrome P-450 isoenzyme P-450 II E1 typically results with chronic alcohol administration, thereby accelerating the metabolism of the organism and of different drugs depending of circumstances. The agents will then reduce their actions. When a drug (eg. paracetamol) is poisonous, it will paradoxically decrease the drug effect, whereas chronic consumption of alcohol is increased by development of active metabolites.
The induction by alcohol of hepatic enzymes may influence the turnover of endogenous vitamins and hormones or even the development of carcinogenic agents.
The drug classes that associate substantially with ethanol include: 1. Depressants of the central nervous system (hypnotics, antidepressants, psychotropic medications, H1-antihistamines, anticonvulsants), the cumulative effects of which are often additive and without any substantial pharmacokinetic component; 2. Antabuse-provoking reaction agents (disulfiram, carbimide, etc.); 3. Vasodilating agents, which can result in an abrupt breakdown; 4. Anti-diabetic pharmaceutical products (poor diabetes control; antabuse reaction); 5. Anticoagulants with coumarin (instable kinetics during drinking spells); 6. Non-steroidal (gastrointestinal toxicity, core associations possible) anti-inflammatory drugs; The collective activities of groups 1 and 2 impact the nervous system. 52

COMMON FOOD INTERACTIONS WITH OTC MEDICATIONS:
The drug which are available without prescriptions are called as Over-the-counter (OTC) medications. Interactions between food and drugs may unintentionally increase or decrease the effect of drug. Most common food includes some herbs, fruits as well as alcohol which may cause unsuccessful therapy and some severe alteration in the health of the patient. Most of the clinically related food-drug interactions are caused by food-induced alterations in the drug's bioavailability.

MOST DANGEROUS FOOD-DRUG (PRE-SCRIBED) INTERACTIONS:Table 5 PREVENTIVE STRATAGIES TO AVOID FOOD-DRUG INTERACTIONS BY CLINICAL PHARMACIST
Avoidance of adverse effects from food-drug-herb interactions may require clinical monitoring in highrisk regimens and populations especially in geriatrics. Both diet history and drug history required for counselling the patients to avoid food-drug interactions. 67 Conventionally, food and drug interactions are recognized when a food or nutrient interferes/alters the action of a drug, especially in the inpatient where monitoring results in rapid diagnosis of therapeutic failure. The reverse situation that is when a drug interferes with nutritional status, it is not easy to be diagnosed, recognized or monitored. Diagnosis of food-drug interactions may even more slowly in the outpatient for several reasons. 68 Above 30% of all the drugs with prescription are found to be taken by Geriatrics. 69 Use of over-thecounter (OTC) drugs is also highest in Geriatrics. 70 Malnutrition status can also hinder with effectiveness of drug or drug release leading to a great risk of drug toxicity. 71 Clinical pharmacists need to be attentive and cautious in observing for possible drug-food interactions and counselling patients regarding their foods or beverages that should avoid when taking certain medications. It is essential for clinical pharmacists to keep up to-date knowledge on possible drugfood interactions of medications. In providing drug information to patients, clinical pharmacists should discuss possible side effects and the way to take medication. 72 It is essential to give information to patients on their medications with related to intake of food. Major consequences of food-drug interactions include decreased, increased or delayed absorption of the drug. Food may also affect the pharmacokinetics (bioavailability, metabolism and excretion) of many drugs. The patient also experiences toxicity or an adverse side effect and may not receive the complete therapeutic benefit of the medications. The Joint Commission on the Accreditation of Healthcare Organizations (JCAHO) needs that a patient's drug profile include possible drug-food interactions, that the clinical pharmacist can call the prescriber whenever there is possibility of a food-drug interactions and document the same and follow-up action should be taken on the prescription, after that patients should be given with instructions and counselling regarding the possibility of food-drug interactions before their discharge from the hospital. 73 Geriatric patients may be at a higher risk of developing food-drug interactions because of their typically consumption of more drugs for their chronic medical conditions/illness. A study "Drug-nutrient interactions in long-term care facilities" found a major relationship between the number of medications a patient consumed and the number of drug-nutrient interactions for which a patient was at risk. 74

Guidance and Counselling to minimize Food-Drug Interactions
The below mentioned information can be given to the patients while dispensing the medicine.
• Read the label of prescription on the container.
If you do not understand or you need more information about your medication, ask your pharmacist or physician.
• Read warnings, directions and interaction precautions printed on all medication labels and package inserts carefully. Even overthe-counter (OTC) medications can cause problems.
• Take your medication with a full glass of water to avoid GI irritations.
• Do not stir your medication into your food and do not take capsules apart (unless directed by your physician). Doing this may affect the efficacy of the medication.
• Do not take vitamin pills/multivitamin tablets or capsules at the same time you take medication. Vitamins and minerals also interact with some medications. • Do not mix or stir your medication into hot drinks because the heat from the drink may destroy the effectiveness of the drug and also it causes some adverse effects.
• Never take any of your medication with alcoholic drinks. It causes some serious unwanted and harmful reactions.
• Don not forgets to tell your pharmacist and physician about all medications that you are taking, both prescribed and over-the-counter (OTC).