Drug-Drug-Dietary interactions in pharmacotherapy of GIT medication: A review

Successful drug therapy depends on the interaction between drug-drug and drug-diet. Drug interactions are a vital reason for causing adverse drug reactions and modify one drug effect by another drug and these kinds of interactions can increase or decrease the effectiveness of the drug. Polypharmacy could be a major risk for Drug-Drug and Drug-food interactions. Food Consumption can alter the effect of drugs by interfering either with their pharmacokinetics or pharmacodynamics processes. Anti-ulcer drugs are used to treat different types of ulcer and that may interact with another drug showing undesirable effects. GIT medications interfere with another type of medication either with at the pharmacokinetic and pharmacodynamic level. The main objective of this article is to review data regarding common Drug-drug & Drug-food interactions related to GIT medications. Data was collected from Google Scholar, PubMed, and Scopus databases, and they were reviewed for publication on drug-drug&drug-food interactions related to GITmedications. This data is very helpful for pharmacists while reviewing and analyzing prescribed medication, especially in geriatrics prescriptions.


INTRODUCTION
Drug interactions are an important, anonymous root of medication errors, which express a notable risk of harm to patients and opportunities for healthcare systems (Kapadia et al., 2013). Polypharmacy is a major risk of causing drug-drug and Drug-food interactions. Polypharmacy is a term used to de ine the administration of more than 5 drugs at a time. "Potential Drug-Drug Interaction" refers to the drug must alter the effect of another drug, when both drugs are simultaneously administered. This review aims to summarize the Drug-drug & food-drug interactions related to GIT medications. Gastrointestinal drugs are classi ied as Antiulcer drugs cimetidine, ranitidine, omeprazole, misoprostol and sucralfate. Antiemetics are ondansetron, domperidone, metoclopramide. Antidiarrhoeal agents are Ispaghula, atropine, codeine, loperamide, sulfasalazine, etc. Drug interactions are classi ied into 3 main types -Drug-drug, Drug-diet and Drug-herb interactions.

Drug-Food interactions
Numerous individuals have the mixed up idea that being common all types of food and herbs are protected but a few herbs and food may interact with prescription drugs regularly taken bring about genuine side effects. Specialist recommend that natural does not mean it is safe. Medicine that is taken by mouth goes through the stomach related framework similarly as food and herbs taken orally do. At the point when drugs and certain food are taken simultaneously, they can interact so that diminishes the adequacy of ingested tranquilize or decrease the absorption of food nutrients. Furthermore, nutrient and herbal supplements are taken with recommended medicine that can bring about adverse reactions. Drug-food cooperation occurs due to food in luences the substances in medication that the patient is taking in luencing the viability of medication being regulated. Old age patients taking at least 3 medications for chronic conditions such as diabetes, hypertension, elevated cholesterol and congestive heart failure that kind patients should be specially observed for such drug-food interactions.

Drug-Drug interaction
Drug interactions are comprehensively split into pharmacokinetic and pharmacodynamics interactions.

Pharmacokinetic Interaction
Pharmacokinetic interactions occurs when the absorption, distribution, metabolism, elimination process of the one drug is altered by another drug and hence such interactions are also called as ADME interactions.

Pharmacodynamics Interactions
Pharmacodynamics interactions happen because of alteration of the activity of one drug by another drug. This may bring about an improved response (synergism) a constricted response (antagonism) or an abnormal response (Niu et al., 2019).

Proton-pump inhibitors and clopidogrel
Combination of clopidogrel and aspirin was utilized for treatment of coronary heart diseases and diminishing the threat of new coronary ischemic occasions. Some adverse gastrointestinal symptoms associated with clopiodogrel and aspirin. PPIs are used to prevent the gastrointestinal symptoms.
Clopidogrel is a pro drug that should be utilized an intrahepatic two advance oxidative cycle. Cytochrome P450 enzymes (CYP1A2, CYP2B6 and CYP2C19) are required for activation and metabolism of clopiodogrel. CYP1A2, CYP2B6 and CYP2C19 enzymes are required to convert the clopidogrel to 2-oxo-clopidogrel, which is then once more oxidized to convert the clopidogrel active metabolite with the help of CYP2B6, CYP2C19, and CYP3A4. CYP2C19 is by all accounts vital in metabolization and activation of clopidogrel. PPIs are inhibiting CYP2C19 enzyme so, activation of clopidogrel is inhibited. Invitro investigations indicated that Lansoprazole, omeprazole drugs are signi icantly inhibiting the CYP2C19 while pantoprazole and rabeprazole drugs are not signi icantly inhibit CYP2C19. A few pharmacodynamics studies concluded a potential clopidogrel PPI interaction. As a result of this interaction there is a reduction of the clopidogrel platelet anti-aggregation effect. So, cardiovascular risk increases with concurrent administration of clopidogrel and PPIs (Chen et al., 2013).

Cimetidine with benzodiazepines
Cimetidine is H2 receptor antagonist, neutralizes the gastric juices in gastrointestinal tract and rise the pH in GIT. Cimetidine elevates the diazepam and lorazepam absorption because elevated gastric pH may increase the weekly basic benzo diazepines absorption. Plasma levels of benzo diazepines were increases. Drowsiness elevated in patients who are attending utilize the cimetidine with diazepam and Lorazepam (McGowan and Dundee, 1982).

Cimetidine with cardiovascular drugs
Mechanism for cimetidine interaction with another drug is hindrance of hepatic metabolism. Cimetidine inhibits the hepatic microsomal enzymes that enzymes required for metabolism of beta blockers. Cimetidine increases the blood concentration of beta blockers and potentiate the actions of beta blockers. Concomitant administration of cimetidine and nifedipine could alter the pulse rate and blood pressure due to the hindrance of liver oxidative metabolism. Cimetidine used along with lidocaine may increases lidocaine concentration and increases the toxicity of lidocaine because of a lessening in oxidative liver metabolism or liver blood stream. Cimetidine increases the plasma levels of quinidine and leads to toxicity of quinidine. Besides, redesigned arrhythmic effects might be observed. Association probably achieved by an obstacle of hepatic drug metabolism of quinidine by cimetidine. As per literature, vital pharmacokinetic clinical effects on cardiovascular medication have been noted with cimetidine, while ranitidine may not have signi icant kinetics impacts on propranolol, nifedipine, lidocaine, quinidine, procainamide (Saltissi et al., 1981).

Proton-pump, Histamine 2 receptor blockers with vitamin B12
Gastric acid is produced by parietal cells and that gastric acid is used to split vitamin B12 from ingested food. Parietal cells also produce the intrinsic factor and this factor required to absorb the vitamin B12. Gastric acid production decreased by PPIs and histamine receptor blockers and it may lead to malabsorption of vitamin B12 (Miller, 2018).

Magnesium-Aluminium Hydroxide Antacid with Ru loxacin
Ru loxacin is an oral luoroquinolone active against the gram negative and gram positive oxygen consuming microbes. Magnesium and aluminium salts present in the acid neutralizers can decrease the extent to which ru loxacin is absorbed. Mechanism of interaction between antacid and quinolones is by all accounts the formation of chelate complexes between the 3-carboxyl and the 4-oxo substituents of quinolones and metal ions. Aluminium along with quinolones forms a stable complex. Reduction in amount of ru loxacin absorbed is a result of concomitant administration of antacid and possibility of this interaction is dependent on the time gap between administrations of the 2 drugs. To avoid this interaction between antacid and ru loxacin, they should be administered with a time gap of at least 4 hr (Lazzaroni et al., 1993).

Methotrexate with PPIs
Methotrexate poison levels are prompted when this drug is used at high dosages with PPIs for example, omeprazole, esomeprazole, and pantoprazole which diminishes methotrexate clearance resulting in raised serum levels of methotrexate and also its metabolite hydroxyl methotrexate. There are two proposed mechanisms for this obstruction of methotrexate elimination induced by PPIs. The irst mechanism is the presence of H+/K+ ATPase in the renal epithelium just as gastric parietal cells. PPIs inhibit renal H+/K+ ATPase which is required for tubular secretion of methotrexate, bringing about an expanded half-life of methotrexate. Another mechanism includes conceivable PPIs inhibits ATPsubordinate ef lux of methotrexate by BCRP in human kidney proximal tubules. Even though it was shown that PPIs inhibit BCRP mediated transport of methotrexate Invitro, the uncertainty of the clinical importance of this interaction is due to the higher half-maximal inhibitory concentration of PPIs when compared to the therapeutic unbound plasma concentration (Chioukh et al., 2014).

Ketoconazole with sucralfate, H2-receptor blockers, PPIs
Ketoconazole, a drug used to treat the fungal infections is decreasingly absorbed with an increasing gastric pH. Gastric pH increases due to administration of antacids, H2-receptor antagonists and proton pump inhibitors. In contrast, in low gastric pH, Ketoconazole is absorbed easily. Bioavailability of ketoconazole decreases due to concurrent administration of ketoconazole with sucralfate, H2 receptor blockers, PPIs. Concurrent administration of ketoconazole with sucralfate, H2 receptor blockers, PPIs should be avoided. If these agents were to be administered concurrently, there should be a time gap of at least 2 hr between the doses (Hoeschele et al., 1994).

Aluminium hydroxide, famotidine with tosloxacin
Tosu loxacin acts against gram positive and gram negative bacteria, including anaerobic microscopic organisms. Between fasting and non fasting conditions, tosu loxacin is absorbed about 1.4 times higher under non fasting conditions. Area under curve of tosu loxacin was diminished essentially 68.4% by concurrent administration of aluminium hydroxide, while an immaterial impact of simultaneous co-organization of famotidine. Absorption of tos loxacin is not diminished by bivalent cations like Fe+2, Mg+2 and Ca+2 co-organization of different luoroquinolones with metal containing acid neutralizers that may diminish the bioavailability of luoroquinolones is ascribed to cooperation with metal particles, delivering chelated mixes which are less ready to permeate membranes (Granneman et al., 1992). Urinary recovery values are diminished essentially 66% by the simultaneous organization of aluminium hydroxide yet were not in luenced by the co-organization of famotidine. The degree of the communication may shift and retention can be quite diminished, synchronous organization of aluminium hydroxide and tosu loxacin should be avoided. Famotidine may give an option in contrast to acid neutralizers to patients who require oral luoroquinolone treatment.

Sonidegib with esomeprazole
Sonidegib, a drug that was recently promoted widely is used for treating locally progressed basal cell carcinoma, a condition that can't be treated with surgery or radiation treatment. Sonidegib is taken by an oral route and it is a weak base. The solubility of sonidegib depends on pH, lower solubility at pH > 4.5 but PPIs are raises the gastric pH because it inhibits gastric acid production. The bioavailability of sonidegib is decreases due to high gastric pH. Sonidegib plasma concentration is diminished by 32-38% when co-administered with esomeprazole. Some adverse reactions revealed in the combination of sonidegib and esomeprazole i.e. abdominal distension, stomach pain, loose bowels, latulence and regurgitation (Jain et al., 2017).

Pantoprazole with vecuronium
Pantoprazole at low doses has potentiated basal contractile jerk reactions and this was followed by paralysis at higher dosages response to stimulation  (Morcos et al., 2017). Cimetidine Any type of food Bioavailability increases (Hansten, 1992). Cimetidine caffeine Caffeine effects increased due to decreases the metabolism of caffeine by cimetidine (Feely and Wood, 1982). Cimetidine ethanol Metabolism of ethanol is decreased by cimetidine.
There is an increase concentration of ethanol (Hansten, 1992).

H2 receptor antagonists
Nicotine H2 receptor antagonists may reduce the clearance of nicotine. Patients should be noticing the expanded nicotine impacts when utilizing the patches or gum for smoking discontinuance (Bendayan et al., 1990). Esomeprazole Any type of food Any kind of food alter the absorption of esomeprazole. One-hour time gap necessary between consumption of meals and esomeprazole (Jain et al., 2017).

Misoprostol
Any kind of food Food reduces the early high peak plasma concentration of misoprostol acid (Jain et al., 2017). Calcium carbonate Oxalic acid rich containing foods (spinach or rhubarb), phytic acid (bran and whole grains).
Oxalic acid and phytic acid decrease calcium absorption. Require minimum 2 hours time gap between calcium intake and foods rich in oxalic acid or phytic acid (Wohlt et al., 2009). sucralfate Food Obstruction of feeding tubes due to precipitation and formation of bezoars. Insoluble aluminium-protein complex formed between aluminium in the sucralfate and the protein in the enteral feeding (Tait et al., 1994). sucralfate Orange juice Orange juice upgrades sucralfate absorption (Tait et al., 1994).
of rat phrenic nerve, indicating a double activity. It might happen because of weak anticholinesterase activity of pantoprazole. Pantoprazole potentiated the vecuronium induced neuromuscular blockade and it is reversed by neostigmine. Pantoprazole reduces the time for neuromuscular blockade in the cumulative dose response curve of vecuronium, proposing an expected interaction between them. Patel et al. (2010) concluded that the Acute and chronic administration of pantoprazole significantly reduced the time for the head drop (rabbit head drop method) by vecuronium infusion. This gives additional proof that pantoprazole produces a neuromuscular blockade. A proposal was made that patients receiving pantoprazole as a treatment for peptic ulcer or pre-sedative medication should be screened, to prevent prolonged paralysis.

Clopidogrel is co-administered with atorvastatin and lansoprazole
Clopidogrel is used for cardiovascular and cerebro vascular diseases. 2 cytochrome enzymes CYP3A4, CYP2C19 is required for activation of clopidogrel.
Fat soluble statin example atorvastatin is mainly metabolized by CYP3A4 which is required to activate clopidogrel. Drug interaction occurs between clopidogrel and atorvastatin due to binding site competition and this coadministration may inhibit clopidogrel activation and decreases the antiplatelet effect. Lansoprazole also a competitive inhibitor due to it is metabolized by CYP3A4 and CYP2C19. Zhang et al. (2015) concluded that coadministration of clopidogrel, atorvastatin and lansoprazole is safe. Effect of clopidogrel is not decreased due to clopidogrel is metabolized by many CYP450 (CYP1A2, CYP2C9, CYP2D6, CYP3A5). The different combined use of CYP3A4, CYP2C19 inhibitors may not enough to inhibit the metabolism of clopidogrel and fatsoluble statins, lansoprazole. The conclusion of his study is a patient diagnosed with Non-ST-elevation acute coronary syndrome and patients who are simultaneously administered clopidogrel, atorvastatin and lansoprazole, the anti platelet effect of clopidogrel did not decreases and adverse effects did not increase over 6 months.

Lansoprazole with luvoxamine
Gastric acid secretion decreased by lansoprazole due to inhibiting the (H +/K +) -ATPase in gastric parietal cells. Lansoprazole is widely metabolized by CYP2C19 and CYP3A4 to two signi icant metabolites, 5-hydroxylansoprazole and lansoprazole sulphone, respectively. Clinically administered as a racemic mixture of the (R) -and (S) -enantiomers, the plasma concentration of (R) -lansoprazole is considerably higher than those of the (S)lansoprazole enantiomer in both broad metabolizers (EMs) and poor metabolizers (PMs). Fluvoxamine is a speci ic serotonin reuptake inhibitor (SSRI), and it is powerful CYP1A2, CYP2C19 inhibitor. At the point when lansoprazole is Co-administered with luvoxamine, there is increases in the plasma concentration of (S) lansoprazole compared with that of the (R) -enantiomer. Fluvoxamine inhibits the metabolism of lansoprazole and it may lead to signi icantly decreases elimination in extensive metabolizers. As an exception, Lansoprazole when metabolized in extensive metabolizers by CYP3A4, Lansoprazole sulphone is the resulting metabolite because CYP2C19 activity is obstructed by luvoxamine, while in the Poor Metabolizers of CYP2C19, luvoxamine somewhat inhibit the development of lansoprazole sulphone but not signi icantly (Yasui et al., 2004).

Ondansetron with droperidol
Droperidol and ondansetron are the irst line drugs used for the treatment of postoperative nausea and vomiting (PONV). Separately the two medications give rise to the delayed QT interval, the clinical impact of combined treatment might be adjusted by drug interactions and result in increases in the risk of arrhythmia. The collaboration among ondansetron and droperidol was shown the additive effect, the two medications act freely of one another through their particular mechanism of action (Miura et al., 2005).

Lansoprazole and clarithromycin
Clarithromycin a drug used to treat bacterial infections when co-administered with proton pump inhibitors including lansoprazole proves to be highly effective in the eradication of H. pylori. Lansoprazole is metabolized with the help of cytochrome P450 enzymes (CYP2C19, CYP3A4). At higher concentration sulfoxidation of lansoprazole catalysed by CYP3A4 and hydroxylation is catalysed by CYP2C19 at lower concentrations. Potentially clarithromycin inhibits CYP3A4 for this reason potent drug interactions occur with those agents that are metabolized by CYP3A4. Clarithromycin signi icantly expanded the Cmax of lansoprazole in all genotype gatherings and signi icantly delayed the half-life of lansoprazole in Poor metabolizers. CYP2C19 is overwhelmingly engaged with lansoprazole metabolism in extensive metabolizers and CYP3A4 is in Poor metabolizers. The bioavailability of lansoprazole is increased by Clarithromycin and a further study of the mechanism behind it showed the P-glycoprotein mediated transport of Clarithromycin back to the intestinal lumen after absorption was inhibited. Clarithromycin alters the lansoprazole pharmacokinetics due to inhibition of both CYP3A4 and P-glycoprotein in poor metabolizers, only P-glycoprotein inhibition in extensive metabolizers (Dabbous et al., 2001).

Domperidone with ketoconazole
Domperidone is an anti-emetic and prokinetic drug. The high portion intravenous domperidone was related to QTc prolongation and arrhythmias. Domperidone is metabolized by CYP3A4 and a substrate of P-glycoprotein. Ketoconazole is a powerful inhibitor of CYP3A and P-glycoprotein, so a pharmacokinetic interaction occurs between ketoconazole and domperidone. The plasma concentrations of domperidone are increasing three-fold when given with ketoconazole because domperidone metabolism inhibited by ketoconazole. The higher concentration of domperidone rises the QT interval. Domperidone impact alone on QTc prolongation is very less and clinically not signi icant. So, Concurrent administration of dompridone and ketoconazole should be avoided (Saito et al., 2005).

Ondansetron and cisplatin
Cisplatin drug (cationic) excretion requires Human natural cation carrier 2 and multidrug and poison expulsion proteins (MATEs). Cisplatin is an anticancer medication used for the treatment of malignant solid tumours. The major signi icant adverse effect of cisplatin is nephrotoxicity. Excretion transporter's like OCT2 and MATE1 (rodents) and MATE2 (humans) are required for the secretion of cisplatin into the urine and they are present in the apical layer of proximal tubular cells. Ondansetron (5HT-3 receptor antagonist) is active against chemotherapy induced nausea and vomiting especially patients who are taking emetogenic cisplatin-based regimens. Ondansteron is strongly inhibits MATEs than OCTs. The risk of cisplatin induced nephrotoxicity increased due to the powerful restraint of MATEs by ondansetron (Boyce et al., 2012).

Ondansetron and metformin
Metformin is utilized to diminish the glucose level in diabetes patients. Metformin pharmacokinetic parameter values are signi icantly altered by ondansetron. Metformin excretion requires some specialized transporters like OCTs and MATEs. Ondansetron is an inhibitor of MATEs transporters. Around 75% Ondanseteron bound to plasma proteins and remaining 25% unbound drug concentration adequate to inhibit the apical MATEs. The unbound ondansetron has decreased the secretion of metformin into the urine, causing the accumulation of metformin in the plasma. The co-administration of Ondansetron and metformin reliably upgraded the glucose-bringing down impact by metformin (Li et al., 2016).

Antacids and aspirin
Chronic use of antacids may potentially reduce serum salicylate concentration in peoples who are taking large doses of aspirin. The mechanism involved in between these two drugs is the reduction in aspirin renal tubular reabsorption due to urinary alkalinization by antacids, bringing about increases the renal salicylate clearance. Antacids should be administered before two hours of aspirin dose because this time gap may decrease the retention of aspirin in uremic patients (D'arcy and Mcelnay, 1987).

Sucralfate and digoxin
Sucralfate is an ulcer defensive, it is an aluminum salt of sulfated sucrose. Digitalis is a cardiac glycoside that is utilized to treat certain heart conditions like a congestive cardiovascular failure (CHF) and atrial arrhythmias. Digitalis can expand blood low all through the body and diminish swelling in the upper and lower limbs. Digoxin absorption and therapeutic effectiveness decreased by sucralfate. There is a time gap required between the administration of sucralfate and digitalis. Digitalis must be administered two hours before (or) 6 hours after sucralfate. Here patients should be advised to notify their doctor if they experience worsening of their heart symptoms (Rey and Gums, 1991).

Food and GIT drugs interactions
Food and drug interactions may diminish or expand the drug effect. Some normally utilized spices, natural products just as alcohol might because the failure (or) decreases the drug therapeutic effect and serious modi ications of the patient's well-being. Some clinically applicable food-GIT drug interactions are brought about by food-instigated changes in the bioavailability of the drug Table 1.

CONCLUSIONS
The drug-drug, drug-food interaction should be notable and recognized.
Antacids change the absorption of numerous medications resulting in a decreased therapeutic effect. The impact of food on drugs brings about a decrease in the drug bioavailability and change in drug clearance. The interaction may bring about genuine hazardous results. Hence pharmacist becomes aware of the need for monitoring of potential Drug-Drug & Drug-Food interactions and educate patients regarding drugs and foods to be avoided when taking certain medication.

ACKNOWLEDGEMENT
I would like to express my sincere gratitude to my guide Dr. Abhishek pal. He is motivated and guided to me to write a review article. I am very thankful to my family and friends; they are given a lot of support and encouragement.