metabolized by a cytochrome p450 enzyme and drug b induces or increases the enzyme's activity, then blood plasma concentrations of drug a will quickly fall as its inactivation will take place more rapidly. as a result, enzymatic induction will cause a decrease in the drug's effect. as in the previous case, it is possible to find paradoxical situations where an active metabolite causes the drug's effect. in this case, the increase in active metabolite a2 (following the previous example) produces an increase in the drug's effect. it can often occur that a patient is taking two drugs that are enzymatic inductors; one inductor and the other inhibitor ;or both inhibitors, which greatly complicates the control of an individual's medication and the avoidance of possible adverse reactions. an example of this is shown in the following table for the cyp1a2 enzyme, which is the most common enzyme found in the human liver. the table shows the substrates (drugs metabolized by this enzyme) and the inductors and inhibitors of its activity: drugs related to cyp1a2 substratesinhibitorsinductors caffeine theophylline phenacetin clomipramine clozapine thioridazine omeprazole nicotine cimetidine ciprofloxacin phenobarbital fluvoxamine venlafaxine ticlopidine enzyme cyp3a4 is the most commonly used substrate in a great number of drugs. over a hundred drugs depend on its metabolism for their activity and many others act on the enzyme as inductors or inhibitors. some foods also act as inductors or inhibitors of enzymatic activity. the following table shows the most common: foods and their influence on drug metabolism,, foodmechanismdrugs affected avocado brassicas (brussels sprouts, broccoli, cabbage) enzymatic inductor acenocoumarol, warfarin grapefruit juice enzymatic inhibition calcium channel blockers: nifedipine, felodipine, nimodipine, amlodipine cyclosporine, tacrolimus terfenadine, astemizole cisapride, pimozide carbamazepine, saquinavir, midazolam, alprazolam, triazolam main article: grapefruit drug interactions soya enzymatic inhibition clozapine, haloperidol, olanzapine, caffeine, nsaids, phenytoin, zafirlukast, warfarin garlic increases antiplatelet activity anticoagulants nsaids, acetylsalicylic acid ginseng to be determined warfarin, heparin, aspirin and nsaids ginkgo biloba strong inhibitor of platelet aggregation factor warfarin, aspirin and nsaids hypericum perforatum (st john's wort) enzymatic inductor (cyp450) warfarin, digoxin, theophylline, cyclosporine, phenytoin and antiretrovirals ephedra receptor level agonist maoi, central nervous system stimulants, alkaloids ergotamines and xanthines kava (piper methysticum) unknown levodopa ginger inhibits thromboxane synthetase (in vitro) anticoagulants chamomile unknown benzodiazepines, barbiturates and opioids hawthorn unknown beta-adrenergic antagonists, cisapride, digoxin, quinidine grapefruit juice can act as an enzyme inhibitor. any study of pharmacological interactions between particular medicines should also discuss the likely interactions of some medicinal plants. the effects caused by medicinal plants should be considered in the same way as those of medicines as their interaction with the organism gives rise to a pharmacological response. other drugs can modify this response and also the plants can give rise to changes in the effects of other active ingredients. there is little data available regarding interactions involving medicinal plants for the following reasons: st john's wort can act as an enzyme inductor. false sense of security regarding medicinal plants. the interaction between a medicinal plant and a drug is usually overlooked due to a belief in the "safety of medicinal plants." variability of composition, both qualitative and quantitative. the composition of a plant-based drug is often subject to wide variations due to a number of factors such as seasonal differences in concentrations, soil type, climatic changes, or the existence of different varieties of chemical races within the same plant species that have variable compositions of the active ingredient. on occasion, an interaction can be due to just one active ingredient, but this can be absent in some chemical varieties or it can be present in low concentrations, which will not cause an interaction. counter interactions can even occur. this occurs, for instance, with ginseng, the panax ginseng variety increases the prothrombin time, while the panax quinquefolius variety decreases it. absence of use in at-risk groups, such as hospitalized and polypharmacy patients, who tend to have the majority of drug interactions. limited consumption of medicinal plants has given rise to a lack of interest in this area. they are usually included in the category of foods as they are usually taken as tea or food supplement. however, medicinal plants are increasingly being taken in a manner more often associated with conventional medicines: pills, tablets, capsules, etc. renal excretion human kidney nephron. only the free fraction of a drug that is dissolved in the blood plasma can be removed through the kidney. therefore, drugs that are tightly bound to proteins are not available for renal excretion, as long as they are not metabolized when they may be eliminated as metabolites. creatinine clearance is used as a measure of kidney functioning but it is only useful in cases where the drug is excreted in an unaltered form in the urine. the excretion of drugs from the kidney's nephrons has the same properties as that of any other organic solute: passive filtration, reabsorption, and active secretion. in the latter phase, the secretion of drugs is an active process that is subject to conditions relating to the saturability of the transported molecule and competition between substrates. therefore, these are key sites where interactions between drugs could occur. filtration depends on a number of factors including the ph of the urine, it having been shown that the drugs that act as weak bases are increasingly excreted as the ph of the urine becomes more acidic, and the inverse is true for weak acids. this mechanism is of great use when treating intoxications (by making the urine more acidic or more alkali) and it is also used by some drugs and herbal products to produce their interactive effect. drugs that act as weak acids or bases weak acidsweak bases acetylsalicylic acid furosemide ibuprofen levodopa acetazolamide sulfadiazine ampicillin chlorothiazide paracetamol chloropropamide cromoglicic acid ethacrynic acid alpha-methyldopamine phenobarbital warfarin theophylline phenytoin reserpine amphetamine procaine ephedrine atropine diazepam hydralazine pindolol propranolol salbutamol alprenolol terbutaline amiloride chlorpheniramine bile excretion bile excretion is different from kidney excretion as it always involves energy expenditure in active transport across the epithelium of the bile duct against a concentration gradient. this transport system can also be saturated if the plasma concentrations of the drug are high. bile excretion of drugs mainly takes place where their molecular weight is greater than 300 and they contain both polar and lipophilic groups. the glucuronidation of the drug in the kidney also facilitates bile excretion. substances with similar physicochemical properties can block the receptor, which is important in assessing interactions. a drug excreted in the bile duct can occasionally be reabsorbed by the intestines (in the enterohepatic circuit), which can also lead to interactions with other drugs. with herbal medicines herb-drug interactions are drug interactions that occur between herbal medicines and conventional drugs. these types of interactions may be more common than drug-drug interactions because herbal medicines often contain multiple pharmacologically active ingredients, while conventional drugs typically contain only one. some such interactions are clinically significant, although most herbal remedies are not associated with drug interactions causing serious consequences. most herb-drug interactions are moderate in severity. the most commonly implicated conventional drugs in herb-drug interactions are warfarin, insulin, aspirin, digoxin, and ticlopidine, due to their narrow therapeutic indices. the most commonly implicated herbs involved in such interactions are those containing st. john’s wort, magnesium, calcium, iron, or ginkgo. examples examples of herb-drug interactions include, but are not limited to: st. john's wort affects the clearance of numerous drugs, including cyclosporin, ssri antidepressants, digoxin, indinavir, and phenprocoumon. it may also interact with the anti-cancer drugs irinotecan and imatinib. salvia miltiorrhiza may enhance anticoagulation and bleeding among people taking warfarin. allium sativum has been found to decrease the plasma concentration of saquinavir, and may cause hypoglycemia when taken with chlorpropamide. ginkgo biloba can cause bleeding when combined with warfarin or aspirin. concomitant ephedra and caffeine use has been reported to, in rare cases, cause fatalities. mechanisms the mechanisms underlying most herb-drug interactions are not fully understood. interactions between herbal medicines and anticancer drugs typically involve enzymes that metabolize cytochrome p450. for example, st. john's wort has been shown to induce cyp3a4 and p-glycoprotein in vitro and in vivo. underlying factors it is possible to take advantage of positive drug interactions. however, the negative interactions are usually of more interest because of their pathological significance, and also because they are often unexpected, and may even go undiagnosed. by studying the conditions that favor the appearance of interactions, it should be possible to prevent them or at least diagnose them in time. the factors or conditions that predispose the appearance of interactions include: old age: factors relating to how human physiology changes with age may affect the interaction of drugs. for example, liver metabolism, kidney function, nerve transmission, or the functioning of bone marrow all decrease with age. in addition, in old age, there is a sensory decrease that increases the chances of errors being made in the administration of drugs. polypharmacy: the use of multiple drugs by a single patient, to treat one or more ailments. the more drugs a patient takes the more likely it will be that some of them will interact. genetic factors: genes synthesize enzymes that metabolize drugs. some races have genotypic variations that could decrease or increase the activity of these enzymes. the consequence of this would, on occasions, be a greater predisposition towards drug interactions and therefore a greater predisposition for adverse effects to occur. this is seen in genotype variations in the isozymes of cytochrome p450. hepatic or renal diseases: the blood concentrations of drugs that are metabolized in the liver and/or eliminated by the kidneys may be altered if either of these organs is not functioning correctly. if this is the case an increase in blood concentration is normally seen. serious diseases that could worsen if the dose of the medicine is reduced. drug dependent factors: narrow therapeutic index: where the difference between the effective dose and the toxic dose is small. the drug digoxin is an example of this type of drug. steep dose-response curve: small changes in the dosage of a drug produce large changes in the drug's concentration in the patient's blood plasma. saturable hepatic metabolism: in addition to dose effects the capacity to metabolize the drug is greatly decreased epidemiology as of 2008, among us adults older than 56, 4% were taking medication and or supplements that put them at risk of a major drug interaction. potential drug-drug interactions have increased over time and are more common in the less-educated elderly even after controlling for age, sex, place of residence, and comorbidity.