drug interaction drug interaction drug interactions occur when a drug's mechanism of action is affected by the concomitant administration of substances such as foods, beverages, or other drugs. the cause is often inhibition of, or less effective action, of the specific receptors available to the drug. this influences drug molecules to bind to secondary targets, which may result in an array of unwanted side-effects. the term selectivity describes a drug’s ability to target a single receptor, rendering a predictable physiological response. for example, the binding of acetylcholine to muscarinic tracheal smooth-muscle receptors (m3) results in smooth muscle contractions. when freely binding receptors interact with agonist- chemicals that activate receptors - and antagonists- that inhibit/ block activation - the opportunity for selective drugs to bind with the intended receptor cells decreases as most receptors are already accounted for. therefore, the drugs are more likely to bind to other receptors relative to the intended receptor, causing different effects. for example, consuming both zolpidem (i.e., ambien) and alcohol together, both which affect the gabaa receptors, results in the overstimulation of this receptor, which can lead to loss of consciousness. the risk of a drug-drug interaction (ddi) increases with the number of drugs used. over a third (36%) of the elderly in the u.s. regularly use five or more medications or supplements, and 15% are at risk of a significant drug-drug interaction. based on pharmacodynamics drug interactions can be additive (the result is what you expect when you add together the effect of each drug taken independently), synergistic (combining the drugs leads to a larger effect than expected), or antagonistic (combining the drugs leads to a smaller effect than expected). on some occasions, it is difficult to distinguish between synergistic or additive interactions, since the individual effects of each drug may vary from patient to patient. a synergistic interaction may be beneficial for patients, but may also increase the risk of overdose. drug interaction predictors enable risk assessment of multiple drugs simultaneously with visualizations of risk per therapeutic class, to indicate a spectrum from no risk to high risk. both synergy and antagonism can occur during different phases of the interaction between a drug and an organism. the different responses of a drug receptor have resulted in several classifications, such as partial agonist, competitive agonist, an inverse agonist. these concepts have fundamental applications in the pharmacodynamics of these interactions. the proliferation of existing classifications at this level and lack of knowledge around drug mechanisms means that it is difficult to offer a clear classification for these concepts. it is possible that authors would misapply any given classification. direct interactions between drugs are also possible and may occur when two drugs are mixed before intravenous injection. for example, mixing thiopentone and suxamethonium can lead to the precipitation of thiopentone. the change in an organism's response upon administration of a drug is an important factor in pharmacodynamic interactions. these changes are extraordinarily difficult to classify given the wide variety of modes of action that exist, and the fact that many drugs can cause their effect through several different mechanisms. this wide diversity also means that in all but the most obvious cases, it is important to investigate and understand these mechanisms. a well-founded suspicion exists that there are more unknown interactions than known ones. effects of the competitive inhibition of an agonist by increases in the concentration of an antagonist. a drug's potency can be affected (the response curve shifted to the right) by the presence of an antagonistic interaction.pa2 known as the schild representation, a mathematical model of the agonist:antagonist relationship or vice versa. nb: the x-axis is incorrectly labeled and should reflect the agonist concentration, not antagonist concentration. pharmacodynamic interactions can occur on: pharmacological receptors: receptor interactions are the most easily defined, but they are also the most common. from a pharmacodynamic perspective, two drugs can be considered to be: homodynamic, if they act on the same receptor. they, in turn, can be: pure agonists, if they bind to the main locus of the receptor, causing a similar effect to that of the main drug. partial agonists if, on binding to one of the receptor's secondary sites, they have the same effect as the main drug, but with a lower intensity. antagonists, if they bind directly to the receptor's main locus but their effect is opposite to that of the main drug. these include: competitive antagonists, if they compete with the main drug to bind with the receptor. the amount of antagonist or main drug that binds with the receptor will depend on the concentrations of each one in the plasma. uncompetitive antagonists, when the antagonist binds to the receptor irreversibly and is not released until the receptor is saturated. in principle, the quantity of antagonist and agonist that binds to the receptor will depend on their concentrations. however, the presence of the antagonist will cause the main drug to be released from the receptor regardless of the main drug's concentration, therefore all the receptors will eventually become occupied by the antagonist. heterodynamic competitors, if they act on distinct receptors. signal transduction mechanisms: these are molecular processes that commence after the interaction of the drug with the receptor. for example, it is known that hypoglycaemia (low blood glucose) in an organism produces a release of catecholamines, which trigger compensation mechanisms thereby increasing blood glucose levels. the release of catecholamines also triggers a series of symptoms, which allows the organism to recognize what is happening and which act as a stimulant for preventative action (eating sugars). should a patient be taking a drug such as insulin, which reduces glycemia, and also be taking another drug such as certain beta-blockers for heart disease, then the beta-blockers will act to block the adrenaline receptors. this will block the reaction triggered by the catecholamines should a hypoglycaemic episode occur. therefore, the body will not adopt corrective mechanisms and there will be an increased risk of a serious reaction resulting from the ingestion of both drugs at the same time. antagonistic physiological systems: where drugs taken together cause adverse reactions because the effect of one substance is indirectly increased in the presence of another. this can occur when a certain drug, which increases the presence of a physiological substance, is introduced into a system with another drug that is amplified by the same substance. an actual example of this interaction is found in the concomitant use of digoxin and furosemide. the former acts on cardiac fibers and its effects are increased if there are low levels of potassium (k) in blood plasma. furosemide is a diuretic that lowers arterial tension but favors the loss of k+. this could lead to hypokalemia (low levels of potassium in the blood), which could increase the toxicity of digoxin. based on pharmacokinetics modifications in the effect of a drug are caused by differences in the absorption, transport, distribution, metabolism, or excretion of one or both of the drugs compared with the expected behaviour of each drug when taken individually. these changes are modifications in the concentration of the drugs. in this respect, two drugs can be homergic if they have the same effect on the organism and heterergic if their effects are different. changes in motility some drugs, such as prokinetic agents, increase the speed with which a substance passes through the intestines. if a drug is present in the digestive tract's absorption zone for a short amount of time, its blood concentration will decrease. the opposite will occur with drugs that decrease intestinal motility. ph: drugs can be present in either ionized or non-ionized form, depending on their pka (ph at which the drug reaches equilibrium between its ionized and non-ionized form). the non-ionized forms of drugs are usually easier to absorb because they will not be repelled by the lipidic bilayer of the cell, most of them can be absorbed by passive diffusion, unless they are too large or polarized (like glucose or vancomycin), in which case they may or may not have specific and non-specific transporters distributed on the entire intestine internal surface, that carries drugs inside the body. obviously increasing the absorption of a drug will increase its bioavailability, so, changing the drug's state between ionized or not can be useful for certain drugs. certain drugs require an acid stomach ph for absorption. others require the basic ph of the intestines. any modification in the ph could change this absorption. in the case of antacids, an increase in ph can inhibit the absorption of other drugs such as zalcitabine (absorption can be decreased by 25%), tipranavir (25%) and amprenavir (up to 35%). however, this occurs less often than an increase in ph causes an increase in absorption. such occurs when cimetidine is taken with didanosine. in this case, a gap of two to four hours between taking the two drugs is usually sufficient to avoid the interaction. drug solubility: the absorption of some drugs can be drastically reduced if they are administered together with food with high-fat content. this is the case for oral anticoagulants and avocado. formation of non-absorbable complexes: chelation: the presence of di- or trivalent cations can cause the chelation of certain drugs, making them harder to absorb. this interaction frequently occurs between drugs such as tetracycline or the fluoroquinolones and dairy products (due to the presence of ca++). binding with proteins. some drugs such as sucralfate binds to proteins, especially if they have a high bioavailability. for this reason its administration is contraindicated in enteral feeding. finally, another possibility is that the drug is retained in the intestinal lumen forming large complexes that impede its absorption. this can occur with cholestyramine if it is associated with sulfamethoxazol, thyroxine, warfarin or digoxin. acting on the p-glycoprotein of the enterocytes: this appears to be one of the mechanisms promoted by the consumption of grapefruit juice in increasing the bioavailability of various drugs, regardless of its demonstrated inhibitory activity on first pass metabolism. based on transport and distribution the main interaction mechanism is competition for plasma protein transport. in these cases the drug that arrives first binds with the plasma protein, leaving the other drug dissolved in the plasma, which modifies its concentration. the organism has mechanisms to counteract these situations (by, for example, increasing plasma clearance), which means that they are not usually clinically relevant. however, these situations should be taken into account if other associated problems are present such as when the method of excretion is affected. based on metabolism diagram of cytochrome p450 isoenzyme 2c9 with the haem group in the centre of the enzyme. many drug interactions are due to alterations in drug metabolism. further, human drug-metabolizing enzymes are typically activated through the engagement of nuclear receptors. one notable system involved in metabolic drug interactions is the enzyme system comprising the cytochrome p450 oxidases. cyp450 cytochrome p450 is a very large family of haemoproteins (hemoproteins) that are characterized by their enzymatic activity and their role in the metabolism of a large number of drugs. of the various families that are present in humans, the most interesting in this respect are the 1, 2 and 3, and the most important enzymes are cyp1a2, cyp2c9, cyp2c19, cyp2d6, cyp2e1 and cyp3a4. the majority of the enzymes are also involved in the metabolism of endogenous substances, such as steroids or sex hormones, which is also important should there be interference with these substances. the function of the enzymes can either be stimulated (enzyme induction) or inhibited (enzyme inhibition). through enzymatic inhibition if drug a is metabolized by a cytochrome p450 enzyme and drug b inhibits or decreases the enzyme's activity, then drug a will remain with high levels in the plasma for longer as its inactivation is slower. as a result, enzymatic inhibition will cause an increase in the drug's effect. this can cause a wide range of adverse reactions. it is possible that this can occasionally lead to a paradoxical situation, where the enzymatic inhibition causes a decrease in the drug's effect: if the metabolism of drug a gives rise to product a2, which actually produces the effect of the drug. if the metabolism of drug a is inhibited by drug b, the plasma concentration of a2 will decrease and so will the final effect of the drug. through enzymatic induction if drug a is