24-09-2013, 02:08 PM
Drug interaction
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INTRODUCTION
A drug interaction is a situation in which a substance (usually another drug) affects the activity of a drug when both are administered together. This action can be synergistic (when the drug’s effect is increased) or antagonistic (when the drug’s effect is decreased) or a new effect can be produced that neither produces on its own. Typically, interactions between drugs come to mind (drug-drug interaction). However, interactions may also exist between drugs and foods (drug-food interactions), as well as drugs and medicinal plants or herbs (drug-plant interactions). People taking antidepressant drugs such as monoamine oxidase inhibitors should not take food containing tyramine as hypertensive crisis may occur (an example of a drug-food interaction). These interactions may occur out of accidental misuse or due to lack of knowledge about the active ingredients involved in the relevant substances.[1]
Pharmacokinetic interactions
Modifications in the effect of a drug are caused by differences in the absorption, transport, distribution, metabolization or excretion of one or both of the drugs compared with the expected behaviour of each drug when taken individually. These changes are basically modifications in the concentration of the drugs. In this respect two drugs can be homergic if they have the same effect in the organism and heterergic if their effects are different.
Absorption interactions
Changes in motility
Some drugs, such as the 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 less time its blood concentration will decrease. The opposite will occur with drugs that decrease intestinal motility.
pH: Drugs can be present in either ionised or non-ionised form, depending on their pKa (pH at which the drug reaches equilibrium between its ionised and non-ionised form).[12] The non-ionized forms of drugs are usually easier to absorb, because they will not be repelled by the lipidic bylayer of the cell, most of them can be absorbed by passive diffusion, unless they are too big or too polarized (like glucose or vancomicyn), in which case they may have or not 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 or not for certain drugs.
Transport and distribution interactions
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 there other associated problems are present such as when the method of excretion is affected.[16]
Metabolism interactions
isoenzyme 2C9haemMany drug interactions are due to alterations in drug metabolism.[17] Further, human drug-metabolizing enzymes are typically activated through the engagement of nuclear receptors.[17] 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.[18] Of the various families that are present in human beings 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.[19] 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. As a result of these interactions the function of the enzymes can either be stimulated (enzyme induction) or inhibited (enzyme inhibition).
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 concentration of A2 that is present in the blood will decrease, as will the final effect of the drug.
Enzymatic induction
If drug A is 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:[19]
Excretion interactions
Renal excretion
nephronOnly 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.[24] 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.