Abstract
Interactions occur when one drug modifies the action of another. This interaction may either increase or decrease the second drug’s action. Sometimes these interactions result in unwanted effects, but some interactions are beneficial and can be exploited therapeutically.
Drug interaction can be described as physicochemical, relating to the properties of the drug or its pharmaceutical preparation, pharmacokinetic due to alterations in the way the body handles the drug or pharmacodynamic where the activity of one drug is affected. The chance of a significant interaction increases markedly with the number of drugs used and the effects of any interaction are often exaggerated in the presence of disease or coexisting morbidity.
Interactions occur when one drug modifies the action of another. This interaction may either increase or decrease the second drug’s action. Sometimes these interactions result in unwanted effects, but some interactions are beneficial and can be exploited therapeutically.
Drug interaction can be described as physicochemical, relating to the properties of the drug or its pharmaceutical preparation, pharmacokinetic due to alterations in the way the body handles the drug or pharmacodynamic where the activity of one drug is affected. The chance of a significant interaction increases markedly with the number of drugs used and the effects of any interaction are often exaggerated in the presence of disease or coexisting morbidity.
Historically, up to one in six drug charts contained a significant drug interaction, but modern electronic prescribing systems are programmed with warnings. An uncomplicated general anaesthetic may use ten or more different agents that may interact with one another or, more commonly, with the patient’s concurrent medication.
Pharmaceutical
These interactions occur because of a chemical or physical incompatibility between the preparations being used. Sodium bicarbonate and calcium will precipitate out of solution as calcium carbonate when co-administered in the same giving set. However, one agent may inactivate another without such an overt indication to the observer; insulin may be denatured if prepared in solutions of dextrose and may, therefore, lose its pharmacological effect. Drugs may also react with the giving set or syringe and therefore need special equipment for delivery, such as a glass syringe for paraldehyde administration. Glyceryl trinitrate is absorbed by polyvinyl chloride; therefore, special polyethylene administration sets are preferred.
Pharmacokinetic
Absorption
In the case of drugs given orally, this occurs either as a result of one drug binding another in the lumen of the gastrointestinal (GI) tract or by altering the function of the GI tract as a whole. Charcoal can adsorb drugs in the stomach, preventing absorption through the GI tract (charcoal is activated by steam to cause fissuring, thereby greatly increasing the surface area for adsorption). Metoclopramide when given as an adjunct for the treatment of migraines reduces GI stasis, which is a feature of the disease, and speeds the absorption of co-administered analgesics. This is an example of a favourable interaction.
P-glycoprotein transport protein (PGP) is an efflux transporter and responsible for transporting a wide range of drugs out of intestinal cells. It is located in the luminal membrane of the entire intestinal membrane and reduces oral bioavailability of many drugs by pumping them back into the lumen of the gut. Drugs which induce PGP, such as rifampicin and phenytoin, may reduce drug bioavailability. Conversely, inhibitors of PGP, such as amiodarone and verapamil, may increase the bioavailability of susceptible drugs.
Distribution
Drugs that decrease cardiac output (such as β-blockers) reduce the flow of blood carrying absorbed drug to its site of action. The predominant factor influencing the time to onset of fasciculation following the administration of suxamethonium is cardiac output, which may be reduced by the prior administration of β-blockers. In addition, drugs that alter cardiac output may have a differential effect on regional blood flow and may cause a relatively greater reduction in hepatic blood flow, so slowing drug elimination.
Chelating agents are used therapeutically in both the treatment of overdose and of iron overload in conditions such as haemochromatosis. The act of chelation combines the drug with the toxic element and prevents tissue damage. Sodium calcium edetate chelates the heavy metal lead and is used as a slow intravenous infusion in the treatment of lead poisoning. Dicobalt edetate chelates cyanide ions and is used in the treatment of cyanide poisoning, which may occur following the prolonged infusion of sodium nitroprusside.
Competition for binding sites to plasma proteins has been suggested to account for many important drug interactions. This is not generally true; it is of importance only for highly protein-bound drugs when enzyme systems are close to saturation at therapeutic levels. One possible exception is the displacement of phenytoin, which is 90% protein-bound, from binding sites by a co-administered drug when therapeutic levels are already at the upper end of normal. In this case a 10% reduction in binding, to 81%, almost doubles the free phenytoin level. Although hepatocytes will increase their metabolism as a result, the enzyme system is readily saturated and this leads to zero-order kinetics and the plasma level remains high instead of re-equilibrating. Most so-called ‘protein-binding’ interactions are actually due to an alteration in metabolic capacity of one drug by the other. The commonest example seen in practice is the administration of amiodarone to a patient taking warfarin. Amiodarone inhibits the metabolism of S-warfarin by CYP2C9, which can significantly increase plasma levels of the active form of warfarin and produce iatrogenic coagulopathy. A similar interaction occurs with the NSAID phenylbutazone.
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