BNF for Children 2011-2012

BNFC 2011–2012 655A1InteractionsTwo or more drugs given at the same time may exerttheir effects independently or may interact. The interactionmay be potentiation or antagonism of one drugby another, or occasionally some other effect. Adversedrug interactions should be reported to the Medicinesand Healthcare products Regulatory Agency (MHRA),through the Yellow Card Scheme (see Adverse Reactionsto Drugs, p. 12), as for other adverse drugreactions.Drug interactions may be pharmacodynamic orpharmacokinetic.Pharmacodynamic interactionsThese are interactions between drugs which have similaror antagonistic pharmacological effects or sideeffects.They may be due to competition at receptorsites, or occur between drugs acting on the samephysiological system. They are usually predictablefrom a knowledge of the pharmacology of the interactingdrugs; in general, those demonstrated with one drugare likely to occur with related drugs. They occur to agreater or lesser extent in most patients who receive theinteracting drugs.Pharmacokinetic interactionsThese occur when one drug alters the absorption, distribution,metabolism, or excretion of another, thusincreasing or reducing the amount of drug available toproduce its pharmacological effects. They are not easilypredicted and many of them affect only a small proportionof patients taking the combination of drugs. Pharmacokineticinteractions occurring with one drug cannotbe assumed to occur with related drugs unless theirpharmacokinetic properties are known to be similar.Pharmacokinetic interactions are of several types:Affecting absorption The rate of absorption or thetotal amount absorbed can both be altered by druginteractions. Delayed absorption is rarely of clinicalimportance unless high peak plasma concentrationsare required (e.g. when giving an analgesic). Reductionin the total amount absorbed, however, may result inineffective therapy.Due to changes in protein binding To a variableextent most drugs are loosely bound to plasma proteins.Protein-binding sites are non-specific and one drug candisplace another thereby increasing its proportion freeto diffuse from plasma to its site of action. This onlyproduces a detectable increase in effect if it is anextensively bound drug (more than 90%) that is notwidely distributed throughout the body. Even so displacementrarely produces more than transient potentiationbecause this increased concentration of free drugresults in an increased rate of elimination.Displacement from protein binding plays a part in thepotentiation of warfarin by sulfonamides, and tolbutamidebut the importance of these interactions is duemainly to the fact that warfarin metabolism is alsoinhibited.Affecting metabolism Many drugs are metabolisedin the liver. Induction of the hepatic microsomal enzymesystem by one drug can gradually increase the rate ofmetabolism of another, resulting in lower plasma concentrationsand a reduced effect. On withdrawal of theinducer plasma concentrations increase and toxicitymay occur. Barbiturates, griseofulvin, many antiepileptics,and rifampicin are the most important enzymeinducers. Drugs affected include warfarin and the oralcontraceptives.Conversely when one drug inhibits the metabolism ofanother higher plasma concentrations are produced,rapidly resulting in an increased effect with risk oftoxicity. Some drugs which potentiate warfarin andphenytoin do so by this mechanism.Isoenzymes of the hepatic cytochrome P450 systeminteract with a wide range of drugs. Drugs may besubstrates, inducers or inhibitors of the differentisoenzymes. A great deal of in-vitro information isavailable on the effect of drugs on the isoenzymes;however, since drugs are eliminated by a number ofdifferent metabolic routes as well as renal excretion,the clinical effects of interactions cannot be predictedaccurately from laboratory data on the cytochromeP450 isoenzymes. Except where a combinationof drugs is specifically contra-indicated, theBNF presents only interactions that have beenreported in clinical practice. In all cases the possibilityof an interaction must be considered if toxiceffects occur or if the activity of a drug diminishes.Affecting renal excretion Drugs are eliminatedthrough the kidney both by glomerular filtration andby active tubular secretion. Competition occursbetween those which share active transport mechanismsin the proximal tubule. For example, salicylates andsome other NSAIDs delay the excretion of methotrexate;serious methotrexate toxicity is possible.Relative importance of interactionsMany drug interactions are harmless and many of thosewhich are potentially harmful only occur in a smallproportion of patients; moreover, the severity of aninteraction varies from one patient to another. Drugswith a small therapeutic ratio (e.g. phenytoin) and thosewhich require careful control of dosage (e.g. anticoagulants,antihypertensives, and antidiabetics) are mostoften involved.Patients at increased risk from drug interactions includethose with impaired renal or liver function.Serious interactions The symbol . has been placedagainst interactions that are potentially serious andwhere combined administration of the drugs involvedAppendix 1: Interactions