Drug interactions. How to recognise and how to manage them

List of Contents

1. Introduction

2. Definition

3. Epidemiology

4. How do Interactions Occur

5. Reasons for increased Drug Interactions

6. Factors of Drug Interactions

7. Types of Drug Interactions

8. Pharmaceutical Drug Interactions

9. Pharmacokinetic Drug Interactions

10. Pharmacodynamic Drug Interactions

11. Guidelines for Drug Interactions

12. Drug Interaction Information Sources

13. Evaluation of Drug Interactions

Introduction

Drug Interactions are an important cause of drug related problems and this includes significant morbidity and mortality. The ability to recognise and manage drug interactions is a crucial role of the pharmacist in optimising patient outcomes. An important skill is to be able to recognise clinically significant drug interactions and provide management advice to the patient and their doctor. This advice may include discussing dose alteration strategies or alternative non-interacting drug combinations.

Typically, interaction between drugs comes to mind (drug-drug interaction). However, interactions may also exist between drugs & foods (drug-food interactions), as well as drugs & herbs (drug-herb interactions). These may occur out of accidental misuse or due to lack of knowledge about the active ingredients involved in the relevant substances.

Drug-drug interactions cause hospitalizations attributed to drugs in the elderly. In most cases they are erroneously interpreted as patient deterioration because of illness, poor adherence to in treatment, or infection. In the United States 25% of ambulatory patients taking drug combinations were at risk for clinically important interactions [1]·

Definition

A drug-drug interaction is defined as a pharmacokinetic or pharmacodynamic influence of drugs on each other, which may result in desired effects, in reduced efficacy and effectiveness or in increased toxicity.

A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own.

Variability in pharmacokinetics (what the body does to the drug) and pharmacodynamics (what the drug does to the body) means that even clinically significant interactions are often unpredictable in the magnitude of their effect[2]

Epidemiology

- The true incidence is difficult to determine because data for drug-related hospital admissions do not separate out drug interactions, focus on ADRs.
- Patients receiving polypharmacy are at risk because 77% of HIV patients on protease inhibitors experience drug interactions.
- There are some patient categories that are at greater risk of experiencing a drug interaction. There are also some drugs, which tend to be involved in the more important clinically significant drug interactions
- High risk patients especially in the elderly are more prone to drug interactions, as they are more sensitive to some pharmacodynamic effects and also tend to be on more drugs. Patients on > 6 drugs have an 80% chance of a drug interaction. Many hospitals in patients are on 6 drugs or more.
- In the early 1990s, patients experienced serious cardiac toxicity after taking antihistamine or prokinetic drugs in combination with macrolide antibiotics or azole antifungals. It was identified that inhibiting cytochrome P450 (CYP450), ЗА isoenzymes resulted in higher plasma drug concentrations. Subsequently, terfenadine, astemizole, and cisapride were withdrawn from the marketplace, in part because of safety concerns about drug interactions.
- High risk drugs include with a narrow therapeutic index, i.e. a relatively small change in the plasma concentration can cause drug toxicity or sub therapeutic effect. Thus, a pharmacokinetic interaction which changes the plasma concentration (up or down) will cause a change in effect.
- Warfarin and the other oral anticoagulants fall in to a special high-risk category. The clinical effect of warfarin is measured from the prothrombin time or IN R and the dose is titrated to provide a sufficient degree of anticoagulation without causing bleeding. Drugs or agents which change the pharmacokinetics of warfarin can have a dramatic clinical effect. Agents that change the supply or synthesis of vitamin к can also alter the pharmacodynamic effect of warfarin.
- Other drug classes with important interactions include antidepressants, antiarrhythmics, antipsychotics, hypoglycaemic agents. Also note that the commonly used drugs Cimetidine and erythromycin are potent enzyme inhibitors.
- Some drugs with a low therapeutic index Lithium, Digoxin, Carbamazepine, Cyclosporin Phenytoin, Phenobarbitone, Theophylline, (Aminophylline) Warfarin131.

How do drug interactions occur?

There are several mechanisms by which drugs interact with other drugs, food, and other substances. An interaction can result when there is an increase or decrease in: the absorption of a drug into the body; distribution of the drug within the body; alterations made to the drug by the body (metabolism); and elimination of the drug from the body. One notable system involved in metabolic drug interactions is the enzyme system comprising the cytochrome P450 oxidizes. This system may be affected by either enzyme induction or enzyme inhibition.

Most of the important drug interactions result from a change in the absorption, metabolism, or elimination of a drug. Drug interactions also may occur when two drugs that have similar (additive) effects or opposite (cancelling) effects on the body are administered together. For example, there may be major sedation when two drugs that has sedation as side effects are given, such as, narcotics and antihistamines.

Another source of drug interactions occurs when one drug alters the concentration of a substance that is normally present in the body. The alteration of this substance reduces or enhances the effect of another drug that is being taken. The drug interaction between warfarin (Coumadin) and vitamin К-containing products is a good example of this type of interaction. Warfarin acts by reducing the concentration of the active form of vitamin к in the body. Therefore, when vitamin к is taken, it reduces the effect of warfarin.

Reasons for increased drug interactions

- Drug abuse and misuse.
- Patients consult several physicians.
- Concurrent use of prescription and non-prescription drugs.
- Patient non-compliance.
- Drug potency.

The remaining drug interactions are in formidable challenge for several reasons. The science of drug interactions is complex and constantly evolving, the patient's medication list is often a moving target with prescription and non-prescription elements, and dozens of new drugs arrive at our pharmacies each year, often with incompletely characterized drug interaction profiles. The risk of harm due to drug interactions can be lessened by awareness of these principles, thoughtful prescribing habits and judicious monitoring when new drugs are added to regimens.

Medicines are often used concomitantly with other drugs, and some degree of drug interaction occurs with concomitant use. Although only a small proportion of this interaction is clinically significant, it sometimes causes serious adverse reactions. For example, drug interactions, particularly with drugs having a narrow therapeutic range, may have serious adverse consequences. Therefore, in the evaluation and clinical application of drugs, appropriate efforts should be made to predict the nature and degree of drug interactions so that patients will not be adversely affected. Humans are genetically diverse, and disease states are likewise diverse. It should, therefore, be kept in mind that drug interactions might readily cause clinically significant changes in blood drug levels (concentration in whole blood, plasma, or serum) in patients having pharmacokinetic parameters markedly deviating from those of the standard population. Drug interactions may occur after administration by any route.

A multiplicity of outcomes is possible when people use drugs. Most commonly the patient benefits from drug therapy; however, adverse events, ranging from minor side effects to death, may occur. One of the consequences of multiple drug use is the risk of one drug influencing the activity, the availability or the effect of a second drug. Drugs have most likely been used in combinations to potentiate their intended effects. Indeed, it may be favourable to use a combination of drugs if that combination is well documented to enhance the effect or to reduce adverse effects. However, physicians may advertently prescribe improper combinations that result in less effect or more adverse drug reactions [1]- Drug-drug interactions can lead to severe side effects and have resulted in early termination of development of drugs, refusal of approval, severe prescribing restrictions and withdrawal of drugs from the market. Whether a given magnitude of effect of an interacting inhibitory drug (i.e., Precipitant drug) on plasma levels of a recipient drug (i.e., Object drug) which results in an increased risk of adverse events depends to a great extent on the therapeutic index of the recipient drug. Even small pharmacokinetic interactions can result in significant pharmacodynamic adverse effects for drugs of a narrow therapeutic index. However, small to moderate pharmacokinetic interactions may not necessarily result in detectable and clinically significant consequences for drugs of a wider therapeutic index. Many physicians and other health care providers have only a rudimentary knowledge regarding drug-drug interactions.

With the seemingly constant flow of new therapeutic agents and new treatment indications for existing medications, polypharmacy is increasingly common. Many drug interactions are avoidable, but those that are not require awareness of the interaction to allow for proper management and appropriate dosage adjustments. The issue of drug interactions is bound to come up. It is therefore prudent to learn about such interactions so they can be effectively managed. Intelligent choices with respect to medication combinations can be made, and doses can be adjusted to keep patients in safe therapeutic zones.

An interaction is said to occur when the effects of one drug are changed by the presence of another drug, food, drink or by some environmental chemical agent. The outcome can be harmful if the interactions cause an increase in the toxicity of the drug. A reduction in efficacy due to an interaction can sometimes be just as harmful as an increase in toxicity (i.e. when antibiotics are combined with ions or antacids, the effects of these antibiotics can be reduced or even abolished in the gut).

Drug interactions may make a drug less effective, cause unexpected side effects or increase the action of a particular drug. Drug interactions fall into three broad categories, Drug - drug interactions Drug-food interactions Drug-condition interactions Drug - drug interactions occur when the administration of a drug results in decreased effectiveness or increased toxicity of other drugs that are also being taken (e.g., Heparin when combined with aspirin increases risk of bleeding).

Drug - food interactions occur when the effectiveness of the drug is decreased or the toxicity increased because of its interaction with foods (e.g., Tetracycline when taken with milk or calcium rich foods it decreases the effect of tetracycline).

Drug - condition interactions may occur when an existing medical condition makes certain drug potentially harmful (e.g., Tobramycin in combination with frusemide in renal failure patient's worse the condition by increasing the nephrotoxicity).

Factors of Drug Interaction

There are multiple factors that can influence the outcome of a drug interaction. These factors are based on the properties of the object drug and the precipitating drug.

Object Drugs

- Those which have low therapeutic index (e.g., Digoxin)
- Those which have a steep dose-response curve (e.g., aminoglycoside antibiotics.)
Precipitant Drugs
- Those which are highly protein bound (e.g., Aspirin), and therefore likely to displace object drugs from protein binding sites.
- Those which stimulate (e.g., rifampicin) or inhibit (e.g., Cimetidine) the metabolism of other drugs.
- Those which affect renal function (e.g., Probenecid) and alter the renal clearance of object drug.

Drug interactions refer to the interference of a drug in the action of another drug or the interference of food or nutrient in the action of drugs. It is estimated that interactions occur in 3 to 5% of patients receiving four drugs, and when 10 to 20 drugs are used, this rate reaches 20%.

Drug interactions may produce beneficial or undesirable. The beneficial effects are those whose purpose is to treat concomitant diseases, enhancing the effectiveness, reducing adverse effects and allowing to reduce the dose, while the undesirable effects may reduce the drug effectiveness, and may produce adverse and even toxic effects in the body, besides increased treatment cost.

The undesirable interactions may be subdivided into severe interactions, which may produce a risk to life or permanent damages, moderate interactions, which require additional treatment, and mild interactions, which do not affect significantly the therapy effect[2]

Types of Drug Interactions

The drug interactions are divided into 3 types they are pharmaceutical drug interaction, pharmacokinetic drug interaction and, pharmacodynamics drug interaction.

Pharmaceutical Drug Interactions

Pharmaceutical interactions can be a pharmacodynamic or pharmacokinetic. Some drug interactions are due to a combination of mechanisms.

These interactions are due to competition at receptor sites or activity of the interacting drugs on the same physiological system. There is no change in the plasma concentrations of interacting drugs.

Pharmaceutical drug interaction is known as drug incompatibilities, occur before the drug administration in the body, when two or more of them are mixed in the syringe or other recipient, and are evidenced by organoleptic alterations, reduced or interrupted activity of one or both drugs or formation of a new compound.

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