10e CHAPTER	Important Drug Interactions in Clinical Practice
Srirang Abkari

ABSTRACT

Drug interactions form an extremely important and often neglected part of clinical medicine. An in-depth knowledge of the types and mechanisms of drug interactions is necessary to prevent adverse events, recognize unexplained happenings in a patient’s condition, and ensure patient safety. Being quite common worldwide, there is an urgent need to focus on drug interactions in clinical practice and sensitize medical professionals regarding its importance. Example-based learning will go a long way in educating doctors regarding drug interactions.

INTRODUCTION

Drug interactions are an important, common but often neglected component of clinical medicine. They may be potentially life-threatening and require regular, systematic consideration in every patient to avoid problems. A thorough understanding of the subject will enable clinicians to prevent many adverse outcomes while treating patients. Drug interactions may make the drug less effective, cause unexpected side effects, or increase the action of a particular drug.

Drug interactions constitute a big problem all over the world. A report from a study in the United States mentions that 30.3% of patients in an ambulatory care unit were at risk of drug–drug interactions (DDIs). An Indian study of patients from a medical department of a tertiary care hospital in Karnataka identified 66% of drug–drug interactions. Another study from Chandigarh found that 8.3% of prescriptions had multiple DDIs. It is interesting to note that the following classes of drugs were most commonly involved in DDI, namely nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, proton pump inhibitors, corticosteroids, etc. The clinical significance of drug interactions is indicated by the fact that about 20–30% of the observed adverse effects cannot be attributed to a single medication but are only caused by interactions.

Drug interactions fall into three broad categories:

Drug–drug interactions occur when two or more drugs react with each other.
Drug-food/beverage interactions result from drugs reacting with foods or beverages.
Drug-condition interactions may occur when an existing medical condition makes certain drugs potentially harmful.

Of the above categories, it is the DDIs that are the most common causes of medication error in developed countries (Table 1). This is especially seen in elderly patients due to polytherapy and has a prevalence of around 20–40%. Indeed, polytherapy significantly increases the complexity of therapeutic management and therefore the risk of clinically important DDIs. This in turn could induce the development of adverse drug reactions (ADRs) or reduce the clinical efficacy. Polytherapy could be a major factor that could determine the “prescribing cascade.” A prescribing cascade occurs when we misunderstand an ADR and new potentially unnecessary medications are administered putting the patient at risk of developing further ADRs.

TABLE 1: Some common drug–drug interactions.
Drug 1	Drug 2	Potential outcome
Angiotensin-converting enzyme inhibitors	Nonsteroidal anti-inflammatory drugs	Hyperkalemia, decline in renal function
Ciprofloxacin	Olanzapine	Ciprofloxacin inhibits cytochrome P450 family 1 subfamily A polypeptide 2 (CYP1A2). As a result, the plasma concentration of olanzapine increases
Digoxin	Furosemide	Hypokalemia may increase the risk of digitalis intoxication
Nitroglycerin	Sildenafil	Increased risk of severe hypotension
Spironolactone	Potassium chloride	Hyperkalemia
Verapamil	Atenolol	Bradycardia and hypotension
Warfarin	Acetyl salicylic Acid	Increased risk of bleeding

CLASSIFICATION

Drug–drug interactions can be classified into two main groups: (1) Pharmacokinetic and (2) pharmacodynamic.

Pharmacokinetic

Involves absorption (reciprocal influencing), distribution (in different body compartments), metabolism, and excretion, all of them being associated with both treatment failure and toxicity; these can influence the effective concentrations at their sites of drug action. This could occur due to the formation of complexes, competition for drug uptake transporters, or may involve the induction of metabolizing enzymes and the efflux transporting system.

Pharmacodynamic

They may be divided into three subgroups:

Direct effect at receptor function
Interference with a biological or physiological control process
Additive/opposed pharmacological effect.

Pharmacodynamic drug interactions can be categorized as additive, synergistic or antagonistic.

A DDI will be able to induce a clinically relevant effect in the presence of drugs with a low therapeutic index, a long half-life, a steep dose-response curve, high-first pass metabolism, a single inhibitable route of metabolism, and a higher binding with plasma proteins (Tables 2 and ). In most of the scenarios, toxic effects are caused by DDI (e.g., β-adrenergic blockers and bronchodilators, diuretics and steroids or digoxin, and rifampicin and verapamil or carbamazepine). However, we may encounter many drug interactions that are therapeutically beneficial (e.g., ivermectin and lopinavir or saquinavir, docetaxel and piperine, resveratrol, and diclofenac).

TABLE 2: Examples of drug classes containing several narrow therapeutic index drugs.
Drug class	Example
Antiarrhythmics	Amiodarone
Anticoagulants	Warfarin
Antiepileptics	Phenytoin
Antineoplastics	Sunitinib
Aminoglycoside antibiotics	Gentamicin
Immunosuppressants	Tacrolimus

TABLE 3: Important drugs involved in cytochrome P450 drug–drug interactions.
Enzymes	Inhibitors	Inducers
CYP1A2	Ciprofloxacin, fluvoxamine, ethinyloestradiol, and interferon alfa-2b	Phenytoin and rifampicin
CYP2C9	Fluconazole	Carbamazepine and rifampicin
CYP2C19	Fluconazole, fluvoxamine, ticlopidine, fluoxetine, clarithromycin, voriconazole, and moclobemide	Lopinavir/ritonavir, rifampicin, and St John’s Wort
CYP2D6	Bupropion, fluoxetine, paroxetine, perhexiline, cinacalcet, doxepin, duloxetine, flecainide, moclobemide, quinine, and terbinafine
CYP3A	• Macrolides, e.g., erythromycin and clarithromycin • Azole antifungals, e.g., voriconazole, itraconazole, ketoconazole, fluconazole, and posaconazole • Protease inhibitors, e.g., indinavir, ritonavir, saquinavir, atazanavir, and fosamprenavir • Nondihydropyridine calcium channel blockers, e.g., diltiazem and verapamil • Grapefruit juice, aprepitant, cimetidine, ciprofloxacin, cyclosporin, fluvoxamine, and imatinib	Carbamazepine, modafinil, phenytoin, phenobarbitone, rifabutin, rifampicin, and St John’s Wort
(CYP1A2: cytochrome P450 family 1 subfamily A polypeptide 2; CYP3A: cytochrome P450, family 3, subfamily A; CYP2D6: cytochrome P450 family 2 subfamily D member 6; CYP2C9: cytochrome P450 family 2 subfamily C member 9; CYP2C19: cytochrome P450 2C19)

Based on its severity, we can categorize drug–drug interactions as minor, moderate, and severe. We do not observe significant troublesome outcomes with minor drug interactions and usually, no particular management of this type of interaction is required. Moderate drug interactions may cause worsening in the clinical condition of a patient; therefore, we should consider treatment to manage such types of interaction. While major drug interactions can lead to potentially life-threatening conditions. In view of this, it is essential to tackle these immediately once they are identified.

Over-the-counter (OTC) drug labels contain information about ingredients, uses, warnings, and directions that are important to read and understand. The label also includes important information about possible drug interactions. Further, drug labels may change as new information becomes known. That is why it is especially important to read the label every time we use a drug. The “Warnings” section of the label provides important drug interaction and precaution information such as when to talk to a doctor or pharmacist before use, the medical conditions that may make the drug less effective or not safe, under what circumstances the drug should not be used, and when to stop taking the drug.

For healthcare professionals the main source of information regarding the DDIs is the summary of product characteristics (SPCs). Sadly, DDIs cannot be listed exhaustively. Therefore, the information on potential DDIs may be inadequate, due to the limited space available in the SPC. We need to adopt therapeutic drug monitoring protocols, particularly in the elderly population who have many comorbidities and are prescribed multiple drugs. This can be an important solution to reduce the occurrence and magnitude of DDIs. This in turn can prevent an increase in health expenditure for the healthcare system and also a legal responsibility for the clinicians.

A pivotal role is played by clinical pharmacists in healthcare settings. As an integral part of the team, we can utilize their professional skills, knowledge, and expertise for improving patient care. They can help us to astutely monitor drug-related problems like potential DDIs and support us in improving patient safety in a hospital setup.

The use of technology like computer-based DDI alert systems to reduce the occurrence of DDIs has also been proposed. However, the sheer number of alerts generated by such a system could lead to alert fatigue both for the physicians and the pharmacists. It can eventually lead to a considerable override of DDI alerts.

CONCLUSION

In conclusion, an acknowledgment of the magnitude of the problem of drug interactions in clinical practice, a thorough understanding of the different types and their underlying mechanisms, a routine drill for checking for potential drug interactions in every patient, and taking the help of a clinical Pharmacist and drug interaction software tools will go a long way in preventing several drugs-related adverse reactions and improve patient safety.

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10e
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Important Drug Interactions in Clinical Practice

Srirang Abkari

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10eCHAPTER

Important Drug Interactions in Clinical Practice

Srirang Abkari

10e
CHAPTER