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Preventing Adverse Drug Reactions (ADRs)

Adverse drug reactions (ADRs) are a frequent, and sometimes deadly, consequence of a modern healthcare system tasked with treating aging patients, many with multiple chronic diseases.

Polypharmacy, defined as regular use of at least five medications, is on the rise and one of its negative consequences is an increased risk of ADRs.

Fortunately, medical advances in pharmacogenetics have proven a cost-effective method to help prevent ADRs.

“Adverse drug reactions (ADRs) remain a challenge in modern healthcare, particularly given the increasing complexity of therapeutics, an ageing population and rising multimorbidity,” wrote Jamie J. Coleman, professor of clinical pharmacology and medical education, and Sarah K. Pontefract, research pharmacist, in an article published in Clinical Medicine.

The authors defined ADRs as unintended, harmful events attributed to the use of medicines and the FDA says they are one of the leading causes of morbidity and mortality in health care.

More Than 2 Million+ Serious ADRs Annually, 100K+ Deaths

It is hard to put a precise number on ADRs annually because of underreporting but the FDA believes that if all ADRs were counted, then they would be the 4th leading cause of death in the U.S. – ahead of pulmonary disease, diabetes, AIDS, pneumonia, accidents, and automobile deaths.

“Studies have estimated that 6.7 percent of hospitalized patients have a serious adverse drug reaction with a fatality rate of 0.32 percent. If these estimates are correct, then there are more than 2,216,000 serious ADRs in hospitalized patients, causing over 106,000 deaths annually,” says the FDA.

These numbers do not include ADRs that occur in outpatient settings or in long-term care (LTC) facilities.

“It is estimated that over 350,000 ADRs occur in U.S. nursing homes each year,” says the FDA. “The exact number of ADRs is not certain and is limited by methodological considerations. However, whatever the true number is, ADRs represent a significant public health problem that is, for the most part, preventable.”

Classifying ADRs: Type A and Type B Reactions

The Clinical Medicine article says that traditionally ADRs have been classified as two types:

  • Type A reactions – sometimes referred to as augmented reactions – which are ‘dose-dependent’ and predictable based on the pharmacology of the drug.

  • Type B reactions – bizarre reactions – which are idiosyncratic and not predictable based on the pharmacology.

There is an alternative classification system called “DoTS” which is based on:

  • D: Dose of the drug
  • T: Time course of the reaction
  • S: Susceptibility factors (such as genetic, pathological, and other biological differences)

“While some ADRs are unpredictable – such as anaphylaxis in a patient after one previous uneventful exposure to a penicillin-containing antibiotic – many are preventable with adequate foresight and monitoring,” wrote the authors.

Medicines that have been particularly implicated in ADR-related hospital admissions include:

  • Antibiotics
  • Anticoagulants
  • Antidiabetics
  • Antiplatelets
  • Cytotoxics
  • Diuretics
  • Immunosuppressants

Two Basic Steps to Prevent ADRs

Medical research has shown that anywhere between 33 percent and 50 percent of ADRs are preventable.

The Clinical Medicine article says there are two basic steps to prevent ADRs:

  • Identify the subgroup of patients who are likely to be susceptible to the adverse effect and modify the treatment choice accordingly.

  • Ensure the treatment plan mitigates any possible adverse effects.

“Knowledge of patient susceptibilities can inform your prescribing decision and reduce the risk of an ADR. A patient's medication history will identify any previous ADRs and therefore preclude re-exposure to the drug. In other cases, susceptibility factors such as age, gender, pregnancy status and ethnicity can help predict the risk of an ADR occurring,” says the article authors.

Pharmacogenomics Can Help ID Those Susceptible to ADRs

Pharmacogenomics, the field of research that studies how a person’s genes affect how he or she responds to medications, can help prevent ADRs. Examples include:

  • Carbamazepine: HLA B*15:02 marker, especially in Han-Chinese, Thai, and Malaysian populations. Clinical context: marker for carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis.

  • Simvastatin: SLZCO1B1 (solute carrier organic anion transporter 1B1) in patients with advanced age, untreated hypothyroidism, excess physical activity, concomitant medications (e.g., fibrates) can cause Statin-induced rhabdomyolysis (rare) whose risk factor is four times greater with single defective allele, 16 times greater with two defective alleles.

  • Abacavir: HLA B*57:01 marker with patients higher CD8 cell count at start of therapy can lead to abacavir-induced hypersensitivity reactions with fever, rash, lethargy, and abdominal and acute respiratory symptoms

“Pharmacogenetics is starting to yield more personalized medicine choices by predicting who is more susceptible to suffer a specific ADR,” said the Clinical Medicine article. “Clinical decision support systems available at the point of care can inform practitioners of any patient specific cautions to treatment or additional monitoring requirements to reduce the risk of harm.”

Treatment Plans Should Consider, Mitigate Possible ADRs

It is important for treatment plans to consider and mitigate any possible ADRs.

“Prudent, safe prescribing is key to reducing errors that can contribute to ADRs,” wrote Coleman and Pontefract.

An example the authors provide is that co-prescription of folic acid with methotrexate will reduce the incidence of adverse effects associated with folate deficiency; and monitoring electrolytes and renal function when treating with renally active drugs or diuretics

Treatment plans that first consider non-pharmacological options and conservative courses of action can help prevent ADRs as they often avoid prescribing medication altogether.

“Overall a systems approach, involving multiple strategies and including the patient and all healthcare professionals, is required to reduce the risk of an ADR and prevent those ‘avoidable’ reactions occurring in practice,” concluded the Clinical Medicine article.  

Asking the Right Questions to Prevent ADRs

Ultimately it may come down to asking the right questions to prevent ADRs.

In the seminal article “A Method for Estimating the Probability of Adverse Drug Reaction”, the authors said asking the right questions when taking medical history of patients can be key to assessing ADR probability:

  • Have you taken the medication before without adverse effects?

  • Did anything else change around the time of possible ADR other than the suspected drug (e.g. other treatments, over-the-counter medicines, disease progression)?

  • Did the reaction occur only after the drug was started?

  • Did the reaction resolve when the drug was stopped (or when a specific treatment was given)?

  • Was there ever intentional or accidental use of the drug following an ADR?

As medicines and vaccines become more prevalent to fight health issues such as the COVID-19 pandemic, the field of pharmacovigilance – the science and activities related to the detection, assessment, understanding and prevention of ADRs – is continuing to evolve.