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Competitive Inhibition

The Root Cause of Unintentional Opioid Misuse

When medications are orally ingested, they travel through the digestive tract until they are systemically absorbed in the intestines. One more step is required before medications are allowed to circulate through the body to exert their desired eff­ects: they are subjected to the scrutiny of the liver, a process referred to as first-pass metabolism.

The liver, which is responsible for detoxifying the body from harmful substances, is also responsible for metabolizing most medications. Upon first pass through the liver, the majority of medications are metabolized to inactive metabolites. The metabolism of active medications to inactive metabolites is typically executed by cytochrome P450 (CYP450) enzymes.

Medications demonstrate varying degrees of binding affinity for CYP450 enzymes, ranging from weak to strong. Binding affinity to a metabolizing enzyme is a measure of how strongly the medication is attracted to that enzyme. Understanding the affinity concept becomes critical when multiple medications of various affinities are competing for one enzyme—a phenomenon known as competitive inhibition.

When a strong-affinity medication is concurrently administered with a weak-aff­inity medication, there is a predictable increase in concentrations of the weak-affinity medication. This is because the strong-affinity medication prevents the metabolism of the weak-a­ffinity medication, which continues to circulate through the body, continually exerting its effect until the enzyme is free of the strong-affinity medication and new metabolism can take place. In these situations, the weak-a­ffinity medication is often referred to as the “victim medication” and the strong-aff­inity medication is referred to as the “perpetrator medication.”

Although most medications are metabolized to inactive metabolites and then excreted from the body, some medications are metabolized to active or more active medications. These medications are referred to as prodrugs. Many opioids, including codeine, hydrocodone, oxycodone, and tramadol are prodrugs.

When the metabolism of a prodrug is inhibited, the active metabolite is not produced, rendering the medication ineffective. Metabolism of a prodrug can be competitively inhibited by a stronger-affinity medication or by a medication that is a true (non-competitive) inhibitor (e.g., amiodarone).

With opioids, medical professionals usually respond to this ineffectiveness by increasing the dose of the opioid. However, increasing the opioid dose will not overcome the inhibition that occurs and the ineffectiveness that results. On the other hand, increasing the opioid dose will compromise safety because the concentrations of the opioid circulating through the body will increase, thereby increasing the risk for opioid-related side effects (e.g., constipation, nausea, vomiting).

Additionally, patients are at risk for opioid-related side e­ffects and adverse drug events when the strong-affinity medication (i.e., perpetrator) is discontinued or the time of administration of both the victim and perpetrator medication is altered. With these types of medication changes, the metabolizing enzyme is suddenly free of inhibition, and the effect of the full opioid dose is suddenly realized. This may result in an unintentional overdose that could result in fatality.