Drug Metabolism

Function

The kidneys are primarily responsible for the excretion of drugs from the body; however, lipophilic drugs readily cross the cell membrane of the kidney tubules and are reabsorbed into the blood.[3] Therefore, lipophilic drugs are first metabolized in the liver before excretion of the drug can be possible. The metabolism of drugs can occur in various reactions, categorized as phase I (modification), phase II (conjugation), and in some instances, phase III (additional modification and excretion).

Phase I modifications alter the lipophilic drug chemical structure through oxidation, reduction, hydrolysis, cyclization/decyclization, and either by removing hydrogen or adding oxygen to more polar molecules. In some instances, this process changes an inactive prodrug into a metabolically active drug. Oxidation typically results in metabolites that still retain some of their pharmacological activity. For example, phase I modification transforms the common anxiolytic drug diazepam into desmethyldiazepam and then further into oxazepam. Both of those metabolites produce similar physiological and psychological effects to diazepam itself. The cytochrome P450 system, also known as microsomal mixed function oxidase, catalyzes most phase I reactions.[3][5]

In phase II modifications, a drug molecule couples with another molecule in a conjugation reaction. Conjugation usually renders the compound pharmacologically inert and water-soluble, allowing the compound to be easily excreted. Conjugation mechanisms include methylation, acetylation, sulphation, glucuronidation, and glycine or glutathione conjugation. These processes can occur in various locations, such as the liver, kidney, lungs, intestines, and other organ systems. An example of phase II metabolism is oxazepam, which conjugates with another molecule called glucuronide. The drug becomes physiologically inactive and is excreted without further chemical modification.[5][6]

Phase III metabolism may also follow phase II metabolism, in which conjugates and metabolites are excreted from the cells. A critical factor in drug metabolism is the enzymatic catalysis of phase I and II processes. The type and concentration of liver enzymes are crucial to the efficient metabolism of drugs. The most commonly used enzymes for medical purposes are monoamine oxidase and cytochrome P450. These 2 enzymes are responsible for metabolizing dozens of biogenic and xenobiotic chemicals.

As the name suggests, monoamine oxidase catalyzes the processing of monoamines such as serotonin and dopamine. Monoamine oxidase inhibitors (MAOI) are used as antidepressants that increase serotonin and dopamine levels in the brain. The cytochrome P450 system is a family of heme-containing isoenzymes, primarily located in the liver and gastrointestinal tract, responsible for metabolizing many drugs and compounds, such as lipids and steroids.[7] Cytochrome P450 catalyzes the metabolism of many psychoactive drugs, including amphetamines and opioids.[8]

Issues of Concern

Drug metabolism can affect the plasma concentrations of drugs, which must be considered. Prescribers must be concerned about drug-drug interactions, as they may negatively impact the patient's health. For example, if rifampin is taken concurrently with imatinib, imatinib's plasma concentrations can be reduced because rifampin can induce CYP3A4 activity and metabolize imatinib at a much faster rate. Thus, imatinib's anticancer activity can be attenuated.[7][8]

Similarly, if the patient takes omeprazole to treat gastroesophageal reflux disease (GERD) concurrently with imatinib, imatinib's plasma concentrations increase. This occurs because omeprazole is a potent inhibitor of CYP3A4, and CYP3A4 metabolizes imatinib. The inhibition of CYP3A4 causes the accumulation of imatinib, leading to toxicities.[7][8][9]

Aging is another factor that affects drug metabolism. Drug metabolism slows with age, making older patients more susceptible to adverse reactions. Prescribers should keep in mind the patient's age when prescribing medication. Genetic polymorphism of drug-metabolizing enzymes can also cause variations in drug effects, leading to patients reacting differently to various drugs.[9]

Clinical Significance

In any pharmacological intervention, the prescriber must consider how and when a specific drug is eliminated from the body. Most of the time, drug clearance occurs according to first-order kinetics; in other words, the clearance rate depends on the drug's plasma concentration. That is, the elimination rate is proportional to the drug's concentration. The rate of this form of clearance depends upon the chemical in question and is often represented by a half-life. This is the time it takes for 50% of the drug to be eliminated from the body. For example, the half-life of cocaine is approximately 1 hour; thus, after 4 hours, only about 6.25% of the initial dose is present within the body.[10]

However, the elimination of some drugs occurs at a constant rate that is independent of plasma concentrations. Ethanol is an example; it is eliminated at a constant rate of about 15 mL/hour regardless of the concentration in the bloodstream. This is called zero-order kinetics and occurs when enzyme binding sites are saturated at low concentrations. Kinetics are of interest in medicine because monitoring drug concentration is often of clinical importance with many medications. Understanding pharmacokinetics, specifically drug elimination, allows providers to alter patient-specific therapies. Therapy aims to achieve a steady-state plasma concentration at which drug metabolism and elimination occur simultaneously.[10][11]

Metabolism is a highly variable process that can be influenced by several factors. One major disruptor of drug metabolism is depot binding, meaning the coupling of drug molecules to inactive sites in the body such that the drug is no longer accessible for metabolism. This can affect the duration of action of pharmacological agents susceptible to depot binding. One notable example is tetrahydrocannabinol (THC), the main psychoactive component of marijuana. THC is highly lipid-soluble, and depot binds in the adipose tissue of users. This interaction drastically slows the drug's metabolism, which is why metabolites of THC can be detected in urine weeks after the patient's last use.[10][11][12][13]

Another factor in drug metabolism is enzyme induction. Enzymes are induced by repeated use of the same chemical. The body becomes accustomed to the constant presence of the drug and compensates by increasing the production of enzymes necessary for the drug's metabolism. This contributes to pharmacological tolerance and is one reason patients need ever-increasing doses of certain drugs to produce the same effect.

Opioids are a prime example. Patients with long-term prescriptions for opioid analgesics notice their medication becomes less effective over time. Notably, induction increases the metabolic rate for all drugs processed via the enzyme induced; for example, chronic amphetamine use causes higher concentrations of CYP2D6. This enzyme is also essential in the metabolism of certain opioids, such as oxycodone; thus, a physician prescribing oxycodone to a patient using amphetamines would have to prescribe a higher dose to produce the desired effect.[11]

In contrast, some drugs have an inhibitory effect on enzymes, making the patient more sensitive to other medications metabolized through the action of those enzymes. A classic example is the inhibition of monoamine oxidase by certain antidepressant drugs. These compounds produce psychotherapeutic effects by blocking the enzyme that breaks down 'pleasure' chemicals in the brain. However, this can cause problems when patients on an MAOI take other drugs, which can cause abnormally high concentrations of these neurochemicals. A patient on an MAOI who uses cocaine, which elevates the concentration of serotonin, dopamine, and norepinephrine, will experience a much more potent effect from the cocaine. This interaction can lead to numerous physiological problems, including tachycardia, hypertension, and serotonin syndrome.[12][14]

Drugs that share elements of their metabolic pathways can also 'compete' for the same binding sites on enzymes, decreasing their metabolism's efficiency. For instance, alcohol and certain sedatives are metabolized by the same member of the cytochrome P450 family. Only a limited number of enzymes exist to break these chemicals down. Thus, if pentobarbital is administered to a patient who is also metabolizing alcohol, the pentobarbital would not be completely metabolized because most of the necessary enzymes would be filled by alcohol molecules; this is one reason that alcohol and other sedative or hypnotic drugs can have a synergistic effect when coadministered.[7][8]

Other Issues

Regardless of whether a drug is renally or hepatically metabolized and eliminated, impairment in either of these systems can cause significant issues. These issues can include altered dosing, dose intervals, and therapeutic effect; the pathway for metabolism can determine if a particular drug can be prescribed and used for a specific patient.[15]

Enhancing Healthcare Team Outcomes

Drug metabolism is an essential clinical concern for the interprofessional healthcare team. Clinicians and pharmacists must work together to prevent clinically significant drug interactions that could affect patients' health.

In a hospital setting, nursing staff monitors for signs of a toxic buildup of metabolites or active drugs. This is especially significant in renal or hepatic insufficiency. In many cases, drugs such as aminoglycoside antibiotics, warfarin, and fluoroquinolones are dosed and monitored by pharmacists, who monitor serum levels of the drugs and renal function.

An interprofessional approach to drug dosing and administration in light of the effects of drug metabolism on patients, whether through impaired metabolism, drug-drug interactions, enzymatic induction, or other factors, provides the best potential for optimal patient care. The interprofessional care approach results in better therapeutic results with fewer adverse events. 

Nursing, Allied Health, and Interprofessional Team Interventions

Interprofessional interventions and monitoring are critical for positive outcomes. Literature suggests that interprofessional interventions are effective when teams are open and willing to collaborate, communicate, share decision-making, and coordinate care, ultimately leading to the integration of the team’s competencies.[16]

Interprofessional team interventions are an effective part of medication management through interventions and monitoring. Medications affect people differently, as mentioned above. As a result, patients may be at an increased risk of adverse events if appropriate measures are not taken. Teams must monitor and intervene when medications are not safe for patients to take or administer or if patients are taking them inappropriately. The goal should always be patient safety. Reporting adverse events is crucial for interprofessional team monitoring. To properly conduct monitoring and interventions, clinical teams should also undergo training.

Training can be conducted on topics such as identifying medication errors to prevent adverse events, effective communication amongst teams, and standardization of medication dispensing. Continuing Medication Credits should be geared toward intervention and monitoring as well. Communication is a critical part of healthcare delivery. Interprofessional teams must continue to advance their approaches to following patients through the continuum of care.

In addition, effective interprofessional training allows for increased quality of care, promotion of collaboration, promote interdisciplinary awareness, respect, and acceptability of the role each discipline plays. However, one should also consider the challenges as well. Each discipline has its own culture and methodology. They have differences in routines, regulations, qualifications, accountability, and professional language. As a result, it makes it difficult to standardize any interventions or monitoring of medications. However, the first step in change is awareness of these challenges. Once these challenges are addressed and each discipline, whether nurses, pharmacists, or physicians, is trained appropriately, they will be able to effectively intervene and monitor medications for improved health outcomes at any stage of treatment.[17]