Pharmacokinetics and pharmacodynamics

Pharmacology is the science of studying the dosage, mechanism of action and curative effect of drugs. The core of pharmacology is the study of pharmacokinetics and pharmacodynamics.

What is pharmacokinetics, pharmacodynamics and pharmacokinetics/pharmacodynamics?

Pharmacokinetics studies the concentration of drugs in the body at different time points. On the other hand, pharmacodynamics studies the relationship between the concentration of a drug and its pharmacological effects.
In practice, pharmacokinetics is often referred to as “the effect of the body on drugs”, and pharmacodynamics is referred to as “the effect of drugs on the body”. Therefore, pharmacokinetics/pharmacodynamics studies the relationship between drug dosage and drug concentration changes caused by changes in pharmacological effects.

Why is knowledge of pharmacokinetics/pharmacodynamics necessary for the optimization of patient treatment in the intensive care unit (ICU)?

In the research and development stage of drugs from pre-clinical research to phase III clinical trials, in order to achieve the maximum efficacy of the drug while reducing its side effects, it is often necessary to consider the pharmacokinetics and pharmacodynamics of the drug. However, critically ill patients are rarely included in studies to determine the dose of the drug (Phase I and Phase IIa clinical trials), and there are very few critically ill patients in subsequent clinical outcome studies (Phase IIb and Phase III clinical trials) . From the perspective of pharmacokinetics, the body’s metabolism of many drugs in critically ill patients will change, resulting in large differences in drug concentration in different patients, and the same patient is in different stages of the disease (such as early treatment and treatment In the late stage, the drug concentration also varies greatly, resulting in many unpredictable pharmacological and toxicological effects. Therefore, when it is assumed that the dosage of the drug in the product instructions is appropriate, when the “standard” dose therapy is used in ICU patients, the drug concentration in the patient’s body is actually not optimal, which may lead to treatment failure. On the other hand, drug concentrations that exceed the therapeutic concentration may also cause drug poisoning.

Drug disposition is divided into four stages designated by the acronym "ADME":Absorption from the site of administration, Distribution within the body, Metabolism, Excretion

Pharmacokinetic and pharmacodynamic (PK/PD)testing,including studies on the absorption,metabolism, distribution and elimination (ADME studies) in the species of laboratory animals used for toxicology testing, to link the pharmacological and toxicological effects to plasma concentration and drug exposure.

Although drug PK/PD changes are common, this problem is ignored for many drugs, because these drugs adjust the drug dose based on the effect of the “needle tip”, and the clinician will be at the bedside according to the patient’s needs. The intended pharmacological action target is to adjust the dose of the drug (for example, adjust the dose of the vasopressor to obtain the target mean arterial pressure). However, many other drugs, such as antibiotics and antiepileptic drugs, do not have simple and easy-to-measure bedside observation endpoints. A more detailed understanding of the PK/PD of these drugs can enable clinicians to ensure that each patient receives the best dose. treatment. Next, we will take antibiotics as an example to emphasize the importance of understanding PK/PD.

Main concepts affecting the pharmacokinetics of antibiotic administration dose

For antibiotics such as β-lactams, glycopeptides, and aminoglycosides used in critically ill patients, lesion-based pharmacokinetic changes are very important, while other drugs (such as linezolid) , Colistin, triazole antifungal drugs). Regardless of the impact of the patient, its own pharmacokinetic properties have great variability. The pharmacokinetic variation related to critical illness is caused by the large difference in drug clearance probability between different patients. Some of these patients have increased renal clearance, while on the other hand, some people suffer from acute kidney injury (AKI). Reduced clearance. If the patient is receiving renal replacement therapy (RRT) or extracorporeal membrane oxygenation therapy, it will also have some unpredictable effects on the elimination of antibiotics. In addition, changes in fluid balance related to fluid resuscitation, edema, and obesity can affect the distribution of drugs in body fluids (defined as the apparent volume of distribution of drugs in body fluids, that is, the concentration of a drug in body fluids and plasma concentrations). ratio). Fluctuations in fluid balance especially affect the volume of distribution of more water-soluble antibiotics such as β-lactams, glycopeptides, and aminoglycosides. In short, these pathophysiological changes lead to large differences in the concentration of drugs in the body. For example, in the DALI study, researchers found that the plasma concentration of β-lactam antibiotics can be more than 500 times different. In the interstitial fluid, which is the most common infection, the difference in drug concentration may be even greater. In fact, it is impossible for us to accurately predict the degree of plasma drug concentration changes. For this reason, it is clinically recommended to monitor as many drugs as possible, although it may not accurately reflect the target site. The exact drug concentration.

The main pharmacodynamic concepts affecting the dosage of antibiotics

Since it is common for pathogens in the ICU to decrease the susceptibility to drugs, the pharmacodynamic changes of drugs are also important. Data from epidemiological studies confirm that the minimum inhibitory concentration (MICs) of bacteria in ICU is often 2-4 times higher than that in general wards. Therefore, in view of the fact that MIC is the denominator of the PK/PD ratio of different types of antibiotics [such as quinolones that use the area under the concentration-time curve (AUC)/MIC to evaluate antibiotics], when the denominator increases, in order to maximize clinical efficacy, corresponding The pharmacokinetic exposure index (molecular) of the drug should also be increased to ensure that this ratio remains optimal (Figure 1).

What happens when we use regular dose drugs in the ICU?

Data from a large-scale, multi-center DALI study showed that the variability of therapeutic doses of β-lactams, glycopeptide antibiotics, triazole and echinocandin antifungal drugs is small (less than 2 times). This “one size fits all” strategy seems to be problematic in critically ill patients. The DALI study and other studies have found a clear antibiotic concentration-effect relationship. These drugs can improve the clinical prognosis and survival of patients by achieving PK/PD goals. rate. In addition, those patients with organ dysfunction may experience drug accumulation and potential adverse reactions, such as acute kidney injury and nervous system toxicity. In view of the large differences in PK and PD between ICU patients and non-ICU patients, it is a big challenge for clinicians to choose the appropriate dosage to ensure the best PK/PD target.

Principles to reduce the impact of PK/PD changes

Evaluation and measurement of changes in the pharmacokinetics and pharmacodynamics of drugs are not necessary to optimize the dosage. The increase in the apparent volume of distribution of the drug is common in the ICU. Therefore, a loading dose (such as 30 mg/kg of vancomycin) is required to quickly reach the therapeutic concentration of the drug. The maintenance dose should be determined based on the estimate of drug clearance. Under normal circumstances, the clearance of many drugs is well related to the predicted value of renal function (such as measured creatinine clearance). When patients are receiving RRT treatment, the different treatment modes and parameter settings in different ICUs mean that there is no standard dose for such patients. In this regard, we need to best describe the existing published descriptions for independent individuals. Do a detailed search of the dosing literature.

The future

If the pharmacokinetics and pharmacodynamics of antibiotics are not monitored, it is difficult to predict them. Therefore, the application of therapeutic drug monitoring to describe the pharmacokinetics of antibiotics, and the use of some professional microbiological methods to measure the MIC value of pathogens are the only methods to determine the true individualized drug dosage to optimize the patient’s prognosis. PK/PD studies can also be used to determine the effective evidence-based doses of some ancient antibiotics and antibiotic combination therapies. These attempts can provide more treatment options for patients with critically ill infections.