Pharmacokinetics Slides 96-124, Teresa's Portion

Injection of a single dose followed by an infusion (or other treatment schedule) to maintain the steady state.

Half-life refers to the amount of time it takes for half of the drug to be eliminated from the body. This means that after one half-life, only 50% of the drug remains in the body, and after each subsequent half-life, the amount of drug in the body is reduced by half. It is an important concept in pharmacology as it helps determine the dosing frequency and duration of a drug to maintain therapeutic levels in the body.

The goal of the continuous-infusion regimen is to increase the plasma concentration of a drug to reach Steady State, which is the time at which the rate of administration equals the rate of elimination. This ensures that the drug is maintained at a therapeutic level in the body, allowing for a consistent and effective treatment.

The ‘average patient’ approach overlooks interpatient variability.

Pharmacokinetic principles can be used to optimize therapy while minimizing side effects and toxicities.

Monitoring drug concentration and correlating it with therapeutic benefits can also be helpful to individualize therapy

Metabolism or excretion refers to the processes by which the active form of a drug is eliminated from the bloodstream. Metabolism involves the chemical alteration of the drug by enzymes in the body, converting it into inactive or less active forms that can be easily eliminated. Excretion, on the other hand, involves the removal of the drug or its metabolites from the body through urine, feces, sweat, or breath. Both metabolism and excretion play crucial roles in eliminating drugs from the bloodstream and preventing their accumulation to toxic levels.

The goal of a "loading dose" in the optimization of dose regimen is to achieve desired plasma levels of a drug faster. This is particularly important in cases such as lidocaine for arrhythmias, where immediate action is required. By administering a higher initial dose, the drug can quickly reach therapeutic levels in the bloodstream, allowing for faster and more effective treatment. This loading dose strategy helps to achieve the desired therapeutic effect in a shorter period of time.

The "maintenance of dose" goal of optimization of dose is to maintain a steady state concentration within the therapeutic window. This means that the goal is to keep the drug concentration in the body at a level that is effective for treating the condition, but not too high that it causes toxicity. By maintaining a steady state concentration within the therapeutic window, the desired therapeutic effects of the drug can be achieved while minimizing the risk of adverse effects.

Fixed-dose/fixed-time regimens consist of both multiple IV injections and multiple oral administrations. This means that patients following this regimen will receive a specific dose of medication at predetermined times, either through intravenous injections or oral administrations. The combination of both delivery methods allows for a more targeted and effective treatment approach, ensuring that patients receive the necessary medication in the most appropriate way for their condition.

CL systemic= CL hepatic + CL renal + …. etc.

Done to achieve desired plasma levels of a drug faster (e.g., lidocaine for arrhythmias).

Most useful for drugs that are eliminated from the body relatively slowly. Such drugs require only a low maintenance dose to keep them at a therapeutic concentration but would not be able to reach the steady state for a long time without a loading dose.

The enterohepatic cycle refers to the process in which drugs are absorbed in the intestines, transported to the liver, and then secreted back into the intestines through the bile. This cycle allows for the reabsorption of drugs, reducing their elimination from the body. As a result, the drug's half-life is prolonged, meaning it remains in the body for a longer duration and has a prolonged action. This can be beneficial in certain cases where maintaining therapeutic drug levels in the body is desired.

Accumulation occurs because most drugs are given at intervals shorter than 5 half-lives and are eliminated exponentially with time.

Accumulation stops when, within the dosing interval, the rate of loss (driven by an elevated plasma concentration) exactly balances the rate of drug administration (steady state).

Excretion= Filtration + Secretion - Reabsorption

When infusion is stopped, plasma concentration declines (washes out) to zero with the same time course observed in approaching the steady state.

A faster rate does not affect the time it takes to reach steady state. Only the steady state concentration changes with a faster infusion rate. (From graph on powerpoint slide 111)

Influence of the rate of drug infusion on the steady state:
Css= Dosing rate/ CL

Although increasing rate of drug infusion increases the rate at which any given concentration in the plasma is achieved, it DOES NOT influence the time required to reach the ultimate steady-state concentration. This is because the steady-state concentration rises directly with the infusion rate.

The process of expelling or removing waste products from the body is known as elimination or clearance. This involves the removal of waste materials, such as urine, feces, and sweat, from the body to maintain proper functioning and balance. Excretion refers to the process of eliminating metabolic waste products, while exoneration refers to being cleared of blame or responsibility. Eruption refers to the sudden appearance of something, usually in a violent or explosive way.

t1/2 is the only determinant of the rate of approaching the steady state.

This rate is only affected by factors that affect the half life

The rate of approach to steady state is not affected by the rate of drug infusion.

Tears are not a process in which a drug is excreted. Drugs can be excreted through various routes such as urine, sweat, breast milk, defecation, and exhaled air. However, tears are not involved in the excretion of drugs from the body.

The proportion of patients whom the Dose Regimen was successful is not a consideration when clinicians design a Dose Regimen. Clinicians focus on factors such as refining and optimizing the regimen for maximum benefit with minimum adverse effects, deciding on the administration method (continuous or intervals), and considering patient and drug factors for achieving steady state. However, the success rate of the regimen in patients is not taken into account during the design process.

Disadvantages:
Increased risk of drug toxicity
Longer time for concentration to fall if excess drug level occurs

Example (aspirin):
CL hepatic= 1500 mL/min x [(200 μg/mL - 134 μg/mL)/ 200 μg/mL]
CL hepatic= 495 mL/min

1. Continuous-infusion regimens
2. Fixed-dose/fixed-time regimens
3. Optimization of dose

Graph on slide 123

Continuous-infusion regimens can be both in fixed-dose/fixed-time interval regimens and involve the single administration of a drug. This means that continuous-infusion regimens can be used in situations where a fixed dose of a drug is given at regular intervals, such as taking one tablet every 4 hours. Additionally, continuous-infusion regimens can also involve the administration of a drug continuously over a period of time, either intravenously or orally. Therefore, the correct answer is that continuous-infusion regimens can be both in fixed-dose/fixed-time interval regimens and involve the single administration of a drug.

First-order process
Exponential approach to steady state
Rate to reach steady state= rate of total elimination

Dose adjustment with Vd

Used to calculate the amount of drug needed to achieve a desired plasma concentration.

Example: Patient with heart failure whose cardiac output is not well controlled due to inadequate levels of digoxin.