Intravenous Infusion and Pharmacokinetics

Fundamentals of Pharmacy: Intravenous Infusion and Pharmacokinetics

Intended Learning Outcomes

By the end of these lectures, students should be able to:

  • Predict plasma drug levels during various phases of intravenous (IV) infusion, including during accumulation, at steady-state (Css), and post-infusion when provided with the infusion rate (R) and pharmacokinetic (PK) parameters (clearance (Cl), elimination rate constant (k), and volume of distribution (V)).

  • Determine the infusion rates necessary to achieve desired plasma concentrations of drugs based on known PK parameters.

  • Estimate drug clearance from known steady-state concentrations achieved with a specific infusion rate.

  • Calculate the elimination rate constant (k) and half-life (t1/2) from plasma concentration data gathered during the post-infusion phase.

  • Compute plasma concentrations resulting from an initial bolus injection followed by continuous infusion, including scenarios involving changes in infusion rates.

Intravenous Infusions - Importance

IV infusions are critical in maintaining a consistent pharmacodynamic effect necessary for effective therapeutic action. Unlike bolus administrations limited to emergencies, IV infusions allow for longer and continuous systemic drug delivery, ensuring predictable drug action over extended periods. This method is particularly valuable in cases needing stable blood concentrations of medications.

Drugs Administered via IV Infusion

Various medications require IV infusion based on their specific therapeutic needs:

  • Bivalirudin: An anticoagulant used in patients with unstable angina during coronary angioplasty.

  • Cladribine: Treats hairy cell leukemia.

  • Cytarabine: Utilized for acute myeloid leukemia.

  • Eptifibatide & Tirofiban: Used in acute coronary syndrome or during interventions to prevent myocardial infarction.

  • Esmolol: Manages supraventricular tachycardia during surgeries.

  • Fentanyl & Remifentanil: Changes in anesthesia protocols for pain management in surgical contexts.
    Each drug has specific dosages and administration protocols crucial for achieving intended outcomes.

Chronic Drug Administration

In chronic drug treatments, a constant drug delivery via IV infusion leads to stable plasma drug concentrations (Cp). This minimizes fluctuations that may adversely affect treatment outcomes, allowing for zero-order pharmacokinetics (constant drug input).

Advantages of IV Infusion

IV infusion provides multiple benefits:

  • Convenience: Especially if the patient has an indwelling catheter.

  • Accurate Dosing: Precise control over drug amounts delivered.

  • Stable Cp: Maintains drug levels within the therapeutic window, avoiding peaks and troughs common in oral dosing.

Pharmacokinetic Principles of IV Infusion

  • 1-Compartment Model: Assumes that drug concentration within a compartment is uniform and changes can be described mathematically.

  • First-Order Elimination: Reflects that elimination rate changes with concentration, typically described by clearance (Cl) or elimination rate constant (k).

  • Steady-State Concentration (Css): At this state, drug input equals drug output, resulting in a consistent concentration over time, dictated by the formula:
    [ Cp_{ss} = \frac{R}{Cl} ]
    When planning therapies, understanding factors impacting Css is paramount.

Equations Governing IV Infusions

Several core equations govern IV infusion pharmacokinetics:

  1. Plasma Concentration over Time:
    [ Cp = \frac{R}{Cl} (1 - e^{-kt}) ]
    This equation describes how drug concentrations increase over time per the first-order kinetics until Css is tied to R and Cl.

  2. Time to Reach Steady-State: It typically requires 3 to 5 half-lives (t1/2) of the drug to reach steady-state concentrations.

Loading Doses

In scenarios requiring rapid attainment of steady-state concentrations, particularly with drugs having long half-lives, a loading dose (DL) is administered. The target concentration is immediately established using:
[ DL = Cp_{ss} * Vd ]
Where Vd is volume of distribution. After administering a loading dose, infusion begins, allowing for net concentration net calculations that reflect both the loading and continuous infusion effects.

Termination of Infusion

Upon cessation of an IV infusion, first-order elimination dictates that plasma concentrations will decrease exponentially. This decay can be modeled as:
[ Cp = CpT * e^{-kt'} ] Where CpT is the concentration at termination. The understanding of the time course of elimination is essential for adjusting subsequent doses or therapeutic interventions.

Estimating Elimination Parameters Post-Infusion

Analysis of the post-infusion drug concentration decay allows the calculation of elimination rate constants (k) and half-times (t1/2), critical for dose adjustments and understanding the duration of drug effects in clinical settings. Effective evaluations help in optimizing therapeutic regimens when changing infusion rates or during drug withdrawal.