OIA1013 TIME COURSE DRUG EFFECT

Introduction to Pharmacokinetics and Pharmacodynamics

Key Definitions

☐ Pharmacokinetics: The study of how drugs move through the body, INCLUDING ng absorption, distribution, metabolism, and excretion (ADME).

☐ Pharmacodynamics: The study of the effects of drugs on the body and the mechanisms of their action.

☐ Time Course of Effect: The relationship between drug concentration and its effect over time, integrating pharmacokinetics and pharmacodynamics.

Pharmacokinetic Parameters

☐ Half-life (t1/2): The time required for the concentration of a drug in the plasma to reduce by half. It is crucial for determining dosing intervals.

☐ Elimination Rate Constant (ke): The rate at which a drug is removed from the body, expressed as a fraction of the drug eliminated per unit time.

☐ Volume of Distribution (Vd): A theoretical volume that relates the amount of drug in the body to the concentration of drug in the plasma.

☐ Clearance (Cl): The volume of plasma from which the drug is completely removed per unit time, indicating the efficiency of elimination.

☐ Bioavailability (F): The fraction of an administered dose of unchanged drug that reaches the systemic circulation.

☐ Steady State Concentration (Css): The point at which the drug's intake and elimination are balanced, leading to a stable concentration in the plasma.

Pharmacokinetic Models

☐ Compartmental Models

☐ One-Compartment Model: Assumes the body acts as a single, homogenous compartment where the drug distributes instantly and uniformly. Example: Aminoglycosides.

☐ Two-Compartment Model: Divides the body into a central compartment (highly perfused organs) and a peripheral compartment (less perfused tissues). Example: Vancomycin, which has a distribution phase of 1-2 hours.

☐ Three-Compartment Model: Further divides the body into plasma, highly perfused tissues, and scarcely perfused tissues. Example: Gentamicin, which shows complex distribution patterns.

☐ Non-Compartmental Models

Non-Compartmental Analysis: Treats the body as a single compartment without assumptions about distribution. It simplifies calculations of pharmacokinetic parameters.

Key Metrics: Includes Area Under the Curve (AUC), Peak Concentration (Cmax), Time of Peak Concentration (Tmax), Terminal Elimination Rate Constant (Lambda_z), and Terminal Half-life (HL_Lambda_z).

Kinetics and Rate Processes

☐ Kinetics: The study of the rates of drug absorption, distribution, metabolism, and excretion.

☐ ADME Processes: These processes influence the onset, duration, and intensity of drug action, which are critical for therapeutic effectiveness.

☐ Rate Constants: For absorption (ka) and elimination (ke), which describe the fraction of drug absorbed or eliminated per unit time.

The image shows the differential equation for the rate of change of area, dA/dt, which is equal to -k*.

☐ First Order Kinetics

First Order Kinetics: The rate of drug elimination is proportional to the drug concentration available at that time, leading to exponential decay in drug concentration over time.

Kinetic Processes in Pharmacology

☐ Linear Kinetic Processes

Linear kinetic processes refer to drug absorption, permeation, or elimination that is dependent on drug concentration, commonly described as first-order kinetics.

First-order kinetics is characterized by a rate of reaction that is directly proportional to the concentration of the drug present.

Most routes of drug administration, particularly oral and certain injectable forms, follow first-order kinetics, allowing for predictable absorption and elimination rates.

First Order Kinetics

☐ Absorption Process:

This model is primarily applicable to oral drug absorption, especially for drugs in solution or rapidly dissolving forms like tablets and capsules.

Intramuscular and subcutaneous aqueous injections can also exhibit first-order kinetics, where the rate of absorption is concentration-dependent.

The half-life of a first-order reaction remains constant regardless of the initial concentration, meaning the time taken for the concentration to decrease by half is consistent.

A child is being given medicine by an adult, with a description of how the drug is absorbed over time.

☐ Elimination Process:

In first-order elimination, the rate of drug elimination is directly proportional to the serum drug concentration, meaning higher concentrations lead to faster elimination rates.

The half-life (t1/2) is a crucial concept in pharmacokinetics, defined as the time required for the concentration of a drug to reduce to half its initial value.

The formula for calculating half-life in first-order kinetics is: t1/2 = 0.693 / kel, where kel is the elimination rate constant.

Zero Order Kinetics

☐ Characteristics of Zero Order Kinetics

Zero-order kinetics occurs when a drug is absorbed or eliminated at a constant rate, independent of its concentration in the body.

This type of kinetics is observed in certain drugs such as alcohol, phenytoin, and salicylates, where a fixed amount is eliminated per unit time.

The rate of reaction remains constant, leading to a linear decrease in drug concentration over time.

A graph showing that the rate of elimination is constant regardless of drug concentration in zero-order elimination kinetics.

☐ Half-Life in Zero Order Kinetics

The half-life in zero-order kinetics is not constant and varies with the initial concentration of the drug.

Understanding the half-life in this context is essential for determining dosing schedules and potential toxicity.

The elimination rate is described as a constant amount of drug removed per time unit, which can complicate therapeutic drug monitoring.

Key Pharmacokinetic Parameters

☐ Elimination Rate Constant (kel)

The elimination rate constant (kel) is a first-order rate constant that indicates the fraction of drug eliminated from the body over time.

For example, an kel of 0.25 per hour means approximately 25% of the remaining drug is excreted each hour.

This constant is influenced by various factors including distribution, biotransformation, and excretion processes.

☐ Apparent Volume of Distribution (Vd)

Vd is a theoretical volume that relates the total amount of drug in the body to its concentration in the plasma.

It is calculated by dividing the dose that reaches systemic circulation by the plasma concentration at time zero (Cp0).

A higher Vd indicates extensive distribution of the drug into body tissues, while a lower Vd suggests limited distribution.

☐ Clearance (Cl)

Clearance is defined as the volume of blood from which all drug is removed per minute, reflecting the body's ability to eliminate drugs.

It is influenced by renal, hepatic, and biliary clearance mechanisms, and is inversely related to half-life.

The relationship between clearance, elimination rate constant, and volume of distribution is crucial for understanding drug dosing and frequency.

Bioavailability and Steady State Concentration

☐ Bioavailability

Bioavailability refers to the percentage of an administered drug dose that reaches systemic circulation, crucial for determining therapeutic effectiveness.

The area under the curve (AUC) is a key measure used to compare bioavailability between different administration routes, particularly non-IV versus IV.

AUC can be calculated by considering the segments of concentration-time curves as trapezoids, allowing for detailed pharmacokinetic analysis.

☐ Steady State Concentration (CSS)

Steady state is achieved when the rate of drug absorption equals the rate of elimination, typically reached after four to five half-lives.

For drugs with short half-lives, steady state is reached quickly, while drugs with long half-lives may require longer periods to achieve therapeutic levels.

A loading dose can be administered to quickly elevate drug concentration to near steady state, facilitating faster therapeutic effects.

Discussion:

1. Key differences between first-order & zero order kinetic in absorption & elimination

In drug absorption & elimination, 1st order is concentration dependent while 0 order is concentration independent where drugs are absorbed & eliminated in a constant rate.1st order has rate of elimination that directly proportional to the drug concentration which higher concentrations lead to higher elimination rates. 0 order has constant rate of elimination regardless the concentration of drug. Half-life of 1st order is constant regardless of concentration while half-life of 0 order is not constant which varies with the initial concentration of drug

(answer)

First-order kinetics refers to a process where the rate of drug absorption or elimination is directly proportional to the drug concentration, while zero-order kinetics indicates a constant rate of absorption or elimination that is independent of concentration. This distinction is crucial for understanding how different drugs behave in the body

2. How do pharmacokinetics & pharmacodynamics interrelate to influence drug effect over time?

Pharmacokinetics describe drug concentration over time while pharmacodynamics describe drug effect over concentration. By combining both of them, we able to obtain the drug effect over time. As drug effect is dependent of the initial concentration while it's elimination rate is dependent of half-life of drug.

(answer)

Pharmacokinetics describes the concentration of a drug in the body over time, while pharmacodynamics relates the drug's effects to its concentration. Together, they provide a comprehensive understanding of the time course of drug effects, illustrating how changes in drug concentration can lead to varying therapeutic outcomes.

3. In what scenarios will two compartment model more appropriate than one compartment model for drug distribution?

Two compartment model is more appropriate for drugs having longer distribution phase (e.g. Vancomycin having distribution phase of 1-2 hours) or having specific site of administration because one compartment allows drug to be distributed instantly & uniformly which may not be suitable for certain drugs . One compartment model assume body to act as single homogenous compartment while two compartment model divides body into central compartment (highly perfused organs) & peripheral compartment (less perfused tissues).

(answer)

A two-compartment model is more suitable for drugs that exhibit slow equilibration with peripheral tissues, such as those that distribute into less perfused areas of the body. This model accounts for the initial rapid distribution phase followed by a slower elimination phase, which is essential for accurately predicting drug behavior in clinical settings.

4. Discuss the significance of the elimination rate constant (kel) in pharmacokinetics and its relationship with half-life.

Elimination rate constant (kel) is a first order rate constant that indicates of drug eliminated from body over time while half-life is the time needed for the concentration of drug to be reduced to half of its original concentration. Constant is influenced by various factors including distribution, biotransformation & exertion process. The elimination rate constant is directly proportional to half-life which elimination rate is concentration dependent.

(answer)

The elimination rate constant (kel) quantifies the fraction of drug eliminated from the body per unit time, directly influencing the drug's half-life. Understanding this relationship is vital for determining dosing regimens, as a higher kel results in a shorter half-life, necessitating more frequent dosing to maintain therapeutic levels.

5. What role does bioavailability play in the assessment of drug efficacy, and how can it be measured?

Bioavailability refers percentage of administered drug dose that reaches systemic circulation which crucial in determining therapeutic effectiveness. Bioavailability is measured by aeua under curve (AUC) between different administration routes, particularly non-IV versus IV. It is calculated considering the segment concentration-time curves as trapezoids, allowing for detailed pharmacokinetics analysis.

(answer)

Bioavailability indicates the percentage of an administered drug dose that reaches systemic circulation, which is critical for evaluating its therapeutic efficacy. It can be measured by comparing the area under the curve (AUC) of drug concentration over time after different routes of administration, providing insights into how formulation and route affect drug absorption.

6. How does the concept of steady-state concentration (CSS) inform clinical decisions regarding drug dosing?

CSS is achieved when rate absorption = rate elimination, usually after 4-5 half-lives. Drugs with short half-life achieve steady state quickly while drugs with long half-lives may required longer period to achieve therapeutic levels. If the drug's having long half-life, the dosage can be divided into multiple loading dose that quickly increase drug concentration to near steady state, facilitating faster therapeutic effects. It is important to administer suitable dose for optimal therapeutic effect.

(answer)

Steady-state concentration (CSS) is achieved when the rate of drug administration equals the rate of elimination, typically taking four to five half-lives. This concept guides clinicians in determining appropriate dosing intervals and the necessity of loading doses to quickly reach therapeutic levels, especially in critical care situations.