15.2
Pharmacokinetic–Pharmacodynamic Relationship: Dose to Pharmacological Effect
A drug’s dosage and pharmacokinetic properties determine how quickly it acts, how intense its effects are, and how long it lasts. Higher doses increas…
A drug’s dosage and pharmacokinetic properties influence the onset, intensity, and duration of its pharmacologic actions.
Higher drug dosage increases its receptor site concentration, yielding a hyperbolic curve when plotting pharmacologic response versus drug dose.
Here, changing to a log-linear scale results in the sigmoidal curve. For one-compartment model drugs, the pharmacologic response is proportional to log drug plasma concentration.
The effect, E, of drug concentration, C, is expressed as follows, which is solved for providing log C.
However, the post-IV dosing drug concentration is calculated differently, and mathematical substitutions yield another equation indicating the slope km/2.3.
Notably, the slope reflects the linear decline of the pharmacologic response over time. A drug with a higher m value requires frequent dosing to overcome rapidly declining responses.
For example, after the IV administration of lysergic acid diethylamide in healthy human subjects, the log concentration and the performance score, a measure of pharmacologic effect, decline linearly with time.
View the full transcript and gain access to JoVE Core videos
Q1: How does drug dosage affect the shape of the dose-response curve?
Higher drug dosage increases receptor site concentration, producing a hyperbolic curve when plotting pharmacologic response versus drug dose. Converting this to a log-linear scale transforms the hyperbolic curve into a sigmoidal curve, which better represents the dose-response relationship and is more useful for analyzing drug effects across a range of concentrations.
Q2: Why is the pharmacologic response proportional to log drug plasma concentration?
For one-compartment model drugs, the pharmacologic response follows a mathematical relationship where effect is proportional to the logarithm of drug plasma concentration. This logarithmic relationship allows the sigmoidal dose-response curve to be linearized, making it easier to predict drug effects and calculate the slope km/2.3, which reflects how rapidly the pharmacologic response declines over time.
Q3: What does the slope value tell us about drug dosing frequency?
The slope km/2.3 represents the linear decline of pharmacologic response over time. Drugs with higher m values show rapidly declining responses, requiring more frequent dosing to maintain therapeutic efficacy. This relationship is crucial for optimizing dosing regimens and ensuring consistent drug effects throughout the treatment period.
Q4: How does intravenous administration affect drug concentration calculations?
After IV administration, drug concentration is calculated differently than other routes, requiring mathematical substitutions of pharmacokinetic parameters into the dose-effect equation. This yields the slope expression km/2.3, which determines how quickly drug concentration and pharmacologic effect decline in the body following IV dosing.
Q5: What factors determine how long a drug's effect lasts in the body?
Effect duration depends on the drug's elimination half-life, receptor desensitization, and redistribution. Drugs with shorter half-lives require more frequent dosing to maintain therapeutic levels. Understanding these factors is essential for optimizing dosing regimens and balancing drug potency with duration of action to achieve therapeutic effects while minimizing adverse reactions.
Q6: How do pharmacokinetic properties influence the onset and intensity of drug action?
A drug's dosage and pharmacokinetic properties directly influence the onset, intensity, and duration of its pharmacologic actions. Higher dosages increase drug concentration at receptor sites, producing stronger effects. The relationship between drug concentration and response follows predictable mathematical patterns, allowing clinicians to optimize dosing strategies for maximum therapeutic benefit.
Q7: Why do centrally acting drugs like LSD show linear decline in effect over time?
Centrally acting drugs exhibit linear decline in log concentration and pharmacologic effect over time because their response is proportional to the logarithm of plasma concentration. In clinical studies, performance scores measuring drug effects decline linearly with time, reflecting the predictable relationship between drug concentration and pharmacologic response characteristic of one-compartment model drugs.