Variability in drug response

Variability in Drug Response

The differences in how individuals respond to the same drug and dose.

Reliable and Reproducible Clinical Effect

The desired outcome of drug therapy, which can be challenging to achieve due to variability in response.

Therapeutic Failure

When a drug does not produce the desired clinical effect in a patient.

Adverse Drug Reaction (ADR)

An unintended and harmful response to a medication.

Compliance

The extent to which a person's behavior (e.g., taking medication, following a diet) coincides with medical or health advice. This includes taking the correct dose, at the correct time, and avoiding prohibited substances. Poor compliance is a major source of variability.

Bioavailability (F)

The fraction of an administered dose of unchanged drug that reaches the systemic circulation. Differences in bioavailability can lead to variability in drug response.

Pharmacokinetic (PK) Variation

Differences between individuals in how the body handles a drug, affecting drug concentrations at the target site and the duration of action. This includes variations in absorption, distribution, metabolism, and excretion.

Pharmacodynamic (PD) Variation

Differences between individuals in the response of the target tissue to a given drug concentration. This involves variations at the drug target, including receptor density, affinity, and signaling.

[Drug] in Systemic Circulation

The concentration of the drug in the bloodstream, which is influenced by pharmacokinetic processes.

Optimal Response

The desired therapeutic effect of a drug without significant adverse effects. Variability can lead to some patients achieving an optimal response while others experience therapeutic failure or ADRs.

Sources of Variability (PK/PD)

Factors that contribute to differences in drug response, categorized as pharmacokinetic or pharmacodynamic.

Dose-Effect Relationship

The relationship between the dose of a drug administered and the resulting effect. Variability can alter this relationship between individuals.

Receptor (as a source of variability)

Variations in receptor density, affinity for the drug, and downstream signaling pathways can lead to pharmacodynamic variability.

Disease States (as a source of variability)

The presence of other illnesses can affect pharmacokinetic processes (e.g., altered drug clearance in renal or hepatic impairment) and pharmacodynamic responses (e.g., altered receptor expression).

Pharmacogenetics (as a source of variability)

Genetically determined differences in drug response due to variations in genes encoding drug-metabolizing enzymes, transporters, or drug targets. Genetic polymorphism is one source of variability in PK.

Environmental Factors (as a source of variability)

External influences such as diet, smoking, and exposure to other chemicals that can affect drug response.

Age

Physiological changes associated with different life stages (e.g., newborns, elderly) can significantly impact pharmacokinetic and pharmacodynamic processes.

Body Composition (as a source of variability)

Differences in body weight, percentage of body fat, and lean body mass can affect drug distribution (Vd) and therefore drug concentrations. Obese individuals may require different doses of water-soluble and lipid-soluble drugs compared to lean individuals of the same weight.

Drug-Drug/Food Interactions (as a source of variability)

The effects of taking multiple medications or consuming certain foods concurrently, which can alter the pharmacokinetics or pharmacodynamics of a drug. Induction or inhibition of enzymes and competition for drug binding are examples.

Inter-individual Variability

The differences in drug response observed between different individuals.

Receptor Density, Affinity, Signaling (as sources of PD variability)

Differences in the number of receptors available, the strength of the drug-receptor interaction, and the efficiency of downstream signaling pathways can lead to variations in pharmacodynamic response.

Formation and Elimination Kinetics of Endogenous Ligands (as a source of PD variability)

Variations in the production and breakdown of natural substances that interact with the same receptors as drugs can influence drug effects.

Polymorphisms (e.g., in target receptors)

Genetic variations in drug target proteins that can alter their function and consequently the response to a drug.

Hyperthyroidism (example of disease affecting PD)

A condition associated with an increase in the number of β-adrenoreceptors, potentially leading to altered responses to adrenergic drugs.

Opposing, Additive, or Synergistic Effects (in drug interactions)

Ways in which the pharmacodynamic effects of multiple drugs can interact.

Tolerance

A decreased response to a drug with prolonged use.

Cross-tolerance

A decreased response to other drugs with similar effects as a result of developing tolerance to one drug.

Renal Changes (nephrotoxicity) associated with diabetes (example of disease affecting PK)

Kidney damage due to diabetes can impair drug excretion, leading to altered drug levels and response.

Genetic Background (as a source of variability)

An individual's unique genetic makeup contributes to variability in drug response through pharmacogenetic mechanisms.

Forgetfulness (as a factor affecting compliance)

A patient's inability to remember to take their medication is a common cause of poor compliance.