Mechanisms of Drug Interaction

Mechanisms of Drug Interaction (PKPD)

Pharmacokinetic Interactions

  • These interactions are those in which one agent (designated by some as the precipitant drug) alters the ADME (Absorption, Distribution, Metabolism, and Excretion) of a second agent (the object drug), leading to a resultant change in the plasma concentration of the latter agent.

Mechanisms of Pharmacokinetic Interactions (GADMED)

  1. Alteration of GI Absorption

    • Interactions involving changes in the absorption of a drug from the GI tract may develop through different mechanisms and vary in clinical importance.

    • Alteration of pH

      • The nonionized form of a drug is absorbed more readily than the ionized form; changes in pH can affect drug ionization.

      • Clinically significant interactions may be rare, and factors beyond pH can impact GI absorption.

    • Other Mechanisms:

      • Complexation and Adsorption: Some drugs may form complexes that hinder absorption.

      • Alteration of Motility/Rate of Gastric Emptying: Changes in how quickly stomach contents move into the intestine can affect absorption.

      • Effect of Food: Certain foods can enhance or inhibit drug absorption.

      • Alteration of Metabolism in GI Tract: Changes in the metabolic activity of the gut can influence drug bioavailability.

      • Alteration of GI Flora: Changes in intestinal bacterial populations can affect drug efficacy.

      • Malabsorption States: Conditions like celiac disease can impair the absorption of drugs.

  2. Alteration of Distribution

    • Displacement from Protein-Binding Sites: This can happen when two drugs that are capable of binding to proteins are administered simultaneously, leading to alterations in plasma levels.

      • Mechanisms:

        • Noncompetitive Displacement: Binding characteristics of one drug may alter when another drug is present.

        • Competitive Displacement: Drugs compete for limited protein-binding sites; the drug with greater affinity will displace the other, affecting drug levels in plasma.

  3. Alteration of Metabolism

    • Stimulation of Metabolism: One drug can enhance the metabolism of another, often by increasing the activity of hepatic enzymes.

      • This process, known as enzyme induction, raises the amounts of drug-metabolizing enzymes, leading to increased metabolism and reduced pharmacologic action of the affected drug.

    • Inhibition of Metabolism: Some drugs can inhibit the metabolism of others, resulting in prolonged and heightened activity of the latter drug.

  4. Alteration of Excretion

    • Clinical significance mostly arises from drugs being excreted in their unchanged form or as active metabolites.

    • Mechanisms:

      • Alteration of Urinary pH: Can influence the reabsorption and clearance of drugs from the renal system.

      • Alteration of Active Transport: Changes affecting renal excretion pathways can impact drug levels.

  5. Alteration of Drug Transport

    • P-glycoprotein serves as a transport system, which may act as a barrier for certain agents.

    • Overlapping substrate specificity with CYP3A4 can lead to interactions where the inhibition or induction of one influences the other.

Pharmacodynamic Interactions

  • These interactions involve drugs having similar or opposing pharmacological effects administered concurrently and situations in which the sensitivity or responsiveness of tissues to one drug is altered by another.

  • They also have been viewed as situations in which there is a change in drug effect without a change in drug plasma concentration.

Mechanisms of Pharmacodynamic Interactions (OSER)

  1. Drugs Having Opposing Pharmacological Effects

    • These are typically easier to identify, though secondary effects of some drugs may obscure their recognition.

  2. Drugs Having Similar Pharmacologic Effects

    • Concurrent use leading to excessive responses occurs frequently, necessitating careful monitoring.

  3. Alteration of Electrolyte Concentrations

    • Some therapeutic agents can affect electrolyte levels, specifically sodium and potassium, necessitating regular monitoring of these concentrations in patients receiving such drugs.

  4. Interactions at Receptor Sites

    • Compounds can compete for receptor binding, altering the expected pharmacologic response.