pharmacokinetics lecture 6

• Clinical Pharmacokinetics (PK) involves the dynamic interactions of drug Absorption, Distribution, Metabolism, and Excretion (ADME) which influence plasma concentrations and target site concentrations.
• Drug in plasma and other body sites are in equilibrium.
• A drug's pharmacological effects are related to its concentration in blood or plasma.

Four Key Parameters Governing Drug Disposition (PK)

• Bioavailability (%F) indicates the fraction of a does that reaches systemic circulation
• Volume of distribution (Vd) relates the amount of drug in the body to plasma concentration
• Clearance describes the rate at which a drug is removed from the body
• Elimination half-time (T1/2) is the time required for plasma concentrations to decrease by 50%

Drug Elimination

• Drug elimination follows first-order processes, where a constant fraction of the drug is eliminated per unit of time.
• Half-life (t1/2) describes the rate of drug elimination.
• Therapeutic requirements often exceed the duration of action following a single dose meaning more drug needs to be administered to remain above the minimum effective concentration (MEC).
• Drugs with short half-lives do not accumulate unless administered frequently.
• Drug accumulation occurs when a drug is repeatedly dosed.
• Steady state is reached after approximately five half-lives, when drug input equals drug elimination
• Elimination half-life (t1/2) guides clinicians in determining the frequency of drug administration to maintain therapeutic blood drug levels.
• Elimination half-life is a "hybrid constant" dependent on volume of distribution and clearance.
• The goal of dosing regimens is to maintain plasma drug levels within the therapeutic range for the duration of therapy.

Factors Affecting Pharmacokinetics

• Individual pharmacokinetics are influenced by physiological, disease, and drug factors.
• These factors primarily affect the elimination half-life through alterations in volume of distribution and clearance.
• Alterations in pharmacokinetics can lead to adverse drug effects, such as toxicity from high drug levels or sub-therapeutic failure from inadequate drug levels.

Drug Interactions

• A drug interaction is a change in the magnitude or duration of a drug's effect due to another drug, food, or environmental factor.
• The incidence of drug interactions increases with the number of drugs administered (polypharmacy) and the duration of drug use.

Pharmaceutical Interactions

• Pharmaceutical interactions are in vitro effects occurring before drug absorption.
• These interactions often occur when drugs are combined in the same syringe or IV fluids or in the GI tract lumen.
• Drug-drug interactions are the most common, resulting from alterations in the physicochemical properties of the affected drug.
• Drug-environment or drug-diet interactions are less common.

Pharmacokinetic Interactions

• Most clinically significant drug interactions result from changes in drug pharmacokinetics.

Absorption Interactions

• Can be affected by stomach pH, GI motility, and P-glycoprotein activity.

Distribution interactions

• May occur due to plasma protein binding or tissue protein binding displacement, as well as changes in tissue blood flow.

Metabolism interactions

• Involve metabolizing enzymes, particularly Phase I mixed-function oxidases (MFOs), which can be inhibited or induced.

Excretion interaction

• May be influenced by urine pH, tubular secretion, and renal blood flow.

Drug Interaction Factors: Induction and Inhibition

• Induction and inhibition of drug metabolism are usually unplanned and can lead to adverse drug effects.
• Occasionally, inhibition may be planned to achieve a desired therapeutic effect.

Induction of P450 Enzymes

• Induction of P450 enzymes increases enzyme expression, primarily through increased gene transcription (mRNA).
• Consequences of induction include increased metabolism of the inducing drug and other co-administered drugs.
• Induction takes days to weeks to manifest clinically.
• The clinical significance of induction is a reduced elimination half-life and decreased blood drug levels, requiring dosage adjustments.

Inhibition of P450 Enzymes

• Inhibition of P450 enzymes occurs when the enzyme is directly inhibited by the affecting drug.
• The onset of inhibition effects on the pharmacokinetics of co-administered drugs is faster than with induction.
• The clinical significance of inhibition is necessitating decreased dosage to accommodate the inhibition effect.

An overview of clinical pharmacokinetics, focusing on drug disposition and elimination processes. Key parameters like bioavailability, distribution volume, clearance, and elimination half-time are discussed. Understanding these parameters is crucial for optimizing drug therapy.