PHAR1057 Kinetics

MEASURING DRUG ACTION

Key Processes

  1. Absorption

  2. Distribution

  3. Metabolism

  4. Excretion

SERUM BLOOD LEVEL

  • Definition: Lab measurement of drug concentration in blood (mg/ml, mcg/ml).

  • Factors influencing serum level:

    • Dosage

    • Absorption

    • Bioavailability

    • Rate of metabolism (half-life)

    • Excretion

  • Drug Distribution Curve: Standard model for understanding serum level behavior.

DISTRIBUTION CURVE

Key Concepts

  1. Minimum Effective Concentration (MEC)

    • Minimum drug quantity required for pharmacologic action.

  2. Toxic Concentration

    • Drug level at which adverse effects occur.

  3. Therapeutic Region

    • Range between MEC and Toxic Concentration for effective therapy.

  4. Peak

    • Highest plasma concentration of drug.

  5. Onset

    • Time required for drug to exert therapeutic effects (reach MEC).

  6. Duration

    • Time drug remains in therapeutic range post-administration.

HALF-LIFE

Definition

  • Time needed for plasma concentration to decrease to half of its peak.

Significance

  • Measures drug elimination rate and influences the distribution curve.

  • Essential for determining dosing and timing of subsequent doses.

CALCULATION OF HALF-LIFE

Example Calculation

  • Initial amount: 50 mg; Half-life: 12 hours.

  • Exponential decay pattern:

    • 12 hrs: 25 mg

    • 24 hrs: 12.5 mg

    • 36 hrs: 6.25 mg

    • 48 hrs: 3.125 mg

    • 60 hrs: 1.5625 mg

    • 72 hrs: 0.78125 mg

    • 84 hrs: 0.390625 mg

    • 96 hrs: 0.1953125 mg

DRUG EFFECT MODEL

Key Points

  • Toxic level: 20

  • Therapeutic range indicated in the graph; includes MEC and peak levels.

  • Illustrates duration and onset of action.

MEASURING DRUG ACTION: INTRAVENOUS vs ORAL

Administration Comparison

  • IV route gives immediate peak levels; oral dosing rises gradually.

THERAPEUTIC INDEX vs RANGE

Definitions

  • Therapeutic Index:

    • Ratio expressing drug dosage safety zone; helpful for clinicians.

  • Therapeutic Range:

    • Actual plasma concentration limits to maintain; influences dosing frequency.

KEEPING IN THE ZONE

Importance

  • Maintain serum drug levels within the therapeutic range.

  • Use multiple doses; include loading doses for rapid effect.

Potential Consequences of Dosing Outside Therapeutic Range

  • Below MEC: Ineffectiveness; Above Toxic Level: Adverse effects.

TYPES OF ADVERSE EFFECTS

Examples

  • Pain Meds: Breakthrough pain vs. respiratory arrest.

  • Anesthetics: Waking up vs. respiratory/cardiac arrest.

  • Antibiotics: Bacterial proliferation vs. liver damage.

  • Insulin: Hyperglycemia and DKA vs. hypoglycemia and coma.

LOADING DOSE

  • Definition: Large initial dose to achieve quick therapeutic concentration.

  • Applications: Used in sepsis, mental health, pain management, anesthesia.

LOADING DOSE vs MAINTENANCE

Drug Administration

  • Drug A (Maintenance only) vs. Drug B (Loading + Maintenance) - illustrates reaching therapeutic range efficiently with loading doses.

DOSE MISSED

  • Implications of missed doses depend on drug’s half-life.

  • May require administration of a loading dose.

DRUG CANDIDATE METRICS

Key Factors

  • Activity: Effectiveness in binding target.

  • Solubility: Absorption efficiency from oral intake.

  • Metabolic Profile/Toxicity: Toxic effects from breakdown by enzymes.

  • Oral Bioavailability: Percentage reaching active form in the target tissue.

  • Half-Life: Duration in active form.


Pharmacokinetic Measurements

  1. Absorption

  2. Distribution

  3. Metabolism

  4. Excretion

Measuring Drug Action

  • Serum Blood Level:

    • Indicates the amount of drug in the blood (mg/ml, mcg/ml).

    • Influenced by factors such as dosage, absorption, bioavailability, metabolism (half-life), and excretion.

    • Drug Distribution Curve: Model used to describe serum levels of a drug over time.

Drug Distribution Curves

  • Comparative Analysis:

    • Oral vs IV administration both utilize drug distribution curves.

Key Concepts in Drug Action

Distribution Curve Parameters

  1. Minimum Effective Concentration (MEC):

    • Minimum amount of drug needed for therapeutic effect.

  2. Toxic Concentration:

    • Level at which drug causes adverse effects.

  3. Therapeutic Region:

    • Range between MEC and Toxic Concentration

    • Ideal zone for effective therapy.

  4. Peak:

    • Highest concentration of a drug in plasma.

  5. Onset:

    • Time required for drug to exhibit therapeutic effects, reaching MEC.

  6. Duration:

    • Time drug remains in the therapeutic range above MEC.

Drug Effect Model

  • Representation of drug action over time exhibiting:

    • Toxic level

    • Peak level

    • Therapeutic range

    • Minimal effective concentration

Half-Life Concept

  • Definition:

    • The time required for plasma concentration of a drug to halve.

    • Critical for determining rate of elimination.

  • Impact:

    • Affects the shape of the drug distribution curve.

    • Essential for drug dosing and timing subsequent doses.

Half-Life Calculation Example

  • Initial Amount: 50mg.

  • Half-life: 12 hours.

  • Exponential Decay:

    • 12 hours: 25mg

    • 24 hours: 12.5mg

    • 36 hours: 6.25mg

    • 48 hours: 3.125mg

    • Pattern continues until negligible amounts remain.

Half-Life Graphs

Half-Life of 12 Hours

  • Initial Peak at 50mg, gradual decline.

Half-Life of 24 Hours

  • Initial Peak at 50mg, similar decline dynamic but slower rate.

Measuring Drug Action - Importance of Half-Life

  • Longer half-life leads to prolonged drug presence during excretion.

  • Different administration routes impact the distribution curve and peak plasma concentration.

Drug Administration Routes Influence

  • IV: Immediate peak

  • IM and SC: Intermediate peaks

  • Oral: Slower rise to peak plasma concentration.

Therapeutic Index and Range

  • Therapeutic Index:

    • Ratio expressing safety zone for drug dosage.

    • Whole number representation for comparisons.

  • Therapeutic Range:

    • Actual plasma concentration limits for safe drug administration.

    • Maintenance of dosage informed by half-life and therapeutic monitoring.

Keeping Within the Therapeutic Range

  • Importance of maintaining serum levels within therapeutic limits:

    • Below MEC: Reduced effect; Above Toxic Level: Increased risks.

    • Examples include pain meds, anesthetics, antibiotics, and insulin with associated risks.

Loading Dose

  • Definition:

    • Large initial dose to quickly achieve therapeutic concentration.

  • Used for conditions like sepsis and rapid induction of anesthesia.

Loading Dose vs Maintenance Dose

  • Drug A: Only maintenance doses achieve therapeutic range gradually.

  • Drug B: Immediate therapeutic range from the first larger loading dose.

Missed Dose Protocol

  • Approach depends on drug's half-life and type of medication.

  • Guidance: "If you miss two doses, call your prescriber."

Factors in Drug Development

  • Activity: Binding efficiency and biological response generation.

  • Solubility: Critical for oral absorption.

  • Metabolic Profile/Toxicity: Evaluates potential toxicity during metabolism.

  • Oral Bioavailability: Measures the active drug reaching tissues.

  • Half-Life: Duration of active presence in the body.