U3-Exposure-Response Relationships 2 PDF
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Saint Louis University
Cristopherson P. Mata
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Summary
This document covers the principles of exposure-response relationships in the context of pharmacology. It explores different drug actions, safety markers, and measurements of drug concentrations in various tissues, fluids, and the body. Exposure-time profiles and variability in drug responses are examined, offering a comprehensive overview of the topic.
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SAINT LOUIS UNIVERSITY DEPARTMENT OF PHARMACY PHARM 314: Biopharmaceutics and Pharmacokinetics UNIT 3 EXPOSURE-RESPONSE...
SAINT LOUIS UNIVERSITY DEPARTMENT OF PHARMACY PHARM 314: Biopharmaceutics and Pharmacokinetics UNIT 3 EXPOSURE-RESPONSE RELATIONSHIPS Compiled by: Cristopherson P. Mata, RPh, MS Pharm Sources: Towzer and Rowland: Essentials of Pharmacokinetics and Pharmacodynamics, 2nd edition Shargel, Leon. Applied Biopharmaceutics and Pharmacokinetics latest Edition, Boston: McGraw Hill, latest edition Katzung, B.G. et al. Basic and Clinical Pharmacology, 13th edition Brenner, G.M. et al. Pharmacology, 4th edition PHARMACODYNAMICS - REVIEW Drugs produce a THERAPEUTIC EFFECT when there is an adequate exposure-time profile at target site. Drugs interact with components within the body (receptors/ site of action) to produce a response. Drugs acting as: Enzyme Inhibitors or Inducers Agonists or Antagonists What are RECEPTORS? RESPONSE → Either clinical (desired) or adverse/ side effects. → All pharmacodynamic responses are BIOMARKERS OF DRUG EFFECTS Clinical Responses & Biomarkers Blood glucose level Blood pressure Relief of pain Remission of symptoms Safety Biomarkers Liver function tests Renal function tests CBC and differential count Signs (initial) of toxicity Quantal Dose-Response Curve ED50 LD50 Therapeutic Index (TI) RESPONSE Assessment of Drug Effects * FEV is a measure of respiratory function Male children suffering from Duchenne dystrophy treated with Prednisone RESPONSE Drug Therapeutic Use Desired Clinical Response Paracetamol Aspirin Salbutamol Carvedilol Simvastatin Warfarin Glimepiride Allopurinol Fluoxetine Lidocaine EXPOSURE MEASUREMENT OF DRUG CONCENTRATION For SYSTEMIC DRUG EXPOSURE Biologic Specimens Invasive methods: 1. Predict the drug concentration in the blood of a 20 mg Plasma drug after 1 hour of oral administration. Serum Whole blood 2. How much of a 100-mg drug is left in the systemic CSF circulation after 24 hours of oral administration? Synovial fluid 3. What should be the dosing interval of a 0.5 mg drug for Non-invasive methods: a patient with kidney problem? Urine Feces 4. When will a Drug X be completely be absent from the Saliva systemic circulation? Breastmilk EXPOSURE MEASUREMENT OF DRUG CONCENTRATION → Used to reflect systemic time course of drugs. → Plasma perfuses all tissues in the body, hence it represents tissue drug concentration. → Blood is the most direct approach to assess the pharmacokinetics of the drug. Why? Blood conc.= conc. delivered to the site of action EXPOSURE MEASUREMENT OF DRUG CONCENTRATION Drug Concentration in Tissues APPLICATIONS ON PHARMACOKINETICS → Difficult method of measuring drug concentration Calculate the optimum dosage regimen. because of its invasiveness. Correlate drug concentration with pharmacologic → Drug measurement in tissues would ascertain if or toxic activity. the drug reached its target organ. Predict plasma, tissue, and urine drug levels with any dosage regimen. Drug Concentration in Urine and Feces Estimate possible accumulation of drugs and/or its → Indirect methods to evaluate drug concentration. metabolites. → Measures the amount of drug that has been Evaluate differences in rate and extent of metabolized and excreted (not the portion active availability between formulations (bioequivalence). in the body). Describe how changes in physiology or disease affect drug absorption, distribution, metabolism, and elimination of the drugs. Explain drug interactions. RELATING RESPONSE TO CONCENTRATION Plasma Drug Effects Concentration TOXIC Max.EC/ ED 99/ Max. Safe Conc. Therapeutic Range CLINICAL Onset of Action Min.EC/ ED 50 Duration of Action SUBCLINICAL.. Onset Time... Time 3 6 9 EXPOSURE-TIME PROFILE Cmax Tmax Cmax, Tmax, and AUC highly depend on the Pharmacokinetics of the Drug VARIABILITY IN DRUG RESPONSE - OVERVIEW Prescribed Administered Concentration Intensity Dose Dose at locus of action of effect Patient Compliance Rate and extent of absorption Drug – Receptor Interaction Medication Errors Body size and composition Functional state Distribution of body fluids Binding in plasma and tissues Rate of elimination Physiologic variables Pathologic factors Genetic factors Interaction with other drugs Development of tolerance
