R3 김대언

1. Advances in the Clinical Pharmacology of Intravenous Anesthetics : Pharmacokinetic, Pharmacodynamic, Pharmaceutical, and Technological Considerations R3 김대언

2. Total intravenous anesthesia • now an appealing, workable alternative to the inhalational anesthesia

3. The "surfing" analogy in anesthesia drug selection and administration • anesthesia and reanimation • necessitate a standard of precision and accuracy in drug administration • anesthesiologist • target drug level within a narrow therapeutic window • adequate anesthesia vs rapid emergence

4. a "surfing" analogy • surfer riding near the crest of wave • target concentration that produce considerable drug effects and recover quickly drug administration is terminated • large reduction in effects with small decrease in concentration

5. Three approaches • the pharmacodynamic approach • feedback mechanism(propofol titration to EEG and muscle relaxant) • the pharmacokinetic approach • TCI • the pharmaceutical approach • unnecessary to hit the target with as much precisions and accuracy as with the other approaches

6. Pharmacokinetic considerations • pharmacologic modeling • fitting mathematical equations to raw pharmacologic data • a set of parameters that describe in quantitative terms a drug's disposition and effect in the body • pharmacokinetic parameters : clearance, distribution volumes, half life • "what the body does to the drug" • pharmacodynamic parameters : potency • "what the drug does to the body"

7. The goal of PK-PD modeling • provide the practitioner with the knowledge necessary to formulate rational dosing scheme • accurately predicting the time course and magnitude of drug effect in any type of patients • to move dose-response analysis

8. pharmacokinetic component : relationship between the drug dose and the time course of drug concentrations in the body • pharmacodynamic component : relationship between the drug concentration in the site of action and the drug effect • prediction regarding latency to peak effect, magnitude of effect, duration of effect

9. Context sensitive half-times : a new pharmacokinetic concept • context sensitive half-times : a new pharmacokinetic concept • context : the duration of the continuous infusion • CSHT : 50% decrement time • alfentanil vs sufentanil vs fentanyl

10. Pharmacodynamic considerations • importance of pharmacodynamic drug interactions and synergy • pharmacodynamic drug interaction : frequently produced by design • modern day anesthesia : at least a two-drug process consisting of an analgesic and a hypnotic agent • anesthesiology is the practice of pharmacologic synergism using CNS depressants

11. propofol-opioid interaction : characterized using EC50 reduction study methodology • opioid-propofol : relation is highly nonlinear • the dosage reduction of one drug produced by an increase in the other is not simply proportional • the substantial pharmacodynamic synergy of the drug combination • isobolographic drug interaction analysis : rational selection of concentration target pairs for propofol and opioid

12. revolutionary advance in our understanding of IV anesthetic clinical behavior • propofol : 3.5ug/ml as loss of consciousness in 50% pts 10-15ug/ml to supress to surgical stimuli 1ug/ml in the presence of opioid adjuvant • by using propofol-opioid ratio : applicable to any anesthetic case • function of opioid pharmacokinetics : play a large part of selection of ratio • long acting fentanyl congeners : low opioid and high propofol • short acting opioid : low propofol

13. play in selecting the appropriate propofol-opioid ratio • hemodynamically compromised pt VS pt prone to nausea and vomiting • isobologram is only a single "slice" through a much larger drug ineraction "surface" • response surface : tool to visualize the nature of the synergy of two drug class

14. Pharmaceutical considerations • remifentanil : a prototype designer drug • by designing molecules with specialized structure-activity relationship • lose its u-receptor agonist activity on ester hydrolysis • very-short-acting pharmacokinetic activity

15. can be titrated up and down as necessary to meet the dynamic needs of the patient during rapid changing conditions of anesthesia and surgery • when rapid recovery is desirable • when the anesthetic requirement rapidly fluctuates • when opioid titration is unpredictable or difficult • when there is a substantial danger to opioid overdose • when "high-dose" opioid technique is advantageous but not going to be mechanically ventilated

16. importance of formulation : propofol as an example • the formulation of a drug can have an important influence on the drug's clinical behavior • propofol : lipid emulsion formulation pain on injection serious allergic reactions inadvertent contamination • prodrug non-lipid excipient lipid-based emulsion • may alter pharmacokinetic and pharmacodynamic characteristic

17. Technical advances calculating pump • simply specifies a delivery rate as mg/hr or ug/kg/mim • do not achieve the pharmacokinetic exactness • patient-controlled analgesia machine

18. computer-controlled infusion pump • by coding a pharmacokinetic model into a computer program and linking it into an electric pump • design target concentration and calculate the necessary infusion rate by TCI system • gradually decrease the rate of infusion based on the pharmacokinetics • change the infusion rate frequently • require knowledge of the therapeutic concentration for clinical application