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Anaesthesiology
Basic Principles of Clinical Pharmacology
Built from Barash Clinical Anesthesia, 9th Edition
What’s inside
13 sections · 199 slides
Overview
- Scope of this topic
- Roadmap of the four sections
- Historical origin of anaesthetic pharmacokinetics
Absorption and routes of administration
- Transfer of drugs across cell membranes
- Passive transport and drug transporters
- The blood-brain barrier and carrier proteins
- Intravenous administration and bioavailability
- Pulmonary first-pass effects after IV injection
- Oral administration and first-pass metabolism
- Sublingual, nasal, and transcutaneous administration
- Intramuscular and subcutaneous administration
- Neuraxial and inhalational administration
Drug distribution
- Determinants of tissue exposure
- Rate of tissue equilibration
- Redistribution after a single bolus
- Limits of redistribution with repeated dosing
Drug elimination
- Definition of elimination and clearance
- Phase I and Phase II biotransformation
- Phase I reactions: hydrolysis
- Phase I reactions: oxidation and reduction
- The cytochrome P450 superfamily
- CYP inhibition by competing substrates
- Phase II conjugation reactions
- Genetic and age-related variation in metabolism
- Renal drug clearance
- Tubular reabsorption and renal impairment
- Hepatic drug clearance: the two variables
- High and low intrinsic clearance
- Intrinsic clearance, extraction ratio, and hepatic clearance
- Effect of hepatic blood flow on clearance
- Liver blood flow and hepatic clearance
- Liver blood flow and hepatic extraction ratio
- Cardiac output as a covariate in dosing
Pharmacokinetic models and concepts
- Why models are needed
- Physiologic (perfusion) models
- Compartment models and their meaning
- Physiologic versus compartment models
- First-order kinetics
- Half-lives and rate constants
- Volume of distribution
- Total drug (elimination) clearance
- Elimination half-life from volume and clearance
- Area under the concentration-time curve and clearance
- Elimination half-life as a composite parameter
- Clearance as the product of rate constant and volume
- Organ disease and nonlinear pharmacokinetics
Compartmental pharmacokinetic models
- The one-compartment model
- Plasma concentration on linear and logarithmic scales
- The two-compartment model
- Two-phase decline in plasma concentration
- Two-compartment model structure
- Volume of the central compartment
- Distributional clearance and steady-state volume
- The three-compartment model
- Three-compartment model structure
- Choosing and interpreting a compartment model
- Two-stage versus population modelling
- Noncompartmental (stochastic) analysis
- Neural networks in pharmacology
- Feed-forward multilayered neural network
Pharmacodynamic principles
- Drug-receptor interactions
- Receptor reserve and the margin of safety
- How receptor binding changes cell function
- Ionophores and G-protein signalling
- Desensitisation, downregulation, and upregulation
- Agonists and partial agonists
- Competitive and noncompetitive antagonists
- Agonism, partial agonism, and antagonism
- Dose-response relationships
- Dose-response curve on linear and logarithmic scales
- Concentration-response relationships
- Hysteresis between concentration and effect
- Plasma concentration and effect during and after infusion
- Steady state and the Cpss50
Combined pharmacokinetic-pharmacodynamic models
- The effect compartment (biophase)
- Three-compartment model with an effect site
- The equilibration rate constant ke0
- Population pharmacokinetic-pharmacodynamic modelling
- Allometric scaling and precision dosing
- Therapeutic threshold and therapeutic window
- Therapeutic and toxic thresholds after fentanyl boluses
Drug interactions
- Scale of the problem in anaesthesia
- In vitro physicochemical interactions
- Local anaesthetic formulation and pH
- Carbon dioxide absorbent and volatile degradation
- Sugammadex and molecular encapsulation
- Fumarates and cysteine inactivation
- Pharmacokinetic interactions: absorption
- Pharmacokinetic interactions: distribution
- Protein binding displacement
- Pharmacokinetic interactions: metabolism
- Opioid prodrugs and CYP2D6
- Prodrug activation blocked by inhibition
- Pharmacodynamic interactions
- Opioid-hypnotic synergy
- Serotonin syndrome
- Management of serotonin syndrome
Clinical application to intravenous anesthetics
- Why global kinetic parameters fail in the operating room
- Rise to steady-state concentration
- Why the simple rule fails for propofol
- Worked example of one-compartment dosing failure
- The BET dosing scheme
- One-compartment dosing versus the BET scheme
- Isoconcentration nomogram for propofol infusion rates
- Pharmacokinetic simulation software
- StanpumpR simulation interface
- Context-sensitive half-time
- Context-sensitive half-times of four synthetic opioids
- Why longer infusions give longer half-times
- Limitations of context-sensitive half-time
- Context-sensitive 25%, 50%, and 75% decrement times
- Context-sensitive time to recovery
- Simulated effect-site concentration and time to emergence
- Soft pharmacology
- Soft hypnotics in development
- Context-sensitive half-times of classic and soft drugs
Target-controlled infusion
- Rationale for target-controlled infusion
- Mathematics behind target-controlled infusion
- Targeting the plasma concentration
- Targeting the effect site
- Targeting the effect site concentration
- Performance of target-controlled infusion models
- Sources of error in target-controlled infusion
- History and availability of TCI systems
- Clinical evidence and patient-controlled uses of TCI
- Time to maximum effect compartment concentration
- Volume of distribution at peak effect
- Worked propofol example at peak effect
- Front-end pharmacokinetics
- Effect of front-end error on estimates of variability
- Interindividual variability: compartmental versus recirculatory models
- Cardiac output and blood-effect-site equilibration
- Definition and importance of front-end kinetics
- Closed-loop infusions
- Closed-loop feedback cycle
- PID and adaptive controllers
- Feedback signals and regulatory barriers
Response surface models of drug interactions
- Rationale for combining an opioid with a hypnotic
- Additive versus synergistic combinations
- Remifentanil shifting the sevoflurane concentration-effect curve
- Isobolograms
- Isoboles for sedation and for analgesia
- Additive, synergistic, and antagonistic isoboles
- The response surface model
- Response surface for the remifentanil-sevoflurane interaction
- Choosing an optimal concentration pair
- Sevoflurane-remifentanil simulation findings
- Optimal concentration pairs for fastest emergence
- Optimal sevoflurane and remifentanil target pairs by case duration
Summary and key points
- Key points: absorption and distribution
- Key points: metabolism and elimination
- Key points: pharmacodynamics
- Key points: interactions and clinical application
- Conclusion
- Substrates for CYP isoenzymes encountered in anesthesiology
- Substrates for CYP isoenzymes encountered in anesthesiology (continued)
- Substrates for CYP isoenzymes encountered in anesthesiology (continued)
- Drugs with significant renal excretion encountered in anesthesiology
- Drugs with significant renal excretion encountered in anesthesiology (continued)
- Classification of drugs according to hepatic extraction ratios
- Classification of drugs according to hepatic extraction ratios (continued)
- Classification of drugs according to hepatic extraction ratios (continued)
- Half-lives and corresponding percentage of drug removed
- Inducers and inhibitors of hepatic drug metabolism
- Inducers and inhibitors of hepatic drug metabolism (continued)
- Serotonergic psychiatric drugs implicated in serotonin syndrome with methylene blue
- Serotonergic psychiatric drugs implicated in serotonin syndrome with methylene blue (continued)
- Serotonergic psychiatric drugs implicated in serotonin syndrome with methylene blue (continued)
- Serotonergic psychiatric drugs implicated in serotonin syndrome with methylene blue (continued)
- Bolus-elimination-transfer scheme for a propofol plasma concentration of 5 micrograms/mL
- References
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- Barash, Cullen, and Stoelting's Clinical Anesthesia, 9th Edition