ANESTHESIA: Pharmacologic Principles

Raisa Cagurangan, M.D. Mustafah Mahboobian, M.D. John Saquilayan, M.D. Jovelyn Tan, M.D.
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Key Points
1. Most drugs must pass through cell membranes to reach their sites of action. Consequently, drugs tend to be relatively lipophilic, rather than hydrophilic. 2. The highly lipophilic anesthetic drugs have a rapid onset of action because they rapidly diffuse into the highly perfused brain tissue. They have a very short duration of action because of redistribution of drug from the central nervous system to the blood. 3. The cytochrome P450 (CYP) superfamily is the most important group of enzymes involved in drug metabolism. It and other drug-metabolizing enzymes exhibit genetic polymorphism.
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Key Points
4. The kidneys eliminate hydrophilic drugs and relatively hydrophilic metabolites of lipophilic drugs. Renal elimination of lipophilic compounds is negligible. 5. The liver is the most important organ for metabolism of drugs. Hepatic drug clearance depends on three factors: the intrinsic ability of the liver to metabolize a drug, hepatic blood flow, and the extent of binding of the drug to blood components. 6. The volume of distribution quantifies the extent of drug distribution. The greater the affinity of tissues for a drug relative to blood, the greater its volume of distribution (i.e., lipophilic drugs have greater volumes of distribution).
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Key Points
7. Elimination clearance is the parameter that characterizes the ability of drug-eliminating organs to irreversibly remove drugs from the body. The efficiency of the body to remove a drug from the body is proportional to the elimination clearance. 8. All else being equal, an increase in the volume of distribution of a drug will increase its elimination half-life; an increase in elimination clearance will decrease elimination half-life. 9. Most drugs bring about a pharmacologic effect by binding to a specific receptor that brings about a change in cellular function to produce the pharmacologic effect.
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Key Points
10. Although most pharmacologic effects can be characterized by both dose-response curves and concentration-response curves, the dose-response curves are unable to determine whether variations in pharmacologic response are caused by differences in pharmacokinetics, pharmacodynamics, or both. 11. Integrated pharmacokinetic pharmacodynamic models allow temporal characterization of the relationship between dose, plasma concentration, and pharmacologic effect.

Key Points
12. Simulations of multicompartmental pharmacokinetic models that describe intravenous anesthetics demonstrate that for most anesthetic dosing regimens, the distribution of drug from the plasma to the pharmacologically inert peripheral tissues has a greater influence on the plasma concentration profile of the drug than the elimination of drug from the body.

Key Points
13. Target-controlled infusions are achieved with computercontrolled infusion pumps worldwide (not yet approved by the Food and Drug Administration [FDA] in the United States) and permit clinicians to make use of the drug concentration effect relationship, optimally accounting for pharmacokinetics and predicting the offset of drug effect. 14. By understanding the interactions between the opioids and the sedative-hypnotics (e.g., response surface models), it is possible to select target concentration pairs of the two drugs that produce the desired clinical effect while minimizing unwanted side effects associated with high concentrations of a single drug.

Key Points
15. The time until a patient regains responsiveness from a single drug anesthetic is determined by the pharmacokinetics of the individual drug, the concentrationeffect relationship, and the duration of administration of the drug (context-sensitive decrement time). For two-drug anesthetics, the time to awakening not only depends on the individual drug pharmacokinetics and the duration of administration of the anesthetics, but it also depends on the pharmacodynamic interactions of the two drugs.

Pharmacokinetics
Passive Diffusion Active Transport CNS, hepatocytes, renal tubular cells, pulmonary capillary endothelium

Routes of Administration
Intravenous Results in rapid increases in drug concentration thus caution on drugs with low therapeutic index Pulmonary endothelium
Can slow the rate at which intravenously administered drugs reach the systemic circulation (e.g. fentanyl) Contains enzymes that may metabolize intravenously administered drugs (e.g. propofol) on first pass and reduce their absolute bioavailability
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Routes of Administration
Oral Safest and most convenient Main determinant of the timing of absorption is gastric emptying into the small intestines NOT used significantly in anesthetic practice because of the limited and variable rate of bioavailability Nasal/Sublingual administration limited by:
Formulation Surface area Require a rapid onset of drug action (e.g. nitroglycerin, fentanyl)
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Routes of Administration
Transcutaneous Drug patches (e.g. scopolamine, nitroglycerin, opioids, clonidine) Extended amount of time to achieve an effective therapeutic concentration limits practical application except for maintenance therapy Attempts to speed up passive diffusion using an electric current has been described for fentanyl
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Routes of Administration
Intramuscular and Subcutaneous Directly dependent on the drug formulation and the blood flow to the depot Subcutaneous route of drug absorption is more variable in its onset because of the variability of subcutaneous blood flow during varying physiologic states

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Routes of Administration
Intrathecal, Epidural, and Perineural Injection Spinal cord primary site of action of many anesthetic agents Direct injection of local anesthetics and opioids into the intrathecal space bypasses the limitations of drug absorption and drug distribution of any other route of administration Epidural and perineural administration of local anesthetics necessitates that the drug be absorbed through the dura or nerve sheath Relative expertise required to perform
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Routes of Administration
Inhalational Large surface area of the pulmonary alveoli available for exchange with the large volumetric flow of blood found in the pulmonary capillaries makes inhalational administration an extremely attractive method New technologies (currently in phase 2 FDA trials) that can rapidly and predictably aerosolize a wide range of drugs and thus approximate intravenous administration
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Drug Distribution
Relative distribution of cardiac output among organ vascular beds determines the speed at which organs are exposed to the drug Flow-limited drug uptake Rate of drug equilibration by the tissue depends on the ratio of blood flow to tissue content

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Redistribution
Single, moderate doses of highly lipophilic drugs have a very short CNS duration of action because of redistribution to the blood and other, less wellperfused tissues Repeated injections allows the rapid establishment of significant peripheral tissue concentrations When the tissue concentrations of a drug are high enough, the decrease in plasma drug concentration below therapeutic threshold becomes solely dependent on drug elimination
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Drug Elimination
Excretion Biotransformation

Elimination clearance (drug clearance) theoretical volume of blood from which drug is completely and irreversibly removed in a unit of time [volume per time]

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Biotransformation
Phase I reactions transform a drug into one or more polar, and hence potentially excretable compounds Phase II reactions conjugating a variety of endogenous compounds to a polar functional group of the drug, making the metabolite even more hydrophilic
Often drugs will undergo a phase I reaction to produce a new compound with a polar functional group that will then undergo a phase II reaction. However, it is possible for a drug to undergo either a phase I reaction alone or a phase II reaction alone.
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Cytochrome P450 (CYP)

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Variations in Drug Metabolism

Genetic Chronologic

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Renal Drug Clearance

Primary role of the kidneys: excrete into urine the unchanged, hydrophilic drugs, and the hepatic-derived metabolites from phase I and phase II reactions of lipophilic drugs. Passive glomerular filtration is a very inefficient process. In order to make renal elimination more efficient, discrete active transporters of organic acids and bases exist in the proximal renal tubular cells
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Renal Drug Clearance

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Hepatic Drug Clearance

Drug elimination by the liver depends on:
intrinsic clearance hepatic blood flow
Changes in either will change hepatic clearance. However, the extent of the change depends on the initial relationship between intrinsic clearance and hepatic blood flow

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Hepatic Drug Clearance

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Pharmacokinetic Models

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 concentration of drug at its site or sites of action

fundamental determinant of a drug's pharmacologic effects

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 tissue drug concentration of an organ

blood flow to the organ concentration of drug in the arterial inflow of the organ capacity of the organ to take up drug diffusivity of the drug between the blood and the organ

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Physiologic versus Compartment Models

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Physiologic or Perfusion models

body tissues grouped according to distribution of cardiac output and capacity for drug uptake.
vessel-rich group lean tissue group vessel-poor group

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 vessel-rich group
Highly perfused tissues with a large amount of blood flow per volume of tissue
brain, lungs, kidneys, and a subset of muscle

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 lean tissue group or fast tissue group

tissues with a balanced amount of blood flow per volume of tissue
majority of muscle and some of the splanchnic bed (liver)

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 vessel-poor group (slow tissue group)

composed of tissues that had a large capacity for drug uptake but a limited tissue perfusion majority of the adipose tissue and the remainder of the splanchnic organs

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 (Price and Price et al)

awakening after a single dose of thiopental
primarily a result of redistribution of thiopental from the brain to the muscle with little contribution by distribution to less well-perfused tissues or drug metabolism

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 fundamental concept of redistribution

applies to all lipophilic drugs

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Perfusion-based physiologic pharmacokinetic models

significant insights into how physiologic, pharmacologic, and pathologic distribution of cardiac output can effect drug distribution and elimination. verification of the predictions of these models requires measurement of drug concentrations in many different tissues
experimentally inefficient and destructive to the system.
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Compartmental Pharmacokinetic Models

simpler mathematical models the body is composed of one or more compartments. compartments are theoretical entities that are used to mathematically characterize the blood concentration profile of a drug.
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Compartmental Pharmacokinetic Models

cardiac output is not a parameter cannot be used to predict directly the effect of cardiac failure on drug disposition

can still quantify the effects of reduced cardiac output on the disposition of a drug

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Pharmacokinetic Concepts

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Rate Constants and Half-Lives

first-order kinetics
one in which a constant fraction of the drug is removed during a finite period of time regardless of the drug amount or concentration. = rate constant of the process
apply not only to elimination, but also to absorption and distribution.

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Rate constants
absolute amount of drug removed is proportional to the concentration of the drug
rate of change of the amount of drug at any given time is proportional to the concentration present at that time. concentration is high, more drugs will be removed

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Rate constants
k units of inverse time, (min-1 or h-1)
If 10% of the drug is eliminated per minute, then the rate constant is 0.1 min-1.

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Half-lives
the rapidity of pharmacokinetic processes the time required for the concentration to change by a factor of 2.
calculated directly from the corresponding rate constants with this simple equation:

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Rate Constants and Half-Lives

First-order processes approach completion
a constant fraction of the drug not an absolute amount, is removed per unit of time.

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 after five half-lives, the process will be almost 97% complete

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Volume of Distribution
quantifies the extent of drug distribution Overall tissue capacity for uptake of a drug
a function of the total mass of the tissues into which a drug distributes and their average affinity for the drug.

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Volume of Distribution
an apparent volume size of hypothetical compartments
the concentration of drug in a reference compartment (central or plasma compartment)

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Volume of Distribution
a Vd total of 10 mg of drug Concentration:2 amount of drug present to relates the total mg/L
the concentration observed in the central Apparent volume of distribution compartment:

=5L

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Volume of Distribution
If drug extensively distributed
the concentration will be lower relative to the amount of drug present equates to a larger volume of distribution.

lipophilic drugs
larger volumes of distribution than hydrophilic drugs.
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Volume of Distribution
a numeric index of the extent of drug distribution does not have any relationship to the actual volume of any tissue or group of tissues.

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 achieve a target plasma concentration:

***any change in state because of changes in physiologic and pathologic conditions can alter the volume of distribution, necessitating therapeutic adjustments.

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Total Drug Clearance (Elimination)

Cl, calculated from the declining blood levels:

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Total Drug Clearance (Elimination)

If a drug is rapidly removed from the plasma
its concentration will fall more quickly than the concentration of a drug that is less readily eliminated.

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Total Drug Clearance (Elimination)

results in a smaller area under the concentration vs time curve, which equates to greater clearance

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 estimation of drug clearance with these models has made important contributions to clinical pharmacology
provided a great deal of clinically useful information regarding altered drug elimination in various pathologic conditions.

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Elimination Half-Life
pharmacokinetic parameter that best describes the physiologic process of drug elimination the time during which the amount of drug in the body decreases by 50%.

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Elimination Half-Life
when a physiologic or pathologic perturbation changes the elimination half-life of a drug
it is not a simple reflection of the change in the body's ability to metabolize or eliminate the drug.

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Elimination Half-Life
Example:
the elimination half-life of thiopental is prolonged in the elderly
the elimination clearance is unchanged and the volume of distribution is increased. elderly patients need dosing strategies that accommodate for the change in the distribution of the drug rather than a decreased metabolism of the drug
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Elimination Half-Life
unable to give insight into the time that it takes for a single or a series of repeated drug doses to terminate its effect. elimination of drug from the body
begins the moment the drug is delivered to the organs of elimination

the rapid termination of effect of a bolus of an IV agent

due to redistribution of drug from the brain to the blood and subsequently other tissue (e.g., muscle).
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Elimination Half-Life
effects of most anesthetics have waned long before even one elimination half-life has been completed,

incapable of providing useful information regarding the duration of action following administration of intravenous agents.
limited utility in anesthetic practice.
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Effect of Hepatic or Renal Disease on Pharmacokinetic Parameters

Diverse pathophysiologic changes
precise prediction of the pharmacokinetics of a given drug in individual patients with hepatic or renal disease.

liver function tests (transaminases)

unreliable predictors of the degree of liver function and the remaining metabolic capacity for drug elimination.
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Effect of Hepatic or Renal Disease on Pharmacokinetic Parameters

In px with hepatic disease
the elimination half-life of drugs metabolized or excreted by the liver is often increased

decreased clearance
poss increased volume of distribution caused by ascites and altered protein binding.

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Effect of Hepatic or Renal Disease on Pharmacokinetic Parameters

hepatic drug clearance reduced,
repeated bolus dosing or continuous infusion of such drugs as benzodiazepines, opioids, and barbiturates may result in excessive accumulation of drug excessive and prolonged pharmacologic effects.

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Effect of Hepatic or Renal Disease on Pharmacokinetic Parameters

Drug concentration at steady-state is inversely proportional to elimination clearance. recovery from small doses of drugs (thiopental & fentanyl)
largely the result of redistribution recovery from conservative doses will be minimally affected by reductions in elimination clearance.
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Effect of Hepatic or Renal Disease on Pharmacokinetic Parameters

In patients with renal failure
almost always better to underestimate a patient's dose requirement observe the response give additional drug if necessary

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Nonlinear Pharmacokinetics
drug distribution and elimination are first-order processes parameters, such as clearance and elimination half-life, are independent of the dose or concentration of the drug

the rate of elimination of a few drugs is dosedependent, or nonlinear.

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Nonlinear Pharmacokinetics
Phenytoin
exhibits nonlinear elimination at therapeutic concentrations

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Nonlinear Pharmacokinetics
in anesthetic practice,
extremely high doses of thiopental used for cerebral protection can demonstrate zero-order elimination

In theory
all drugs are cleared in a nonlinear fashion.

In practice
the capacity to eliminate most drugs is so great that this is usually not evident, even with toxic concentrations.
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Nonlinear Pharmacokinetics
Elimination of drugs
involves interactions with either enzymes catalyzing biotransformation reactions or carrier proteins for transmembrane transport

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Compartmental Pharmacokinetic Models

One-Compartment Model illustrate the basic relationships among clearance, volume of distribution, and the elimination half-life. the body is seen as a single homogeneous compartment. Drug distribution after injection assumed instantaneous no concentration gradients within the compartment concentration can decrease only by elimination of drug from the system.
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One-Compartment Model
All else being equal, the greater the clearance, the shorter the elimination half-life;
the larger the volume of distribution, the longer the elimination half-life. the elimination half-life depends on clearance and volume of distribution
characterize the extent of drug distribution and efficiency of drug elimination respectively.

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Two-Compartment Model
two discrete phases in the decline of the plasma concentration: 1. distribution phase - first phase after injection - very rapid decrease in concentration. - rapid decrease in concentration largely caused by passage of drug from the plasma into tissues. 2. a slower decline of the to drug elimination. concentration owing

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Two-Compartment Model
Elimination
begins immediately after injection its contribution to the drop in plasma concentration is initially much smaller than the fall in concentration because of drug distribution.

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 central compartment
To which the drug is injected from which the blood samples for measurement of concentration are obtained, that drug is eliminated only from the central compartment.
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 plasma concentration of drugs with twocompartment kinetics is equal to the sum of two exponential terms:

t = time Cp(t) = plasma concentration at time t, A = y-axis intercept of the distribution phase line = hybrid rate constant of the distribution phase B = y-axis intercept of the elimination phase line = hybrid rate constant of the elimination phase.

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 Immediately after injection, the first term represents a much larger fraction of the total plasma concentration than the second term. After several distribution half-lives, the value of the first term approaches zero, and the plasma concentration is essentially equal to the value of the second
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Multicompartmental Models
drug is initially distributed only within the central compartment. the initial apparent volume of distribution is the volume of the central compartment. Immediately after injection
the amount of drug present is the dose the concentration is the extrapolated concentration at time t = 0, which is equal to the sum of the intercepts of the distribution and elimination lines.
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Multicompartmental Models
volume of the central compartment
is important in clinical anesthesiology
it is the pharmacokinetic parameter that determines the peak plasma concentration after an intravenous bolus injection Hypovolemia, for example, reduces the volume of the central compartment. If doses are not correspondingly reduced, the higher plasma concentrations will increase the incidence of adverse pharmacologic effects.
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Multicompartmental Models
Immediately after intravenous injection
all of the drug is in the central compartment.

Simultaneously, three processes begin.

Drug moves from the central to the peripheral compartment, which also has a volume, V2. As soon as drug appears in the peripheral compartment, some passes back to the central compartment
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 third process
begins immediately after administration of the drug irreversible removal of drug from the system via the central compartment.

rapidity of the decrease in the central compartment concentration after intravenous injection
the magnitude of the compartmental volumes, the intercompartmental clearance, the elimination clearance.
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 At equilibrium, the drug is distributed between the central and the peripheral compartments volume of distribution at steady-state (Vss )
ultimate volume of distribution sum of V1 and V2. Extensive tissue uptake of a drug is reflected by a large volume of the peripheral compartment, which, in turn, results in a large Vss.

the elimination clearance is equal to the dose divided by the area under the concentration versus time curve.
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Three-Compartment Model
After intravenous injection of some drugs; the initial, rapid distribution phase is followed by a second, slower distribution phase before the elimination phase becomes evident. plasma concentration is the sum of three exponential terms:

t = time Cp(t) = plasma concentration at time t, A = intercept of the rapid distribution phase line = hybrid rate constant of the rapid distribution phase B = intercept of the slower distribution phase line = hybrid rate constant of the slower distribution phase G = intercept of the elimination phase line = hybrid rate constant of the elimination phase.
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the drug is injected into and eliminated from the central compartment. Drug is reversibly transferred between the central compartment and two peripheral compartments, which accounts for two distribution phases. three compartmental volumes: V1, V2, and V3, whose sum equals Vss; three clearances: the rapid intercompartmental clearance, the slow intercompartmental clearance, and elimination clearance

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 Currently, most pharmacokinetic models are developed using population pharmacokinetic modeling
pharmacokinetic parameters
concentration vs time data from the entire group of subjects in a single stage, using nonlinear regression methods.

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Noncompartmental (Stochastic) Pharmacokinetic Models

employ mathematical techniques to characterize a pharmacokinetic data set that attempt to avoid any preconceived notion of structure yield the pharmacokinetic parameters that summarize drug distribution and elimination.

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Noncompartmental (Stochastic) Pharmacokinetic Models

basic assumptions
all of the elimination clearance occurs directly from the plasma the distribution and elimination of drug is a linear and first-order process the pharmacokinetics of the system does not vary over the time of the data collection (timeinvariant).

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Noncompartmental (Stochastic) Pharmacokinetic Models

main advantage
a general description of drug absorption, distribution, and elimination can be made without resorting to more complex mathematical modeling techniques.

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Noncompartmental (Stochastic) Pharmacokinetic Models

mean residence time (MRT)
main unique parameter of noncompartmental analysis

the average time a drug molecule spends in the body before being eliminated.

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Noncompartmental (Stochastic) Pharmacokinetic Models

MRT
fail to capture the contribution of extensive distribution versus limited elimination to allow a drug to linger in the body fail to describe the situation in which the drug effect can dissipate by redistribution of drug from the site of action back into blood and then into other, less well-perfused tissues

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Pharmacodynamics

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Pharmacodynamics
deals with the effects of drugs on biologic systems Receptor interactions Dose response phenomena Mechanism of action

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Drug receptor Interactions

Drug drug specific receptor change in cellular function
Cell membrane-bound proteins Cytoplasmic/Nucleoplastic

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Desensitization and Down-Regulation of Receptors

Prolonged exposure desensitization lower maximal effects

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Agonists, Partial Agonists, and Antagonists

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Dose response relationship

determine the relationship between increasing doses of a drug and the ensuing changes in pharmacologic effects
Potency Drug receptor affinity Efficacy Population pharmacodynamic variability

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 The potency of the drugthe dose required to produce a given The maximal effect indicates the rate of increase in effect as the dose is increased and is a reflection of the affinity of the receptor for the drug. The maximum effect is referred to as the efficacy of the drug.
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Concentration-Response Relationships
The magnitude of the pharmacologic effect is a function of the amount of drug present at the site of action, so increasing the dose increases the peak effect.

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Concentration-Response Relationships
The perfusion of the organ on which the drug acts The tissue:blood partition coefficient of the drug The rate of diffusion or transport of the drug from the blood to the cellular site of action The rate and affinity of drugreceptor binding The time required for processes initiated by the drug-receptor interaction to produce changes in cellular function
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Context-Sensitive Decrement Times The context-sensitive half-time is defined as the time required for the drug concentration of the plasma to decrease by 50%, where the context is the duration of the infusion. During an infusion, drug is taken up by the inert, peripheral tissues.18 Once drug delivery is terminated, recovery occurs when the effect site concentration decreases below a threshold concentration for producing a pharmacologic effect (e.g., MACAWAKEthe concentration where 50% of patients follow commands rate of elimination of the drug from the body can give some indication for the time required to reach a subtherapeutic effect site drug concentration For drugs with multicompartmental kinetics, the elimination half-life will always overestimate the time to recovery from anesthetic drugs. . 10 3

here redistribution describes the drug returning from all tissue compartments, not just from the brain, into plasma as opposed to the previous usage that described redistribution of drug from brain to blood and into inert tissues. To characterize the contribution of redistribution to the time required to reach a subtherapeutic drug concentration, the duration of infusion must be taken into account. The time required for the drug concentration of the plasma to decrease by 50% increases as the duration of infusion increases.

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Target-Controlled Infusions Target controlled infusion(TCI) is an infusion system which allows the anesthetist to select the target blood concentration required for a particular effect and then to control the depth of anaesthesia by adjusting the requested target concentration, which includes the instantaneous calculation of the infusion rate necessary to obtain and maintain a given therapeutic blood concentration of drug based on average pharmacokinetic parameters.

the amount of drug to be administered into the central compartment to maintain the target concentration = (drug eliminated from the central compartment + plus drug distributed from the central compartment to peripheral compartments) - drug returning to the central compartment from peripheral compartments

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Time to Maximum Effect Compartment Concentration

the delay between attaining a plasma concentration and an effect-site concentration is presumed to be a result of transfer of drug between the plasma compartment, VC, and an effect compartment, Ve, as well as the time required for a cellular response.

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Volume of Distribution at Peak Effect Although the plasma concentration can be brought rapidly to the targeted drug concentration by administering a bolus dose to the central compartment (C VC) and then held there by a computercontrolled infusion,the time for the effect site to reach the target concentration will be much longer than TMAX (4 minutes for propofol effect-site concentration to reach 95% of that targeted)

Volume of distribution over time is calculated by dividing the total amount of drug remaining in the body by the plasma drug concentration at each time, t. The time-dependent volume at the time of peak effect (or TMAX) is VDPE
The product of the targeted effect-site concentration and VDPE plus the amount lost to elimination in the time to TMAX becomes the proper bolus dose that will attain the target concentration at the effect site as rapidly as possible without overshoot 10 7

Front-End Pharmacokinetics
The term front-end pharmacokinetics refers to the intravascular mixing, pulmonary uptake, and recirculation events that occur in the first few minutes during and after intravenous drug administration.39

These kinetic events and the drug concentration versus time profile that results are important because the peak effect of rapidly acting drugs occurs during this temporal window.

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Response Surface Models of Drug-Drug Interactions

During the course of an operation, the level of anesthetic drug administered is adjusted to ensure amnesia to ongoing events, provide immobility to noxious stimulation, and blunt the sympathetic response to noxious stimulation
it is possible to achieve an adequate anesthetic state with a high dose of a sedative-hypnotic alone (i.e., a volatile anesthetic or propofol), the effect-site drug concentration necessary is often associated with excessive hemodynamic depression58 and excessively deep plane of hypnosis that may be associated with long-standing morbidity or mortality administration of two volatile anesthetics or a volatile anesthetic and propofol produce a net-additive effect, the combination of an opioid and a sedative-hypnotic are synergistic for most pharmacologic effects

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