Handbook of Clinical Anesthesia

Chapter 7

Pharmacologic Principles

Anesthetic drugs are administered with the goal of rapidly establishing and maintaining a therapeutic effect while minimizing undesired side effects (Gupta DK, Henthorn TK: Pharmacologic principles. In Clinical Anesthesia. Edited by Barash PG, Cullen BF, Stoelting RK, Cahalan MK, Stock MC. Philadelphia: Lippincott Williams and Wilkins, 2009, pp 137–164).

  1. Pharmacokinetic Principles: Drug Absorption and Routes of Administration
  2. Transfer of Drugs Across Membranes.Even the simplest drug that is directly administered into the blood to exert its action must move across at least one cell membrane to its site of action.
  3. Because biologic membranes are lipid bilayers composed of a lipophilic core sandwiched between two hydrophilic layers, only small lipophilic drugs can passively diffuse across the membrane down its concentration gradient.
  4. For water-soluble drugs to passively diffuse across the membrane down its concentration gradient, transmembrane proteins that form a hydrophilic channel are required.
  5. Intravenous (IV) administrationresults in rapid increases in drug concentration. Although this can lead to a very rapid onset of drug effect, for drugs that have a low therapeutic index (the ratio of the IV dose that produces a toxic effect in 50% of the population to the IV dose that produces a therapeutic effect in 50% of the population), rapid overshoot of the desired plasma concentration can potentially result in immediate and severe side effects.

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  1. Bioavailabilityis the relative amount of a drug dose that reaches the systemic circulation unchanged and the rate at which this occurs. For most intravenously administered drugs, the absolute bioavailability of drug available is close to unity, and the rate is nearly instantaneous.
  2. The pulmonary endothelium can slow the rate at which intravenously administered drugs reach the systemic circulation if distribution into the alveolar endothelium is extensive such as occurs with the pulmonary uptake of fentanyl. The pulmonary endothelium also contains enzymes that may metabolize intravenously administered drugs (propofol) on first pass and reduce their absolute bioavailability.
  3. Oral administrationis not used significantly in anesthetic practice because of the limited and variable rate of bioavailability.
  4. Because of this extensive first-pass metabolism, the oral dose of most drugs must be significantly higher to generate a therapeutic plasma concentration.
  5. Highly lipophilic drugs that can maintain a high contact time with nasal or oral (sublingual) mucosa can be absorbed without needing to traverse the gastrointestinal (GI) tract. Sublingual administration of drug has the additional advantage over GI absorption in that absorbed drug directly enters the systemic venous circulation, so it is able to bypass the metabolically active intestinal mucosa and the hepatic first-pass metabolism.
  6. Transcutaneous Administration.A few lipophilic drugs (e.g., scopolamine, nitroglycerin, fentanyl) have been manufactured in formulations that are sufficient to allow penetration of intact skin.
  7. Intramuscular and Subcutaneous Administration. Absorption of drugs from the depots in the subcutaneous tissue or in muscle tissue directly depends on the drug formulation and the blood flow to the depot.
  8. Intrathecal, Epidural, and Perineural Injection.The major downside to these three techniques is the relative expertise required to perform regional anesthetics relative to oral, IV, and inhalational drug administration.
  9. Inhalational Administration. The large surface area of the pulmonary alveoli available for exchange with the large volumetric flow of blood found in the pulmonary

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capillaries makes inhalational administration an extremely attractive method (approximates IV administration) by which to administer drugs.

  1. Drug Distribution

The relative distribution of cardiac output among organ vascular beds determines the speed at which organs are exposed to drug. The highly perfused core circulatory components (the brain, lungs, heart, and kidneys) receive the highest relative distribution of cardiac output and therefore are the initial organs to reach equilibrium with plasma drug concentrations. Drug transfer to the less well-perfused, intermediate-volume muscle tissue may take hours to approach equilibrium, and drug transfer to the poorly perfused, large cellular volumes of adipose tissue does not equilibrate for days.

  1. Redistribution
  2. As soon as the concentration of drug in the brain tissue is higher than the plasma concentration of drug, a reversal of the drug concentration gradient takes place so that the lipophilic drug readily diffuses back into the blood and is redistributed to the other tissues that are still taking up drug.
  3. Although single, moderate doses of highly lipophilic drugs have very short central nervous system (CNS) durations of action because of redistribution of drug from the CNS to the blood and other less well-perfused tissues, repeated injections of a drug allow the rapid establishment of significant peripheral tissue concentrations.

III. Drug Elimination

Drug elimination is the pharmacokinetic term that describes all the processes that remove a drug from the body. Although the liver and the kidneys are considered the major organs of drug elimination, drug metabolism can occur at many other locations that contain active drug metabolizing enzymes (e.g., the pulmonary vasculature, red blood cells), and drugs can be excreted unchanged from other organs (e.g., the lungs).

  1. Elimination clearance(drug clearance) is the theoretical volume of blood from which drug is completely and irreversibly removed in a unit of time.

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  1. Biotransformation Reactions. Most drugs that are excreted unchanged from the body are hydrophilic and therefore readily passed into urine or stool. Drugs that are not sufficiently hydrophilic to be able to be excreted unchanged require modification (enzymatic reactions) into more hydrophilic, excretable compounds.
  2. Phase I reactionsmay hydrolyze, oxidize, or reduce the parent compound.
  3. Cytochrome P450 enzymes(CYPs) are a superfamily of constitutive and inducible enzymes that catalyze most phase I biotransformations. CYP3A4 is the single most important enzyme, accounting for 40% to 45% of all CYP-mediated drug metabolism.
  4. CYPs are incorporated into the smooth endoplasmic reticulum of hepatocytes and the membranes of the upper intestinal enterocytes in high concentrations (Table 7-1).

Table 7-1 Substrates for CYP Isoenzymes Encountered in Anesthesiology

CYP3A4

CYP2D6

CYP2C9

CYP2C19

Acetaminophen
Alfentanil
Alprazolam
Bupivacaine
Cisapride
Codeine
Diazepam
Digitoxin
Diltiazem
Fentanyl
Lidocaine
Methadone
Midazolam
Nicardipine
Nifedipine
Omeprazole
Ropivacaine
Statins
Sufentanil
Verapamil
Warfarin

Captopril
Codeine
Hydrocodone
Metoprolol
Ondansetron
Propranolol
Timolol
Captopril
Codeine
Hydrocodone

Diclofenac
Ibuprofen
Indomethacin

Diazepam
Omeprazole
Propranolol
Warfarin

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  2. Phase II reactionsare known as conjugation or synthetic reactions. Similar to the cytochrome P450 system, the enzymes that catalyze phase II reactions are inducible.
  3. Genetic Variations in Drug Metabolism.Drug metabolism varies substantially among individuals because of variability in the genes controlling the numerous enzymes responsible for biotransformation.
  4. Chronologic Variations in Drug Metabolism. The activity and capacity of the CYP enzymes increase from subnormal levels in the fetal and neonatal period to reach normal levels at about 1 year of age. Neonates have a limited ability to perform phase II conjugation reactions, but after normalizing phase II activity over the initial year of life, advanced age does not affect the capacity to perform phase II reactions.
  5. Renal Drug Clearance. The primary role of the kidneys in drug elimination is to excrete into urine the unchanged hydrophilic drugs and the hepatic derived metabolites from phase I and II reactions of lipophilic drugs. In patients with acute and chronic causes of decreased renal function, including age, low cardiac output states, and hepatorenal syndrome, drug dosing must be altered to avoid accumulation of parent compounds and potentially toxic metabolites (Table 7-2).
  6. Hepatic Drug Clearance. Drug elimination by the liver depends on the intrinsic ability of the liver to metabolize the drug and the amount of drug available to diffuse into the liver (hepatic blood flow) (Table 7-3).

Table 7-2 Drugs with Significant Renal Excretion Encountered in Anesthesiology

Aminoglycosides

Nor-meperidine

Atenolol

Pancuronium

Cephalosporins

Penicillins

Digoxin

Procainamide

Edrophonium

Pyridostigmine

Nadolol

Quinolones

Neostigmine

Rocuronium

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Table 7-3 Classification of Drugs Encountered in Anesthesiology According to Hepatic Extraction Ratios

Low

Intermediate

High

Diazepam
Lorazepam
Methadone
Phenytoin
Rocuronium
Theophylline
Thiopental

Alfentanil
Methohexital
Midazolam
Vecuronium

Alprenolol
Bupivacaine
Diltiazem
Fentanyl
Ketamine
Lidocaine
Meperidine
Metoprolol
Morphine
Naloxone
Nifedipine
Propofol
Propranolol
Sufentanil

  1. Pharmacokinetic Models

The concentration of drug at its tissue site or sites of action is the fundamental determinant of a drug's pharmacologic effects.

  1. Physiologic vs. Compartment Models
  2. Awakening after a single dose of thiopental is 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; this fundamental concept of redistribution applies to all lipophilic drugs.
  3. Drug concentrations in the blood are used to define the relationship between dose and the time course of changes in the drug concentration.
  4. Pharmacokinetic Concepts
  5. Rate Constants and Half-Lives.The disposition of most drugs follows first-order kinetics. A first-order kinetic process is one in which a constant fraction of the drug is removed during a finite period of time regardless of the drug's amount or concentration. Rather than using rate constants, the rapidity of

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pharmacokinetic processes is often described with half-lives, which is the time required for the concentration to change by a factor of 2. After five half-lives, the process is almost 97% complete (Table 7-4). For practical purposes, this is essentially 100%, so there is a negligible amount of drug remaining in the body.

Table 7-4 Half-Lives and Percentage of Drug Removed

Number of Half-Lives

Percentage of Drug Removed

Percentage of Drug Remaining

0

100

0

1

50

50

2

25

75

3

12.5

87.5

4

6.25

93.75

5

3.125

96.875

  1. Volume of distributionquantifies the extent of drug distribution (overall capacity of tissues versus the capacity of blood for that drug). If a drug is extensively distributed, then the concentration will be lower relative to the amount of drug present, which equates to a larger volume of distribution. The apparent volume of distribution is a numeric index of the extent of drug distribution that does not have any relationship to the actual volume of any tissue or group of tissues. In general, lipophilic drugs have larger volumes of distribution than hydrophilic drugs.
  2. Elimination half-lifeis the time during which the amount of drug in the body decreases by 50%. Although 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 is attributable to redistribution of drug from the brain to the blood and subsequently other tissue (muscle). Therefore, the effects of most anesthetics have waned long before even one elimination half-life has been completed. Thus, the elimination half-life has limited utility in anesthetic practice.
  3. Effect of Hepatic or Renal Disease on Pharmacokinetic Parameters.Diverse pathophysiologic changes preclude precise prediction of the pharmacokinetics of a given

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drug in individual patients with hepatic or renal disease.

  1. When hepatic drug clearance is reduced, repeated bolus dosing or continuous infusion of such drugs as benzodiazepines, opioids, and barbiturates may result in excessive accumulation of drug as well as excessive and prolonged pharmacologic effects.
  2. Because recovery from small doses of drugs such as thiopental and fentanyl is largely the result of redistribution, recovery from conservative doses is minimally affected by reductions in elimination clearance.
  3. Compartmental Pharmacokinetic Models
  4. One-Compartment Model. Although the one-compartment model is an oversimplification for most drugs, it does serve to illustrate the basic relationships among clearance, volume of distribution, and the elimination half-life (Fig. 7-1).
 

Figure 7-1. The plasma concentration versus time profile plotted on both linear (dashed line, left y-axis) and logarithmic (dotted line, right y-axis) scales for a hypothetical drug exhibiting one-compartment, first-order pharmacokinetics.

 

Figure 7-2. The logarithmic plasma concentration versus time profile for a hypothetical drug exhibiting two-compartment, first-order pharmacokinetics. Note that the distribution phase has a slope that is significantly larger than that of the elimination phase, indicating that the process of distribution is not only more rapid than elimination of the drug from the body but that it is also responsible for the majority of the decline in plasma concentration in the several minutes after drug administration.

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  1. Two-Compartment Model. There are two discrete phases in the decline of the plasma concentration (Fig. 7-2). To account for this biphasic behavior, one must consider the body to be made up of two compartments, a central compartment, which includes the plasma, and a peripheral compartment.
  2. Three-Compartment Model. After IV injection of some drugs, the initial, rapid distribution phase is followed by a second, slower distribution phase before the elimination phase becomes evident.
  3. In general, the model with the smallest number of compartments or exponents that accurately reflects the data is used.
  4. Pharmacodynamic Principles

Pharmacodynamic studies focus on the quantitative analysis of the relationship between the drug concentration in the blood and the resultant effects of the drug on physiologic processes.

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VII. Drug–Receptor Interactions

Most pharmacologic agents produce their physiologic effects by binding to a drug-specific receptor, which brings about a change in cellular function. The majority of pharmacologic receptors are cell membrane–bound proteins, although some receptors are located in the cytoplasm or the nucleoplasm of the cell.

  1. Desensitization and Downregulation of Receptors. Receptors are dynamic cellular components that adapt to their environment. Prolonged exposure of a receptor to its agonist leads to desensitization; subsequent doses of the agonist produce lower maximal effects.
  2. Agonists, Partial Agonists, and Antagonists. Drugs that bind to receptors and produce an effect are called agonists. Partial agonistsare drugs that are not capable of producing the maximal effect, even at very high concentrations. Compounds that bind to receptors without producing any changes in cellular function are referred to as antagonists.Competitive antagonists bind reversibly to receptors, and their blocking effect can be overcome by high concentrations of an agonist (competition). Noncompetitive antagonistsbind irreversibly to receptors.
  3. Dose–response relationshipsdetermine the relationship between increasing doses of a drug and the ensuing changes in pharmacologic effects (Fig. 7-3).
 

Figure 7-3. Schematic curve of the effect of a drug plotted against dose. In the left panel, the response data are plotted against the dose data on a linear scale. In the right panel, the same response data are plotted against the dose data on a logarithmic scale, yielding a sigmoid dose–response curve that is linear between 20% and 80% of the maximal effect.

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Figure 7-4. The changes in plasma drug concentration and pharmacologic effect during and after an intravenous infusion. Cp = plasma concentration.

  1. Concentration–Response Relationships(Fig. 7-4). 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. Larger doses have a more rapid onset of action because pharmacologically active concentrations at the site of action occur sooner. Increasing the dose also increases the duration of action because pharmacologically effective concentrations are maintained for a longer time.

VIII. Drug Interactions

Ten or more drugs may be given for a relatively routine anesthetic (Table 7-5).

  1. Clinical Applications of Pharmacokinetic and Pharmacodynamics to the Administration of Intravenous Anesthetics

Computer simulation is required to meaningfully interpret dosing and to accurately devise new dosing regimens.

  1. Rise to Steady-State Concentration. The drug concentration versus time profile for the rise to steady state is the mirror image of its elimination profile.
  2. Infusion Dosing Schemes. Based on a one-compartment pharmacokinetic model, a stable steady-state plasma concentration (Cp, ss) can be maintained by administering an infusion at a rate that is proportional to the elimination of drug from the body.

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Table 7-5 Drug Interactions During the Perioperative Period

Opioid to decrease volatile anesthetic requirements
Mixing acidic drugs (thiopental) with basic drugs (opioids, muscle relaxant), resulting in a precipitate
Absorption of drugs (nitroglycerin, fentanyl) by plastics
Drugs that alter absorption by impact on gastric pH (ranitidine) or rate of gastric emptying (metoclopramide)
Vasoconstrictors are added to local anesthetic solutions to prolong their duration of action at the site of injection and to decrease the risk of systemic toxicity from rapid absorption.
Drugs that inhibit or induce the enzymes that catalyze biotransformation reactions can affect clearance of other concomitantly administered drugs (e.g., phenytoin shortens the duration of action of the nondepolarizing neuromuscular junction blocking agents). Pharmacodynamic interactions in which drugs interact directly or indirectly at the same receptors (opioid antagonists directly displace opioids from opiate receptors) may also occur.

  1. Isoconcentration Nomogram. To make the calculations of the various infusion rates required to maintain a target plasma concentration for a drug that follows multicompartment pharmacokinetics, a clinician needs access to a basic computer and the software to perform the appropriate simulations.
  2. Context-Sensitive Decrement Times. During an infusion, drug is taken up by the inert peripheral tissues. After drug delivery is terminated, recovery occurs when the effect site concentration decreases below a threshold concentration for producing a pharmacologic effect.
  3. Target-Controlled Infusions. By linking a computer with the appropriate pharmacokinetic model to an infusion pump, it is possible for the physician to enter the desired target plasma concentration of a drug and for the computer to nearly instantaneously calculate the appropriate infusion scheme to achieve this concentration target in a matter of seconds.
  4. Time to Maximum Effect Compartment Concentration (TMAX). By simultaneously modeling the plasma drug concentration versus time data (pharmacokinetics) and the measured drug effect (pharmacodynamics), an estimate of the drug transfer rate constant between plasma and the putative effect site can be estimated.

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  1. Volume of Distribution at Peak Effect.It is possible to calculate a bolus dose that will attain the estimated effect site concentration at TMAX without overshoot in the effect site.
  2. Front-end pharmacokineticsrefers to the intravascular mixing, pulmonary uptake, and recirculation events that occur in the first few minutes during and after IV drug administration. 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.
  3. Closed-Loop Infusions. When a valid and nearly continuous measure of drug effect is available, drug delivery can be automatically titrated by feedback control. Such systems have been used experimentally for control of blood pressure, oxygen delivery, blood glucose, neuromuscular blockade, and depth of anesthesia.
  4. Closed-loop systems for anesthesia are the most difficult systems to design and implement because the precise definition of anesthesia remains elusive, as does a robust monitor for anesthetic depth.
  5. Because modification of consciousness must accompany anesthesia, processed electroencephalographic (EEG) parameters that correlate with level of consciousness, such as the bispectral index, EEG entropy, and auditory evoked potentials, make it possible to undertake closed-loop control of anesthesia.
  6. 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. To limit side effects, an opioid and a sedative–hypnotic are often administered together (synergistic for most pharmacologic effects).

Editors: Barash, Paul G.; Cullen, Bruce F.; Stoelting, Robert K.; Cahalan, Michael K.; Stock, M. Christine

Title: Handbook of Clinical Anesthesia, 6th Edition

Copyright ©2009 Lippincott Williams & Wilkins

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