Pharmacokinetics of Opioids Significance for Clinical Use in Anesthesia

In order to bind to the specific receptor sites within the CNS, opioids either given intravenously (i.v.), intramuscularly (i.m.), subcutaneously (s.c.) or orally (p.o.), have to penetrate various lipid layers. These barriers present a physiological obstacle, which all centrally active agents need to overcome (Figure III-15).

When a drug is administered, a portion is bound to plasma proteins and a portion remains free in the plasma. The portion of the drug, which is free in the plasma, is then available to cross membranes to reach several destinations of interest. First, it

Figure III-15. When a drug is administered, a portion is bound to plasma proteins and a portion remains free in the plasma. This unbound portion is then available to cross membranes while also being delivered to the liver and kidney for metabolism and elimination. At the same time it is delivered to miscellaneous non-target tissues, where it is bound like a plasma reservoir. And finally, it is delivered to the target organ, the CNS, where the desired effect is produced

Figure III-15. When a drug is administered, a portion is bound to plasma proteins and a portion remains free in the plasma. This unbound portion is then available to cross membranes while also being delivered to the liver and kidney for metabolism and elimination. At the same time it is delivered to miscellaneous non-target tissues, where it is bound like a plasma reservoir. And finally, it is delivered to the target organ, the CNS, where the desired effect is produced may be delivered to the liver and kidney for metabolism and elimination. Second, it may be delivered to miscellaneous non-target tissues where it may be bound or produce unwanted effects. Third, it may be delivered to the target organ where the desired effects are produced. The pharmacokinetics of a drug is affected by the uptake, distribution, elimination, and biotransformation of the drug within the biological system. Pharmacokinetic variables determine the drug concentration in plasma and tissue that result from a given dose.

Pharmacodynamics describes the relationship between drug concentration and drug response. It affects the intensity and duration of response produced by the drug at the receptor site. In order to induce an action, the opioid has to pass through the blood-brain barrier (BBB) membrane. The following factors affect the rate of membrane penetration:

• Molecular size

• Lipid solubility

• Plasma protein binding and hence the portion of free drug

• Degree of ionization, since only non-ionized molecules can cross the BBB. For a drug to produce an effect, it must leave the plasma and pass through membranes to reach its eventual receptor site. The rate and extent to which a drug penetrates membranes is determined by the above listed factors. Thus molecular size, lipid solubility, plasma protein binding, and the degree of ionization ultimately determine the rapidity of onset, time to peak effect, and duration of action of any given drug. A smaller molecule will tend to pass more readily through cell membranes. Greater lipid solubility allows a drug to pass through lipid containing biological membranes including the blood-brain barrier with greater ease. Binding of drugs to plasma proteins and red cell membranes leaves less free drug available to penetrate and reach receptor sites. Similarly, ionization of a drug hinders its ability to cross cell membranes. Charged molecules will either be repelled by like charges on membranes or attracted to unlike charges on membranes, and in either case, be less effective in passing through membranes to reach receptor sites.

There is a dynamic relationship between these four factors. Ideally, if a drug is to have a rapid onset of action (i.e., be able to penetrate membranes rapidly) it would have a very small molecular size, a high degree of lipid solubility, have minimal protein binding and minimal ionization at physiologic pH. Clinically, alfentanil as well as remifentanil have the most rapid onset of action of any of the opioids, primarily because of their minimal ionization at physiologic pH. Fentanyl, on the other hand, in spite of its extraordinary lipid solubility, has a slower onset of action, compared to alfentanil and sufentanil, largely due to a high degree of protein binding and a high degree of ionization at physiologic pH. Sufentanil's onset of action is intermediate between fentanyl and alfentanil because of intermediate lipid solubility and ionization. All of the newer opioids are more lipid soluble than morphine and, as a result, in spite of modest differences in ionization and protein binding, all will be expected to have a more rapid onset of action following intravenous administration.

Lipid solubility also plays a role in affecting the elimination of a drug. A drug with a high degree of lipid solubility will be readily stored in lipid containing tissues and, as a result, will be released from those tissues more slowly into plasma and consequently will be eliminated at a slower rate. In general, drugs with a high degree of lipid solubility will therefore have a longer beta elimination half-life than those drugs with relatively small lipid solubility. The lower lipid solubility of alfentanil contributes to its shorter beta elimination half-life compared to fentanyl. Since alfentanil is significantly less lipid soluble, its volume of distribution is smaller and, as a result, more of the administered drug will be delivered to the liver for metabolism and elimination resulting in a faster decay of concentration and termination of effect.

All the opioids have a relatively small molecular size. Lipid solubility is defined as the octanol/water coefficient at pH 7.4 for each drug. Morphine has poor lipid solubility resulting in slow membrane penetration. Thus, morphine enters the CNS slowly and displays a slow onset of action. Sufentanil, fentanyl, and to a lesser degree alfentanil, have much higher degrees of lipid solubility and on this basis would be expected to have a more rapid onset of action following intravenous administration.

Protein binding at pH 7.4 represents the percentage of drug, which will be either bound to plasma proteins, including albumin and alpha-l acid glycoprotein, or to red cell membranes. All of the new short-acting opioids have a relatively high degree of protein binding. A pharmacokinetic consequence of high protein binding is that lesser amounts of drug will be available in free form to penetrate membranes to produce a CNS effect. High protein binding also contributes to a smaller volume of distribution. Finally, plasma protein binding limits the amount of free drug available for elimination by the hepatic and renal systems, which would tend to reduce clearance rate. The percent of a drug that is non-ionized at pH 7.4 is tabulated

Table III-3. Difference in lipophilicity of various opioid agonists and antagonists as reflected in the heptane/water and heptane/phosphate buffer distribution

Agonist

Heptane/water distribution-coefficient

Methylmorphine

0.00001

Normorphine

0.00001

Dihydromorphine

0.00001

Morphine

0.00001

Levorphanol

0.0092

Etorphine

1.42

Pethidine

3.4

Fentanyl

19.35

Methadone

44.9

Antagonist

Heptane/phosphate buffer distribution coefficient

Naltrexone

0.008

Naloxone

0.02

Diprenorphine

Adapted from [68]

in Table III-3. A drug, which is non-ionized at physiologic pH, will more readily cross membranes to reach receptor sites and produce an effect. Fentanyl at a pH of 7.4 is approximately 90% ionized and 10% non-ionized. Alfentanil is just the opposite, i.e., approximately 90% non-ionized and 10% ionized, with sufentanil intermediate. The minimal ionization of alfentanil at physiologic pH contributes to its ease of membrane penetrance and partially explains its rapid onset of action. Since sufentanil's degree of ionization is intermediate, it would be expected to have a more rapid onset of action than fentanyl, although perhaps not as fast as alfentanil. All of these factors must be considered when determining the eventual clinical properties of an administered opioid.

Since the rate of penetration of physiological membranes closely correlates with lipophilicity of agents, the character of the opioid determines the amount of molecules being able to dissolve in a fatty solution. Since the central nervous system mainly consists of fatty-like substances, i.e. the cerebrosides, more of an agent with a high lipophilic character will enter brain tissue, where it mediates its pharmacological activity. For instance, an agent like morphine is a more hydrophilic compound, suggesting that it takes relatively long to enter the brain (Table III-3). Indeed about 45min will elapse before a maximum effect is seen clinically. An agent like fentanyl is highly lipophilic; it therefore quickly enters the brain initiating a maximal effect within five minutes.

Following intravenous injection, approximately 85% of the drug is bound unspecifically to plasma and tissue proteins. Of the residual 15% only a portion is bound in the plasma in a non-ionized form. As a remainder, approximately only 1% of the originally injected amount will penetrate the blood-brain barrier, where

Figure III-16. Distribution of agents in various organ tissues given intravenously. Difference in distribution depends on physicochemical properties such as the degree of binding to protein-rich organs, their lipophilicity, and the degree of ionization. Note, many centrally active agents unspecifically bind to peripheral protein rich organs from where they later re-enter the blood stream, and after crossing the blood-brain barrier are able to induce an effect

Figure III-16. Distribution of agents in various organ tissues given intravenously. Difference in distribution depends on physicochemical properties such as the degree of binding to protein-rich organs, their lipophilicity, and the degree of ionization. Note, many centrally active agents unspecifically bind to peripheral protein rich organs from where they later re-enter the blood stream, and after crossing the blood-brain barrier are able to induce an effect the lipophilicity determines the speed of transfer from the plasma into the biophase, i.e. the central compartment in the CNS where the agent binds to the receptor sites. From the different pharmacokinetic properties of the various opioids (Figure III-16) different pharmacodynamics with different time of onset, the time until maximal effect and the duration of effect will evolve.

While lipophilicity is one determinant affecting the speed of onset, (i.e. how fast the molecules cross the blood-brain barrier), the other determinant is the amount of drug being present in a free, non-ionized form (i.e. the amount of molecules being able to penetrate the blood-brain barrier). Therefore, high amounts of non-ionized molecules in the plasma result in a fast onset of action. For instance, alfentanil and remifentanil have > 80% of the drug being present in a non-ionized form (Table III-4). Besides their lipophilicity, it is because of this property that these two agents demonstrate the fastest onset of action, being around 1 min.

Following injection, there are two distinct phases of declining drug concentrations in the plasma (Figure III-17).

Table III-4. Comparative pharmacokinetic data of various opioids

Opioid

Elimination

Clearance (Cl;

Volume of

Protein

Distribution

half life

ml/kg/min)

distribution

binding (%)

coefficient

(mm; t^)

(Vd; L/kg)

(lipophilicity)

Fentanyl

219

13.0

4.0

84

955

Alfentanil

94

6.4

0.86

92

129

Sufentanil

64

12.7

2.0

92

1727

Morphine

177

14.7

3.2

60

1.0

Remifentanil

5-14

30-40

0.2-0.4

70

18

Pethidine

192

12.0

2.8

?

32

Meptazinol

124

132

4.99

27

65

Methadone

50-4500

?

3-4

60-90

57

The time required for the plasma concentration to decline by 50% is referred to as its "half-life". The alpha half-life (t 1/2 a) represents the rate of distribution, while the terminal elimination or beta half-life (t 1/2 6) represents the rate of elimination. The half-life for the distribution and elimination phases can be calculated from the straight lines in the Figure III-17 which are extrapolated from the plasma concentration decay curve [69]

Following injection and binding to the receptor site, a pharmacodynamic effect is initiated. The offset of action, however, is determined how fast the drug dissociates from the receptor and how fast it leaves the cerebral compartment returning

I.V. Bolu3 Time After Dose

Figure III-17. Depicted is a plot of plasma concentration, using a two-compartment model for distribution, following an intravenous bolus dose of a drug. There are two distinct phases of declining drug concentration in the plasma. The first phase (alpha phase), the distribution phase, represents the rapid movement of drug from the plasma into the tissues. The second phase (beta phase), the elimination phase, represents a less rapid decline in drug plasma concentration due to removal of the drug from the body via metabolism and excretion into the blood stream from where it is metabolized by the liver which inactivates the agent. For instance, another highly lipophilic agent is buprenorphine. Its offset of action, however, is mainly determined by the rate it dissociates from the receptor. This rate is very slow, resulting in a long duration of action of up to 10 h. Another highly lipophilic opioid is fentanyl, which enters brain tissue relatively fast it, however, also leaves the brain relatively fast. Because most of the drug is being stored in protein-rich organs, which act like reservoirs (Figure III-18), And, because there is always a flow of molecules re-diffusing into the blood, the opioid enters the brain. Because of this redistribution from the storage sites, and in spite of a high clearance, duration of action is long. The longest duration of action, which is due to the high amounts of storage sites, is that of methadone. Exceeding all other opioids (Table III-4) its duration of action is about 24 h. It is because of this long duration, that this opioid needs only to be taken once a day.

Figure III-18. Following intravenous injection of a highly lipophilic agent like fentanyl most of the drug is bound non-specifically by protein-rich organs. Only the concentration in the cerebrospinal fluid actually reflects the concentration present at the receptor sites, which is lower by the order of several magnitudes than plasma concentration. Data derived from the animal and adapted from [74]

Figure III-18. Following intravenous injection of a highly lipophilic agent like fentanyl most of the drug is bound non-specifically by protein-rich organs. Only the concentration in the cerebrospinal fluid actually reflects the concentration present at the receptor sites, which is lower by the order of several magnitudes than plasma concentration. Data derived from the animal and adapted from [74]

When using fentanyl for anesthesia, it is of major importance to recognize that the speed of recovery is closely linked to recirculation of the opioid from peripheral storage sites into the blood stream. This is because, after initial injection, most of the drug is bound to protein-rich organs with a volume of distribution (Vd) of 4.0L/kg. These parts of the body do not participate in the mediation of opioid effects. For instance, the lungs act like a filter after initial intravenous injection [73] (Figure III-18).

This volume of distribution is in contrast to alfentanil, which has a value of only 0.89 L/kg. Since most of the drug, which quickly enters the brain, also leaves it very fast, there is a fast onset and a short duration of action. Also, because the drug is accessible for metabolization and does not hide within the storage sites, it is inactivated by the liver. In contrast, fentanyl with its high volume of distribution may induce late effects when residual amounts of fentanyl diffuses from skin, musculature or fatty tissue, inducing a "rebound" of effects. Therefore, the end of action of an opioid is not only determined by receptor concentration. The volume of distribution of the agent is a pharmacokinetic variable, which has the most of impact on the duration of action. It therefore is conceivable that this duration of action is less predictable with fentanyl.

Aside from the volume of distribution, biotransformation within the liver is the important rate-limiting step in the degradation of fentanyl and many other opioids (Figure III-19). After fentanyl prolonged recovery times are possible

Figure III-19. Schematic representation of biotransformation within the liver, and why elimination of an opioid from the central compartment depends on hepatic flow and why clearance rate depends on the activity of liver enzymes

[75] because only the amount of the drug present in the circulation can effectively be removed from the blood via metabolism. Since the metabolism rate within the liver is greatly affected by local perfusion changes or by a decreased metabolism capacity (e.g. liver insufficiency), this may result in a decrease in the elimination rate (i.e. clearance) with a corresponding increase in the duration of action [76].

There are two opioids where plasma and receptor concentrations lie close to each other, i.e. alfentanil and remifentanil. This is because the volume of distribution for alfentanil is very low (Table III-4) while remifentanil is rapidly metabolized by tissue and plasma esterase. It is because of this close correlation of plasma concentration and pharmacodynamic effects that the onset and the offset of these two agents can be predicted [77].

From such data it can be concluded that the plasma concentration of an opioid does not reflect the actual concentration at the receptor site, the amount that actually induces a pharmacodynamic effect. It was because of this difference that the concept of "effect-site concentration" (the actual biophase) was developed. Whereby the effect-site concentration (Ce) "tries" to equilibrate with plasma concentration (Cp) but only attains a fraction of the original Cp at its peak concentration, afterwards Cp falls below Ce. At this point, no further effect site uptake occurs, and a reverse diffusion out of the effect site may begin. Such pharmacokinetic changes explain the following phenomena:

• A delay in drug effect after a bolus injection.

• Initial drug plasma concentration is far in excess of the biophase required to induce an effect.

• The biophase is only a fraction of plasma concentration, an effect, which is due to redistribution to other compartments.

• Drug effect depends more on other factors than just plasma drug concentration such as partition coefficient, volumes of distribution, etc.

Such difference of concentrations in the various compartments also is seen after bolus injection of fentanyl in human volunteers. There, the distribution of the opioid in the central blood compartment and its accumulation in the peripheral organ compartment underlines the importance of the peripheral compartment site (Table III-5).

Several investigators set out to create a conceptual and mathematical model to depict the data derived from experimental drug plasma concentration decay curves. This resulted in the conceptual three-compartment model (Figure III-20) using the mathematical descriptor

Drug kinetic behavior is described conceptually thru this model (Figure III-20). Right after an intravenous bolus the drug leaves the central compartment (CAJ via three routes:

1. Exponentially from CA1 (blood compartment) to CA2, the vessel-rich compartment consisting of muscle, lungs, gut, kidney, spleen.

Table III-5. Difference of distribution of the opioid fentanyl in the various compartment sites in a volunteer. Note, the high concentration in the peripheral compartment site 60 minutes after application

Time (min.) Percent of initial dose

Central compartment Peripheral compartment Elimination

0

100

0

0

0.5

69.8

24.7

5.5

1.0

49.2

41.5

9.3

2.0

25.2

60.8

14.0

3.0

13.9

69.7

16.4

5.0

6.0

75.2

18.8

10

3.7

74.8

21.5

60

2.7

55.5

41.8

120

1.9

38.7

59.4

240

0.9

18.2

Adapted from [78]

2. Exponentially from CAj to CA3, the vessel poor compartment (i.e. the fatty tissue acting like a reservoir)

3. Exponentially from CAj to the environment (i.e. the elimination) also a blood vessel rich compartment consisting of hepatic or renal clearance, enzymatic and/or non-enzymatic degradation.

Figure 111-20. Schematic illustration of the three-compartment model with the central (blood), the peripheral compartment - a virtual space comprising of internal organs, fatty tissue, musculature and connecting tissue - and the CNS compartment. They are saturated differently with the agent, while there is a rapid exchange of concentration among the different compartments

Figure 111-20. Schematic illustration of the three-compartment model with the central (blood), the peripheral compartment - a virtual space comprising of internal organs, fatty tissue, musculature and connecting tissue - and the CNS compartment. They are saturated differently with the agent, while there is a rapid exchange of concentration among the different compartments

Figure III-21. The different compartments participating in the pharmacokinetics of an opioid, where the effect-site (Ve) is the actual site of action, and after binding, a pharmcodynamic effect is initiated

Only a tiny fraction goes from CA1 (blood compartment) to Ve (i.e. the brain receptors). It is the conceptual effect site Ve, which as a compartment is very small when compared to V2, V3 and elimination (Figure III-21).

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