Pharmacokinetics of opioid agonists and antagonists

6 Pharmacokinetics of opioid agonists and antagonists J. G. B O V I L L

All opioid agonists have similar pharmacological activity. They cause doserelated analgesia and respiratory depression, reduce intestinal motility and cause nausea and vomiting. However, there are considerable differences between the various opioids with respect to potency and the speed of onset and duration of effects. Alfentanil has a rapid onset and a relatively short duration of action whereas for morphine the onset is slow and it has a long duration. Some of these differences are due to variations in affinity for and binding to the opioid receptors. However, differences in the physicochemical and pharmacokinetic properties between the opioids are also of principal importance. Important pharmacokinetic parameters for commonly used opioids are given in Table 1. Table 1. Pharmacokineticparameters of commonlyused opioids. (1/kg)

Clearancerate (ml rain I kg-1)

t1~3 (h)

3.4 4.4 6.1 4.0 0.7 1.7

2.3 7.7 10.7 12.6 5.t 12.7

1.7 6.7 35 3.6 1.6 2.7

Vds s

Morphine Pethidine Methadone Fentanyl Alfentanil Sufentanil

Pharmacokinetics, as its name implies, is that branch of pharmacology concerned with the kinetics, or rates of change, of a drug in the body, including its absorption, distribution and elimination by metabolism and excretion. The overall pharmacokinetic disposition of a drug is determined by a variety of factors, including: (i) molecular size; (ii) degree of ionization; (iii) lipid solubility; (iv) protein binding; and (v) biotransformation. The opioid analgesics have similar molecular weights, which range from 247 Da (pethidine) to 386 Da (sufentanil), thus molecular size is not a limiting factor in drug transport within the body. For comparison the molecular weight of leu-enkephalin is 630 Da and that of [3-endorphin is 3300 Da. The other factors listed above vary considerably among the opioids. Bailli~re's Clinical Anaesthesiology--

Vol. 5, No. 3, December 1991 ISBN 0-7020-1526-1

593 Copyright9 1991,by Bailli~reTindall All rightsof reproductionin any form reserved

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IONIZATION

The degree of ionization of a drug is determined by its dissociation constant (pKa), sometimes also called the ionization constant, and the pH of the solution. For basic drugs, the relationship between the non-ionized fraction (Fn) and pH is given by the formula 10PH-pK~ F,1 + 10 pH-pKr' and this is shown graphically in Figure 1. Non-ionized molecules are in general 1000-10 000 times more lipid soluble than the ionized form, and thus can diffuse more readily across lipid barriers such as cell membranes and the blood-brain and placental barriers. The opioids are all basic drugs which, with the exception of alfentanil, have pKa values greater than 7.4, so that the ionized form of the drug predominates in blood. The pKa of alfentanil is 6.5 so that only 11% of its molecules are ionized at pH 7.4, compared with 80--92% for fentanyl and sufentanil. Thus access of alfentanil to the central nervous system (CNS) and, therefore, the onset of its CNS effects would be expected to be more rapid than for other opioids. This has been confirmed for their electroencephalographic (EEG) effects (Scott et al, 1985; Cook and Scott, 1986). The half-time for plasma-brain equilibration is 1.1 min for alfentanil, 5.8 min for sufentanil and 6.4 min for fentanyl. The pK~ is also an important determinant of the absorption of a drug from the gastrointestinal tract. Except for very weak bases (pK~ < 3), basic drugs are not absorbed from the stomach. As can be seen from Figure 1, all opioids

100 ,s

pKa6.5 pKa8.0

80-

:" .," : z

pKa9.3 "0 E 0 ""7 C 0

/

[ .. ..

40-

t

I

[ ...

-= 6 0 -

z

/ / I

I I I

....

/ /

20-

I

/ /

I

~s s 0

I

0

2

4

I

I

I

I

6

8

10

12

14

pH

Figure 1. Graphicalrepresentation of the changein the non-ionizedfractionwith pH for drugs

with different values of pKa, correspondingto alfentanil (pKa 6.5), sufentanil (pKa 8.0) and methadone (pKa 9.3).

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will be fully ionized in the acid environment of the stomach (pH 2-4). The small intestine, where the pH varies between 5 and 8, offers a more favourable opportunity for absorption, because of the higher proportion of non-ionized molecules and also because of its enormous surface area. These differences in pH within the gastrointestinal tract result in an enterohepatic recirculation loop for opioids and other basic drugs. This can be illustrated for fentanyl (pKa8.4). In plasma, with a pH 7.4, fentanyl is 91% ionized, whereas any fentanyl in the stomach will be fully ionized. There will, therefore, be a concentration gradient across the gastric mucosa for non-ionized molecules, which will enter the stomach and become ionized, and so will not be absorbed (ion trapping). When they reach the alkaline duodenum or ileum they can be absorbed into the portal bloodstream. It has been suggested that enterohepatic recirculation may contribute to delayed postoperative respiratory depression when opioids are used intraoperatively (Stoeckel et al, 1979). However, even if most of this was reabsorbed from the duodenum, because of the large 'first-pass' hepatic metabolism, little would reach the systemic circulation. Because of its lower pKa, conditions for ion trapping and subsequent reabsorption are more favourable for alfentanil. Furthermore, alfentanil has a lower hepatic extraction than fentanyl so that a higher proportion of the reabsorbed drug would be expected to reach the systemic circulation. In rats given fentanyl or alfentanil by infusion to steady state, 1.8 + 0.33% of the administered dose of fentanyl and 2.6+0.83% of the dose of alfentanil was found in the stomach contents (Bj6rkman et al, 1990). Ion trapping can also occur in other body compartments that have a pH lower than blood, e.g. the cerebrospinal fluid, breast milk and in the fetus. Neonates have a lower blood pH than older children (7.30-7.35) and hypoxia will result in even lower values (7.2-7.25). INFLUENCE OF PH Changes in blood pH can alter the disposition of opioids. The HendersonHasselbalch equation predicts for bases that alkalosis (e.g. due to hyperventilation) will increase the non-ionized fraction in plasma. Alkalosis also increases lipid solubility and protein binding, with corresponding changes in the volume of distribution. The volume of distribution of sufentanil was increased in neurosurgical patients hyperventilated to an end-tidal CO2 partial pressure of between 2.9 and 3.7 kPa (Schwartz et al, 1989). Hyperventilation did not influence plasma clearance, but as a result of the increase in distribution volume, elimination half-life was increased from 143 + 51 min (mean_+ sD) in a normocapnic control group to 232 + 60min in patients rendered hypocapnic. These changes are greater than those reported for fentanyl (Cartwright et al, 1983). The difference is most likely related to the differences in pKa between the drugs and the more pronounced effect produced by alkalosis with fentanyl than with sufentanil (Table 2). The changes are less marked with alfentanil and thus hyperventilation is less likely to alter its pharmacokinetics significantly.

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Table 2. Changes in the percentage of un-ionized drug, plasma free fraction and lipid solubility (octanol : water partition coefficient) with changes in pH. pH

7.0

7.2

7.4

7.6

7.8

3.8 9.1 76.0

5.9 13.7 83.4

9.1 20.1 88.8

13.7 28.5 92.6

20.1 38.7 95.2

Percentage un-ionized

Fentanyl Sufentanil Alfentanil Free fraction Femanyl Sufentanil Alfentanil Lipid solubility Fentanyl Sufentanil Alfentanil

24.3 9.7 8.4 343 794 109

16.0 7.5 7.9 532 1196 121

816 1757 128

10.2 5.4 7.3 1230 2497 134

1814 3400 138

In addition to altering pharmacokinetics, changes in blood pH may also alter an opioid's pharmacodynamics. Uptake of morphine by the brain is increased during respiratory alkalosis (Schulman et al, 1984). Analgesia is enhanced by respiratory alkalosis in patients given pethidine (Kaufman et al, 1976) and in animals given morphine (Eisenstein et al, 1980). It is to be expected that this also applies to fentanyl and its analogues. LIPID SOLUBILITY

The standard method of estimating lipid solubility is by measuring the partitioning between a lipid and an aqueous phase for the ionized and the non-ionized drug. For opioids these measurements are made at pH 2 (when the drug will be fully ionized) and at pH 10 (when the drug will be fully non-ionized). Lipid solubility at an intermediate pH, when the drug is partially ionized, is then calculated as the partition coefficient at that pH, according to the formula (Meuldermans et al, 1982) 1 1 ~t = 1 + 10pH-pK~'Kiq 1 + 10pK~-pH''~ni where X is the partition coefficient at the chosen pH, hi is the partition coefficient of the fully ionized drug and )tni is the partition coefficient of the fully non-ionized drug. The alcohol, n-octanol, is commonly used as the lipid phase, although n-heptane is also used. The partition coefficient is, of course, determined by the chemical structure of the drug. A phenyl ring confers high lipid solubility, which explains the high lipophilicity of the phenylpiperidine opioid analgesics. Other lipophilic structures are -CH2 a n d - C H 3 , while - O H , - C O O H , - ~ O and -OCH3 are hydrophilic elements. Since lipid solubility and ionization are intimately related it is not surprising that lipid solubility is altered by changes in pH (Table 2). Lipid

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solubility and protein binding are the primary determinants of distribution volume. Drugs that are lipid soluble tend to have large volumes of distribution whereas high binding to plasma protein retains the drug in the plasma, resulting in a low distribution volume. The lipid solubility of alfentanil is lower than that of fentanyl or sufentanil (Table 2). However, it is sufficiently high to allow rapid access of the drug to the opioid receptors in the CNS. Indeed, the moderate lipid solubility of alfentanil may contribute to its rapid onset of action, since fewer molecules will be bound to non-specific lipid sites within the brain and more will be available to interact with the receptor. The apparent volume of distribution of alfentanil in the brain is about 20 times less than that of fentanyl (Bj6rkman et al, 1990) and thus it will take longer to fill this compartment in the case of fentanyl. Using simulated brain concentration curves for humans, based on tissue-blood partition data measured in rats, Bj6rkman et al (1990) found that the maximum fentanyl concentrations after a single intravenous bolus were reached after 10 min, compared with only 1 min in the case of alfentanil. Extremely high lipid solubility may indeed inhibit centrally acting drugs since their diffusibility will be reduced because of extensive binding in the lipid layers of cell membranes. Despite the lipid solubility of sufentanil, its potential to enter the CNS, expressed as the product of the octanol-water partition coefficient and the free fraction in plasma, is similar to that of fentanyl. This, together with the evidence from Cook and Scott (1986), suggests that its high lipid solubility does not limit equilibration of sufentanil with opioid receptor sites. The high lipid solubility of sufentanil should theoretically be reflected in a volume of distribution larger than that of fentanyl. The fact that this is not so is due to the higher percentage of sufentanil bound to plasma proteins. This restricts sufentanil to the plasma compartment to a greater extent than fentanyl. Only 8% of sufentanil in plasma is distributed in plasma water and thus freely mobile throughout the extracellular fluid, compared with 17% for fentanyl (Meuldermans et al, 1982). The lower volume of distribution of sufentanil results in a shorter terminal half-life than that of fentanyl, since both drugs have similar clearance values. PROTEIN BINDING

In the blood, drugs have variable binding to plasma proteins. Most drug assays measure total drug concentration, i.e. protein-bound plus free (unbound) drug. The rate of diffusion of a drug from the blood to the site of action, and thus its effect, is proportional not to the total concentration but to the concentration of free drug. The protein binding of the opioids varies from 63% for morphine to 93% for sufentanil. Morphine binds mainly to albumin, whereas, like most basic drugs, fentanyl and its analogues are bound to the acute phase protein cq-acid glycoprotein (AAG). Only 44% of fentanyl is bound to AAG, compared with 83% of sufentanil and 92% alfentanil (Meuldermans et al, 1982). The contribution of A A G binding as a percentage of total protein binding is less than 20% for morphine, about

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40% for methadone and 60% for pethidine. The concentration of A A G is increased following trauma and surgery, in patients with chronic inflammatory diseases or malignancy, and decreased in neonates, during pregnancy and in women taking oral contraceptives. The amount of alfentanil required during surgery is significantly higher in patients with Crohn's disease than in other patients undergoing similar surgery (Gesink-van der Veer et al, 1989). Following surgery the increase in A A G concentrations may persist for 48h or more. The Consequences for altered opioid pharmacodynamics in the postoperative period are unknown. INFLUENCE OF A G E Neonates

As with many drugs, opioid pharmacokinetics vary with age. Important differences exist, for example, between neonates and older children. The pharmacokinetics of fentanyl were very variable in neonates undergoing surgery (Koehntop et al, 1986). Terminal half-life was comparable to that in adults, but clearance increased with age during the neonatal period (Koehntop et al, 1986; Gauntlett et al, 1988). Greeley and de Bruijn (1988) studied sequential sufentanil pharmacokinetics in three patients who underwent surgery for complex cardiac malformations during the first week of life and a second procedure 16-25 days later. Sufentani110 txg/kg combined with pancuronium and oxygen was given as a single bolus for anaesthesia for all procedures and arterial blood concentrations were measured by radioimmunoassay for up to 20 h. Sufentanil clearance during the first study in the three infants was 1.7, 4.3 and 6.7mlmin lkg-1, and this increased dramatically during the second study to 12.9, 18.8 and 19.3 mlmin -1 kg -1, respectively. There were corresponding decreases in the terminal half-life of sufentanil by 13%460% over this period. There was a small increase in Vas,. The authors attributed these changes to improved hepatic blood flow and improved liver metabolism. In a previous study by the same authors, the clearance of sufentanil in children aged less than 1 month was 6.7mlmin-lkg -1, about 40% of the value in infants and older children (Greeley et al, 1987). The reduced clearance in the early neonatal period is probably due to immaturity of the cytochrome P-450 isoenzyme responsible for opioid metabolism. P-450 activity in neonates is only 25-50% of that in adults. Halothane decreases the metabolic capacity of cytochrome P-450 isoenzymes and its coadministration will further reduce the clearance of opioids in neonates (Kreiter and van Dijke, 1983). Part of the variability in fentanyl clearance in the study of Koehntop et al (1986) may have been caused by the use of halothane in some of their patients. In neonates a raised intra-abdominal pressure can markedly decrease clearance of opioids (Greeley and de Bruijn, 1988). Koehntop et al (1986) found that this prolonged the terminal half-life of fentanyl 1.5-3 times. Gauntlett et al (1988) reported two neonates who had intra-abdominal surgery in whom fentanyl clearance ceased for a 10-h period. This was

OPIOID AGONISTS AND ANTAGONISTS

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probably due to the combination of an immature liver enzyme system and a severely compromised liver blood flow. The dose of fentanyl needed in neonatal anaesthesia is considerably lower than for older children or adults (Yaster, 1987). Respiratory depression occurs at significantly lower doses or plasma concentrations of opioids in neonates than in older children (Koehntop et al, 1986; Booker, 1989). This may be related to increased permeability of the blood-brain barrier in neonates. A more likely explanation, however, is the difference in protein binding between neonates and older children. There is a significant correlation between the free fraction in plasma and brain extraction of a drug (Robinson and Rappoport, 1986) and its pharmacodynamic effect (Lemmens et al, 1989). The free fraction of sufentanil is about 2.5 times greater in neonates than in children and adults (Meistelman et al, 1990). This difference is due to the much lower concentration of A A G in neonates (0.37 + 0.07 g/l, mean + si)) than in children (0.7 + 0.19 g/l) and adults (0.74+0.12g/l). A A G concentration is dependent on gestational age; the concentration in premature infants born at 30-35 weeks' gestation is only 60% that in full-term infants (Notarianni, 1990). This has important implications for the use of opioids in these patients. Morphine is a popular analgesic for paediatric patients, including neonates, often being given by a continuous intravenous infusion. Neonates are considered to be more sensitive to the respiratory depressant effects of morphine (Yaster, 1987). This can be explained, at least partially, by age-related differences in the development of opioid receptors, but it is equally likely that impaired clearance and thus higher morphine concentrations also contribute (Besunder et al, 1988). The pharmacokinetics of morphine in neonates has been described by Lynn and Slattery (1987) who studied two groups of patients receiving a morphine infusion, one group aged 1-4 days postnatal and the other aged 17-65 days. The mean morphine clearance in the former group was 74% lower than in the older children and the terminal half-life was 77% longer. Morphine is eliminated primarily by conjugation with glucuronide. This phase II metabolic pathway is markedly impaired in neonates, to a much greater extent than phase I reactions (Besunder et al, 1988). The steadystate concentration obtained with a continuous intravenous infusion is a function of clearance. Because of their reduced clearance of morphine and other opioids, neonates will achieve higher plasma concentrations than older children given the same infusion rate. The rate of elimination will also be less in neonates. This can explain the increased sensitivity to, and the prolonged action of, morphine in these patients. Children

In paediatric cardiovascular patients, sufentanil clearance in children aged over 2 months varied between 13 and 18 ml min -1 kg -1, values not dissimilar from those in young adults (Greeley et al, 1987). Davis et al (1987) studied the pharmacokinetics of high-dose sufentanil (15 txg/kg given over i min) in children undergoing cardiac surgery for repair of congenital heart defects.

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Terminal half-lives and plasma clearance were similar in infants younger than 10 months and in those older than 10 months who were not surface cooled. The mean half-life was 54 min, considerably shorter than in adults, and the clearance was also higher than the adult value, 23 mlmin -1 kg -1. The younger patients, however, had a smaller distribution volume. In children in whom surface cooling was used, the terminal half-life of sufentanil was markedly prolonged (120 _+36 min, mean + SD), In a study in 18 children aged from 3 months to 14 years there was a weak but significant correlation between age and alfentanil clearance, but the mean clearance for the whole group (7.9 ml min -1 kg -1) was within the adult range (Goresky et al, 1987). Meistelman et al (1987) also found alfentanil clearance in children to be similar to that in adults, although there was considerable variability in clearance rates (between 2.7 and 8.3 mlmin -1 kg-1). Roure et al (1987) compared the pharmacokinetics of alfentanil in children aged between 10 months and 6.5 years with those in ten adults. The apparent volume of distribution (Vd~) did not differ between the two groups. However, the terminal half-life was significantly shorter and plasma alfentanil clearance greater in the children. The increased clearance in these young children can be explained by an increase in hepatic microsomal enzyme activity. There is a marked acceleration in the rate of oxidative metabolic activity after birth and this metabolic capacity often exceeds that in adults between 2-3 months and 2-3 years (Morselli et al, 1980).

The elderly Elderly patients are believed to be more sensitive to the depressant effects of opioids, but it is not certain whether this is due to age-related changes in pharmacodynamics or pharmacokinetics, both of which may be altered by concomitant disease often present in elderly patients. Lemmens et al (1988a) found decreased dose requirements for alfentanil in elderly patients but no difference in pharmacodynamics compared with young adults. They concluded that pharmacokinetic differences were responsible for decreased dose requirement in the elderly. In contrast Scott and Stanski (1987) found no age-related changes in the pharmacokinetics of alfentanil, but reported that brain sensitivity, as determined by EEG changes, decreased significantly with age. Plasma clearance of fentanyl in one study was similar in elderly and younger patients but the volume of distribution was smaller in the elderly (Singleton et al, 1988). Sitar et al (1989) found that older patients metabolize alfentanil more slowly than their younger counterparts. The terminal half-life, total volume of distribution and plasma clearance of sufentanil were similar in patients aged 70-80 years and in those aged 22-57 years (Matteo et al, 1990), although elderly patients had significantly smaller initial volumes of distribution (310+ 109ml/kg versus 491+ ll2ml/kg, mean + SD). It was the opinion of the authors that age-related differences in the action of sufentanil were due to pharmacodynamic differences. The effect of age on the concentration of AAG, the principal binding protein for the phenylpiperidine opioids, has not been well established. In the elderly it is often difficult to discriminate between pure age-related

OPIOID AGONISTS AND ANTAGONISTS

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changes and those caused by factors such as concomitant disease or medication. In addition there is a large intrasubject variability in AAG levels and a normal diurnal variation (Yost and de Vane, 1985). A recent study has provided good evidence that age p e r se has no effect on AAG concentration. Veering et al (1990) studied plasma AAG and human serum albumin concentrations in 68 healthy subjects, aged 20-90 years, undergoing elective minor surgical, gynaecological or orthopaedic procedures. None had taken any medication for at least 1 month before the study, and patients with diseases or conditions known or suspected to be associated with alterations in serum proteins were excluded. The authors found that in healthy subjects albumin concentrations decreased with increasing age, whereas age, uncomplicated by disease, did not influence AAG concentration. When considering the relationship between age and opioid pharmacokinetics it may be important also to take account of gender. Lemmens et al (1990) found a significant decrease in alfentanil clearance with age in female patients but no correlation in males. There are also differences between caucasians and orientals. Asians had shorter alfentanil terminal half-lives (58 min compared with 90 min in Europeans) and smaller volumes of distribution (Aun et al, 1988). These differences may be due to a better demethylation capability in Asians. INFLUENCE OF RENAL DISEASE Although the kidneys play a very minor role in the elimination of most opioids, renal disease can none the less influence their pharmacokinetic profile, secondary to alterations in plasma proteins and intra- and extravascular volumes. The clearance and elimination of alfentanil are unaltered in patients with chronic renal failure, but the steady-state volume of distribution (Vd~) is significantly increased (Chauvin et al, 1987). However, when corrected for differences in protein binding, Vd~ of unbound alfentanil was similar in renal and control patients. The pharmacokinetics of sufentanil are not altered in patients with chronic renal disease undergoing renal transplant surgery (Fyman et al, 1988). The pharmacokinetics of sufentanil was examined in six young patients, mean age 12 years, undergoing renal transplantation for chronic renal failure, and compared with a matched group, free from renal disease, undergoing elective non-renal surgery (Davis et al, 1988). There were no differences in pharmacokinetic parameters between the groups, although sufentanil clearance (12.8 +_12.0 versus 16.4+6.1 mlmin -1 kg -I) and terminal half-life (89.7 + 15.7 versus 76.0+32.8min) were more variable in the patients with renal failure. However, arterial samples for determination of sufentanil concentrations were obtained only until 180 min after drug administration. This sampling period is really too short to allow accurate estimates of pharmacokinetic variables. In a similar study, this group has also shown that the pharmacokinetics of alfentanil is not altered by chronic renal failure (Davis et al, 1989).

602

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The pharmacokinetics of morphine was not altered in patients with advanced renal failure (S~iwe and Odar-Cederl6f, 1987; Sear et al, 1989a). However, the terminal half-lives of morphine-3-glucuronide and morphine6-glucuronide were significantly prolonged, from about 4 h in non-uraemic patients to between 14 and 119 h in patients with renal failure (S~iwe and Oder-Cederl6f, 1987). Since glucuronides are water-soluble compounds excreted by the kidneys, this finding is not surprising. Impaired elimination of morphine glucuronide was also reported by Wolff et al (1988). They found a long terminal half-life of morphine in all patients (9.2+2.5h). Impaired renal filtration was suggested as the cause of increased concentrations of morphine glucuronide during general anaesthesia (Sear et al, 1989b). Patients with renal insufficiency have impaired elimination of morphine glucuronides (Wolff et al, 1988). Morphine-6-glucuronide is pharmacologically active with a high affinity for opioid receptors. It can cross the blood-brain barrier and its accumulation is thought to be responsible for the prolonged action of morphine in patients with renal failure (Osborne et al, 1986). INFLUENCE OF HEPATIC DISEASE The primary route of elimination for opioids is by hepatic metabolism. For fentanyl and sufentanil, hepatic extraction in high and intrinsic hepatic clearance is greater than liver blood flow. The clearance of these drugs will, therefore, be dependent on liver blood flow and factors decreasing this will slow elimination and prolong effect. Anaesthesia and surgery decrease hepatic blood flow and drug clearance (Runciman and Mather, 1987). Conversely, because the liver has such a large reserve capacity of metabolizing enzymes, the elimination of these drugs is unlikely to be significantly altered in patients with hepatic disease until liver function becomes severely compromised. Interestingly, sufentanil pharmacokinetics were unaltered in patients with cirrhosis (Chauvin et al, 1989). In contrast to fentanyl and sufentanil, alfentanil has a hepatic extraction of only 0.3-0.5 (Chauvin et al, 1986) and alfentanil clearance can be influenced by liver blood flow and enzyme capacity. Compared with control patients, those with cirrhosis had lower total plasma clearance of alfentanil (1.6 ml min - 1 kg - 1 versus 3.1 ml min - 1kg - 1) and a more prolonged elimination half-life (219 min versus 97 min) but similar volumes of distribution (Ferrier et al, 1985). Decreased alfentanil clearance and prolonged elimination have also been reported in patients with abnormal liver function tests but without clinically significant hepatic disease (Sharer et al, 1986). In children with cholestatic disease, alfentanil's pharmacokinetics were not significantly altered (Davis et al, 1989). ABDOMINAL AORTIC SURGERY

In patients undergoing elective abdominal aortic reconstructive surgery, the terminal half-life of fentanyl, sufentanil and alfentanil are markedly pro-

OPIOID AGONISTS AND ANTAGONISTS

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longed compared with general surgical patients (Hudson et al, 1984, 1989, 1991). The clearance of the opioids was similar to values reported for patients undergoing general surgery, and the slow elimination was accounted for by a markedly increased volume of distribution. Several factors could explain the altered pharmacokinetics in these patients. The researchers sampled blood for up to 24 h, which would have resulted in a more accurate estimation of the terminal phase of elimination and thus more accurate pharmacokinetic parameters. However, these patients received considerable quantities of intravenous fluids during and after surgery and this could have increased Vdsc Since clearance was not altered, it is unlikely that liver blood flow was significantly affected by surgery. METABOLISM

For the phenylpiperidine opioids, biotransformation occurs primarily via hepatic phase I metabolism, catalysed by the cytochrome P-450 isoenzyme system. The major metabolic pathways are N-dealkylation and odemethylation, both in animals (Lavrijsen et al, 1988a) and humans (Bovill et al, 1988; Meuldermans et al, 1988). The terminal elimination half-life of alfentanil is significantly prolonged and clearance is decreased in patients treated with erythromycin, an inhibitor of hepatic metabolic processes (Bartkowski et al, 1989). This antibiotic can delay recovery and prolong postoperative.respiratory depression (Bartkowski and McDonnell, 1990). Markedly raised plasma concentrations of midazolam, associated with unconsciousness, occurred in an 8-year-old boy given oral midazolam 0.5 mg/kg as premedication, followed by an intravenous infusion of erythromycin (Hiller et al, 1990). It was assumed that this effect was due to altered hepatic clearance of midazolam caused by the erythromycin. Genetic polymorphism of the cytochrome P-450 isoenzymes may be an important cause of the large interpatient differences in drug metabolism. The best known of these polymorphisms is the sparteine-debrisoquine type which involves the P-450 IID1 enzyme, debrisoquine hydroxylase (Mayer, 1987). There are considerable differences in the prevalence of the abnormal phenotype between ethnic groups. Between 5% and 10% of caucasians are poor metabolizers of sparteine-debrisoquine; the remainder are designated as extensive metabolizers. The abnormal phenotype is inherited as an autosomal recessive trait. The cytochrome P-450 IID1 enzyme is also involved in the formation of morphine from codeine (Mortimer et al, 1990). This is clinically relevant since morphine is thought to be responsible for most of the analgesic effect of codeine. Codeine increases the pain threshold in extensive metabolizers but is without effect in poor metabolizers and may be contraindicated in this group (Desmeules et al, 1989). It has been suggested that the metabolism of alfentanil might also be subject to polymorphic oxidation by the same P-450 enzymes involved in the genetic polymorphism of debrisoquine (Henthorn et al, 1989a). It has also been suggested that genetic polymorphism may be involved in the metabolism of fentanyl since both fentanyl and alfentanil competitively

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inhibited debrisoquine hydroxylase in vitro (Henthorn et al, 1989a). However, in a study using human liver microsomes (Lavrijsen et al, 1988b) and in subjects who were poor metabolizers of debrisoquine but had a normal metabolic pattern for alfentanil, it has been disproved that polymorphism of debrisoquine hydroxylase is not involved in alfentanil metabolism (Meuldermans et al, 1988; Henthorn et al, 1989b). Neither fentanyl nor alfentanil has metabolites that are pharmacologically active. However, one of the metabolites of sufentanil, desmethyl sufentanil, is pharmacologically active with a potency of about one tenth of that of the parent substance. This metabolite is thus approximately equipotent with fentanyl (Weldon et al, 1985). In contrast to the phenylpiperidine opioids, the main route for morphine biotransformation is by phase II conjugation to morphine-3-glucuronide and morphine-6-glucuronide. Only 5-10% of a dose of morphine is excreted unchanged in the urine. Morphine-6-glucuronide occurs in significant quantities after administration of morphine and its concentration in plasma exceeds that of the parent drug by a factor of 9 : 1 within 30 rain of intravenous administration of morphine (Osborne et al, 1990). This metabolite is pharmacologically active with an affinity for the ~1 and ~2 opioid receptors similar to that of morphine (Abbott and Palmour, 1988) and may be responsible for a considerable proportion of the effects of parenteral morphine. Morphine-6-glucuronide is a ventilatory depressant, with a potency substantially in excess of that of free morphine (Pelligrino et al, 1989). Even allowing for its slower penetration into the brain, it may be that 50% or more of the respiratory depression observed by l h following systemic administration of morphine is due to this metabolite, and this contribution will subsequently increase with time (Pelligrino et al, 1989). It makes a significant contribution to morphine intoxication in patients with renal failure (Osborne et al, 1986). Hasselstr6m et al (1989) reported a patient with postoperative renal failure, given 165 mg morphine over 3 days, who required a naloxone infusion for 10 days. In addition to morphine, high concentrations of morphine metabolites were present in the plasma. These decayed with a half-life of 2-5 days and were unaffected by peritoneal dialysis. The pharmacokinetics of morphine and its metabolites have recently been studied in volunteers using highly specific assay techniques. Osborne et al (1990) gave morphine sulphate by different routes of administration. After intravenous administration, morphine 6-glucuronide and morphine 3glucuronide were detectable in the plasma within 5 min of injection, and their concentration exceeded that of morphine by 0.5 h and 0.1 h, respectively. After enteral administration, glucuronides occurred in quantities similar to those seen after intravenous injection, but with an obvious lag time. The availability of morphine was low following administration by all enteral routes. After oral administration, the terminal half-lives of both glucuronide metabolites were markedly longer than with the other routes. The data from this study are summarized in Table 3. Hanna et al (1991) investigated the pharmacokinetics of intravenous morphine sulphate 120jxg/kg and morphine-6-glucuronide 30 ~g/kg and 60 Ixg/kg given to healthy volunteers.

605

OPIOID AGONISTS AND ANTAGONISTS

Table 3. Pharmacokinetic data for morphine (M), morphine-3-glucuronide (M-3-G) and morphine-6-glucuronide (M-6-G) following morphine administered by different routes. Data (mean + so) are corrected to a 10 mg dose of morphine and 70 kg weight (from Osborne et al, 1990 with permission). Morphine route Intravenous

Oral

Sublingual

Buccal

0.1+0.04 0.1 + 0.04

0.3+0.12 0.4+0.17 0.5 + 0,25

0.72+0.56 0.85+0.53 0.6 + 0.18

0.74+0.44 0.4+0.19 0.9 + 0.36

1.7+0.9 3.9+1.5 2.6+-0.69

1.3-+0.5 9.5+_8.6 10.7_+9.2

1.7+0.5 3.2+1.9 3.2+1.7

2.6+1.3 2.5_+0.7 3.2+-1.8

AUC (area under the curve) (nmolhl 1) M M-3-G M-6-G

227 + 41.1 1765 + 302 313 +-87

44 + 13.3 2178 + 808 371 + 159

48 + 10.3 1665 + 485 298 + 81

54 _+19.8 1546 + 444 297 + 122

Cmax(nmoll 1) M M-3-O M-6-G

294+53.5 407 + 99.7 79.5+-15.1

21.2+8.1 440 + 125 83.9+-26.0

19.3+4.5 385 -+81.0 74.4+18.8

15.8+6.2 326 _+79.6 68.8+21.5

0.25+-0.13 0.73 + 0.22

0.84+-0.40 1.25+0.4 1.4 + 0.5

8.7+-2.8 43.6+-9.6 10.8-+2.2

1.7+0.15 41.6+6.4 9.3+-1.1

1.5+0.6 31.9+11.2 7.8+-3.5

20 + 8.7

22 + 6.0

Lag time (h) M M-3-G M-6-G t1/2~ (h)

M M-3-a M-6-G

Tmax (h)

M M-3-6 M-6-G Urinary excretion (%)* M M-3-G M-6-G Bioavailability (%) M

1.7_+1.30 2.2+1.1 2.3 _+1.1

1.8_+1.75 2.3_+0.9 2.6 _+.0.7 2.0_+0.5 40.6+-9.1 9.5+2.6 25 + 10.7

* Urinary excretion for M-3-G and M-6-G is expressed as a percentage of the dose of morphine administered.

S u b j e c t i v e side-effects such as light h e a d e d n e s s , s e d a t i o n , n a u s e a a n d itching were similar following both drugs but of s h o r t e r d u r a t i o n following the g l u c u r o n i d e . T h e p h a r m a c o k i n e t i c disposition of m o r p h i n e in this study was similar to t h a t r e p o r t e d by O s b o r n e et al (1990). T h e t e r m i n a l half-lifes of m o r p h i n e a n d m o r p h i n e 6 - g l u c u r o n i d e were similar, b u t the a p p a r e n t v o l u m e s of d i s t r i b u t i o n a n d total b o d y clearance were significantly smaller for the g l u c u r o n i d e . T h e total b o d y clearance of m o r p h i n e has b e e n r e p o r t e d as e q u a l to or e v e n exceeding liver b l o o d flow (Mazoit et al, 1987), raising the possibility of e x t r a h e p a t i c m e t a b o l i s m . C o n j u g a t i o n to g l u c u r o n i d e has b e e n d e m o n strated in the k i d n e y a n d gut w a l l i n a n i m a l s ( I w a m a t o a n d K l a s s e n , 1977) a n d in the h u m a n fetus (Pacifici a n d R a n e , 1982). I n a m o r e r e c e n t study in six a d u l t p a t i e n t s n o e v i d e n c e could be f o u n d for gut wall m e t a b o l i s m of

606

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morphine (Mazoit et al, 1990). In these patients total body clearance of morphine exceeded hepatic clearance by 38% and it was concluded that extrahepatic clearance of morphine probably occurred through the kidneys. These findings have implication for patients after a kidney transplant and may explain why morphine clearance sometimes changes abruptly in these patients (Moore et al, 1984). Glucuronidation of morphine has been shown to occur in the human brain (Wahlstr6m et al, 1988). Glucuronidation is induced by oral contraceptive steroids (Shenfield and Griffin, 1991). As expected, morphine clearance by glucuronidation is increased in women taking oral contraceptives (Watson et al, 1987). After intravenous morphine, clearance was 1.46 + 0.361 h -1 kg -1 in women taking oral contraceptives compared with 1.0 + 0.121 h -~ kg - t in a control group. PLACENTAL TRANSFER Being moderately-to-highly lipid soluble, fentanyl and its newer analogues cross the placental barrier rapidly. In a maternal-fetal sheep preparation, fentanyl was detected in fetal blood as early as 1 min after intravenous administration in the ewe, and peak fetal concentrations occurred at 5 min (Craft et al, 1983). Plasma levels were always lower in the fetus. In humans, plasma concentrations of alfentanil and sufentanil are also higher in maternal than in neonatal blood (Gepts et al, 1986; Meuldermans et al, 1986). However, free (unbound) concentrations were similar in mothers and neonates. This was because of the lower amount of protein binding in the neonates due to lower concentrations of AAG. There is an overall fall in A A G levels during pregnancy, with about a 30% reduction at term (Notarianni, 1990). This will result in higher free fractions of opioids and possibly increased sensitivity to their effects. Neonates may potentially be at risk when opioids are administered to lactating mothers. The mean pH of milk (7.2) is lower than that of plasma so ion trapping of basic drugs in the milk will occur. Wittels et al (1990) studied opioid concentrations in breast milk and neonatal neurobehaviour following administration of pethidine or morphine intravenously (via patientcontrolled analgesia) and orally to mothers after elective caesarean section. Significant concentrations of opioids and metabolites were found in samples of milk obtained from 12 to 96h postpartum. In the pethidine group the metabolite norpethidine was persistently elevated. Neonates in this group had significantlymore depression ofneurobehaviour. In the morphine group, neonates were more alert and better oriented on their third day of life. CARDIAC SURGERY AND CARDIOPULMONARY BYPASS

The pharmacokinetics of fentanyl and its analogues have been extensively studied in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Not surprisingly, the disposition of opioids in these patients is different from that in patients undergoing non-cardiac surgery. Most studies

OPIOID AGONISTS AND ANTAGONISTS

607

have involved patients with good left ventricular function undergoing coronary artery surgery, so that congestive failure was not a complicating factor. The biggest difference between cardiac and non-cardiac operations is the use of CPB. Hypothermia, haemodilution, use of non-pulsatile flow and altered regional blood flow can be expected profoundly to alter the pharmacokinetics of drugs used during cardiac surgery. General reviews of the effects of CPB on pharmacokinetics have been published (Buylaert et al, 1989; Holley et al, 1982). In patients given a single large bolus of fentanyl at the start of anaesthesia, there were large decreases in plasma fentanyl concentrations at the start of bypass, probably due to haemodilution. Thereafter, during bypass, fentanyl concentrations remainly fairly constant, suggesting that clearance by the liver was markedly reduced (Bovill and Sebel, 1980; Koska et al, 1981). The volume of distribution of fentanyl was increased and terminal half-life was prolonged. The mean terminal half-life of alfentanil in patients given an alfentanil infusion during coronary artery surgery was 5.1 h (range 1.5-10 h) (Robbins et al, 1990). Hug et al (1983) assessed alfentanil pharmacokinetics before and after bypass. Alfentanil 125 txg/kg was injected as a bolus at induction of anaesthesia, and a second 125 txg/kg bolus was given approximately 30min after the end of bypass. The pharmacokinetic parameters before bypass were similar to those in non-cardiac surgical patients. After bypass, the terminal half-life was significantly prolonged compared with the pre-bypass period (195 + 31 min versus 72 + 6 min, mean + SEM). This was apparently due to an increased volume of distribution since alfentanil clearance did not change. The concentration of sufentanil fell by 30-55 % with the start of CPB, but remained stable during the period of hypothermia (Okutani et al, 1988). Plasma concentrations increased during rewarming, and were similar in the first post-CPB sample to the value immediately before CPB. Flezzani et al (1987) investigated sufentanil disposition during cardiopulmonary bypass in ten patients undergoing coronary artery surgery anaesthetized with diazepam and enflurane. Ten minutes before the expected start of CPB, a computercontrolled infusion of sufentanil was pharmacokinetically programmed to achieve and maintain a plasma sufentanil concentration of 5 ng/ml. Plasma concentrations (mean + SEM)immediately before CPB were 3.8 + 0.4 ng/ml; they decreased to 2.5 _+0.3 ng/mlimmediately after the start of CPB, and then slowly rose to 4.7 + 0.4 ng/ml by the end of CPB, even though the infusion rate was exponentially decreasing during this period. The accumulation of sufentanil when infused in this manner during CPB suggests that pharmacokinetic parameters from healthy normothermic patients are not entirely appropriate for use by computer-controlled infusion schemes for cardiac surgery. In children undergoing corrective cardiac surgery, plasma fentanyl concentrations remained essentially unchanged over a 140-min period during CPB with profound hypothermia to 18-25~ (Koren et al, 1987). These authors also investigated the disposition of fentany130 txg/kg given as a bolus over lmin in four piglets during normothermia (37~ and hypothermia (29~ Each piglet served as its own control. During hypothermia fentanyl plasma concentrations were considerably higher than during normothermia.

608

J.G. BOVILL

Terminal half-lives were similar, but distribution volume and total body clearance were significantly smaller during hypothermia. Apart from the effects ofhypothermia and haemodilution, sequestration of opioids in the extracorporeal circuit may also be a factor in drug disposition during CPB. Fentanyl, but not alfentanil, is adsorbed on to a Shiley bubble oxygenator circuit (Skacel et al, 1986). Both fentanyl and sufentanil are sequestrated on to the Scimed membrane oxygenator circuit (Rosen and Rosen, 1986; Rosen et al, 1988). At 25~ the capacity of this membrane for sufentanil uptake was 11 ng/cm 2, increasing to 24 ng/cm 2 at 37~ This is much less than the capacity of the same device for fentanyl, 130 ng/cm 2 (Rosen et al, 1988). This is an enormous capacity, corresponding to a saturated absorption of 5-6 mg fentanyl for a standard adult oxygenator. One cannot, of course, extrapolate these findings to other makes of oxygenator, since opioid binding will be dependent on the composition and structure of the material used, and this differs among the various manufacturers. Data from the study of Okutani et al (1988) suggested that relatively large amounts of sufentanil were sequestrated during hypothermic CPB, although the authors felt that sufentanil absorption in the bypass circuit was unlikely to have been a major factor. They suggested that significant pulmonary sequestration may have occurred, with subsequent release with rewarming and restoration of ventilation. It is known that many drugs, including opioids, can be retained in substantial quantities in the lungs. The first-pass uptake of fentanyl, pethidine, alfentanil and sufentanil in the lungs exceeds 60-90% (Roerig et al, 1987; Taeger et al, 1988; Boer et al, 1989, 1990). In patients who are taking propranolol the uptake of fentanyl by the lungs was significantly reduced, from 83% in patients taking no propranolol to 53% in those taking 30-120 mg per day (Roerig et al, 1989). In one patient taking 120 mg propranolol per day, the first-pass pulmonary uptake of fentanyl was only 23% of the injected dose. The pharmacodynamic implications of such interactions need to be assessed in future studies. ANTAGONISTS A major disadvantage of naloxone relates to its short duration of action compared with that of most opioid agonists. The terminal half-life of naloxone is about 1-1.5 h. Since it is structurally very similar to morphine, it is not surprising that the major metabolite of naloxone is the glucuronide, naloxone-3-glucuronide. The enzyme that catalyses this glucuronidation, UDP-glucuronyl-transferase, is present both in liver microsomes and in the brain. Enzymatic formation of naloxone-3-glucuronide has been demonstrated in post-mortem human brain tissue (Wahlstr6m et al, 1988). An alternative to naloxone in the future could be nalmefene. This is a pure opioid antagonist derived from naltrexone and it has terminal half-life of 8.5 h (Dixon et al, 1986). In a volunteer study, nalmefene restored the slope of the ventilatory response to carbon dioxide to normal for 6 h after administration of morphine, compared with 1.5 h after naloxone (Konieczko et al, 1988).

OPIOID AGONISTSAND ANTAGONISTS

609

SUMMARY

A major reason for clinical variations between opioids is differences in their physicochemical and pharmacokinetic properties. Important factors are pKa, lipid solubility and protein binding. Opioids are basic drugs that, with the exception of alfentanil, have pKa values greater than 7.4, so that the ionized form of the drug predominates in the blood. The pKa of alfentanil is 6.5 so that 90% of alfentanil is non-ionized at pH 7.4. This facilitates its access into the CNS. pKa is also an important determinant of absorption from the gastrointestinal tract. Opioid pharmacokinetics are also affected by changes in blood and tissue p H (e.g. during respiratory alkalosis). While morphine is mainly bound to albumin, the most important binding protein for the fentanyl analogues is al-acid glycoprotein (AAG). Change in the concentration of this protein can affect opioid pharmacodynamics, and has special relevance during pregnancy and in the newborn. Because of immaturity of the cytochrome P-450 isoenzyme system, neonates metabolize opioids much less efficiently than older children or adults. Generally the pharmacokinetics of an opioid are similar in children and in young adults, although often clearance is greater in young children. In elderly patients the influence of age on opioid pharmacokinetics is less well defined and many of the clinical differences between young and elderly patients in their responses to opioids may be due to pharmacodynamic differences or attributable to concomitant diseases or medication. The pharmacokinetics of these drugs are also influenced by renal and hepatic disease, although the extent is very drug dependent. The elimination of morphine metabolites is especially affected by decreases in renal filtration. Not surprisingly, cardiac surgery with cardiopulmonary bypass markedly affects opioid pharmacokinetics. Apart from changes in distribution volume and hepatic clearance, sequestration of opioids on to the extracorporeal circuit may be important for some opioids. Significant uptake of opioids by the lungs has also been demonstrated.

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