The Pharmacology of Sufentanil

Contrary to the short acting opioids alfentanil and remifentanil, the relative long acting and the most potent opioid sufentanil should be used as the basic analgesic agent in all major surgical procedures, which are likely to result in intense nociceptive activity. Due to its high stereospecificity to the receptor site (Figure III-35) it is characterized by the widest therapeutic margin of safety (fentanyl 277, alfentanil 10, 80, sufentanil 26, 716) [13, 102, 103, 104, 105].

Table III-12. Difference in affinity of various opioids to the three main opioid receptior sites p, k, and 8 as reflected in receptor binding and displacement studies in guinea pig brain homogenates (Ki in nmol/L). The lower the dose, which is necessary to displace 50% of a radioactive labeled ligand from the binding site, the better the affinity. Note, low Ki of sufentanil to the p-site reflects high affinity

Table III-12. Difference in affinity of various opioids to the three main opioid receptior sites p, k, and 8 as reflected in receptor binding and displacement studies in guinea pig brain homogenates (Ki in nmol/L). The lower the dose, which is necessary to displace 50% of a radioactive labeled ligand from the binding site, the better the affinity. Note, low Ki of sufentanil to the p-site reflects high affinity

Opioid

Displacement

Displacement

Displacement

of 3H-D-Ala-

of 3H-D-Ala-

of 3H-Ethyl-

Me-Phe-Gly-

D-Leu-

ketocyclazocine

ol2-enkephalin

enkephalin at

at K-site

at |-site

S-site

Morphine

1.8 ± 0.26

90 ± 16

317 ± 68

Pethidine

185 ± 51

4345±1183

5140±789

Pentazocine

7.0 ± 1.6

106 ± 10

22.2 ± 4.1

Fentanyl

7.0 ± 0.81

151 ± 21

470 ± 68

Sufentanil

1.58 ± 0.38

23.4 ± 7.2

124 ± 11

Adapted from [107]

Adapted from [107]

At the same time it is a drug with a relative high affinity to and an intense intrinsic activity of the ^-opioid receptor (Table III-12). This accounts for a 800fold higher potency than morphine, and a 5-7fold higher analgesic effectiveness than fentanyl.

Due to its high receptor specificity, which goes in hand with a wide therapeutic margin of safety, clinically this is manifested in practically no cardiovascular depression. In addition, the high intrinsic activity, which parallels with a high analgesic potency, only low amounts of the agent have to be administered in order to achieve a desired effect. This is of advantage as there is a lower load for liver enzymes for degradation. Even in the case of an accidental overdose, no side effects have to be expected from the cardiovascular system.

Being a derivative of the fentanyl series, it has a similar antitussive, respiratory depressive and bradycardiac effect. Also, as demonstrated in the octanol/water partition coefficient (Table III-13), it has a high lipophilicity, suggesting that there is a rapid transfer through the blood-brain barrier, which partly accounts for its fast onset of action within 2 min.

In addition, the higher portion of non-ionized molecules of sufentanil, which accounts for 20%, suggests a faster onset of action than fentanyl where only 8.5% are present in the plasma as non-ionized molecules, which are able to pass through the blood-brain barrier. Therefore, time until max effect is 3-4 min for sufentanil, which however is 5-8 min for fentanyl. Contrary, the hydrophilic compound morphine has an even much longer duration until max. effect being around 15 min, while after remifentanil and after alfentanil time until max. effect is around 1 min.

Aside from the short onset of action, the volume of distribution (Table III-13) also differs among the different fentanyl analogues. With 4.0L/kg for fentanyl there is a Vd of 2.9L/kg for sufentanil, suggesting that there is a lesser likelihood of a re-diffusion phenomenon with late opioid-related overhang. This is also reflected in the faster plasma clearance and a shorter terminal elimination half-life (t1/2B), which is 164 min after sufentanil and 219 min after fentanyl respectively. The lowest volume of distribution is seen with alfentanil (0.86 L/kg) implying little redistribution of the agent from peripheral tissue. Although remifentanil has a relatively large volume of distribution, there is no rediffusion of the agent back into the central blood compartment. This is because the fentanyl analogue is metabolized by blood and tissues esterase resulting in the shortest duration of action being around 7 min [86].

Due to the higher analgesic potency of sufentanil there is a better depression of nociceptive induced stress reactions as mirrored in a more stable blood pressure, pulmonary artery pressure and heart rate [18, 108]. Especially the stress-related hormonal changes such as the usual increase in epinephrine, norepinephrine, corti-coids, ADH, vasopressine, and mineralcorticoids are not increased during most intense nociceptive stimulation [109, 110].

It also has been noted that in comparison to fentanyl, sufentanil when given in equianalgesic dosages, results in a longer duration of analgesia, which, however, is accompanied by a lesser respiratory depressive effect (Figure III-36). Such difference is accounted to an uncoupling of analgesia and respiratory depression in the lower dose-range of sufentanil, making this agent a more favorable analgesic in the postoperative period [111, 112].

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