Reasons For Difference In Potency Of Opioids

In contrast to the analgesics that have a peripheral site of action (e.g. acetylsalicylic acid; ASA), opioids act at the relay station of nociceptive-propagating pathways at the synapse of nerve conduction. Within the nerve, pain impulses are transmitted as a change in electric conduction. And in order to guarantee maintenance of the nociceptive impulse, the excitatory impulse releases a neurotransmitter at the terminal nerve. Due to its chemical configuration, the transmitter fits exactly into a binding site at the opposite nerve ending resulting in an increase of excitability and a change in the electrical nerve conduction. Opioids have the property of binding to specific receptor sites at pre- and post terminal nerve endings resulting in an inhibition of a release of the excitatory neurotransmitter. The continuity of the impulse is interrupted, the nociceptive signal is no longer transmitted and thus can no longer be perceived as such (Figure II-11). Due to the difference in stereoconfiguration, opioids differ in their affinity (i.e. goodness of fit) at these binding sites (Figure II-18).

This explains why different opioids are characterized by a large variety in potency. In addition, opioids also differ in their intrinsic activity (i.e. the degree of conforma-tional change of the receptor site) resulting in different intracellular effects. Taken together affinity and intrinsic activity results in the efficacy of a drug within the system (Figure II-19).

Thus, binding properties are reflected in varying analgesic potencies. Contrary, the intensity of binding with the receptor site (i.e. the intensity with which the opioid adheres to the binding site) is reflected in the duration of effects (Table II-6 and Figure II-20)[32, 14, 33]. For instance opioid analgesics such as sufentanil or lofentanil have an exceptional goodness of fit to the opioid receptor site, which results in high potency. On the other hand, the low dissociation coefficient from the receptor of buprenorphine or lofentanil is characterized by a long duration of action, while the high association coefficient demonstrates increase of affinity to the binding site.

Contrary to agonists, antagonists are able to displace an opioid from its receptor binding site and take up his position. Displacement is only possible because the antagonist has a greater affinity to the binding site. Therefore, affinity of an opioid antagonist is expressed in its antagonistic potency. Naloxone or naltrexone have a very high affinity to the receptor and easily displace an opioid whereas levallorphan is five times weaker (Figure II-21). In order to induce a similar antagonistic effect, a higher dose of levallorphan is necessary.

Figure II-18. The relative affinity of different opioid ligands to the ^-receptor site as reflected in their amount to displace a radioactive ligand. It can be seen that ligands with high potency (i.e. lofentanil, carfentanil) clinically also show high affinity while opioids with an asterix reflect antagonistic property at the |-site

Figure II-18. The relative affinity of different opioid ligands to the ^-receptor site as reflected in their amount to displace a radioactive ligand. It can be seen that ligands with high potency (i.e. lofentanil, carfentanil) clinically also show high affinity while opioids with an asterix reflect antagonistic property at the |-site

In order to induce increasing effects with opioids, the goodness of fit not only is a prerequisite. Of additional importance is the conformational change the receptor undergoes after binding, which is expressed in the "the intrinsic activity". An opioid must, therefore, not only fit to the receptor; it must also induce a chain reaction in the transmembrane receptor domain resulting in a net effect (Figure II-19). The reaction after opioid binding seems to depend on the side chain of the molecule. Thus it appears that one portion of the opioid molecule provides the binding to the receptor whereas another portion is responsible for the induction of a conformational change (i.e. intrinsic activity), which will either be of agonistic or antagonistic nature. In a sensitive and specific opiate-receptor assay, the guinea pig ileum with its dense accumulation of receptor binding sites, it was possible to demonstrate receptor affinity and pharmacological efficacy (Figure II-22).

intrinsic activity

Property > of drug

Spw/ínns/íirtÑpfJ

n

>

Property ^ of drug

EfFECI

/ j

system

Figure 11-19. Schematic drawing illustrating affinity and intrinsic activity of a ligand, both of which are necessary to induce an effect

Figure 11-19. Schematic drawing illustrating affinity and intrinsic activity of a ligand, both of which are necessary to induce an effect

This assumption is underlined by the effects induced by "pure" opioid antagonists such as naloxone or naltrexone, which also have a good fit with the receptor site, however when given on their own do not induce an analgesic effect. For instance, if naloxone is given by itself, the compound does not induce effects similar to its parent compound oxymorphone (Figure II-14). Also, in contrast to a potent opioid like fentanyl, the antagonist naloxone has a lower dissociation coefficient resulting in a shorter duration of action, which may result in a reoccurrence of an opioid-like effects such as respiratory depression. However, due to its high

Table II-6. Relative values of affinity and duration of action of different opioids, when compared to morphine (= 1).

Morphine

Buprenorphine

Alfentanil

Fentanyl

Lofentanil

Association coefficient affinity

l

SO

l

lO

lOO

Dissociation coefficient (duration)

l

4

l/8

l/4

lO

Potency of analgesia

l

3O-4O

4O

l25

lOOO

Source: Adapted from [33, 34, 35]

xône Buprenorphine

Sufentanil

Naloxone

t 1

levor^hano

Pentazocine

Morphine i

Codeine *

Propoxyphene

Intrinsic Activity

Figure II-20. Difference in affinity and intrinsic activity of various opioids. Note, that codeine has a similar intrinsic activity as sufentanil. However, due to the higher affinity of the latter the net analgesic potency is much larger association coefficient (i.e. affinity), it induces a rapid displacement of the agonist and a reversal of all opioid effects.

On the other hand mixed agonist/antagonists, such as pentazocine, nalorphine, levallorphan, nalbuphine and butorphanol, demonstrate characteristics, which enable them to displace a pure agonist at the receptor site (antagonistic effect), but at the same time when administered by themselves, they induce opioid related effects such as analgesia and respiratory depression (agonistic effects; Table II-7). Such dual activity is only possible by means of their intrinsic activity at two distinct and different receptor sites: one the antagonistic activity at the and its agonistic action art the K-receptor site. And lastly, partial agonists like meptazinol and buprenorphine induce their analgesic potency via the ^-opioid receptor. Although having a high affinity, their analgesic ceiling effect at the higher dose range is due to a lesser intrinsic activity, resulting in a lesser net analgesic appearance than pure agonists. Such difference in the characteristic traits of opioids can be summarized as follows:

1. The affinity to the receptor (displacement properties or extrinsic activity)

2. The intensity of binding to the receptor (duration of effect)

3. The ability to change the conformation of the receptor (intrinsic activity)

4. The competitive potency (antagonism)

5. The degree of metabolism (duration of effect)

Figure II-21. The comparable degree of intrinsic and affinity of various opioids and their antagonists

Note the relatively high antagonistic potency of buprenorphine, however, is due to its high affinity to the receptor site resulting in the displacement of a ligand at the preoccupied receptor site.

Table 11-7. Relative potencies of different mixed agonists/antagonists and partial agonists when compared to morphine (a pure agonist) and naloxone (a pure antagonist)

Generic name

Trade name

Antagonistic potency

Agonistic potency

Morphine

Morphine

O

l

Naloxone

Narcane

l

O

Butorphanol

Stadol

0.025

ll

Nalbuphine

Nubain

O.4

O.8

Pentazocine

Talwin

O.O4

O.4

Meptazinol

Meptid

O.O2

O.25

Buprenorphine

Buprenex

O.5

30

Figure II-22. Close correlation between pharmacologic potency of various opioid agonists in the guinea pig ileum (i.e. ID50 the concentration required to inhibit the contraction of the intestine by 50%) and their affinity for the opiate receptor site in the same tissue (i.e. KD, the concentration required to inhibit 50% of stereospecific binding of radioactive labeled naloxone)

Figure II-22. Close correlation between pharmacologic potency of various opioid agonists in the guinea pig ileum (i.e. ID50 the concentration required to inhibit the contraction of the intestine by 50%) and their affinity for the opiate receptor site in the same tissue (i.e. KD, the concentration required to inhibit 50% of stereospecific binding of radioactive labeled naloxone)

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