Agonists Antagonists Their Potency And Mode Of Action

Based on their interactions with the various receptor subtypes, opioid compounds can be divided into agonist, agonist/antagonist, and antagonist classes (Table II-4).

By definition an agonist is a drug that has affinity for and binds to cell receptors to induce changes in the cell that stimulate physiological activity. The agonist opioid drugs have no clinically relevant ceiling effect to analgesia. As the dose is raised, analgesic effects increase in a log linear function, until either analgesia is achieved or dose-limiting adverse effects supervene. Efficacy is defined by the

Optical Isomers Morphine

Figure II-12. Generally opioids exist in optical isomers, which are a mirror image in the molecular form. Only the levorotatory (levo)-isomer, which in solution rotates plane-polarized light to the left, produces the characteristic analgesic effect of an agent. The dextrorotatory isomer is totally inactive. This sterospecificity of opiate action supports the concept of selective receptor binding to a site, which is able to distinguish in "handedness or goodness of fit" of an opioid molecule maximal response induced by administration of the active agent. In practice, this is determined by the degree of analgesia produced following dose escalation through a range limited by the development of adverse effects. Potency, in contrast, reflects the dose-response relationship.

Potency is influenced by pharmacokinetic factors (i.e. how much of the drug enters the body systemic circulation and then reaches the receptors) and by affinity to drug receptors. The concepts of efficacy and potency are illustrated in the following

Table II-4. Classification of opioid analgesics into agonists, agonist/antagonists, partial agonists and antagonist classes

Agonists

Antagonists

Agonist/antagonists

Partial agonists

Morphine Codeine Oxycodone Pethidine

Diamorphine (heroin)

Hydromorphone

Levorphanol

Methadone

Fentanyl

Sufentanil

Remifentanil

Tramadol

Dextropropoxyphene

Phenazocine

Dipipanone

Naloxone Naltrexone Nalmefene Diprenorphine

Nalorphine

Pentazocine

Nalbuphine

Butorphanol

Dezocine

Meptazinol Buprenorphine figure, which shows the dose-response curves for two drugs with a full agonistic and a partial agonistic action. If the logarithm of dose is plotted against response an agonist will produce an S-shaped or sigmoid curve. The efficacy of the two drugs, defined by maximum response is the same. The full agonist produces the same response as a partial agonist but at a lower dose, and therefore is described as more potent (Figure II-13).

An antagonist by definition is an agent that has no intrinsic pharmacological action but can interfere with the action of an agonist. Competitive antagonists bind to the same receptor and compete for receptor sites, whereas non-competitive antagonists block the effects of the agonist in some other way.

Contrary the mixed agonist/antagonists analgesics can, in turn, be subdivided into the mixed agonist/antagonists and the partial agonists, a distinction also based on specific patterns of drug-receptor interaction. Both the partial agonist and the agonist/antagonist drugs have a ceiling effect for analgesia, and although they produce analgesia in the opioid-naive patient, in theory they can precipitate withdrawal in patients who are physically dependent on morphine-like drugs. For these reasons, they have been considered generally to have a limited role in the management of patients with cancer pain.

The mixed agonist/antagonist drugs produce agonist effects at one receptor and antagonist effect at another. Pentazocine is the prototype agonist/antagonist: it has agonist effects at the k-receptors and weak to medium antagonistic action at the

Full Agonist

Images Respiratory Depression

Dose

Figure II-13. Typical dose-response curves of a full agonist, a partial agonist and an antagonist on opioid-related effects

^-receptor Thus in addition to analgesia, pentazocine may produce ^-mediated psychotomimetic effects not seen with full or partial agonists. When a mixed agonist/antagonist is administered together with an agonist, the antagonist effect at the ^-receptor can generate an acute withdrawal syndrome.

A partial agonist has low intrinsic activity (efficacy) so that its dose-response curve exhibits a ceiling effect at less than the maximum effect produced by a full agonist (Figure II-11). Buprenorphine is the main example of a partial agonist opioid. Increasing the dose of such a drug above its ceiling does not result in any further increase in response. This phenomenon is illustrated in the figure in which buprenorphine is the partial agonist. The full agonist is more potent than the partial agonist (in the lower part of the curve it will produce the same response at a lower dose), but is less effective than both coadministered ligands because of its ceiling effect.

When a partial agonist is administered together with an agonist, displacement of the agonist can cause a net reduction in pharmacological action, which may be sufficient to generate an acute withdrawal syndrome. While this is a theoretical possibility with morphine and buprenorphine, no such interaction has been reported clinically. Similarly, it has been suggested that the effects of morphine may be blocked in a patient switched from buprenorphine, because of the prolonged action of buprenorphine and the assumption that it will "antagonize" the effect of morphine. This has been one of the reasons, why buprenorphine has not been in cancer pain management. However, the recent development of a transdermal formulation of buprenorphine may encourage its use in chronic cancer pain (and chronic non-cancer pain). An analgesic ceiling with buprenorphine is only reached at doses of 8-16 mg or more in 24 h [22, 23]. When used in usual recommended doses (e.g., two patches of 70 ^g/h of transdermal buprenorphine, equivalent to 3-4 mg per 24 h) buprenorphine can be considered a full ^-agonist since at these doses its effect will lie on the linear part of the dose-response curve [24].

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