Chapter 7 Opioids
Pharmacokinetics
7. What are the potency, time of onset, and duration of action of opioids dependent on? How rapid is the effect-site equilibration time of morphine relative to the other opioids?
8. What is the latency time to peak effect of opioids (i.e., bolus front-end kinetics) after a bolus injection?
9. How is the time to steady-state concentration after starting a continuous infusion defined and measured? How is remifentanil different from other opioids when used as a continuous infusion?
10. What is context-sensitive half-time (CSHT)? What are some clinical implications of the CSHT?
Pharmacodynamics
Adverse effects
12. What are the effects of opioids on the cardiovascular system?
13. What are the effects of opioids on ventilation?
14. What are the effects of opioids on the central nervous system?
15. What are the effects of opioids on the thoracoabdominal muscles? How can they be treated?
16. What are the effects of opioids on the gastrointestinal system?
17. What are the effects of opioids on the genitourinary system?
18. What is the mechanism by which opioids are thought to cause nausea and vomiting?
Special populations
Unique features of individual opioids
27. How does the onset time of morphine compare with the other opioids? What are some potential drawbacks of the administration of morphine?
28. How does fentanyl compare with morphine with regard to its effect-site equilibration time? What is the potency of fentanyl relative to morphine?
29. What are some routes for the administration of fentanyl?
30. How are the effects of fentanyl terminated? How does the context-sensitive half-time of fentanyl compare with other opioids?
31. What are some systemic clinical effects associated with the administration of fentanyl?
32. What are some clinical uses of fentanyl in anesthesia practice?
33. How does sufentanil compare with the other opioids with respect to its effect-site equilibration time and its context-sensitive half-time?
34. What is the potency of sufentanil relative to morphine?
35. What are some systemic clinical effects associated with the administration of sufentanil?
36. How does alfentanil compare with the other opioids with respect to its effect-site equilibration time and its context-sensitive half-time?
37. What are some clinical uses of alfentanil?
38. How does remifentanil compare with the other opioids with respect to its effect-site equilibration time and its context-sensitive half-time?
39. What is the potency of remifentanil relative to morphine?
Answers*
Structure activity relationships
1. Opioids that are commonly used in anesthesia practice include morphine, meperidine, fentanyl, sufentanil, alfentanil, and remifentanil. The only clinically significant opioids that occur naturally and are derived from the poppy plant are papaverine, codeine, and morphine. Papaverine lacks any opioid activity. Morphine is considered the prototype opioid with which all other opioids are compared. (115, Figure 10-1)
Mechanism of action
2. Opioids exert their effects through their agonist actions at the opioid receptors. Opioids bind to the opioid receptors in the ionized state. After an opioid binds to a receptor, there are at least two mechanisms by which opioids alter the activity of the cell. The main action of opioids appears to be through the interaction with G-proteins, resulting in inhibition of the activity of adenylate cyclase and increasing potassium conductance. This ultimately results in hyperpolarization of the cell and leads to a suppression of synaptic transmission. The second mechanism by which opioids may produce their effect is through the interference of calcium ion intracellular transport in the presynaptic cells. This results in interference with the release of neurotransmitters from the presynaptic cell and again suppresses synaptic transmission. Neurotransmitters that are affected by this mechanism of action of opioids include acetylcholine, dopamine, norepinephrine, and substance P. (116, Figure 10-2)
3. Opioid receptors are located in various tissues throughout the central nervous system and exert their therapeutic effects at multiple sites. They inhibit the release of substance P from primary sensory neurons in the dorsal horn of the spinal cord, mitigating the transfer of painful sensations to the brain (spinal analgesia). Opioid actions in the brainstem modulate nociceptive transmission in the dorsal horn of the spinal cord through descending inhibitory pathways. Opioids probably change the affective response to pain through actions in the forebrain (supraspinal analgesia). Three classical opioid receptors have been identified: μ, κ, and δ. More recently, a fourth opioid receptor, ORL1 (also known as NOP), has also been identified, but its function is quite different from that of the classical opioid receptors. Although the existence of opioid receptor subtypes (e.g., μ1, μ2, etc.) has been proposed, it is not clear from molecular biology techniques that distinct genes code for them. The responses evoked by opioid agonists at the μ receptor include spinal and supraspinal analgesia, ventilatory depression, gastrointestinal effects (nausea, vomiting, and ileus), and sedation. The responses evoked by agonists at the delta receptor include the modulation of the μ receptor. The responses evoked by agonists at the κ receptor were almost the same as the μ receptor but lacked any ventilatory depression effect. (116-117, Table 10-2)
4. Endorphins and enkephalins are endogenous neurotransmitters that normally bind to and activate opioid receptors. (Table 10-2)
Metabolism
5. Opioids are transformed and excreted by different metabolic pathways. Codeine is a prodrug and its metabolite, morphine, is the active compound. Codeine is partly metabolized by O-demethylation into morphine, a metabolic process mediated by the liver microsomal isoform CYP2D6. Genetic variation in the metabolic pathway of codeine can drastically alter its clinical effects. Patients who lack CYP2D6 because of deletions, frame shift, or splice mutations (i.e., approximately 10% of the white population) or whose CYP2D6 is inhibited (e.g., patients taking quinidine) do not benefit from codeine even though they exhibit a normal response to morphine.
Morphine is metabolized by hepatic conjugation and subsequent excretion by the kidney. Morphine has a high hepatic extraction ratio (first pass effect), when administered orally, which decreases its effect significantly than when injected intravenously. The hepatic first pass effect of orally administered morphine also results in high morphine-6-glucuronide levels.
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