Morgan & Mikhail Chap 10(Analgesic Agents) Flashcards
Opioids
Mechanisms of Action
Opioids bind to specific receptors located throughout the central nervous system,
gastrointestinal tract, and other tissues. Three major opioid receptor types were first identified (Table 10–1): mu (μ, with subtypes μ1 and μ2), kappa (κ), and delta (δ).
Additional opioid receptors include nociceptin and the opioid growth factor receptor
(also known as OGFR or zeta).
Opioids inhibit voltage-gated
calcium channels and activate inwardly rectifying potassium channels. Opioid effects vary based on the duration of exposure, and opioid tolerance leads to changes in opioid responses.
Although opioids provide some degree of sedation and in some species can produce
general anesthesia when given in large doses, they are principally used to provide
analgesia.
Opioid receptor activation inhibits the presynaptic release and postsynaptic
response to excitatory neurotransmitters (eg, acetylcholine, substance P) released by nociceptive neurons. Transmission of pain impulses can be selectively modified at
the level of the dorsal horn of the spinal cord with intrathecal or epidural administration of opioids. Opioid receptors also respond to systemically administered opioids.
Modulation through a descending inhibitory pathway from the periaqueductal gray
matter to the dorsal horn of the spinal cord may also play a role in opioid analgesia.
Although opioids exert their greatest effect within the central nervous system, opioid receptors have also been identified on somatic and sympathetic peripheral nerves.
Certain opioid side effects (eg, constipation) are the result of opioid binding to receptors in peripheral tissues (eg, the gastrointestinal tract), and there are now selective antagonists for opioid actions outside the central nervous system (alvimopan and methylnaltrexone)
Pharmacokinetics: Opioids
A. Absorption
Rapid and complete absorption follows the intramuscular or subcutaneous injection of
hydromorphone, morphine, or meperidine, with peak plasma levels usually reached
after 20 to 60 min. A wide variety of opioids are effective by oral administration, including oxycodone, hydrocodone, codeine, tramadol, morphine, hydromorphone, and
methadone. Oral transmucosal fentanyl citrate absorption (fentanyl “lollipop”) provides rapid onset of analgesia and sedation in patients who are not good candidates for oral,
intravenous, or intramuscular dosing of opioids.
The low molecular weight and high lipid solubility of fentanyl also favor
transdermal absorption (the transdermal fentanyl “patch”). The amount of fentanyl absorbed per unit of time depends on the surface area of skin covered by the patch and also on local skin conditions (eg, blood flow).
Fentanyl is often administered in small doses (10–25 mcg) intrathecally with local anesthetics for spinal anesthesia and adds to the analgesia when included with local anesthetics in epidural infusions. Morphine in doses between 0.1 and 0.5 mg and
hydromorphone in doses between 0.05 and 0.2 mg provide 12 to 18 h of analgesia after intrathecal administration. Morphine, hydromorphone, and fentanyl are commonly
included in local anesthetic solutions infused for postoperative epidural analgesia.
B. Distribution
After intravenous administration, the distribution half-lives of the opioids are short (5–20 min). The low lipid solubility of morphine delays its passage across the blood–brain barrier, however, so its onset of action is slow, and its duration of action is prolonged. This contrasts with the increased lipid
solubility of fentanyl and sufentanil, which are associated with a faster onset and shorter duration of action when administered in small doses. Interestingly, alfentanil has a more rapid onset of action and shorter duration of action than fentanyl following a bolus
injection, even though it is less lipid soluble than fentanyl.
The time required for fentanyl or sufentanil concentrations to decrease by half (the “halftime”)
is context sensitive; the context-sensitive half-time increases as the total dose of
drug or duration of exposure, or both, increase
C. Biotransformation
With the exception of remifentanil, all opioids depend primarily on the liver for biotransformation. They are metabolized by the cytochrome P (CYP) system, conjugated in the liver, or both. Because of the high hepatic extraction ratio of opioids, their clearance depends on liver blood flow.
Codeine is a prodrug that becomes active after it is metabolized by CYP2D6 to
morphine.
The ester structure of remifentanil makes it susceptible to hydrolysis (in a manner similar to esmolol) by nonspecific esterases in red blood cells and tissue (see Figure 10–1), yielding a terminal elimination half-life of less than 10 min. Remifentanil biotransformation is rapid, and the duration of a remifentanil infusion has little effect on
wake-up time (Figure 10–2). The half-time of remifentanil remains approximately 3 min
regardless of the dose or duration of infusion.
D. Excretion
The end products of morphine and meperidine biotransformation are eliminated by
the kidneys, with less than 10% undergoing biliary excretion. Because 5% to 10% of morphine is excreted unchanged in the urine, kidney failure prolongs morphine duration of action. The accumulation of morphine metabolites (morphine 3-glucuronide and morphine 6-glucuronide) in patients with kidney failure has been associated with
prolonged narcosis and ventilatory depression. In fact, morphine 6-glucuronide is a
more potent and longer-lasting opioid agonist than morphine.
Effects on Organ Systems: Opioids (Cardio and Respiratory)
A. Cardiovascular
In general, opioids have minimal direct effects on the heart. Meperidine tends to
increase heart rate (it is structurally similar to atropine and was originally synthesized as an atropine replacement), whereas larger doses of morphine, fentanyl, sufentanil, remifentanil, and alfentanil are associated with a vagus nerve–mediated bradycardia.
Opioids do not depress cardiac contractility, provided they are administered alone
(which is almost never the case in surgical anesthetic settings). Nonetheless, arterial blood pressure often falls as a result of opioid-induced bradycardia, venodilation, and
decreased sympathetic reflexes. The inherent cardiac stability provided by opioids is greatly diminished in practice when other anesthetic drugs, including benzodiazepines, propofol, or volatile agents, are added.
Effects on Organ Systems: Opioids (Cerebral, Gastro, Endocrine)
C. Cerebral
The effects of opioids on cerebral perfusion and intracranial pressure must be separated from any effects of opioids on Paco2. In general, opioids reduce cerebral oxygen consumption, cerebral blood flow, cerebral blood volume, and intracranial pressure but
to a much lesser extent than propofol, benzodiazepines, or barbiturates, provided
normocarbia is maintained by artificial ventilation.
Stimulation of the medullary chemoreceptor trigger zone is responsible for
opioid-induced nausea and vomiting. Curiously, nausea and vomiting are more common following smaller (analgesic) than very large (anesthetic) doses of opioids. Repeated dosing of opioids (eg, prolonged oral dosing) will reliably produce tolerance, a phenomenon in which progressively larger doses are required to produce the same
response. This is not the same as physical dependence or addiction, which may also be associated with repeated opioid administration. Prolonged dosing of opioids can also produce “opioid-induced hyperalgesia,” in which patients become more sensitive to painful stimuli. Infusion of large doses of (in particular) remifentanil during general anesthesia can produce acute tolerance, in which much larger than usual doses of opioids will be required for immediate, postoperative analgesia. Relatively large doses
of opioids are required to render patients unconscious (Table 10–3). However, even at very large doses opioids will not reliably produce amnesia. The use of opioids in epidural and intrathecal spaces has revolutionized acute and chronic pain management
Unique among the commonly used opioids, meperidine has minor local anesthetic
qualities, particularly when administered into the subarachnoid space. Meperidine’s clinical use as a local anesthetic has been limited by its relatively low potency and propensity to cause typical opioid side effects (nausea, sedation, pruritus) at the doses
required to induce local anesthesia. Intravenous meperidine (10–25 mg) is more effective than morphine or fentanyl for decreasing shivering in the postanesthetic care unit, and meperidine appears to be the best agent for this indication.
Uses and Doses of Opioids
Opioid Drue Interactions
Cyclooxygenase Inhibitors
Mechanisms of Action
Many over-the-counter nonsteroidal anti-inflammatory agents (NSAIDs) work through
inhibition of cyclooxygenase (COX), the key step in prostaglandin synthesis. COX
catalyzes the production of prostaglandin H1 from arachidonic acid. The two forms of the enzyme, COX-1 and COX-2, have differing distributions in tissue. COX-1 receptors are widely distributed throughout the body, including the gut and platelets. COX-2 is produced in response to inflammation
COX-1 and COX-2 enzymes differ further in the size of their binding sites: the
COX-2 site can accommodate larger molecules that are restricted from binding at the
COX-1 site. This distinction is in part responsible for selective COX-2 inhibition.
Agents that inhibit COX nonselectively (eg, ibuprofen) will control fever, inflammation, pain, and thrombosis. COX-2 selective agents (eg, celecoxib, etoricoxib) can be used
perioperatively without concerns about platelet inhibition or gastrointestinal upset.
Curiously, while COX-1 inhibition decreases thrombosis, selective COX-2 inhibition increases the risk of myocardial infarction, thrombosis, and stroke. All NSAIDs except low-dose aspirin increase the risk of stroke or myocardial infarction. Acetaminophen
inhibits COX in the brain without binding to the active site of the enzyme (unlike
NSAIDs) to produce its antipyretic activities. Acetaminophen analgesia may result from modulation of the endogenous cannabinoid vanilloid receptor systems in the brain, but the actual mechanism of action remains speculative. Acetaminophen has no major
effects on COX outside the brain.
Pharmacokinetics: COX
Effects on Organ Systems: COX
Gabapentin and Pregabalin
