Fig. 12.1
Chemical structures of select opioid agonists and antagonist (naloxone)
Pharmacokinetics
Pharmacokinetics includes the processes of absorption, distribution, metabolism, and excretion. With respect to opioids, these processes characterize the concentration of administered opioid that reaches its receptor action sites with time. Opioid pharmacokinetics are primarily influenced by several variables including the route of administration, protein binding, pK a, and lipid solubility.
Route of Administration
Opioid absorption varies with route of administration. When given orally, the majority of morphine derivatives display reduced bioavailability as a result of significant first-pass metabolism within the liver. Indeed, the bioavailability of oral morphine has been shown to vary between 35 and 75 %. To avoid the first-pass effect as well as variable gastrointestinal (GI) absorption, opioids are most often clinically administered intravenously (IV) during the perioperative period. Parenteral opioid utilization also provides a more rapid attainment of peak plasma concentration and subsequent physiologic effects.
Protein Binding
Opioids circulate as a variable fraction bound to plasma proteins, which are primarily albumin and alpha1-acid glycoprotein (AAG). The unbound or free fraction of opioid is proportional to its volume of distribution, whereby the free form is able to traverse biologic membranes into peripheral tissues. Opioid-protein binding is also pH dependent so that reduced pH results in decreased binding and greater free fraction to interact with opioid receptors. The importance of opioid-protein binding may be seen clinically with the inherently decreased AAG concentrations found in newborns and infants, with subsequent rise in opioid free fraction, resulting in lower dosing thresholds for both anesthesia as well as respiratory depression. In contrast, elevated AAG levels occur in a variety of pathophysiologic states including burn injuries, trauma infection, the postoperative period, and other inflammatory states.
pK a
In order to gain access to their central nervous system (CNS) receptor sites, opioids must traverse biologic lipid membranes, most notably the blood–brain barrier. This property is heavily dependent on their degree of ionization and lipid solubility. Opioids may be classified as weak bases with pK a values typically greater than 7.4, excluding alfentanil and remifentanil, which possesses pK a values of ~6.5 and ~7.07, respectively. Thus, the majority of opioids compounds remain in the charged or ionized state at physiologic pH, leaving a minority in the uncharged state with ability to penetrate the CNS.
Lipophilicity
The lipophilicity of opioids may also be quantified numerically via the octanol–buffer partition coefficient, wherein a greater value signifies greater hydrophobicity of the drug and consequently increased distribution and membrane permeability. For example, morphine possesses an octanol–buffer partition coefficient 1, while that of fentanyl is 955. These physicochemical properties are evident clinically in that morphine administration has been shown to result in a much slower time-to-peak effect (20 min) in comparison to fentanyl (3–4 min) or its analogues, alfentanil and remifentanil (within 2 min).
Elimination
The elimination of opioids primarily occurs via enzymatic metabolism within the liver. This biotransformation produces hydrophilic rather than lipophilic compounds ultimately suitable for renal excretion. The necessary metabolic reactions may be subdivided into phase 1, oxidative or hydrolytic reactions via the liver’s cytochrome P450 (CYP) pathway, and phase 2, conjugation reactions, namely, glucuronidation via uridine diphosphate glucuronosyltransferase (UGT). The majority of opioids undergo CYP enzymatic metabolism with notable exceptions including the glucuronidation of morphine and hydromorphone. Because the CYP pathway is ubiquitous in drug metabolism, opioids metabolized by these means are potentially subject to changes in clearance by other coadministered medications that either induce or inhibit the CYP3A4.
Opioid plasma half-life values vary from minutes to hours (Table 12.1). In contrast to its relatively brief onset and duration of effect, an opioid such as fentanyl displays a relatively long plasma half-life due to its high lipophilicity causing significant redistribution into peripheral tissues. These tissues in turn may serve as a depot or reservoir, allowing the drug to slowly reenter the circulation. Duration of action of intravenous anesthetics has historically been related to the elimination half-life. This method does not accurately account for the effect of redistribution to the central plasma compartment during continuous anesthetic infusions. Thus, Hughes et al. defined the context-sensitive half-time as the time required for the plasma drug concentration to decrease by half after infusion discontinuation. The “context” therefore represents the total infusion time.
Table 12.1
Characteristics of select opioid agonists
Opioid agonist | Bolus dose (IV) | Peak effect | Plasma half-life | Context-sensitive half-time (3 h infusion) |
|---|---|---|---|---|
Morphine | 0.02–0.05 mg/kg | 30 min | 3–4 h | |
Hydromorphone | 0.002–0.005 mg/kg | 15 min | 2–4 h | |
Methadone | 0.02–0.05 mg/kg | 20 min | >24 h | |
Meperidine | 0.25–0.5 mg/kg | 7 min | 2–4 h | |
Fentanyl | 0.5–1 mcg/kg | 3 min | 1 h | 2 h |
Sufentanil | 0.1–0.2 mcg/kg | 3 min | 1 h | <0.5 h |
Alfentanil | 5–15 mcg/kg | 2 min | 15 min | 1 h |
Remifentanil | 0.1–0.3 mcg/kg | 1.5 min | 10 min |
Pharmacodynamics
Opioid pharmacodynamics encompasses their mechanism of action through the binding of opioid receptors in order to produce biochemical and physiologic effects. Evidence supporting the notion of multiple opioid receptor subtypes stems from radiolabeling and physiologic studies performed during the 1970s. Four principal classes of opioid receptors have ultimately been confirmed via molecular cloning, including the MOP, or mu-opioid receptor (μ); DOP, or delta-opioid receptor (δ); KOP, or kappa-opioid receptor (κ); and, most recently, NOP, or nociceptin/orphanin FQ receptor (ORL-1).
The activation of specific opioid receptor subtypes has been shown to produce a variety of physiologic and behavioral effects (Table 12.2). Perhaps the best known effect is that of analgesia, which is predominantly produced by activation of opioid MOP receptors. In addition to analgesia, MOP receptor activation also may result in unwanted effects including respiratory depression and dependence (see side effects).
The mechanism by which opioids produce analgesia resides in their inhibitory influence on neuronal pain pathways. Opioid agonists bind their corresponding opioid receptors located on the presynaptic terminals of nociceptive Aδ- and C-fibers within the spinal cord. This opioid-GPCR interaction results in the characteristic inhibition of the adenylyl cyclase enzyme responsible for the conversion of adenosine triphosphate (ADP) to cAMP. Reduced intracellular cAMP concentrations subsequently lead to the inhibition of voltage-gated calcium channels, thereby preventing the release of pronociceptive neurotransmitters, including substance P, gamma-aminobutyric acid (GABA), and calcitonin gene-related peptide (CGRP). Opioid agonists also produce analgesia supraspinally by impeding the release of inhibitory neurotransmitter GABA within the brain’s periaqueductal gray (PAG) matter region. This inhibition of GABA subsequently disinhibits the release of norepinephrine (NE) and serotonin (5-HT) to the spinal posterior (dorsal) horn, which in turn blunts afferent nociceptive pathways.
Table 12.2
Physiologic effects of the opioid receptor subtypes
Effect | Receptor | |||
|---|---|---|---|---|
MOP (μ) | DOP (δ) | KOP (κ) | NOP (ORL1) | |
Analgesia | +++ | ++ | ++ | − |
Sedation | ++ | − | ++ | − |
Respiratory depression | +++ | ++ | − | − |
Decreased gastrointestinal motility | ++ | ++ | + | − |
Euphoria | +++ | − | − | − |
Dissociative and deliriant effects | − | − | +++ | − |
Miosis | ++ | − | − | − |
Pharmacogenetics
Clinical opioid dosing has been shown to vary by as much as 40 %, and a portion of this variability is thought to occur as a result of genetic differences affecting opioid pharmacokinetics and pharmacodynamics. One allelic disparity may be seen in the CYP2D6 enzyme responsible for codeine metabolism, wherein individuals with poor enzyme activity possess reduced codeine efficacy as a result of decreased codeine metabolism to morphine. Similarly, single-nucleotide polymorphisms in the OPRM1 gene responsible for the opioid mu-receptor protein have been associated with significantly increased opioid requirements as well as decreased opioid-induced miosis and respiratory depression. Pharmacogenetics provides a continued area of interest in Anesthesia-related research in hopes of providing insight into the heterogeneity of patient responsiveness and effective opioid therapy.
Indications and Usage
The anatomical distribution of opioid receptors has been localized to the brain and spinal cord of the CNS as well as throughout nerves innervating peripheral tissues. Opioid receptor activation at these sites has been shown to elucidate an array of physiologic and behavioral effects, many of which have been harnessed for patient benefit in the perioperative period.
Analgesia
Opioids are often administered to provide analgesia for both acute and chronic pain states. These effects are mediated through direct inhibition of nociceptive pathways as well as attenuation of pain perception, likely through the sense of euphoria and sedating effects. Morphine and related opioid compounds selectively block nociception while sparing the somatosensory discrimination of proprioception, light touch, and temperature change. An important feature of opioid analgesia is that opioids are more effective in relieving continuous, dull quality pain often accompanying tissue injury and inflammation, rather than sharp, intermittent, or neuropathic pain.
When administered with analgesic dosing, opioids have proven clinically relevant in conjunction with the inhalational maintenance of anesthesia by significantly reducing the minimum alveolar concentration (MAC). When combined with sevoflurane, fentanyl has also been demonstrated to reduce the MAC associated with blocking the adrenergic response to surgical incision and laryngoscopy with tracheal intubation.
Sedation and Anxiolysis
Opioids have been shown to produce drowsiness and cognitive impairment. These effects may be amplified by concomitant use of other anxiolytics such as benzodiazepines. The involved areas of the brain are thought to be similar to those affected by known sedative–hypnotic class medications such as propofol and the benzodiazepine midazolam, as brain imaging has revealed these areas show a similar decrease in signaling after morphine administration. Additionally, these sleep-inducing and anxiolytic effects assist analgesic properties by decreasing attention to noxious stimuli.
Potent opioids such as fentanyl and its derivatives are often used as anesthetic adjuncts, reducing the required concentrations of volatile anesthetics needed for general anesthesia. However, if opioids are utilized as a primary anesthetic, the additional need for unconsciousness and amnesia must be addressed. These aspects of a complete general anesthetic may be supplied with the coadministration of a benzodiazepine or element of volatile agent.
Respiratory Depression
Equianalgesic doses of opioids cause similar respiratory depression by binding to MOP and DOP receptors within the medulla. The depressant mechanism on medulla is twofold, involving inhibition of respiratory rhythm and hence rate and reduced sensitivity of medullary chemoreceptors to carbon dioxide. Typical analgesic doses of opioids are sufficient to produce increased PaCO2 levels. Although respiratory depression may be the greatest safety concern involving opioids, this effect may be employed therapeutically in certain instances. For example, opioid administration may be used to treat subjective dyspnea or “air hunger,” resulting in agitation, seen in chronic pulmonary disease and congestive heart failure, or to depress the spontaneous rate in patients receiving mechanical ventilation. As with sedation, the concomitant use of anxiolytics such as benzodiazepines acts synergistically in depressing respiration.
Cardiovascular Stability
Opioids given in typical therapeutic doses generally do not compromise hemodynamic stability, which allows their use during times when cardiac demand poses a concern. High doses of opioids, such as those used for anesthetic induction, are known to cause reproducible bradycardia. Animal studies using fentanyl suggest that MOP receptor action within the nucleus ambiguous of the medulla decreases the inhibitory effect of GABA on cardiac vagal tone, thereby disinhibiting the parasympathetic reduction in heart rate. This decrease in heart rate coupled with the reduction in preload and inotropy has allowed morphine to be a well-established therapy in reducing myocardial oxygen consumption in acute myocardial infarction and providing symptom relief from angina.
Cough Reflex Suppression
Most opioids possess antitussive properties, blunting the cough reflex possibly through a mechanism of inhibition of the cough center within the medulla.
Miosis
Pupillary constriction has been long recognized as a diagnostic clinical finding of opioid exposure independent of tolerance. This phenomenon has proven clinically relevant in the diagnosis of opioid intoxication because other causes of sedation or respiratory depression typically result in mydriasis. The mechanism of opioid-induced miosis stems from the disinhibition of the Edinger–Westphal nucleus, allowing the parasympathetic ciliary ganglion to subsequently activate pupillary constriction.
Side Effects and Toxicity
Despite their many effective clinical uses, the administration of opioids may result in a number of profound side effects. Many opioid-induced side effects have been attributed to specific receptor subtypes (Table 12.2). The central and peripheral receptor distribution often corresponds with their observed toxicity, including respiratory depression and reduced GI motility, respectively. Additional caution should be implemented in patients with known hepatic or renal insufficiency, as found with advanced age, because these disease states may exacerbate opioid toxicity through impaired metabolism and clearance, respectively.
Respiratory Depression
Respiratory depression remains the leading cause of mortality in acute opioid toxicity. Therapeutic doses of opioids are sufficient to cause respiratory depression with a characteristic decrease in respiratory rate that may also exhibit irregular rhythm. In addition, higher doses may cause reduced tidal volumes and decreased pulmonary compliance by affecting neuronal input to the upper airway, chest, diaphragm, and accessory muscles.
This dose-dependent respiratory depression may be worsened by a number of clinical factors including coadministered medications such as benzodiazepines, bimodal extremes of age, decreased stimulation with sleep or analgesia, and disease states resulting in lung dysfunction or reduced responsiveness to elevated PaCO2. Furthermore, because opioids reduce the sensitivity of medullary chemoreceptors to elevated PaCO2, oxygen therapy during this time may lead to precipitous apnea by eliminating the hypoxia serving as the sole respiratory driving force. Obstructive sleep apnea has been shown to be a significant risk factor for respiratory depression in patients receiving opioids.
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