Fentanyl
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Mechanism of action
Fentanyl binds to opioid receptors, especially the mu opioid receptor, which are coupled to G-proteins. Activation of opioid receptors causes GTP to be exchanged for GDP on the G-proteins which in turn down regulates adenylate cyclase, reducing concentrations of cAMP. Reduced cAMP decreases cAMP dependant influx of calcium ions into the cell. The exchange of GTP for GDP results in hyperpolarization of the cell and inhibition of nerve activity.
The aim of the present study was to describe the activity of a set of opioid drugs, including partial agonists, in a cell system expressing only mu opioid receptors. Receptor activation was assessed by measuring the inhibition of forskolin-stimulated cyclic adenosine mono phosphate (cAMP) production. Efficacies and potencies of these ligands were determined relative to the endogenous ligand beta-endorphin and the common mu agonist, morphine. Among the ligands studied naltrexone, WIN 44,441 and SKF 10047, were classified as antagonists, while the remaining ligands were agonists. Agonist efficacy was assessed by determining the extent of inhibition of forskolin-stimulated cAMP production. The rank order of efficacy of the agonists was fentanyl = hydromorphone = beta-endorphin > etorphine = lofentanil = butorphanol = morphine = nalbuphine = nalorphine > cyclazocine = dezocine = metazocine >or= xorphanol. The rank order of potency of these ligands was different from that of their efficacies; etorphine > hydromorphone > dezocine > xorphanol = nalorphine = butorphanol = lofentanil > metazocine > nalbuphine > cyclazocine > fentanyl > morphine >>>> beta-endorphin. These results elucidate the relative activities of a set of opioid ligands at mu opioid receptor and can serve as the initial step in a systematic study leading to understanding of the mode of action of opioid ligands at this receptor. Furthermore, these results can assist in understanding the physiological effect of many opioid ligands acting through mu opioid receptors.
Diabetic neuropathy is one of the most frequent complications of diabetes mellitus. Therefore, the present study was designed to investigate the anti-hyperalgesic mechanism of fentanyl in a mouse model of streptozotocin-induced diabetic neuropathy. The antinociceptive response was assessed by recording the latency in a tail-flick test. The tail-flick latency in diabetic mice was significantly shorter than that in non-diabetic mice. Fentanyl, at doses of 3 and 10 ug/kg, s.c., produced a dose-dependent increase in the tail-flick latencies in diabetic mice. While fentanyl (3 ug/kg, s.c.) did not produce a significant inhibition of the tail-flick response in non-diabetic mice, it significantly prolonged the tail-flick latency in diabetic mice to the same level as the baseline latency in non-diabetic mice. Although pretreatment with naloxone (3 mg/kg, s.c.) completely antagonized fentanyl-induced antinociception in non-diabetic mice, it had no effect on the antinociceptive effect of fentanyl in diabetic mice. Pretreatment with either of the voltage-gated sodium channel openers fenvarelarte and veratridine practically abolished the antinociceptive effects of fentanyl in diabetic mice. However, neither fenvarelate nor veratridine affected the antinociceptive effect of fentanyl in non-diabetic mice. These results suggest that the anti-hyperalgesic effect of fentanyl is mediated through the blockade of sodium channels in diabetic mice, whereas opioid receptors mediate the antinociceptive effect of fentanyl in non-diabetic mice.
Tolerance to opioids frequently follows repeated drug administration and affects the clinical utility of these analgesics. Studies in simple cellular systems have demonstrated that prolonged activation of opioid receptors produces homologous receptor desensitization by G-protein receptor kinase mediated receptor phosphorylation and subsequent beta-arrestin binding. To define the role of this regulatory mechanism in the control of the electrophysiological and behavioral responses to opioids, we used mice having a targeted disruption of the G-protein receptor kinase 3 (GRK3) gene. Mice lacking GRK3 did not differ from wild-type littermates neither in their response latencies to noxious stimuli on the hot-plate test nor in their acute antinociceptive responses to fentanyl or morphine. Tolerance to the electrophysiological response to the opioid fentanyl, measured in vitro in the hippocampus, was blocked by GRK3 deletion. In addition, tolerance to the antinociceptive effects of fentanyl was significantly reduced in GRK3 knockouts compared to wild-type littermate controls. Tolerance to the antinociceptive effects of morphine was not affected by GRK3 deletion although morphine tolerance in hippocampal slices from GRK3 knockout mice was significantly inhibited. Tolerance developed more slowly in vitro to morphine than fentanyl supporting previous work in in vitro systems showing a correlation between agonist efficacy and GRK3-mediated desensitization. The results of these studies suggest that GRK3-mediated mechanisms are important components of both electrophysiologic and behavioral opioid tolerance. Fentanyl, a high efficacy opioid, more effectively produced GRK3-dependent effects than morphine, a low efficacy agonist.
G protein-coupled receptor desensitization is typically mediated by receptor phosphorylation by G protein-coupled receptor kinase (GRK) and subsequent arrestin binding; morphine, however, was previously found to activate a c-Jun N-terminal kinase (JNK)-dependent, GRK/arrestin-independent pathway to produce mu opioid receptor (MOR) inactivation in spinally-mediated, acute anti-nociceptive responses. In the current study, we determined that JNK2 was also required for centrally-mediated analgesic tolerance to morphine using the hotplate assay. We compared JNK activation by morphine and fentanyl in JNK1(-/-), JNK2(-/-), JNK3(-/-), and GRK3(-/-) mice and found that both compounds specifically activate JNK2 in vivo; however, fentanyl activation of JNK2 was GRK3-dependent, whereas morphine activation of JNK2 was GRK3-independent. In MOR-GFP expressing HEK293 cells, treatment with either arrestin siRNA, the Src family kinase inhibitor PP2, or the protein kinase C (PKC) inhibitor Go6976 indicated that morphine activated JNK2 through an arrestin-independent Src- and PKC-dependent mechanism, whereas fentanyl activated JNK2 through a Src-GRK3/arrestin-2-dependent and PKC-independent mechanism. This study resolves distinct ligand-directed mechanisms of JNK activation by mu opioid agonists and understanding ligand-directed signaling at MOR may improve opioid therapeutics.
Opioids are the most effective and widely used drugs in the treatment of severe acute and chronic pain. They act through opioid receptors that belong to the family of G protein-coupled receptors. Three classes of opioid receptors (mu, delta, kappa), expressed in the central and peripheral nervous system, have been identified. The analgesic effect of opioids is mediated through multiple pathways of opioid receptor signaling (e.g., G(i/o) coupling, cAMP inhibition, Ca(++) channel inhibition). The standard exogenous opioid analgesics used in the operating room are fentanyl, sufentanil, morphine, alfentanil, and remifentanil.
Pharmacodynamics
Fentanyl produces strong analgesia through its activation of opioid receptors. It has a duration of action of several hours and a wider therapeutic index as patients develop tolerance to opioids. Fentanyl is associated with a risk of addiction and abuse and should not be mixed with alcohol or benzodiazepines.
Pharmacokinetics
Half-life
The half life of fentanyl is 7 hours. The half life of fentanyl sublingual spray is 5-12 hours.
Fentanyl kinetics were studied in patients with cirrhosis and in patients with normal hepatic and renal function undergoing surgery under general anaesthesia, the latter group served as the controls. Plasma fentanyl concentrations declined bi-exponentially in the controls with an average elimination half-life (T1/2 beta) of 263 min; total plasma clearance (Cl) as 10.8 mL/kg/min, and total apparent volume of distribution (V beta) 3.81 L/kg. No significant change was observed in patients with cirrhosis: T1/2 beta was 304 min, Cl 11.3 mL/kg/min and V beta 4.41 L/kg. These data suggest that the elimination half-life of fentanyl is not primarily influenced by the rate at which it is metabolized in the liver.
Fentanyl was administered intravenously and transdermally to eight surgical patients to determine the systemic bioavailability and rate of absorption of the transdermally administered drug. Serum fentanyl concentrations reached a plateau approximately 14 hr after placement of the transdermal fentanyl delivery system. This plateau was maintained until removal of the system at 24 hr. The decline in serum fentanyl concentrations after removal of the transdermal system had a terminal half-life of 17.0 +/- 2.3 hr (mean +/- SD), considerably longer than the terminal elimination half-life seen after intravenous administration of fentanyl in the same patients (6.1 +/- 2.0 hr). ...
... In order to determine the bioavailability and absorption of fentanyl from OTFC, 12 volunteers were given intravenous fentanyl citrate or OTFC 15 ug/kg on each of two occasions. On a third occasion, the authors assessed oral administration (gastrointestinal absorption) by giving eight of the same volunteers the same dose of a solution of fentanyl citrate to swallow. In each study, arterial blood samples were taken over 24 hr for analysis of plasma fentanyl. After intravenous (iv) administration of fentanyl ... the terminal elimination half-life was 425 +/- 102 min. ...
Following IV administration of fentanyl citrate in healthy individuals, the estimated initial distribution half-life was about 6 minutes, the second distribution half-life was about 1 hour, and the terminal half-life was about 16 hours.
Studies of IV fentanyl suggest that clearance of the drug may be decreased and half-life increased in geriatric patients. Although the pharmacokinetic profile of fentanyl in healthy Caucasian adults 65 years of age or older (mean age: 71 years) generally was similar to that in adults 18-45 years of age following application of a fentanyl transdermal system labeled as delivering 100 ug/hour for 72 hours, the mean half-life of the drug was longer in geriatric individuals compared with younger adults (34.4 versus 23.5 hours).
Absorption
Fentanyl sublingual tablets are 54% bioavailable, transmucosal lozenges are 50% bioavailable, buccal tablets are 65% bioavailable, sublingual spray is 76% bioavailable, and nasal spray is 20% more bioavailable than transmucosal (or approximately 64% bioavailable). Fentanyl transmucosal lozenges reach a Cmax of 0.4±0.1ng/mL for a 200µg dose and 2.5±0.6ng/mL for a 1600µg dose with a Tmax of 20-40 minutes. The AUC was 172±96ng\*min/mL for a 200µg dose and 1508±1360ng\*min/mL for a 1600µg dose. Fentanyl sublingual spray reached a Cmax of 0.20±0.06ng/mL for a 100µg dose and 1.61±0.60ng/mL for an 800µg dose with a Tmax of 0.69-1.25 hours, decreasing as the dose increased. The AUC was 1.25±0.67ng\*h/mL for a 100µg dose and 10.38±3.70ng\*h/mL for a 800µg dose. Fentanyl transdermal systems reached a Cmax of 0.24±0.20ng/mL with a Tmax of 3.6±1.3h for a 25µg/h dose. The AUC was 0.42±0.35ng/mL\*h. Fentanyl nasal spray reaches a Cmax of 815±301pg/mL with a Tmax of less than 1 hour for a 200µg/100µL dose. The AUC was 3772pg\*h/mL.
Within 72 hours, 75% of a dose of fentanyl is excreted in the urine with <7% unchanged, and 9% is excreted in the feces with <1% unchanged.
The intravenous volume of distribution is 4L/kg (3-8L/kg). The oral volume of distribution is 25.4L/kg. In hepatically impaired patients, the intravenous volume of distribution ranges from 0.8-8L/kg. Fentanyl crosses the blood brain barrier and the placenta.
Total plasma clearance of fentanyl is 0.5L/hr/kg (0.3-0.7L/hr/kg) or 42L/hr. Following an intravenous dose, surgical patients displayed a clearance of 27-75L/h, hepatically impaired patients displayed a clearance of 3-80L/h, and renally impaired patients displayed a clearance of 30-78L/h.
Because release of fentanyl from fentanyl transdermal systems and percutaneous permeability of the drug are temperature dependent, serum fentanyl concentrations could theoretically increase by approximately one-third in patients with a body temperature of 40 °C. Patients who develop a fever while using fentanyl transdermal system should be observed closely for manifestations of opiate toxicity, and dosage of the drug should be adjusted accordingly. Patients should be cautioned to avoid strenuous exertion that leads to increased core body temperature while wearing the transdermal system. Because application of heat over the fentanyl transdermal system increases mean systemic exposure and peak plasma concentrations of the drug by 120 and 61%, respectively, and has resulted in fatal overdosage, patients wearing a fentanyl transdermal system should be advised to avoid exposing the application site or surrounding area to direct external heat sources.
... The aim of this study was to characterize fentanyl pharmacokinetics in pregnant sheep after intravenous and transdermal dosing during surgical procedure performed to ewe and fetus. Pharmacokinetic parameters reported for non-pregnant sheep and nominal transdermal dose rate were utilized for a priori calculation to achieve analgesic fentanyl concentration (0.5-2 ng/mL) in maternal plasma. A total of 20 Aland landrace ewes at 118-127 gestational days were used. In the first protocol, 1 week before surgery, 10 animals received 2 ug/kg fentanyl intravenous bolus, and on the operation day, transdermal fentanyl patches at nominal dose rate of 2 ug/kg/hr were applied to antebrachium, and ewes were then given a 2 ug/kg intravenous bolus followed by an intra-operative 2.5 ug/kg/hr infusion. In the second protocol, 10 animals received fentanyl only as transdermal patches on the operation day and oxycodone for rescue analgesia. The data were analyzsed with population pharmacokinetic modelling. Intra- and post-operative fentanyl concentrations were similar and slightly lower than the a priori predictions, and elimination and distribution clearances appeared slower during than before or after the surgery. Transdermal patches provided sustained fentanyl absorption for up to 5 days, but the absorption rate was slower than the nominal dose rate and showed a high interindividual variability.
Metabolism
Fentanyl is metabolized to a number of inactive metabolites. Fentanyl is 99% N-dealkylated to norfentanyl by cytochrome P450. It can also be amide hydrolyzed to despropionylfentanyl, or alkyl hydroxylated to hydroxyfentanyl which is N-dealkylated to hydroxynorfentanyl.
Fentanyl does not appear to be metabolized in skin when administered transdermally. Data from clinical studies and from studies using a human keratinocyte cell assay indicate that about 92% of a dose delivered from the fentanyl transdermal system is accounted for as unchanged drug in systemic circulation. Total plasma clearance of fentanyl is reported to be about 500 mL/hour per kg (range: 300-700 mL/hour per kg) or 42-53 L/hour.
Fentanyl citrate is metabolized extensively in the liver and the intestinal mucosa. Animal studies indicate that the drug undergoes oxidation via the microsomal enzymes in the liver and intestinal mucosa (principally cytochrome P-450 [CYP] isoform 3A4) to form norfentanyl; the drug also undergoes hydrolysis to form 4-N-anilinopiperidine and propionic acid. Norfentanyl has been shown to be pharmacologically inactive in animal studies. Fentanyl is excreted in the urine as inactive metabolites and as unchanged drug. Less than 10% of a dose is excreted in urine unchanged and only about 1% is excreted in the feces as unchanged drug.
This study was undertaken to determine if metabolites of fentanyl might be useful in the detection and monitoring of substance abuse. The presence of fentanyl and two of its metabolites in the urine and saliva of seven female patients receiving small doses (110 +/- 56 micrograms) of fentanyl was studied up to 96 hr from the time of administration. Fentanyl and its two metabolites (norfentanyl and despropionylfentanyl) were extracted from samples and analyzed by gas chromatography/mass spectrometry. Unchanged fentanyl was detectable in urine in all patients immediately postoperatively and in 3 of 7 patients at 24 hr. By 72 hr, fentanyl was undetectable. Norfentanyl was present in larger quantities than fentanyl immediately postoperatively and was detected in all patients at 48 hr and in 4 of 7 patients at 96 hr. Despropionylfentanyl was not detected in any of the urine specimens tested. Neither fentanyl nor its metabolites could be detected consistently at any time in saliva. Saliva testing does not appear to be a viable alternative to urine testing based on this study. Urinary norfentanyl might be considered as the substance of choice when testing for fentanyl abuse.
Fentanyl has known human metabolites that include Norfentanyl and Phenylacetaldehyde.
Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system.
Route of Elimination: Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system and mostly eliminated in urine. Within 72 hours of IV fentanyl administration, approximately 75% of the dose is excreted in urine, mostly as metabolites with less than 10% representing unchanged drug.
Half Life: 7 hours (range 3-12)
Protein binding
Fentanyl is 80-85% bound to plasma proteins. In one study, a 0.1µg/L solution of fentanyl was 77.9±1.1% bound to human serum albumin and 12.0±5.4% bound to α-1 acid glycoprotein. A 0.1µg/L solution of norfentanyl, the primary metabolite of fentanyl, was 7.62±1.2% bound to human serum albumin and 7.24±1.9% bound to α-1 acid glycoprotein.
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