Fentanyl concentrations

Fever/External heat Serum fentanyl concentrations may increase by approximately one third for patients with a body temperature of 40°C (104°F) because of temperature-dependent increases in fentanyl release from the transdermal system and increased skin permeability. 

Following removal of transdermal system, 17 hr are required for 50% decrease in serum fentanyl concentrations... 

The transdermal system provides continuous systemic delivery of fentanyl for 72 h. The amount of drug released from the system per hour is proportional to the surface area. Following application of the patch to the skin, a depot of fentanyl concentrates in the upper skin layers. This is then available to the systemic circulation. There is an initial rise in blood fentanyl concentration after application followed by a leveling off that occurs 12 to 24 h later. Peak blood concentrations occur between 24 and 72 h after application. The skin does not appear to metabolize fentanyl when delivered transdermally. 

More recently, head hair samples obtained from surgery patients who received fentanyl were analyzed by RIA. Wang et al. detected fentanyl equivalents in eight subjects. Concentrations ranged from 0.013 to 0.048 ng/mg. No correlation between hair fentanyl concentration and administered dose was found for the 13 fentanyl subjects. 

All treatments delivered fentanyl for the first 20 min of every hour for 24 h. The three IDDS treatments employed currents of 150, 200, and 250 pA, while the IV treatment infused 50 pg of fentanyl. Blood samples were collected, and serum fentanyl concentrations were measured using a specific radioimmunoassay. Plasma data collected during and immediately following the 1st, 13th, and 25th treatments are shown in Fig. 4. The gradual upward shifts in concentration over time indicate a baseline increase due to incomplete fentanyl clearance between the hourly doses. For all treatment types, serum fentanyl concentrations rapidly increased within a few minutes after the start of each dose. 

The donor solution pH and fentanyl concentration were very similar to the pH and concentration of the donor formulation used in the clinical study. 

Fig. 4 Mean serum fentanyl concentrations for 12 healthy volunteers receiving fentanyl intermittently (20 min each hour over a 24 h administration period) from an iontophore-tic system at three currents, and from IV fentanyl infusion (50 pg for 20 min hourly). Serum fentanyl concentrations were measured during and immediately after the 1st, 13th, and 25th doses. (From Ref. l)...

The effect of obstetric epidural administration of a mixture of 8 ml of bupivacaine (0.25%) with fentanyl 50 micrograms has been studied in 40 offspring (183). Fetal distress occurred in 11 babies, five of whom needed resuscitation there was no correlation between fetal distress and plasma fentanyl concentrations in the neonates. 

In Hungs prehminary study [5] comparing nebulizer and intravenous administration of fentanyl, delivery of 2000 pg of a nebulized mixture of free (50%) and liposomal-encapsulated (50%) fentanyl (FLEF) to volunteers resulted in a peak plasma concentration of 1.15 ng/mL at 22 min. One important feature of the FLEF was that the plasma concentration decreased slowly after the single 2000 pg dose. At 8 and 24 h after inhalation, fentanyl concentration values were 0.25 0.14 ng/mL and 0.12 0.16 ng/mL, respectively (Figure 111.2). 

In a subsequent study by the same author, five doses of 4000 pg FLEF were administered at 12-h intervals. The time to reach the peak concentration after each administration ranged from 12.5 to 19.2 min and the fentanyl concentration was maintained within the analgesic therapeutic concentration (0.6-3 ng/mL). The bioavailability of inhaled FLEF is 12-20%, which is consistent with the bioavailability of most drugs administered via the pulmonary system (10-20%). 

Administration of 1500 pg of AeroLEF and 200 pg of IV fentanyl achieved similar fentanyl concentrations the achievement of maximal concentration of fentanyl within the dosing period allows subjects to safely administer therapeutic doses of fentanyl with AeroLEF and offers the potential for the patient to individualize the consumed dose of AeroLEF matched to their perception of meaningful analgesia during dosing. 

Opioids maybe administered in a variety of routes including oral (tablet and liquid), sublingual, rectal, transdermal, transmucosal, intravenous, subcutaneous, and intraspinal. While the oral and transdermal routes are most common, the method of administration is based on patient needs (severity of pain) and characteristics (swallowing difficulty and preference). Oral opioids have an onset of effect of 45 minutes, so intravenous or subcutaneous administration maybe preferred if more rapid relief is desired. Intramuscular injections are not recommended because of pain at the injection site and wide fluctuations in drug absorption and peak plasma concentrations achieved. More invasive routes of administration such as PCA and intraspinal (epidural and intrathecal) are primarily used postoperatively, but may also be used in refractory chronic pain situations. PCA delivers a self-administered dose via an infusion pump with a preprogrammed dose, minimum dosing interval, and maximum hourly dose. Morphine, fentanyl, and hydromorphone are commonly administered via PCA pumps by the intravenous route, but less frequently by the subcutaneous or epidural route. 

Figure 16.1. Screening method for fentanyl analogs in blood using LC-MS/APCI. Monitored ions [M + H]+ were chosen from full scan spectra. The blood sample was spiked with fentanyl, its three analogs and internal standard to the concentration of 5 ng/mL [6].

Figure 7.6 Cumulative receiver concentrations of fentanyl, caffeine, and atenol vs time across cultured human buccal tissue (average SD, N = 3). Results from internal study by Absorption Systems Company.

The interior volume of the theater, estimated from illustrations, was probably less than three hundred thousand cubic feet, i.e., about 10,000 cubic meters. Based on doses used for anesthesia, a concentration of as little as 2-3 mg per cubic meter of a super-potent Fentanyl derivative might be sufficient for a building that size, if instantaneous incapacitation is not required. This assumes continuous inhalation for about 30 minutes. Thus, if evenly distributed, the total amount of drug required might be in the range of a few dozen grams - almost certainly less than a pound. If the Russian authority pumped in 5x the effective dose (as it claimed), its uneven distribution in the air would likely have caused many deaths. But only one in six died. 

Fentanyl transdermal system Fentanyl transdermal systems contain a high concentration of the potent schedule II opioid agonist, fentanyl. Schedule II opioid substances have the highest potential for abuse and associated risk of fatal overdose due to respiratory depression. Fentanyl can be abused and is subject to criminal diversion. The high content of fentanyl in the patches may be a particular target for abuse and diversion. 

Discontinuation - Upon system removal, it takes 17 hours or more for the fentanyl serum concentration to fall by 50% after system removal. Titrate the dose of the new analgesic based on the patient s report of pain until adequate analgesia has been attained. For patients requiring discontinuation of opioids, a gradual downward titration is recommended because it is not known at what dose level the opioid may be discontinued without producing the signs and symptoms of abrupt withdrawal. 

Unlike isoflurane, desflurane may stimulate the sympathetic nervous system at concentrations above 1 MAC. Sudden and unexpected increases in arterial blood pressure and heart rate have been reported in some patients, accompanied by increases in plasma catecholamine and vasopressin concentrations and increased plasma renin activity. These pressor effects may increase morbidity or mortality in susceptible patients. The mechanism of sympathetic activation is unclear but does not appear to be baroreceptor-mediated. Clonidine, esmolol, fentanyl and propofol partially block the response but lignocaine (lignocaine) is ineffective. 

Most of the haemodynamic effects of opioids are related to decreased central sympathetic outflow, specific vagal effects or, in the case of morphine and pethidine, histamine release. Fentanyl and its analogues do not cause histamine release. All opioids, with the exception of pethidine, produce bradycardia by actions on the afferent fibres of the vagus and the nucleus tractus solitarius and nucleus commissuralis, which have very high densities of opioid receptors. Pethidine often produces tachycardia, possibly due to its structural similarity to atropine. In isolated heart or heart-muscle preparations, opioids produce a dose-related negative inotropic effect, but only at concentrations 100 to several thousand times those found clinically. 

Figure 12 In vitro permeation through human skin and in vivo animal data after dermal application of fentanyl MDTS. (a) Absorption of fentanyl across human epidermis. Comparison of a fentanyl MDTS and Duragesic 50 TS. (b) Mean plasma concentration of fentanyl after a fentanyl MDTS and Duragesic 50 TS in male pigs (n = 7).

Clinical use The indications for levobupivacaine include wound infiltration (0.25 % solution), nerve conduction block (0.25 - 0.5 %), spinal analgesia (0.5 %) and epidural anesthesia (0.5 to 0.75 %). For labour analgesia, lower concentrations of levobupivacaine are recommended when administered as epidural injection (0.125 to 0.25 % up to 25 mg) or infusion (0.25 %). The maximum dose for ilioinguinal or iliohypogastric block in children is 1.25 mg/kg/side (0.25 to 0.5 % solutions). For postoperative pain management, levobupivacaine can be applied epidurally in combination with the opioids fentanyl or morphine or with the a2-agonist clonidine. 

Poklis, A. and R. Backer, Urine concentrations of fentanyl and norfentanyl during application of Duragesic transdermal patches, J. Anal. Toxicol., 28(6), 422—425, 2004. 

Veselis, R.A. et al., Impaired memory and behavioral performance with fentanyl at low plasma concentrations, Anesth. Analg., 79, 952, 1994. 

A 61-year-old woman undergoing mitral valve surgery received fentanyl, midazolam, nitrous oxide, and propofol infusion 3 mg/kg/hour during a 5-hour anesthetic. She developed lactic acidosis soon after the completion of surgery and required reintubation and ventilation. The peak lactate concentration, which occurred 1 day later, was 14.3 mmol/1. There was also mild disturbance of liver function. She eventually recovered. 

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