알펜타닐

Intravenous administration of an opioid antagonist such as naloxone should be employed as a specific antidote to manage respiratory depression. The duration of respiratory depression following overdosage with ALFENTA may be longer than the duration of action of the opioid antagonist. Administration of an opioid antagonist should not preclude immediate establishment of a patent airway, administration of oxygen, and assisted or controlled ventilation as indicated for hypoventilation or apnea. If respiratory depression is associated with muscular rigidity, a neuromuscular blocking agent may be required to facilitate assisted or controlled ventilation. Intravenous fluids and vasoactive agents may be required to manage hemodynamic instability. (L1712)

The study aims to investigate the possible mechanism of the synergistic analgesic effect of propofol-alfentanil combination. The synergistic analgesic effects of propofol-alfentanil combination in Sprague-Dawley (SD) rats were analyzed through the von Frey test. Then, we examined the activity of phospholipase C (PLC) and the intracellular levels of Ca(2+) and adenosine 3', 5'cyclic monophosphate (cAMP) in primary neuronal cells of fetal SD rats. We detected the intracellular Ca(2+) concentration by fluorescence and flow cytometry. The PLC activity of the primary neuronal cells was assayed using the EnzChek() Direct Phospholipase C Assay Kit. The cAMP content of the cells was assayed using the cAMP Direct Immunoassay Kit (Fluorometric). Both propofol and alfentanil treatments depressed cAMP levels and PLC activity, but propofol-alfentanil combination decreased these parameters to a greater extent than alfentanil treatment alone. Propofol and alfentanil both inhibited Ca(2+) channel, but propofol-alfentanil combination suppressed this channel to a greater extent than alfentanil treatment alone. Fluorescent image analysis revealed that both propofol and alfentanil reduced the intracellular levels of Ca(2+), and propofol-alfentanil combination showed weaker signals than alfentanil alone. Propofol-alfentanil combination significantly reduced intracellular Ca(2+) level, cAMP level and PLC activity. Propofol and alfentanil exert synergistic analgesic effects through the adenylyl cyclase pathway.

To investigate a possible connection between erythromycin administration and reduced elimination of alfentanil, a controlled crossover study of alfentanil pharmacokinetics was undertaken. Six subjects were monitored for alfentanil plasma levels for 8 hr after alfentanil was administered. These measurements were obtained after a 0, 1, and 7 day course of erythromycin. Elimination half-life increased significantly (p < 0.01) after 7 days from the control value of 84.0 + or - 8.2 min to 131.4 + or - 43.5 min. Clearance was decreased significantly (p < 0.05) from 3.9 + or - 0.8 ml/kg/min to 2.9 + or - 1.2 ml/kg/min after 7 days. Values after 1 day were intermediate. Distribution volume did not change significantly. Subjects differed sharply in their sensitivity to erythromycin. Because of the interaction between erythromycin and alfentanil, ... patients who are receiving erythromycin should be given alfentanil in reduced amounts or should avoid the drug completely.

Previous work has demonstrated that direct injections of methylnaloxonium, a relatively lipophobic quaternary opiate antagonist, in the area of the nucleus raphe pontis significantly attenuated alfentanil induced rigidity. It was hypothesized that other hindbrain sites, particularly the other raphe nuclei, might play a role in this rigidity. Therefore, a study was performed in which 57 rats, divided into four groups, were implanted with chronic guide cannulae directed at brain sites anterior, lateral, or posterior to the nucleus raphe pontis. After each animal was pretreated with intracerebral injections of methylnaloxonium, alfentanil (0.5 mg/kg) was administered subcutaneously. Electromyographic activity was recorded from the gastrocnemius muscle as a measure of hindlimb rigidity. Each animal was subsequently injected at 4 to 5 day intervals with methylnaloxonium two additional times at sites 1 and 2 mm deeper, respectively, than the initial injection. Data were thus obtained on animals treated with either methylnaloxonium or saline at 3 successive histologically identified sites which were either anterior, lateral or posterior to the nucleus raphe pontis. The administration of methylnaloxonium into two specific sites in the region just lateral to the nucleus raphe pontis significantly (F(1,38) = 18.68 and 5.02 respectively, p less than 0.05) reversed the rigidity produced by systemic alfentanil administration. There was a weak effect of methylnaloxonium injections anterior to the nucleus raphe pontis but this could not be localized to any one site. These results suggest that discrete brainstem regions involved in opiate action can be sensitively and selectively identified by direct intracranial injections of a lipophobic opiate antagonist.

Alfentanil, a short-acting and powerful analgesic, when injected peripherally to rats (0.5 mg/kg) produced a catatonic state characterized by a rigid akinesia. The present study was designed to explore the neuroanatomical location of the opiate receptors mediating the alfentanil induced catatonia. The catatonic effect of alfentanil was measured using a bar test and depression of locomotor activity in rats tested in photocell cages during an active nocturnal phase of their cycle. Methylnaloxonium HCl, a quaternary derivative of naloxone which does not readily cross the blood-brain barrier, injected into the lateral ventricle significantly reduced the catatonia at doses of 0.125-2.0 micrograms as measured in both the locomotor and bar test. Methylnaloxonium HCl perfusion of similar doses directly into the nucleus raphe pontis, but not in the caudate nucleus significantly antagonized the catatonia. These data complement results on alfentanil induced muscular rigidity where EMG indices of rigidity in rats were reversed by microinjections of low doses of methylnaloxonium HCl (0.125 and 0.5 microgram) in the nucleus raphe pontis, but not the caudate nucleus even at a high dose (4.0 micrograms). Together these results suggest that the region of the nucleus raphe pontis is an important neural substrate for opiate induced muscular rigidity, and that the catatonic state produced by opiates depends on more diffuse opiate receptor activation of which one important component may be the nucleus raphe pontis.

For more Interactions (Complete) data for Alfentanil (11 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 680(SRC), determined from a structure estimation method(2), indicates that alfentanil is expected to have low mobility in soil(SRC). The pKa of alfentanil is 6.5(3), indicating that this compound will exist partially in cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of the cation from moist soil is not expected because cations do not volatilize(SRC). Volatilization of neutral alfentanil from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 9.7X10-20 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Alfentanil is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.4X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2017).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 680(SRC), determined from a structure estimation method(2), indicates that alfentanil is expected to adsorb to suspended solids and sediment(SRC). An pKa of 6.5(3) indicates alfentanil will exist partially in the cation form at pH values of 5 to 9 and, therefore, volatilization of the cation from water surfaces is not expected to be an important fate process(SRC). Volatilization from water surfaces of neutral alfentanil is not expected(4) based upon an estimated Henry's Law constant of 9.7X10-20 atm-cu m/mole(SRC), developed using a fragment constant estimation method(5). Alfentanil is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(4). According to a classification scheme(6), an estimated BCF of 12(SRC), from its log Kow of 2.16(7) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low. Biodegradation data in water were not available(SRC, 2017).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), alfentanil, which has an estimated vapor pressure of 6.4X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase. Particulate-phase alfentanil may be removed from the air by wet and dry deposition(SRC). Alfentanil contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

As an opioid-class analgesic, alfentanil shares common adverse effects with this medication group, including respiratory depression, reduced gastrointestinal motility, sedation, nausea, vomiting, constipation, and intestinal bloating. Notably, alfentanil tends to induce less intense respiratory depression than fentanyl. This is likely attributed to alfentanil's lower total body clearance, smaller volume of distribution, and shorter half-life when compared to other commonly used similar opioid analgesics, such as fentanyl and sufentanil. Additional adverse effects, more specific to alfentanil, include hypotension, chest wall rigidity, bradycardia, and tachycardia.

... In one study, 0.88 ng of alfentanil per mL was measured in colostrum 4 hr following maternal administration of 60 ug per kg of body wt. Measurable concn were not present 28 hr following administration.

/Alfentanil/ passes into breast milk and may harm /the/ baby(1).

IDENTIFICATION AND USE: Alfentanil is a Schedule II Controlled Substance. An opioid analgesic, alfentanil may be useful for anesthesia, analgesia, or sedation similar to fentanyl. HUMAN STUDIES: Alfentanil injection exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Acute overdose with Alfentanil injection can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. When alfentanil was given in high doses for anesthesia induction, chest wall rigidity occurred frequently. Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of Alfentanil injection with serotonergic drugs. ANIMAL STUDIES: Alfentanil is a potent and short-acting mu opioid agonist that produces both antinociceptive effects and muscle rigidity. Male and female Beagle dogs were administered 0, 0.08, 0.31 or 1.25 mg/kg IV alfentanil daily for 4 weeks. There was a dose-related incidence of ataxia, catatonia, and apnea during the first few days. Dogs in the high-dose group experienced sporadic apnea, convulsions and dyskinesia. Alfentanil was administered daily to male and female rats in doses of 0, 0.08, 0.31 and 1.25 mg/kg IV for 4 weeks. Death occurred within 2 hours of alfentanil administration and were attributed to suffocation. Transient muscle rigidity, exophthalmos and loss of righting reflex were observed in all groups. Female rats were administered IV alfentanil 0, 0.08, 0.31 or 1.25 mg/kg from day 16 of pregnancy through a 3-week lactation period. Cannibalism occurred in 2 of 19 high-dose litters. Birth weight was lower in the 0.31 mg/kg group. Survival rates were lower in the offspring of the 0.31 and 1.25 mg/kg groups, but no teratogenic effects were observed. The mutagenicity potential of alfentanil was assessed in the Ames test, micronucleus test and the mouse dominant lethal test. There was no evidence of mutagenicity in any test.

Symptoms of alfentanil toxicity are similar to those of other opioid-class medications and include skeletal muscle rigidity, cardiac depression, respiratory depression, and constriction of the pupils.

Opiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited. Opioids also inhibit the release of vasopressin, somatostatin, insulin and glucagon. Alfentanil's analgesic activity is, most likely, due to its conversion to morphine. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability.

Using a structure estimation method based on molecular connectivity indices(1), the Koc of alfentanil can be estimated to be 680(SRC). According to a classification scheme(2), this estimated Koc value suggests that alfentanil is expected to have low mobility in soil. The pKa of alfentanil is 6.5(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

/HUMAN EXPOSURE STUDIES/ Forty healthy, young volunteers received intravenously, in a double-blind and random fashion, 7.5 or 15 micrograms/kg of alfentanil, 1.5 or 3 micrograms/kg of fentanyl, or saline. The ventilatory response to CO2 was measured before and at 4, 20, 30, 50, 80, and 120 min post-treatment. Mental and psychomotor functions were measured before and at 10, 40, 100, 130, and 180 min post-treatment. Low and high-dose fentanyl caused significant respiratory depression up to 30 and 80 min post-treatment, respectively, while there was no depression with low-dose alfentanil and only at 4 min with high-dose alfentanil. The fentanyl to alfentanil potency ratio for respiratory depression was 13:1. High-dose fentanyl caused more intense and prolonged mental effects than other treatments. Neither drug affected learning or recall, although high-dose fentanyl impaired motor activity. Nausea and vomiting rates were similar between high-dose alfentanil and low-dose fentanyl.

/HUMAN EXPOSURE STUDIES/ Hypothermia is common in surgical patients and victims of major trauma; it also results from environmental exposure and drug abuse. In most cases, hypothermia results largely from drug-induced inhibition of normal thermoregulatory control. Although opioids are given to a variety of patients, the thermoregulatory effects of opioids in humans remain unknown. Accordingly, the hypothesis that opioid administration impairs thermoregulatory control was tested. Eight volunteers were studied, each on 3 days: (1) a target total plasma alfentanil concentration of 100 ng/mL, (2) control (no drug), and (3) a target alfentanil concentration of 300 ng/mL. Each day, skin and core temperatures were increased sufficiently to provoke sweating. Temperatures subsequently were reduced to elicit peripheral vasoconstriction and shivering. Mathematical compensations were made for changes in skin temperature using the established linear cutaneous contributions to control of sweating (10%) and to vasoconstriction and shivering (20%). From the calculated thresholds (core temperatures triggering responses at a designated skin temperature of 34 degrees C) and unbound plasma alfentanil concentrations, the individual concentration-response relationship was determined. The concentration-response relationship for all the volunteers was determined similarly using total alfentanil concentrations. In terms of unbound concentration, alfentanil increased the sweating threshold (slope = 0.021 +/- 0.016 degrees C.ng-1.mL; r2 = 0.92 +/- 0.06). Alfentanil also significantly decreased the vasoconstriction (slope = -0.075 +/- 0.067 degrees C.ng-1.mL; r2 = 0.92 +/- 0.07) and shivering thresholds (slope = -0.063 +/- -0.037 degrees C.ng-1.ml; r2 = 0.98 +/- 0.04). In terms of total alfentanil concentration (degrees C.ng-1.mL), the sweating threshold increased according to the equation: threshold (degrees C) = 0.0014 [alfentanil] + 37.2 (r2 = 0.33). In contrast, alfentanil produced a linear decrease in the core temperature, triggering vasoconstriction: threshold (degrees C) = -0.0049[alfentanil] + 36.7 (r2 = 0.64). Similarly, alfentanil linearly decreased the shivering threshold: threshold (degrees C) = -0.0057 [alfentanil] + 35.9 (r2 = 0.70). The observed pattern of thermoregulatory impairment is similar to that produced by most general anesthetics: a slight increase in the sweating threshold and a substantial, linear decrease in the vasoconstriction and shivering thresholds.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including alfentanil hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Alfentanil hydrochloride/

Schedule II shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. ... Opiates. Unless specifically excepted or unless in another schedule any of the following opiates, including its isomers, esters, ethers, salts and salts of isomers, esters and ethers whenever the existence of such isomers, esters, ethers, and salts is possible within the specific chemical designation, dextrorphan and levopropoxyphene excepted:. Alfentanil (DEA Code Number: 9737) is included on this list.

Alfentanil (DEA Code Number: 9737) is a Schedule II controlled substance.

Schedule II Controlled Substance: (A) The drug or other substance has a high potential for abuse; (B) The drug or other substance has a currently accepted medical use in treatment in the United States or a currently accepted medical use with severe restrictions; and (C) Abuse of the drug or other substances may lead to severe psychological or physical dependence.

Analgesics, Opioid; Narcotics; Anesthetics, Intravenous

MEDICATION

MEDICATION (VET)

For the management of postoperative pain and the maintenance of general anesthesia.

Alfentanil HCl Injection USP, for intravenous use (equivalent to 500 ug/mL alfentanil base).

Alfenta is a sterile, non-pyrogenic, preservative free aqueous solution containing alfentanil hydrochloride equivalent to 500 ug per mL of alfentanil base for intravenous injection. The solution, which contains sodium chloride for isotonicity, has a pH range of 4-6. Each mL contains: Active: Alfentanil base 500 ug. Inactive: Sodium Chloride 9 mg and Water for Injection Q.S.