Actions of Limifen in details
Limifen is a very short-acting potent narcotic analgesic for IV use.
Pharmacotherapeutic Class: ATC Code: N01AH02.
Pharmacology: Pharmacodynamics: Limifen is a potent fast- and short-acting narcotic analgesic, chemically related to fentanyl. After IV administration of Limifen action sets in almost instantly, the onset of action amounts to only 1 quarter of that of an equianalgesic dose of fentanyl. The maximum analgesic and respiratory depressant effect occurs within 1-2 min (30 min with morphine).
The duration of action of Limifen is only 1/3 of that of an equianalgesic dose of fentanyl and is clearly dose-related. For analgesia lasting >60 min, an infusion is preferable. Its depressant effects on respiratory rate and alveolar ventilation last also shorter than those of fentanyl; in most cases, the duration of analgesia exceeds that of the respiratory depression. The duration and degree of respiratory depression tend to be dose-related.
High doses (>120 mcg/kg) of Limifen induce sleep and can be used for induction of anesthesia. The induction is smooth, pain-free and devoid of cardiovascular and hormonal stress responses to intubation.
Limifen has a very wide safety margin. In rats, the ratio of LD50/ED50 for the lowest level of analgesia, for Limifen is 1080 compared with 4.6, 69.5 and 277 for pethidine, morphine and fentanyl, respectively.
In common with other narcotic analgesics, Limifen can, depending upon the dose and speed of administration, cause muscle rigidity as well as euphoria, miosis and bradycardia.
At doses up to 200 mcg/kg, Limifen failed to produce a significant increase in histamine levels or clinical evidence of histamine release.
Recovery after Limifen administration is rapid and smooth with a low incidence of post-operative nausea and vomiting.
All actions of Limifen are immediately and completely reversed by a specific narcotic antagonist eg, naloxone.
Pharmacokinetics: Limifen is a synthetic opioid with mc-agonist pharmacologic effects, used only IV. Distribution: The sequential distribution t½ of Limifen are 0.4-2.2 min and 8-32 min. The low degree of ionisation (11% at pH=7.4) contributes to a rapid but limited tissue distribution. Reported volumes of distribution are 1.27-4.81 L (volume of distribution of the central compartment) and 12.1-98.2 L (volume of distribution at steady-state). Plasma protein-binding of Limifen is about 92%.
Metabolism: Limifen is mainly metabolised in the liver. Only 1% of unchanged Limifen is found in urine. Metabolites are inactive and 70-80% of them are eliminated via the urine.
Elimination: Limifen is rapidly eliminated after IV administration. Terminal elimination t½ of 83-223 min have been reported. The plasma clearance in young subjects averages 356 mL/min and decreases with age. Only 1% of unchanged Limifen is found in urine. Once steady-state has been reached after infusion, the elimination t½ remains unaltered. When the administration is discontinued, the patient awakes rapidly without narcotic after effects.
Special Populations: Pediatrics: Protein-binding in newborns is 75% and increases in children to 85%. The plasma clearance in newborns is approximately 7.2±3.2 mL/kg/min and 4.7±1.7 mL/kg/min in children between 4.5-7.75 year. The volume of distribution at steady-state was 1230±520 mL/kg in newborns and 163.5±110 mL/kg in children. The t½ is 146±57 min in newborns and 40.2±8.9 min in children.
Hepatic Impairment: After administration of a single IV dose of 50 mcg/kg, the terminal t½ in cirrhotic patients is significantly longer than in controls. The volume of distribution remains unchanged. The free fraction of Limifen increases in cirrhotic patients to 18.5% compared with 11.5% in controls. This increase in free fraction together with a reduction in clearance from 3.06 mL/min/kg in controls to 1.6 mL/min/kg in cirrhotic patients will result in a more prolonged and pronounced effect.
Renal Impairment: The volume of distrubution and clearance of the free fraction is similar in renal failure patients and healthy controls. The free fraction of Limifen in patients with renal failure is increased to 12.4-19% compared with 10.3-11% in controls. This may result in an increase in clinical effect of Limifen.
Toxicology: Preclinical Safety Data: Preclinical effects observed were only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
How should I take Limifen?
A nurse or other trained health professional will give you Limifen in a hospital. Limifen is given through a needle placed in one of your veins.
Limifen administration
IV: Administer IV slowly over 3 minutes or by IV continuous infusion.
Limifen pharmacology
Limifen is an opioid analgesic with a rapid onset of action.
At doses of 8 to 40 mcg/kg for surgical procedures lasting up to 30 minutes, Limifen provides analgesic protection against hemodynamic responses to surgical stress with recovery times generally comparable to those seen with equipotent fentanyl dosages.
For longer procedures, doses of up to 75 mcg/kg attenuate hemodynamic responses to laryngoscopy, intubation and incision, with recovery time comparable to fentanyl. At doses of 50 to 75 mcg/kg followed by a continuous infusion of 0.5 to 3 mcg/kg/min, Limifen attenuates the catecholamine response with more rapid recovery and reduced need for postoperative analgesics as compared to patients administered enflurane. At doses of 5 mcg/kg, Limifen provides analgesia for the conscious but sedated patient. Based on patient response, doses higher than 5 mcg/kg may be needed. Elderly or debilitated patients may require lower doses. High intrasubject and intersubject variability in the pharmacokinetic disposition of Limifen has been reported.
The pharmacokinetics of Limifen can be described as a three-compartment model with sequential distribution half-lives of 1 and 14 minutes; and a terminal elimination half-life of 90 to 111 minutes (as compared to a terminal elimination half-life of approximately 475 minutes for fentanyl and approximately 265 minutes for sufentanil at doses of 250 mcg). The liver is the major site of biotransformation.
Limifen has an apparent volume of distribution of 0.4 to 1 L/kg, which is approximately one-fourth to one-tenth that of fentanyl, with an average plasma clearance of 5 mL/kg/min as compared to approximately 8 mL/kg/min for fentanyl.
Only 1% of the dose is excreted as unchanged drug; urinary excretion is the major route of elimination of metabolites. Plasma protein binding of Limifen is approximately 92%.
In one study involving 15 patients administered Limifen with nitrous oxide/oxygen, a narrow range of plasma Limifen concentrations, approximately 310 to 340 ng/mL, was shown to provide adequate anesthesia for intra-abdominal surgery, while lower concentrations, approximately 190 ng/mL, blocked responses to skin closure. Plasma concentrations between 100 to 200 ng/mL provided adequate anesthesia for superficial surgery.
Limifen has an immediate onset of action. At dosages of approximately 105 mcg/kg, Limifen produces hypnosis as determined by EEG patterns; an anesthetic ED90 of 182 mcg/kg for Limifen in unpremedicated patients has been determined, based upon the ability to block response to placement of a nasopharyngeal airway. Based on clinical trials, induction dosage requirements range from 130 to 245 mcg/kg. For procedures lasting 30 to 60 minutes, loading dosages of up to 50 mcg/kg produce the hemodynamic response to endotracheal intubation and skin incision as comparable to those from fentanyl. A pre-intubation loading dose of 50 to 75 mcg/kg prior to a continuous infusion attenuates the response to laryngoscopy, intubation and incision. Subsequent administration of Limifen infusion administered at a rate of 0.5 to 3 mcg/kg/min with nitrous oxide/oxygen attenuates sympathetic responses to surgical stress with more rapid recovery than enflurane.
Requirements for volatile inhalation anesthetics were reduced by thirty to fifty percent during the first 60 minutes of maintenance in patients administered anesthetic doses (above 130 mcg/kg) of Limifen as compared to patients given doses of 4 to 5 mg/kg thiopental for anesthetic induction. At anesthetic induction dosages, Limifen provides a deep level of anesthesia during the first hour of anesthetic maintenance and provides attenuation of the hemodynamic response during intubation and incision.
Following an anesthetic induction dose of Limifen, requirements for Limifen infusion are reduced by 30 to 50% for the first hour of maintenance.
Patients with compromised liver function and those over 65 years of age have been found to have reduced plasma clearance and extended terminal elimination for Limifen, which may prolong postoperative recovery. Repeated or continuous administration of Limifen produces increasing plasma concentrations and an accumulation of the drug, particularly in patients with reduced plasma clearance.
Bradycardia may be seen in patients administered Limifen. The incidence and degree of bradycardia may be more pronounced when Limifen is administered in conjunction with non-vagolytic neuromuscular blocking agents or in the absence of anticholinergic agents such as atropine.
Administration of intravenous diazepam immediately prior to or following high doses of Limifen has been shown to produce decreases in blood pressure that may be secondary to vasodilation; recovery may also be prolonged.
Patients administered doses up to 200 mcg/kg of Limifen have shown no significant increase in histamine levels and no clinical evidence of histamine release.
Skeletal muscle rigidity is related to the dose and speed of administration of Limifen. Muscular rigidity will occur with an immediate onset following anesthetic induction dosages. Preventative measures may reduce the rate and severity.
The duration and degree of respiratory depression and increased airway resistance usually increase with dose, but have also been observed at lower doses. Although higher doses may produce apnea and a longer duration of respiratory depression, apnea may also occur at low doses.
During monitored anesthesia care (MAC), attention must be given to the respiratory effects of Limifen. Decreased oxygen saturation, apnea, decreased respiratory rate, and upper airway obstruction can occur.
References
- NCIt. "Alfentanil: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
- EPA DSStox. "Alfentanil: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
Reviews
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Information checked by Dr. Sachin Kumar, MD Pharmacology
