What Is Remifentanil?

Remifentanil is chemically named 4- (methoxycarbonyl) -4-[(1-oxopropyl) phenylamino] -1-piperidine propanoate, with a density and a boiling point of 1.171g / cm3 and 487.8ºC, respectively. , White or off-white lyophilized loose bulk. It is mainly used clinically for general anesthesia induction and maintenance of analgesia during general anesthesia.

Chinese name: Remifentanil
Foreign name: Remifentanil

CAS number: 132875-61-7
Molecular formula: C20H28N2O5
Molecular weight: 376.44700

Remifentanil Compounds

Remifentanil Basic Information

Chinese name

Chinese alias: 4- (methoxycarbonyl) -4-[(1-oxopropyl) phenylamino] -1-piperidine propanoic acid methyl ester

English name: Remifentanil

English alias: 3- [4-methoxycarbonyl-4-[(1-oxopropyl) phenylamino] -1-piperidine] propanoic acid methyl ester; remifetanil; Remifentanil [INN: BAN]; 1-piperidinepropanoic acid 4- (methoxy-carbonyl) -4-((1-oxopropyl) phenylamino) -methyl ester; Ultiva; Remifentanil (INN); remifnetanil; Ultiva (TN); Remifentanyl; methyl 1- (3-methoxy-3-oxopropyl) -4- (N-propanoylanilino ) piperidine-4-carboxylate; 4- (methoxycarbonyl) -4-<(1-oxopropyl) phenylamino> -1-piperidinepropanoic acid methyl ester; Remifentanil; DEA No. 9739;

CAS number: 132875-61-7

Molecular formula: C ₂₀ H ₂₈ N ₂ O ₅

Structural formula:

Molecular weight: 376.44700

Exact mass: 376.20000

PSA: 76.15000

LogP: 1.93820

Remifentanil Properties

Density: 1.171g / cm ³

Boiling point: 487.8ºC at 760mmHg

Flash point: 248.8ºC

Refractive index: 1.541

Vapor pressure: 1.15E-09mmHg at 25 ° C ^[1]

Remifentanil molecular structure data

1. Molar refractive index: 101.07

2. Molar volume (cm / mol): 321.2

3. Isotonic specific volume (90.2K): 840.2

4. Surface tension (dyne / cm): 46.8

5. Polarizability (10-24cm3): 40.06

Remifentanil Computational Chemistry Data

1. Hydrophobic parameter calculation reference value (XlogP): 1.9

2.Number of hydrogen bond donors: 0

3.Number of hydrogen bond acceptors: 6

4.Number of rotatable chemical bonds: 9

5.Number of tautomers: none

6. Topological molecular polar surface area 76.2

7.Number of heavy atoms: 27

8.Surface charge: 0

9.Complexity: 523

10.Number of isotope atoms: 0

11. Determine the number of atomic stereocenters: 0

12. Uncertain number of atomic stereocenters: 0

13. Determine the number of chemical bond stereocenters: 0

14. Uncertain number of chemical bond stereocenters: 0

15.Number of covalent bond units: 1

Remifentanil synthesis method

4-methoxycarbonyl-4-[(1-oxopropyl) phenylamino] piperidine was dissolved in acetonitrile, and the resulting solution was added to methyl acrylate at room temperature, followed by stirring at 50 ° C for 2 h to obtain remifentanil.

Remifentanil uses

Used to relieve pain during anesthesia. ^[2]

Remifentanil Pharmacology and Toxicology

Remifentanil Pharmacology

Remifentanil is a fentanyl -type opioid receptor agonist. It quickly reaches blood-brain balance in the human body in about 1 minute, and is rapidly hydrolyzed in tissues and blood, so it has fast onset and short maintenance time. Fentanyl analogs are significantly different. Remifentanil has a dose-dependent analgesic effect and side effects, and has synergistic effects with hypnotics, inhaled anesthetics, and benzodiazepines. Remifentanil's mu opioid receptor agonism can be antagonized by naloxone. In addition, remifentanil can also cause respiratory depression, skeletal muscle (such as chest wall muscle) rigidity, nausea and vomiting, hypotension and bradycardia, etc., within a certain dose range, the effect increases with increasing dose. Intravenous injection of remifentanil hydrochloride at a dose of up to 30 g / kg (completed within 1 minute) does not cause an increase in plasma histamine concentration.

Remifentanil Toxicology

Genotoxicity: Remifentanil's prokaryotic cell gene mutation test, rat liver cell extraprogrammed DNA synthesis test (UDS), gene disruption test (CHO cell), and mouse micronucleus test were all negative; however, metabolic activation Agent, mutagenic effect appeared in vitro mouse lymphocyte test.

Reproductive toxicity: General reproductive toxicity: remifentanil 0.5mg / kg (calculated based on body surface area mg / m2, equivalent to 40 times the maximum clinically recommended human dose) for more than 70 days of continuous intravenous injection, fertility in male rats Decreased; female rats were intravenously administered remifentanil 1 mg / kg for 15 days before mating, and their fertility was not affected. Teratogenic sensitivity toxicity: Rats and rabbits were injected intravenously with remifentanil 5mg / kg and 0.8mg / kg respectively (calculated based on body surface area mg / m2, equivalent to 400 times and 125 times the maximum clinically recommended human dose ) No teratogenic effect. Pregnant rabbits and rats were injected with radiolabeled remifentanil and found to pass through the placenta and into the fetus. Perinatal toxicity: Intraperitoneal injection of remifentanil 5mg / kg (calculated based on body surface area mg / m2, which is equivalent to 400 times the maximum clinically recommended human dose) in rats. No significant effects on development and reproduction. Others: Glycine (commonly used as an excipient for intravenous injection) is an excipient of this product. After intrathecal injection of glycine without remifentanil in dogs, excitement, pain, hind limb dysfunction, and ataxia appeared, so this effect can be considered to be caused by glycine; but the above animal performance has nothing to do with the intravenous administration of this product . ^[3]

Remifentanil Pharmacokinetics

After intravenous administration, remifentanil works quickly, reaching an effective concentration in 1 minute, and the duration of the effect is only 5-10 minutes. The drug concentration decay is in accordance with the three-compartment model. Its distribution half-life (t1 / 2) is 1 minute; elimination half-life (t1 / 2) is 6 minutes; terminal half-life (t1 / 2) is 10-20 minutes; effective biological half-life 3-10 minutes, regardless of the dose and duration of administration. The plasma protein binding rate is about 70%, which mainly binds to -1-acid glycoprotein. The steady-state distribution volume is about 350ml / kg, and the clearance is about 40ml / min / kg. Remifentanil metabolism is not affected by plasma cholinesterase and anticholinesterase drugs, and is not affected by liver, kidney function and age, weight, and sex. It is mainly metabolized by non-specific esterase hydrolysis in plasma and tissues. About 95% of remifentanil is excreted in the urine after metabolism, and the main metabolite activity is only 1/4600 of remifentanil. This product has no change in metabolism rate and no accumulation in the body after long-term infusion or repeated injection. ^[3]

Remifentanil indications

For general anesthesia induction and maintenance of analgesia during general anesthesia.
Used as an anesthetic aid. ^[4]

Remifentanil Usage and Dosage

This product can only be used for intravenous administration, especially for continuous intravenous infusion.

Before administration of this product, one of the following injections must be dissolved and quantitatively diluted to a solution with a concentration of 25 g / ml, 50 g / ml or 250 g / ml: (1) sterile water for injection; (2) 5% glucose injection; ( 3) 0.9% sodium chloride injection; (4) 5% glucose sodium chloride injection; (5) 0.45% sodium chloride injection. This product does not contain any antibacterial and preservatives, so it should be kept sterile during the dilution process, and it should be used as soon as possible after preparation. If it needs to be stored, it should be stored at room temperature for no more than 24 hours, and the unused dilution should be discarded. .

This product can be used with lactated Ringer's solution or 5% glucose lactated Ringer's solution to perform a rapid intravenous infusion after dilution with the above injection.

For continuous infusion and administration of this product, a quantitative infusion device must be used. When possible, a dedicated intravenous infusion channel should be used.

After discontinuation of this product, the infusion channel should be cleaned to prevent unintentional input of residual remifentanil, and to avoid respiratory depression and chest wall muscle rigidity when other drugs are administered through the same infusion channel.

The clinically recommended dosage of this product is shown in the following table:

Adult dosing table

Note: * MAC is the minimum alveolar concentration. When inducing a single-dose injection, the administration time of this product should be greater than 60 seconds.

At the above recommended doses, this product significantly reduces the amount of hypnotics required to maintain anesthesia. Therefore, isoflurane and propofol should be administered as the recommended doses above to avoid excessive anesthesia.

1. Anesthesia induction: This product should be administered with hypnotic drugs (such as propofol, thiopental, midazolam, laughter, sevoflurane or halothane) for induction of anesthesia. Adults are given intravenously continuously at an infusion rate of 0.5-1 g per kg of body weight. An initial dose of 0.5-1 g per kg of body weight can also be given before the intravenous drip, and the static thrust time should be greater than 60 seconds.

2. Anesthesia maintenance of tracheal intubated patients: After tracheal intubation, the infusion rate of this product should be reduced according to other anesthetic drugs according to the instructions in the table above. Due to the rapid onset of action and short duration of action, the rate of administration during anesthesia can be increased by 25-100% or decreased by 25-50% every 2-5 minutes to obtain a satisfactory pharmacological response to the mu opioid receptor. When the patient responded that the anesthesia was too shallow, a 0.5-1 g / kg intravenous bolus was administered every 2-5 minutes to deepen the depth of anesthesia.

Relative to the actual weight of obese patients, the central clearance and steady-state distribution volume of this product have a better correlation with the standard weight. It is recommended to reduce the dosage of such patients and calculate based on the standard weight.

In general, the loading dose is 0.5 to 1.0 µg / kg. The maintenance dose is 0.25 4µg / (kg · min), if necessary, 2µg / (kg · min) can be used, or intermittent intermittent injection of 0.25 1.0µg / (kg · min). ^[3]

Remifentanil adverse reactions

1. Hypotension and bradycardia are dose-dependent and have been reported to cause severe cardiovascular depression and cardiac arrest.

2. Central nervous system: There have been reports of typical opioid central nervous system effects, including euphoria, sedation, dizziness, fatigue, headache, and speech disorders at high doses. There were also reports of excitement.

3. Respiratory system: can cause dose-related respiratory depression, can cause suffocation and hypoxia.

4. Musculoskeletal system: Myotonia may occur after treatment (incidence is similar to alfentanil), which is related to the dosage and the speed of administration.

5. Gastrointestinal tract: postoperative nausea and vomiting.

6. Skin: Rare burning sensation at the injection site, occasional rash and / or itching.

7. Eyes: There have been reports of visual changes after discontinuation and nystagmus at high doses.

8. Others: Warmth, chills and fever, allergic reactions (such as shock) may occur after administration; continuous low-dose intravenous infusion of remifentanil will not cause acute opioid tolerance. ^[4]

Remifentanil Taboo

1. Those who are allergic to remifentanil or other fentanyl derivatives are contraindicated.

2. Disabled in patients with myasthenia gravis.

3. Disable bronchial asthma patients.

It is not recommended for children under 4.2 years without clinical medication information.

5. Remifentanil can pass through the placental barrier. Maternal application may cause neonatal respiratory depression, so it is not recommended for pregnant women.

6. Remifentanil is secreted by breast milk, so it is not recommended for lactating women.

7. Remifentanil is prohibited from epidural or intrathecal administration.

8. Remifentanil is administered in the same route as blood products such as blood, serum and plasma. ^[4]

Remifentanil notes

1. This product is a narcotic drug under special national management. It must strictly abide by the state's regulations on narcotic drugs. Both the hospital and the ward's medicine storage should be double-locked. The color of the prescription should be distinguished from other prescriptions. Responsible custodians at all levels should abide by the transfer system and must not be negligent.

2. This product can cause respiratory depression and suffocation. It should be administered by a qualified and experienced anesthesiologist under the condition of complete monitoring of respiratory and cardiovascular function and auxiliary facilities.

3. At the recommended dosage, this product can cause muscle rigidity. The occurrence of muscle rigidity is related to the dose and rate of administration. Therefore, single-dose injection should be given slowly and the administration time should not be less than 60 seconds. Use of muscle relaxants in advance can prevent muscle rigidity.
The muscle rigidity caused by this product must be treated according to the clinical condition of the patient. Severe muscle tonicity during induction of anesthesia should be given neuromuscular blockers and / or additional hypnotic agents, and intubated ventilation. The muscle rigidity found during the use of this product can also be treated by stopping the administration or reducing the rate of administration. The muscle rigidity can be resolved within a few minutes after stopping the administration; or the opioid receptor antagonist can be given, but this will reverse or It is generally not recommended to inhibit the analgesic effect of this product. In the event of life-threatening muscle rigidity, a rapidly acting neuromuscular blocker should be given or the infusion should be interrupted immediately.

4. Arrhythmia, chronic obstructive pulmonary disease, reduced respiratory reserve capacity and coma of traumatic brain injury, increased intracranial pressure, brain tumors and other patients who are liable to fall into respiratory depression.

5. This product must be discontinued for more than 14 days before monoamine oxidase inhibitors (such as furazolidone, procarbazine) are discontinued, and a small dose should be tried first, otherwise unpredictable serious complications will occur.

6. Respiratory depression should be handled properly when using this product, including reducing the infusion rate by 50% or temporarily interrupting the infusion. This product has not been found to cause recurrent respiratory depression even after prolonged administration, but due to the residual effect of combined anesthetic drugs, respiratory depression will still occur in some patients 30 minutes after stopping the infusion. Therefore, ensure that the patient leaves the recovery room before leaving. It is important that you are fully awake and have sufficient spontaneous breathing.

7. This product can cause dose-dependent hypotension and bradycardia. An appropriate amount of anticholinergic drugs (such as glucopyrrole or atropine) can be given in advance to inhibit these reactions. Hypotension and bradycardia can be treated by reducing the infusion rate of this product or combining drugs, using infusions, boosters or anticholinergics when appropriate.

8. The analgesic effect disappears 5-10 minutes after stopping the administration of this product. For patients who are foreseeing the need for postoperative analgesia, appropriate alternative analgesics should be given before discontinuing the administration of this product, and sufficient time must be given to maximize their effect. The choice of analgesics should be suitable for the specific conditions and care of the patient Level.

9. In the case of non-narcotic induction, this product should not be used with the target of the patient's consciousness as a medicinal effect.

10. This product does not contain any antibacterial and preservatives, so it should be kept sterile during the dilution process, the diluted solution should be used in time, and the unused dilution should be discarded.

11, patients with impaired liver and kidney function do not need to adjust the dose. Patients with severely impaired liver and kidney function are more sensitive to remifentanil respiratory depression and should be monitored during use.

12, athletes use with caution. ^[3]

Remifentanil medication during pregnancy

This product can pass through the placental barrier and there is a risk of neonatal respiratory depression during maternal application. This product can be excreted through breast milk, so pregnant women and lactating women are not recommended. When it must be used, the doctor should weigh the pros and cons.

Remifentanil for children

The medication for children 2-12 years is the same as for adults. Due to the lack of clinical data, it is not recommended for children under 2 years of age.

Remifentanil for the elderly

As the patient ages, the pharmacological effects of remifentanil increase. In elderly patients over 65 years of age, the initial dose is half of the adult dose, and the continuous intravenous drip should be reduced. ^[3]

Remifentanil Drug Interactions

1. Remifentanil has a synergistic effect with thiopental, isoflurane, propofol and other anesthetics. When combined, the dose of the latter should be reduced to 50% to 75% of the original dose. Dosage should be adjusted individually based on patient response.

2. Combined with barbiturates, benzodiazepines (such as midazolam), central muscle relaxants, chloral hydrate, eclovinol, opioid analgesics, sodium oxybutyrate, etc. Can cause increased respiratory depression. ^[4]

Remifentanil overdose

Symptoms of overdose include asphyxia, chest wall muscle rigidity, epilepsy, hypoxia, hypotension, and bradycardia. If overdose or suspected overdose, discontinue administration immediately, maintain open airways, inhale oxygen, and maintain normal cardiovascular function. If respiratory depression is related to muscle rigidity, neuromuscular blockers or mu opioid antagonists need to be given and assisted with breathing. Infusions and boosters and other ancillary methods can be used to treat hypotension. Glucose or atropine is used to treat bradycardia or hypotension. Opiate antagonists such as naloxone are used as specific antidote for severe respiratory depression or muscle rigidity. ^[3]

Remifentanil Expert Reviews

Remifentanil is a newly synthesized pure opioid receptor agonist, which has the characteristics of fast onset, short duration of action, fast elimination, no accumulation, independence of liver and kidney function, rapid awakening, and strong controllability. Compared with other opioid analgesics, it is more suitable for outpatient surgery and endoscopy. Some studies have reported that the remifentanil group is shorter than the fentanyl group in wake-up time, and the awake score is significantly improved. Retention time. Although apnea is more common in the remifentanil group, the pharmacological properties of remifentanil are rapidly degraded, and the slight accumulation of C02 promotes the rapid recovery of spontaneous breathing, thereby avoiding hypoxemia. Studies have found that infusion of remifentanil, the respiratory recovery caused by hypoxia stimulation is faster than infusion of alfentanil. In addition, because of the rapid onset of remifentanil, remifentanil can significantly reduce the amount of propofol used, reducing the average cost of medication, but it should be noted that the remifentanil group significantly increased bradycardia and hypotension, Atropine and ephedrine should be given symptomatic treatment. Currently, remifentanil combined with propofol is used for painless gastroscopy. The analgesia effect is good during surgery, and the incidence of postoperative nausea and vomiting is low. ^[5]