Advances In The Pharmacology And Clinical Use Of Remifentanil

Remifentanil is a new kind ofμ-opioid receptor agonist, and opioids is essentialto balance anesthesia. Remifentanil has a powerful analgesic potency. Theesterase-based metabolism of remifentanil makes its pharmacokinetics independent ofhepatic and renal function. Remifentanil is of rapid onset and a short duration;providing a safe and does-controlled analgesic. Nowadays, remifentanil has been usedextensively in a number of countries in clinic.Remifentanil is a piperidine derivative, a 3-{4-methoxycarbonyl-4-[(1-oxopropyl)-phenylamino]-1-piperidine}propanoic acid, methyl ester. Remifentanil,whose molecular formula is C₂₀H₂₈N₂O₅·HCL and molecular mass is 412.91, has aconfiguration very similar to the other piperidine derivatives. It is a synthetic opioid,supplied as remifentanil hydrochloride, a white lyophilized powder. It is supplied as1mg, 2mg, and 5mg vials that must be reconstituted and diluted to 25 mg·L^-1 or 50mg·L^-1 of a pH of±3.0 and a pKa of 7.07 before administration. It undergoesspontaneous degradation, but at a pH＜4, it is stable for 24 h. It is lipid-soluble, withan octanol/water partition coefficient of 17.9 at pH 7.4. The present formulation alsocontains glycine, therefore it can not be used in vertebral canal. Remifentanil also cannot be mixed with propofol and blood products for infusion.Remifentanil is of a rapid onset aider intravenous injection. The pharmacokinetics of remifentanil is adequately described by a 3-compartment model,distribution half-life time (t_1/2α) of 0.5～1.5min, elimination half-life time (t_1/2β) of5～8 min and clearance with a terminal elimination half-life time(t_1/2γ) of 0.7～1.2 h,context-sensitive half-time (t_1/2cs)of 3～5min, volume of distribution at steady state(Vdss) of 0.2～0.3L·kg^-1, clearance of 30～40ml·kg^-1min-^-1, and plasma proteinbinding rate of 70%～90% (70% of remifentanil in plasma bind toα₁ acidglycoprotein). The effect of the age on distribution of remifentanil is significant inchildren and the elder. In children, the ratio of total body fluid, extracellular fluid orblood volume to body weight are higher than that of adults. So when the drug is givenintravenously and diluted in extracellular, its volume of distribution is larger inchildren. The t_1/2αand Vdss are maximum in infants. Following the decreasing oftotal body fluid, the elderly tend to have a smaller volume of distribution and aslightly lower clearance.The molecular structure of remifentanil contains an esterlinkage that makes it susceptible to metabolism by nonspecific esterases in blood andother tissues, especially in red blood cell. Remifentanil is metabolized by esterhydrolysis. The major metabolite, about 99%, of remifentanil is its carboxylic acidmetabolite (GI-90291) , remifentanil acid. Another minor metabolic pathway is toremoved alkylation at N-end, 90% of the metabolites are also eliminated by kidney.The metabolic rate of remifentanil are independent of plasma cholinesterase, hepaticand renal function. Gender has no effect on remifentanil's pharmacokinetics.Remifentanil can pass through the placenta and be metabolized quickly.Remifentanil has strong affinity for theμ-opioid receptor and less or so for the[delta]-and [kappa]-receptors, and it is competitively antagonized by naloxone. Theanalgesic effect of remifentanil is a dose-dependent increases, and has the ceilingeffect. Its effect is about 20～30times stronger than that of alfentanil when the doesare equal. Remifentanil causes a dose-dependent suppression of the EEG. Its effect oncerebral blood flow, intracranial pressure, and cerebral metabolic rate seem similar to that of otherμ-opioids, It has been used successfully in patients with mildly increasedintracranial pressure presenting for surgery. The administration of remifentanil, likeotherμ-opioids, results in dose-dependent respiratory depression. The degree ofrespiratory depression of remifentanil is dependent not only on the dose administered,but also on multiple factors such as age and body weight etc. If required,remifentanil's respiratory depressant effect can be reversed by naloxone. The changesin hemodynamic variables seem to be dose-independent. As remifentanil used ininduction and maintenance of anesthesia, it can lead to hypotension and bradycardia.Remifentanil can abolish spontaneous esophageal motility and delay gastric emptying.Remifentanil is usually used in induction and maintenance of anesthesia.Remifentanil attenuates the haemodynamic response to tracheal intubation.Target-controlled infusion (TCI), a convenient technique, can provide a stableplasma concentration of remifentanil. Now TCI remifentanil with propofol have beenfrequently used in TIVA.In children, the pharmacology and clinical feature of remifentanil are similar toadult. The time of extubation and recovery is not dose-related, even more dosage inchildren. Remifentanil with midazolam have been used in pediatric bone marrowaspiration, other traumatogenic diagnostic procedures and controlled hypotension inoperation on the middle ear.It has been reported that bolus doses and infusion rates should decrease to onethird in the elder compared with the young. Remifentanil decreases the response tolaryngoscopy. There are significant individual variability in elder. The time ofrecovery can prolong.Quick postoperative wake-up is a special requirement of neurosurgery anesthesia,aimed to monitor the neurological function. Based on remifentanil, the balanceanesthesia provides stable hemodynamics, quick postoperative wake-up and nopostoperative respiratory depression. Its effect on intracranial pressure (ICP) seems similar to that of otherμ-opioids. Remifentanil has been used successfully in patientswith mildly increased intracranial pressure presenting for surgery.Remifentanil is an excellent opioid for cardiovascular surgery anesthesia. Stablehemodynamics, less neurotransmitter "stress response", rare bradycardia andhypotensive would appear if remifentanil is administered slowly. Remifentanil has itsspecial advantages in heart operation as a "fast-channel" opioids. A remifentanil-based regimen is more effective in the provision of optimal analgesia-sedation than astandard fentanyl-based regimen. The remifentanil-based regimen allow a more rapidemergence from sedation and facilitate earlier extubation to examine the neurologicalfunction. In the patients undergoing carotid endarterectomize surgery, remfentanilallow a more quickly and completely postoperative wake-up than fentanyl, so as toexamine the postoperative nerval function examination.Remifentanil has been used successfully in organ transplantation surgery, such ascardiac, lung and liver, without adverse effects. The immunosuppressant regimensthat can decrease the immune function of the patients, may also render patients moresensitive to anesthesia and surgery. So remifentanil must be used cautiously in thesepatients.Remifentanil is an ideal analgesic for obstetric induction for it can attenuate thestress response and has less influence on the neonates in general anesthesia. Althougha part of neonates may show brief respiratory depression, mask oxygen inhalationwould release this type of symptom smoothly, and naloxone or tracheal intubation areunnecessary. PCIA remifentanil appears to provide better analgesia than meperidinethroughout labor and delivery and has minimal maternal or neonatal side effects.It is an effective pathway that uses remifentanil in postoperative analgesia, butremifentanil constant infusion is needed for patients transport. Because of respiratorydepression effect of remifentanil, monitoring is necessary during the transportprocedure. Besides of analgesic effect, remifentanil also plays a role of sedation. Remifentanil shorten the mechanical ventilation time and the time fromoff-mechanical ventilation to extubation. It is feasible to use remifentanil in ICUpatients with spontaneous breathing.Surgical procedures on the vertebral column may result in spinal cord damage, soimmediate monitoring somatosensory evoked potentials (SSEPs) or intraoperativewake-up is needed to ensure that there are no neurological deficits. Remifentanil hassimilar influence on SSEPs to fentanyl, nevertheless, remifentanil is suitable forvertebral column surgery even more for its non accumulation in body andpostoperative quick wake-up.In view of its ultra-short half-life, rapid offset and rapid recovery, remifentanilmay be ideal in the setting of outpatient anesthesia, such as gastroscopy, enteroscopyand induced abortion procedure. Coadministration of remifentanil and propofolprovides a powerful analgesia and rapid recovery, and remifentanil decreases thebolus dose of propofol needed to achieve a lower plasma-effect compartmentconcentration and abates analgesia resulting from propofol injection and shortensrecovery time to a clinically significant degree. Remifentanil and midazolamadministered together at sedative doses display a major synergistic interaction.Midazolam decreases the side effects and anxiety resulting from remifentanil to reachthe ideal sedation and analgesia. Compared with the other modes of balanceanesthesia, it does cut down the consumption of patients in and out of the operationroom and shorten the time that stay in ICU.Large dose of remifentanil or when coadministration with other agents mayinduce bradycardia and hypotension. The rates of postoperative nausea and vomitingis 43% and 20% respectively. Bolus doses of remifentanil may result in chest wallrigidity which is dose-dependent too. The other side effects of remifentanil includeskin pruritus (16%), anxiety (2%), fever (5%), dizziness and nystagmus etc.In a word, the current studies have demonstrated that remifentanil has a powerful analgestic potency, a rapid onset, a short duration and a constancy context-sensitivehalt-time, and its metabolism is independent of hepatic and renal function.Remifentanil is mainly used in the induction and maintenance of anesthesia. Forthermore, its use on anesthesia for "fast-channel" cardiac surgery, neurosurgery,obstetrical surgery and minor operation in outpatients department, even for patientswith documented hepatic or renal failure has significant advantages. So remifentanil isan ideal opioid analgesic.