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Recent advances - MGMC Dr. S. Parthasarathy MD., DA., DNB, MD (Acu), Dip. Diab. DCA, Dip. Software statistics, PhD(physiology) Remifentanil • Remifentanil is a selective µ opioid agonist with an analgesic potency similar to that of fentanyl • Remifentanil is structurally unique because of its ester linkage, which renders it susceptible to hydrolysis to inactive metabolites by nonspecific plasma and tissue esterases • Its action culminated by metabolism and not redistribution • So no accumulation and re entry to act again • The pharmacokinetics are unchanged in renal or hepatic failure • No big individual changes • Analgesia – 1- 2 µg/kg ( 30 -60 seconds)bolus • Followed by 0.1 µg/kg/minute • Start acting in one minute and finish in ten minutes • Reduction of MAC by 60 % • Pediatrics – same doses but in old age 50 % reduction start • 20 µg/kg – anesthetic dose • For postoperative analgesia, remifentanil should be initially administered by continuous infusion at a rate of 0.1 µg/kg/min. • The infusion rate may be adjusted every 5 minutes in 0.025 µg/kg/min increments to balance the patient’s level of analgesia and respiratory rate • suppression of the transient sympathetic nervous system response to direct laryngoscopy and tracheal intubation. • safely in coronary artery bypass graft (CABG) and neurosurgery with good results. • Long duration surgeries – ideal Context sensitive half life MAC • As a part of sedation technique, remifentanil, in the dosages of 0.05 to 0.10 µg/kg/min in combination with midazolam, 2 mg IV, provides effective sedation and analgesia during monitored anaesthesia care • Obstetric use – contradictory – but now a lot of articles on remifentanyl infusion for labour analgesia • Remifentanyl should not be mixed with blood – esterases • Remifentanyl contains glycine – hence epidural and spinal use – no • Only by infusions Summary • • • • • Synthetic Opioid Ester moiety – esterases 1 µg/kg – infusion -- 0.1 µg/kg/minute 1 minute – 10 minutes Analgesia, Symp. Suppresion , MAC reduction, MAC and post operative analgesia.labour • No with blood • Glycine – no to neuraxial use • Context sensitive half life Remimazolam • Midazolam is the parent compound of remimazolam. • As the name indicates, this new drug is midazolam incorporating pharmacokinetic properties of remifentanil. Midazolam with characters of remifentanyl Nonspecific esterases • remimazolam acts on GABA receptor, specifically GABAalpha. • Other drugs acting on GABA receptors are propofol (GABA-beta), etomidate (GABA-alpha), and thiopentone (GABA-alpha), all commonly used anesthetics. • GABA is the main inhibitory neurotransmitter in the central nervous system. • • • • • dose-independent ester hydrolysis organ-independent elimination Onset time of 1- 3 minutes Context sensitive half life – 7 minutes 0.075 mg / kg Clinical uses • Single dose for premedication • Bolus followed by supplemental doses for procedural sedation. • Intravenous anesthetic along with an opioid (as part of total intravenous anesthesia) • Intensive care unit (ICU) sedation • Bretazanil and imidazanil are newer benzodiazepine agonists with less tolerance Flumazenil Flumazenil • flumazenil is a specific benzodiazepine receptor antagonist • primarily available by injection only, • It reverses the effects of benzodiazepines by competitive inhibition at the benzodiazepine binding site on the GABA A receptor. Uses • Benzodiazepine overdose • Zolpidem overdose • Hepatic encephalopathy • Radiolabeled with the radioactive isotope carbon-11 flumazenil may be used as a radio ligand in neuroimaging -- with positron emission tomography to visualize the distribution of GABA A receptors in the human brain. Pharmacokinetics • The onset of action is rapid and usually effects are seen within one to two minutes. ( 1 mg dose) • The peak effect is seen at six to ten minutes. The recommended dose for adults is 200 μg every 1–2 minutes until the effect is seen, to a maximum of 3 mg per hour. • It is available as a clear, colourless solution for intravenous injection, containing 500 μg in 5ml Dependence also • the gold standard for treatment of high-dose benzodiazepine dependency is 8–10 days of low dose, slow infusion of flumazenil • It rapidly reverses the unconsciousness, respiratory depression, sedation, amnesia and psychomotor dysfunction produced by the benzodiazepines according to the dose. • It has no effect on EEG, cerebral metabolism and has no anticonvulsant properties • No effect on TCADs or opioids or barbiturates • Midaz > diaz > lorazepam Pearls • Many benzodiazepines have longer half-lives than flumazenil. • repeat doses of flumazenil may be required to prevent recurrent symptoms of overdosage. • hepatically metabolised to inactive compounds which are excreted in the urine • Subjects who are physically dependent on benzodiazepines may suffer benzodiazepine withdrawal symptoms, including seizure, Pharmacokinetics • Initial distribution half-life is 4 to 11 minutes • the terminal half-life is 40 to 80 minutes. • half-life to 1.3 hours in patients with moderate hepatic impairment • 2.4 hours in severely impaired patients. • Compared to adults, the elimination half-life in pediatric patients was more variable, averaging 40 minutes (range: 20 to 75 minutes). Summary • • • • • • • Benzodiazepine receptor antagonist Uses Not useful in ?? Dependence Dose Side effects Liver ? • Thank you