MD., DA., DNB, MD (Acu), Dip. Diab. DCA, Dip. Software statistics, 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 with characters of remifentanyl 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 GABA-alpha. 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