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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
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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.
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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
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Benzodiazepine receptor antagonist
Uses
Not useful in ??
Dependence
Dose
Side effects
Liver ?
• Thank you