Methoxyflurane Past and Present

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Methoxyflurane Past and Present By Dr. Masoud
Saghafinia Trauma research center of Baqiatallah
medical sciences university Anesthesiologist
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Methoxyflurane Introduction

• It is first time introduced in USA in 1960
• 2,2 dichloro 1,1 difluoro-ethyl methyl ether
• Fluorinated hydrocarbon
• Boiling Point 104C
• Flash Point 62.8C
• Mildly pungent odour

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History

• Methoxyflurane was introduced in the 1960s
• Original use for general anaesthesia
• Single agent or in combination with N2O
• Excellent muscle relaxation with cardiac and
  respiratory stability
• Noted reduction in post-operative analgesics with
  Methoxyflurane
• ANAESTHETIC USE NOW A CONTRAINDICATION FOR
  Methoxyflurane

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Methoxyflurane methabolites

• Almost 75 of Methoxyflurane methabolitis are
  methabolised by human body
• Methoxy difluroacetic acid
• Fluore ion
• Dichloro acetic acid

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FDA Withdrawal of Methoxyflurane

• Methoxyflurane previous supplied in USA
• Indication included Anaesthesia and Analgesia
  (obstetrics/minor procedures)
• In 2005, FDA withdrew of Methoxyflurane due to
  Safety Concerns
• Previously withdrawn in USA by Abbott
  Laboratories in 2001
• Commercial Reasons
• In public notice, FDA cited serious, irreversible
  and potentially fatal nephrotoxicity and
  hepatotoxicity

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Nephrotoxicity

• From late 1960s cases of renal toxicity
  associated with Methoxyflurane use reported
• Characterised by tubular necrosis within kidneys
• Believed to be due to oxalic acid and serum
  fluoride
• Metabolic Byproducts
• Study by Kharash1 demonstrated that toxicity
  caused by metabolic by-products dichloroacetic
  acid and serum fluoride
• Nephrotoxicity specific to Methoxyflurane

1. Kharasch, E. D.,et al New insights into the
mechanism of methoxyflurane nephrotoxicity and
implications for anesthetic development (part 2)
Identification of nephrotoxic metabolites.
Anesthesiology, 2006 105, 737-45
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Nephrotoxicity

• Mazze and Cousins demonstrated renal damage to
  be Dose Related
• Large and Prolonged Anaesthetic doses cause
  toxicity
• Sub-clinical Renal Toxicity associated with gt 2.5
  MAC hours of use
• MAC Minimum Alveolar Concentration
• Maximum analgesic dose (6mL) 0.59 MAC hours
• Less than ¼ of dose known to cause reversible
  damage!
• No reports of occurrence in Australia

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Methoxyflurane in kidney

• The inhalation anesthetic agents causes renal
  function disorder.
• Urin flow?
• GFR?
• Renal perfusion?
• Electrolitis filtration?
• These changes are disappear immediately after
  operation.

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Renal intoxication severity depends on blood
Methoxyflurane and Fluore ion level
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Hepatotoxicity

• Various reports of hepatic damage, including
  hepatitis with Methoxyflurane Use
• Rarely reports and predominantly with Anaesthetic
  use
• Considered idiosyncratic reaction by reviewers

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Methoxyflurane in Liver

• It has no toxic methabolite for the liver
• There are some reports related to hepatic
  disfunction due to use it.
• It causes a syndrom like Halotane hapatitis.
• These changes are reversible in human

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Anaesthesia versus Analgesia

• Significant difference dose administered for
  Analgesic and Anaesthetic Use
• Anaesthetic Dose
• 40 60mL
• Analgesic Dose
• 3 6mL

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Drug Regulatory Agency Evaluation

• Australian Regulatory Agency (TGA) reviewed
  safety of Methoxyflurane for Analgesic Use in
  2006
• Clinical Evaluator concluded
• Risk of clinically important Nephrotoxicity
  relates the use of methoxyflurane in anaesthetic
  doses and is acceptably low when the drug is used
  for analgesia
• Hepatotoxicity is rare and does not appear to be
  more common with methoxyflurane than with other
  halogenated anaesthetic agents

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present

• Methoxyflurane approved in 7 countries
• Australia, New Zealand, GCC, Moldova
• Predominantly used by Ambulance Service
• More than 2.5 million doses supplied in 30 years
• Excellent safety profile
• Common adverse effects include cough, drowsiness,
  nausea, dry throat

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Summary

• Methoxyflurane associated Nephrotoxicity reported
  with Anaesthetic use of Methoxyflurane
• Nephrotoxicity is dose related
• Analgesic doses not reported to cause renal
  damage
• Independent Clinical Expert from Government
  Agency considers product safe for analgesic use

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Dose linearity of inhaled fentanyl (FT) with
comparative pharmacokinetics to transmucosal
fentanyl (A)

• Background Cancer patients frequently experience
  breakthrough pain which is a transitory flare of
  moderate or severe pain occurring on top of
  otherwise controlled, persistent pain. Fentanyl
  TAIFUN (FT), a novel breath-actuated dry powder
  inhaler is being developed for the treatment of
  breakthrough cancer pain in patients with ongoing
  opiate therapy. Methods A randomized,
  open-label, crossover phase I study with 5
  periods derived pharmacokinetics after fentanyl
  oromucosal (Actiq, A) and pulmonary (FT)
  administration in 30 healthy volunteers. Each
  single dose of study medication (200 mcg A or
  100, 200, 400 or 800 mcg FT) was administered
  following premedication with 50 mg of naltrexone
  with a minimum of 7 days between doses.
  Pharmacokinetic parameters were calculated from
  the plasma concentrations using a
  non-compartmental model. Results The plasma
  concentrations of FT increased proportionally to
  the increasing dose and t1/2 was independent of
  the dose. FT had a linear elimination phase. FT
  had a substantially faster absorption and higher
  peak fentanyl concentration (Cmax) than A. Median
  Tmax was 1 and 60 min for FT and A, respectively.
  Moreover, there was an 8-fold increase in
  bioavailability of fentanyl during the first 20
  min when 200 mcg FT is compared to 200 mcg A.
  Conclusions The plasma concentrations from FT
  increases proportionally to the increasing dose
  while t1/2 is independent of the dose, and there
  is a linear elimination phase. Overall, FT is
  substantially more bioavailable than A during the
  important first 2030 minutes after
  administration. Inhalation of FT allows an
  immediate and comparable availability of fentanyl
  suggesting potential for rapid pain relief.