PENTHRANE

Clinical safety rating: caution

Comprehensive clinical and safety monograph for PENTHRANE (PENTHRANE).

How it works

Penthrane (methoxyflurane) is a volatile halogenated ether anesthetic that potentiates GABA-A receptor activity and inhibits NMDA receptors, leading to neuronal hyperpolarization and central nervous system depression. It also sensitizes the myocardium to catecholamines and produces nephrotoxic fluoride ions via metabolism.

What the body does with it

Metabolism	Primarily hepatic via cytochrome P450 enzymes (CYP2E1), releasing inorganic fluoride ions; approximately 50% is metabolized.
Excretion	Approximately 50% of absorbed methoxyflurane is eliminated unchanged by the lungs; the remainder is metabolized, primarily via hepatic CYP450 isoenzymes, with fluoride ion and other metabolites excreted renally. Biliary/fecal elimination is negligible (<1%).
Half-life	Terminal elimination half-life ranges from 1.5 to 4 hours, reflecting slow washout due to high fat solubility and prolonged release from adipose tissue. Clinically, this can lead to prolonged sedation and risk of fluoride-induced nephrotoxicity.
Protein binding	40–50% bound to plasma proteins, primarily albumin.
Volume of Distribution	Vd approx 2.0–3.5 L/kg, reflecting extensive distribution into adipose tissue and slow equilibration.
Bioavailability	Inhalation: 100% via pulmonary route (no first-pass metabolism). Not administered orally or parenterally in clinical use.
Onset of Action	Inhalation: 2–5 minutes for anesthetic induction; analgesic effects occur within 3–5 minutes via low-dose intermittent inhalation (e.g., via Pentthrane inhaler).
Duration of Action	Anesthetic effects last 15–30 minutes after a single administration; analgesic effects persist for 30–60 minutes after discontinuation of low-dose inhalation. Clinical note: Accumulation with repeated dosing extends duration significantly.

Classification & Brands

Dosing & administration

0.2-0.5% inspired concentration via inhalation for analgesia; for general anesthesia, up to 2% inspired via vaporizer.

Dosage form	LIQUID
Renal impairment	No specific GFR-based dose adjustments; use with caution in severe renal impairment due to potential nephrotoxicity from fluoride ions.
Liver impairment	No specific Child-Pugh based modifications; use with caution in severe hepatic impairment due to potential hepatotoxicity.
Pediatric use	Not recommended for children due to risk of nephrotoxicity and hepatotoxicity; alternative agents preferred.
Geriatric use	Use lower inspired concentrations (e.g., 0.2-0.5%) and monitor closely for hypotension and respiratory depression; consider reduced dose due to decreased renal and hepatic function.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for PENTHRANE (PENTHRANE).

Breastfeeding	Unknown if excreted in human milk. M/P ratio not established. Caution advised; consider benefits of breastfeeding vs. potential risk to infant.
Teratogenic Risk	First trimester: Limited human data; animal studies show fetal toxicity at high doses. Potential risk of congenital anomalies cannot be excluded. Second and third trimesters: May cause fetal hypotension and bradycardia; avoid prolonged or high-dose exposure. Near term: Risk of neonatal respiratory depression.
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

Not approved for use in the United States; has been associated with fatal hepatotoxicity and nephrotoxicity, particularly when used at high doses or for prolonged periods.

Side Effect Profile

Serious Effects

Absolute Contraindications

Hypersensitivity to halogenated anesthetics; known or suspected susceptibility to malignant hyperthermia; significant hepatic or renal impairment; concurrent use of nephrotoxic agents.

Clinical Precautions

Precautions

Hepatotoxicity and nephrotoxicity due to fluoride ion accumulation; myocardial sensitization to catecholamines; malignant hyperthermia risk; respiratory depression; dose-dependent renal impairment.

Clinical Tips & Counseling

Drug interactions

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PENTHRANE

Clinical safety rating: caution

Comprehensive clinical and safety monograph for PENTHRANE (PENTHRANE).

How it works

What the body does with it

Metabolism	Primarily hepatic via cytochrome P450 enzymes (CYP2E1), releasing inorganic fluoride ions; approximately 50% is metabolized.
Excretion	Approximately 50% of absorbed methoxyflurane is eliminated unchanged by the lungs; the remainder is metabolized, primarily via hepatic CYP450 isoenzymes, with fluoride ion and other metabolites excreted renally. Biliary/fecal elimination is negligible (<1%).
Half-life	Terminal elimination half-life ranges from 1.5 to 4 hours, reflecting slow washout due to high fat solubility and prolonged release from adipose tissue. Clinically, this can lead to prolonged sedation and risk of fluoride-induced nephrotoxicity.
Protein binding	40–50% bound to plasma proteins, primarily albumin.
Volume of Distribution	Vd approx 2.0–3.5 L/kg, reflecting extensive distribution into adipose tissue and slow equilibration.
Bioavailability	Inhalation: 100% via pulmonary route (no first-pass metabolism). Not administered orally or parenterally in clinical use.
Onset of Action	Inhalation: 2–5 minutes for anesthetic induction; analgesic effects occur within 3–5 minutes via low-dose intermittent inhalation (e.g., via Pentthrane inhaler).
Duration of Action	Anesthetic effects last 15–30 minutes after a single administration; analgesic effects persist for 30–60 minutes after discontinuation of low-dose inhalation. Clinical note: Accumulation with repeated dosing extends duration significantly.

Classification & Brands

Dosing & administration

0.2-0.5% inspired concentration via inhalation for analgesia; for general anesthesia, up to 2% inspired via vaporizer.

Dosage form	LIQUID
Renal impairment	No specific GFR-based dose adjustments; use with caution in severe renal impairment due to potential nephrotoxicity from fluoride ions.
Liver impairment	No specific Child-Pugh based modifications; use with caution in severe hepatic impairment due to potential hepatotoxicity.
Pediatric use	Not recommended for children due to risk of nephrotoxicity and hepatotoxicity; alternative agents preferred.
Geriatric use	Use lower inspired concentrations (e.g., 0.2-0.5%) and monitor closely for hypotension and respiratory depression; consider reduced dose due to decreased renal and hepatic function.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for PENTHRANE (PENTHRANE).

Breastfeeding	Unknown if excreted in human milk. M/P ratio not established. Caution advised; consider benefits of breastfeeding vs. potential risk to infant.
Teratogenic Risk	First trimester: Limited human data; animal studies show fetal toxicity at high doses. Potential risk of congenital anomalies cannot be excluded. Second and third trimesters: May cause fetal hypotension and bradycardia; avoid prolonged or high-dose exposure. Near term: Risk of neonatal respiratory depression.
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

Not approved for use in the United States; has been associated with fatal hepatotoxicity and nephrotoxicity, particularly when used at high doses or for prolonged periods.

Side Effect Profile

Serious Effects

Absolute Contraindications

Hypersensitivity to halogenated anesthetics; known or suspected susceptibility to malignant hyperthermia; significant hepatic or renal impairment; concurrent use of nephrotoxic agents.

Clinical Precautions

Precautions

Hepatotoxicity and nephrotoxicity due to fluoride ion accumulation; myocardial sensitization to catecholamines; malignant hyperthermia risk; respiratory depression; dose-dependent renal impairment.

Clinical Tips & Counseling

Drug interactions

Loading safety data…