PENTHRANE
Clinical safety rating
cautionComprehensive clinical and safety monograph for PENTHRANE (PENTHRANE).
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.
| 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. |
| Molecular Weight | 165 |
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. |
| 1st trimester | Use only if clearly needed. Methoxyflurane crosses the placenta and may cause fetal effects. No well-controlled studies in human pregnancy; animal studies show adverse effects at high doses. |
| 2nd trimester | Use cautiously. Potential for uterine relaxation and fetal depression. Avoid prolonged or high-concentration exposure. |
| 3rd trimester | Avoid near term due to risk of uterine relaxation and neonatal respiratory depression. Use only if benefit outweighs risk. |
Clinical note
Comprehensive clinical and safety monograph for PENTHRANE (PENTHRANE).
| Placental transfer | Rapidly crosses the placenta; fetal concentrations approximate maternal levels after prolonged exposure. Evidence from animal and human studies confirms significant transfer. |
| Breastfeeding | Methoxyflurane is excreted into breast milk in low concentrations. Due to potential for infant exposure and lack of safety data, caution is advised. Consider pumping and discarding milk for 24 hours after exposure. |
| Lactation Rating | L4 - Possibly Hazardous |
| 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 | Monitor maternal vital signs (heart rate, blood pressure, oxygen saturation). Fetal heart rate monitoring during prolonged use. Assess uterine tone and fetal movements. Post-delivery: Monitor neonate for respiratory depression if used near term. |
| Fertility Effects | No human data on fertility impairment. Animal studies show no significant reproductive toxicity at clinically relevant doses. |
■ 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.
| Serious Effects |
Known hypersensitivity to methoxyflurane or other halogenated anestheticsHistory of malignant hyperthermiaClinically significant hepatic dysfunctionRenal failure or significant impairment (risk of nephrotoxic fluoride metabolites)Concurrent use of tetracyclines (potential for nephrotoxicity)
| Precautions | Hepatotoxicity and nephrotoxicity due to fluoride ion accumulation; myocardial sensitization to catecholamines; malignant hyperthermia risk; respiratory depression; dose-dependent renal impairment. |
| Food/Dietary | No direct food interactions are documented. However, methoxyflurane metabolism may be affected by hepatic enzyme inducers or inhibitors. Avoid excessive consumption of grapefruit juice as it may inhibit CYP2E1, potentially altering drug metabolism. Maintain adequate hydration to help reduce the risk of nephrotoxicity. |
| Clinical Pearls | Penthrane (methoxyflurane) is a volatile inhalational anesthetic with potent analgesic properties at subanesthetic doses. It is primarily used for emergency pain relief via a handheld inhaler (Penthrox). Key clinical pearls: (1) Nephrotoxicity is dose-dependent due to inorganic fluoride metabolites; limit exposure to a maximum of 6 mL over a week. (2) Avoid concurrent use of tetracyclines or aminoglycosides due to increased nephrotoxic risk. (3) Caution in patients with renal impairment, hepatic disease, or malignant hyperthermia susceptibility. (4) Rapid onset of analgesia within 2-5 breaths; monitor for excessive sedation or respiratory depression. (5) Do not use in patients with cardiovascular instability or hypovolemia as it can cause myocardial depression. |
| Patient Advice | Penthrane is used to relieve moderate to severe pain from trauma or procedures. · Inhale from the device as instructed; do not swallow the liquid. · You may feel drowsy or dizzy; avoid driving or operating machinery for at least 24 hours after use. · Do not consume alcohol or take other central nervous system depressants without consulting your doctor. · Report any signs of kidney injury such as decreased urination, swelling, or fatigue. · Use only as directed and do not exceed the prescribed dose or duration. · Keep the inhaler out of reach of children and do not share with others. |
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