Methoxyflurane - Pharmacodynamics

Pharmacodynamics

Cardiovascular effects

The effects of methoxyflurane on the circulatory system resemble those of diethyl ether. In dogs, methoxyflurane anesthesia causes a moderate decrease in blood pressure with minimal changes in heart rate, and no significant effect on blood sugar, epinephrine, or norepinephrine. Bleeding and increased arterial partial pressure of carbon dioxide (PaCO₂) both induce further decreases in blood pressure, as well as increases in blood glucose, epinephrine and norepinephrine. In humans, methoxyflurane produces some decrease in blood pressure, but cardiac output, stroke volume, and total peripheral resistance are only minimally depressed. Its effect on the pulmonary circulation is negligible, and it does not predispose the heart to cardiac dysrhythmias.

Respiratory effects

Unlike diethyl ether, methoxyflurane is a significant respiratory depressant. In dogs, methoxyflurane causes a dose-dependent decrease in respiratory rate and a marked decrease in respiratory minute volume, with a relatively mild decrease in tidal volume. In humans, methoxyflurane causes a dose-dependent decrease in tidal volume and minute volume, with respiratory rate relatively constant. The net effect of these changes is profound respiratory depression, as evidenced by CO₂ retention with a concomitant decrease in arterial pH (this is referred to as a respiratory acidosis) when anesthetized subjects are allowed to breathe spontaneously for any length of time.

Gastrointestinal effects

In a series of 500 consecutive obstetric patients, Boisvert and Hudon observed vomiting in 12 (4.8%) patients during or after administration of methoxyflurane anesthesia. These findings compared favorably with those reported for cyclopropane (42%), trichloroethylene (28%) and halothane (4.6%). In another study of 645 obstetric patients, Romagnoli and Korman observed 8 cases (1.2%) of postoperative vomiting, one of whom was retching before the administration of the anesthetic.

Analgesic effects

Although the high blood solubility of methoxyflurane is often undesirable, this property makes it useful in certain situations—it persists in the lipid compartment of the body for a long time, providing sedation and analgesia well into the postoperative period. There is substantial data to indicate that methoxyflurane is an effective analgesic and sedative agent at subanesthetic doses. Supervised self-administration of methoxyflurane in children and adults can briefly lead to deep sedation, and it has been used as a patient controlled analgesic for painful procedures in children in hospital emergency departments. During childbirth, administration of methoxyflurane produces significantly better analgesia, less psychomotor agitation, and only slightly more somnolence than trichloroethylene.

In 1968, Robert Wexler of Abbott Laboratories developed the Analgizer, a disposable inhaler that allowed the self-administration of methoxyflurane vapor in air for analgesia. The Analgizer consisted of a polyethylene cylinder 5 inches long and 1 inch in diameter with a 1 inch long mouthpiece. The device contained a rolled wick of polypropylene felt which held 15 milliliters of methoxyflurane. Because of the simplicity of the Analgizer and the pharmacological characteristics of methoxyflurane, it was easy for patients to self-administer the drug and rapidly achieve a level of conscious analgesia which could be maintained and adjusted as necessary over a period of time lasting from a few minutes to several hours. The 15 milliliter supply of methoxyflurane would typically last for two to three hours, during which time the user would often be partly amnesic to the sense of pain; the device could be refilled if necessary. The Analgizer was found to be safe, effective, and simple to administer in obstetric patients during childbirth, as well as for patients with bone fractures and joint dislocations, and for dressing changes on burn patients. When used for labor analgesia, the Analgizer allows labor to progress normally and with no apparent adverse effect on Apgar scores. All vital signs remain normal in obstetric patients, newborns, and injured patients. The Analgizer was widely utilized for analgesia and sedation until the early 1970s, in a manner that foreshadowed the patient-controlled analgesia infusion pumps of today. The Analgizer inhaler was withdrawn in 1974, but use of methoxyflurane as a sedative and analgesic continues in Australia and New Zealand in the form of the Penthrox inhaler. Trials of methoxyflurane as an analgesic in emergency medicine are going on in the UK.