Folenda Mechanism of Action

Pharmacology: Pharmacodynamics: Propofol is a short-acting anesthetic given by IV for the induction and maintenance of general anesthesia. It is also used for sedation in adult patients undergoing surgery in conjunction with local or general anesthesia, induction is rapid, as is recovery. Propofol has no analgesic activity and supplementary analgesia may be required.
After intravenous injection of Propofol 10 mg/mL, a hypnotic effect occurs quickly. The induction time is dependent on the injection speed and is normally 30-40 seconds. The duration of effect is short as a result of rapid metabolization and excretion (4-6 minutes). The mechanism of action is not completely known, as with all general anesthetics. However, it is believe that Propofol produces its sedative or anesthetic effect by means of positive modulation of the inhibitory effect of the neurotransmitter GABA through the ligand-gated GABA_A receptors.
Limited studies on the duration of action of anesthesia with Propofol in children indicate that the safety and efficacy remain unchanged up to duration of 4 hours.
Pharmacokinetics: Propofol is up to 98% bound to plasma protein.
After intravenous administration, the initial progression of the blood concentration (alpha base) is characterized by a large decrease due to the rapid distribution in the organism. The half-life for this phase is 1.8-4.1 minutes. The decreased in the blood concentration is slower during the elimination or beta phase. The half-life for this phase was calculated at 34 to 64 minutes. A so-called deep compartment can be identified over a longer period of observation. The half-life for this phase (gamma phase) of the blood concentration is 184-382 minutes. The initial distribution volume V amounts to 22-76l, and the total distribution volume Vdβ is 387-1,587l. Propofol has a large distribution volume and is quickly eliminated from the body (total clearance: 1.5-2 L/min). The elimination occurs through metabolization, primarily in the liver, where inactive conjugates of Propofol and the corresponding hydroquinone are formed depending on the blood flow, which undergo renal excretion. Propofol is predominantly metabolized in the liver, Glucuronides of the Propofol and glucuronides as well as sulphates conjugates 2.6-diisopropyl-1.4-quinol are found as metabolites. 40% of the administered dose is present in the form of glucuronide of Propofol. All metabolites are inactive. Approximately 88% of the applied Propofol is excreted in the urine in the form of metabolites, and approximately 0.3% is unchanged in the stool.
Toxicology: Preclinical safety data: Acute toxicity: The intravenous LD50 in mice is 53, and in rats it is 42 mg Propofol/kg of body weight.
Chronic toxicity: Chronic toxicity trials have been carried out on rats and dogs. Doses of 10-30 mg Propofol/kg of body mass were administered daily or 2-3x per week for up to one month as an infusion. There were no indications of toxic effects or pathological changes.
Mutagenic effect: In-vitro studies in Salmonella thyphimurium (Ames test) and Saccharomyces cerevisiae as well as in-vivo studies in mice and Chinese hamsters did not show any indications of a mutagenic effect.
Reproduction toxicity: Propofol 10 mg/mL crosses the placenta. Embryo toxicity studies in rats and rabbits did not provide any indication of a teratogenic effect.
Published studies in animals (including primates) at doses resulting in light to moderate anesthesia demonstrates that the use of anesthetic agents during the rapid brain growth or synaptogenesis results in cell loss in the developing brain that can be associated with prolonged cognitive deficiencies. The clinical significance of these non-clinical findings is not known.
Propofol 10 mg/mL passes into breast milk. There is no experience in humans with use during pregnancy and the lactation period.
Carcinogenicity: Long-term studies regarding the potential for causing tumors have not been carried out.