Propofol

178.27100

178.27

218-206-6

YI7VU623SF

758909|5105

DTXSID6023523

C29384

Light-straw-colored liquid

N01AX10|N - Nervous system

2907199090

20.23000

3.63900

Liquid

1.540 g/cm³ @ Temp: 20 °C

18 °C

242 °C

107.5ºC

1.513-1.515

H2O: 124 g/L (20 ºC)

0-6ºC

5.6 mm Hg ( 100 °C)

11.1(at 20 °C)

11.1 (at 20 °C)|pKa = 11.10 @ 20 °C

III

6.1(b)

UN 2810

3

R22; R36/37/38

S26-S37/39

SL0810000

Xn

Propofol should not be used if there is evidence of separation of the emulsion phases.

P301 + P312 + P330-P305 + P351 + P338

H302-H315-H319-H335

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl propofol, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.|Propofol injection. (a) Specifications. The drug is a sterile, nonpyrogenic, oil-in-water emulsion containing 10 milligrams of propofol per milliliter. ... (1) Dogs. (i) The drug is indicated for use as an anesthetic as follows: As a single injection to provide general anesthesia for procedures lasting up to 5 minutes; for induction and maintenance of general anesthesia using incremental doses to effect; for induction of general anesthesia where maintenance is provided by inhalant anesthetics. ... (2) Cats. (i) The drug is indicated for use as an anesthetic as follows: As a single injection to provide general anesthesia for short procedures, for induction and maintenance of general anesthesia using incremental doses to effect, and for induction of general anesthesia where maintenance is provided by inhalant anesthetics.

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P261, P264, P270, P271, P280, P301+P312, P302+P352, P304+P340, P305+P351+P338, P312, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, and P501|Aggregated GHS information provided by 1492 companies from 17 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Propofol was detected in a 1,500 liter advanced waste treatment finished water sample taken in Pomona, California on September 25, 1974(1). Propofol was detected with one occurrence in over 4000 wastewater survey sample extracts during a chemical analysis program prescribed by the USEPA(2).

INDOOR: Propofol has been identified in textile floor covering emissions(1).

Overdosage may increase pharmacologic and adverse effects or cause death. IV LD50=53 mg/kg (mice), 42 mg/kg (rats). Oral LD50 (as a solution in soybean oil)=1230 mg/kg (mice), 600 mg/kg (rats)

Liver test abnormalities are not common among patients during or after propofol anesthesia when given for a few hours. Indeed, propofol can be used safely in patients with cirrhosis and may be the preferred anesthetic agent in patients with minimal hepatic encephalopathy. However, isolated case reports of hepatitis arising within days or weeks after propofol anesthesia for minor procedures have been published. The pattern of serum enzyme elevations was usually hepatocellular and some instances were accompanied by jaundice and prolongation of prothrombin time activity (Case 1). Immunoallergic features and autoantibodies during the liver injury were absent. In most published instances, other diagnoses such as ischemic hepatitis and hepatitis C were not completely excluded.

Droperidol may compete with propofol for binding sites in the chemoreceptor trigger zone; concurrent use of propofol and droperidol to control nausea and vomiting is less effective than using propofol alone.

95 to 99%, primarily to serum albumin and hemoglobin

Propofol's production and use as an intravenous anesthetic(1) may result in its release to the environment through various waste streams(SRC). Propofol has been identified in textile floor covering emissions(2).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 2700(SRC), determined from a log Kow of 3.79(2) and a regression-derived equation(3), indicates that propofol is expected to have slight mobility in soil(SRC). Volatilization of propofol from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.1X10-6 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Propofol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.1X10-3 mm Hg(SRC), determined from a fragment constant method(5). Propofol may biodegrade in soil based on the biodegradability of the structurally similar compound, 2,6-dimethylphenol, which achieved 30-100 percent and 94 percent biodegradation in activated sludge screening tests after 14 days and 5 days, respectively(6,7).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 2700(SRC), determined from a log Kow of 3.79(2) and a regression-derived equation(3), indicates that propofol is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 2.1X10-6 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 23 days and 170 days, respectively(SRC). However, volatilization from water surfaces is expected to be attenuated by adsorption to suspended solids and sediment in the water column. The volatilization half-life from a model pond is about 6.5 years when adsorption is considered(5). According to a classification scheme(6), an estimated BCF of 170(SRC), from an estimated log Kow(2) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is high(SRC). Propofol may biodegrade in the aquatic environment based on the biodegradability of the structurally similar compound, 2,6-dimethylphenol, which achieved 30-100 percent and 94 percent biodegradation in activated sludge screening tests after 14 days and 5 days, respectively(8,9).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), propofol, which has an estimated vapor pressure of 3.1X10-3 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase propofol is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 7.3 hrs(SRC), calculated from its rate constant of 5.3X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3).

The rate constant for the vapor-phase reaction of propofol with photochemically-produced hydroxyl radicals has been estimated as 5.3X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 7.3 hrs at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Propofol is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(2) nor to directly photolyze due to the lack of absorption in the environmental UV spectrum (>290 nm).

An estimated BCF of 170 was calculated for propofol(SRC), using a log Kow of 3.79(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is high(SRC).

The Koc of propofol is estimated as 2700(SRC), using a log Kow of 3.79(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that propofol is expected to have slight mobility in soil.

The Henry's Law constant for propofol is estimated as 2.1X10-6 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that propofol is expected to volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 23 days(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 170 days(SRC). However, volatilization from water surfaces is expected to be attenuated by adsorption to suspended solids and sediment in the water column. The volatilization half-life from a model pond is about 6.5 years when adsorption is considered(3). Propofol's Henry's Law constant indicates that volatilization from moist soil surfaces may occur(SRC). Propofol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.1X10-3 mm Hg(SRC), determined from a fragment constant method(4).

DRINKING WATER: Propofol was detected in a 11,750 liter finished drinking water sample taken in Seattle, Washington on November 5, 1976(1).

/Propofol/ ... injectable emulsion is not recommended for use in nursing mothers because /propofol/ ... injectable emulsion has been reported to be excreted in human milk and the effects of oral absorption of small amounts of propofol are not known.

Occupational exposure to propofol may occur through inhalation and dermal contact with this compound at workplaces where propofol is produced or used. Monitoring data indicate that the general population may be exposed to propofol via inhalation of ambient air, ingestion of food and drinking water, and dermal contact with this compound and other products containing propofol. (SRC)

Used for induction and/or maintenance of anaesthesia and for management of refractory status epilepticus.|FDA Label

Propofol is the mostly commonly used parenteral anesthetic agent in the United States, extensively used for minor and outpatient surgical procedures because of its rapid onset and reversal of action, and in intensive care units (ICUs) for maintenance of coma. Propofol has been associated with rare instances of idiosyncratic acute liver injury; in addition, prolonged high dose propofol therapy can cause the “Propofol infusion syndrome” which is marked by bradyarrhythmias, metabolic acidosis, rhabdomyolysis, hyperlipidemia and an enlarged or fatty liver.

Anesthetics

Propofol is indicated for the induction of general anesthesia. It is also indicated for the maintenance of anesthesia utilizing balanced techniques with other appropriate agents such as opioids and inhalation anesthetics.|Propofol is indicated for the sedation in critically ill patients confined to intensive care units.|Propofol has successfully controlled seizures in status epilepticus.|Propofol appears to have significant antiemetic action and is a good choice for sedation or anesthesia in patients at high risk for nausea and vomiting.

Compromised cardiovascular function may be aggravated by cardiovascular-depressant and hypotensive effects.|Caution is also recommended in geriatric, debilitated, and/or hypovolemic patients, because they may require lower induction and maintenance doses.|Substantial decreases in mean arterial pressure and cerebral perfusion may occur in patients with existing impaired cerebral circulation or increased intracranial pressure.|Rarely, a clinical syndrome including bronchospasm, erythema, and hypotension has occured shortly after administration of propofol, and sequelae including anoxic brain damage and death have been reported. /SRP: May be from metabisulfite./|For more Drug Warnings (Complete) data for PROPOFOL (17 total), please visit the HSDB record page.

Propofol is a sedative-hypnotic agent for use in the induction and maintenance of anesthesia or sedation. Intravenous injection of a therapeutic dose of propofol produces hypnosis rapidly with minimal excitation, usually within 40 seconds from the start of an injection (the time for one arm-brain circulation).

Drugs used to induce drowsiness or sleep or to reduce psychological excitement or anxiety. (See all compounds classified as Hypnotics and Sedatives.)|Ultrashort-acting anesthetics that are used for induction. Loss of consciousness is rapid and induction is pleasant, but there is no muscle relaxation and reflexes frequently are not reduced adequately. Repeated administration results in accumulation and prolongs the recovery time. Since these agents have little if any analgesic activity, they are seldom used alone except in brief minor procedures. (From AMA Drug Evaluations Annual, 1994, p174) (See all compounds classified as Anesthetics, Intravenous.)

Rapid - time to onset of unconsciousness is 15-30 seconds, due to rapid distribution from plasma to the CNS. Distribution is so rapid that peak plasma concentrations cannot be readily measured. Duration of action is 5-10 minutes.|It is chiefly eliminated by hepatic conjugation to inactive metabolites which are excreted by the kidney.|60 L/kg [healthy adults]|23 - 50 mL/kg/min|The initial apparent volume of distribution is 13 to 76 L/kg.|Propofol is rapidly and extensively distributed in the body. It crosses the blood-brain barrier quickly, and its short duration of action is due to rapid redistribution from the CNS to other tissues, high metabolic clearance and high lipophilicity.|Approximately 70% of a dose is excreted in the urine within 24 hours after administration, and 90% is excreted within 5 days. Clearance of propofol ranges from 1.6 to 3.4 liters per minute in healthy 70 kg patients. As the age of the patient increases, total clearance of propofol may decrease. Clearance rates of 1.4 to 2.2 liters per minute in patients 18 to 35 years of age have been reported, in contrast to clearance rates of 1.0 to 1.8 liters per minute in patients 65 to 80 years of age.|The pharmacokinetics of propofol were best described by a three-compartment model. Weight was found to be a significant covariate for elimination clearance, the two intercompartmental clearances, and the volumes of the central compartment, the shallow peripheral compartment, and the deep peripheral compartment; power functions with exponents smaller than 1 yielded the best results. The estimates of these parameters for a 70-kg adult were 1.44 l/min, 2.25 l/min, 0.92 l/min, 9.3 l, 44.2 l, and 266 l, respectively. For patients older than 60 yr the elimination clearance decreased linearly. The volume of the central compartment decreased with age. For children, all parameters were increased when normalized to body weight. Venous data showed a decreased elimination clearance; bolus data were characterized by increases in the volumes of the central and shallow peripheral compartments and in the rapid distribution clearance (Cl2) and a decrease in the slow distribution clearance (Cl3). Pharmacokinetics of propofol can be well described by a three-compartment model. Inclusion of age and weight as covariates significantly improved the model. Adjusting pharmacokinetics to the individual patient should improve the precision of target-controlled infusion and may help to broaden the field of application for target-controlled infusion systems.|An iv dose of 14C-propofol (0.47 mg/kg) administered to 6 male volunteers was rapidly eliminated with 88% recovered in the urine in 5 days and <2% in feces. The dose was cleared by metabolism with <0.3% excreted unchanged. The major metabolites were the glucuronic acid conjugate of propofol and the glucuronic acid and sulfate conjugates of its hydroxylated derivative, 2,6-diisopropyl-1,4-quinol. Propofol glucuronide accounted for about 53% of the urinary radioactivity and was the major metabolite in plasma from 30 min post dose. The blood concentration of propofol declined in a biphasic manner from a maximum mean value of 0.44 ug/ml, 2 min after injection. The half-lives of the first and second exponential phases, mean values 5 min and 97 min respectively, varied widely among subjects. A proportion of the dose was cleared slowly, probably due to slow release from less well perfused tissues. Propofol accounted for 94% of the total blood radioactivity at 2 min but only about 6% from 3 to 8 hr post dose. Propofol has a volume of distribution equivalent to about 3 to 4 times body weight, and a mean total body clearance of 2.2 l/min.

Hepatically metabolized mainly by glucuronidation at the C1-hydroxyl. Hydroxylation of the benzene ring to 4-hydroxypropofol may also occur via CYP2B6 and 2C9 with subsequent conjugation to sulfuric and/or glucuronic acid. Hydroxypropofol has approximately 1/3 of hypnotic activity of propofol.|Hepatic; rapidly undergoes glucuronide conjugation to inactive metabolites. An unidentified route of extrahepatic metabolism may also exist, suggested by the fact that propofol clearance exceeds estimated hepatic blood flow.|To determine the cytochrome P450 (CYP) isoforms involved in the oxidation of propofol by human liver microsomes. The rate constant calculated from the disappearance of propofol in an incubation mixture with human liver microsomes and recombinant human CYP isoforms was used as a measure of the rate of metabolism of propofol. The correlation of these rate constants with rates of metabolism of CYP isoform-selective substrates by liver microsomes, the effect of CYP isoform-selective chemical inhibitors and monoclonal antibodies on propofol metabolism by liver microsomes, and its metabolism by recombinant human CYP isoforms were examined. The mean rate constant of propofol metabolism by liver microsomes obtained from 6 individuals was 4.2 (95% confidence intervals 2.7, 5.7) nmol/min/mg protein. The rate constants of propofol by microsomes were significantly correlated with S-mephenytoin N-demethylation, a marker of CYP2B6 (r=0.93, P<0.0001), but not with the metabolic activities of other CYP isoform-selective substrates. Of the chemical inhibitors of CYP isoforms tested, orphenadrine, a CYP2B6 inhibitor, reduced the rate constant of propofol by liver microsomes by 38% (P<0.05), while other CYP isoform-selective inhibitors had no effects. Of the recombinant CYP isoforms screened, CYP2B6 produced the highest rate constant for propofol metabolism (197 nmol/min/nmol P450). An antibody against CYP2B6 inhibited the disappearance of propofol in liver microsomes by 74% /and SRP: reduced in vitro metabolism by blocking CYP 2B6/. Antibodies raised against other CYP isoforms had no effect on the metabolism of propofol. CYP2B6 is predominantly involved in the oxidation of propofol by human liver microsomes.|Propofol has known human metabolites that include (2S,3S,4S,5R)-6-[2,6-Di(propan-2-yl)phenoxy]-3,4,5-trihydroxyoxane-2-carboxylic acid and 4-hydroxy-propofol.

Initial distribution phase t_1/2α=1.8-9.5 minutes. Second redistirubtion phase t_1/2β=21-70 minutes. Terminal elimination phase t_1/2γ=1.5-31 hours.|Terminal elimination half-life is 3 to 12 hours; prolonged administration may result in longer duration.|...The first-stage elimination half-life (t1/2 beta) of propofol /SRP: administered mixed with lidocaine/ in children was shorter (mean 9.3 +/- 3.8 (s.d.) min) than the values found in adults. This pharmacokinetic alteration may have clinical significance following repeated administration or continuous infusion of propofol.|An intravenous dose of 14C-propofol (0.47 mg/kg) /was/ administered to six male volunteers... . ...The half-lives of the first and second exponential phases, mean values 5 min and 97 min respectively, varied widely among subjects.

The action of propofol involves a positive modulation of the inhibitory function of the neurotransmitter gama-aminobutyric acid (GABA) through GABA-A receptors.

If overdosage occurs, /propofol/... injectable emulsion administration should be discontinued immediately. Overdosage is likely to cause cardiorespiratory depression. Respiratory depression should be treated by artificial ventilation with oxygen. Cardiovascular depression may require repositioning of the patient by raising the patients legs, increasing the flow rate of iv fluids, and administering pressor agents and/or anticholinergic agents.

/HUMAN EXPOSURE STUDIES/ There have been very rare reports of rhabdomyolysis associated with the administration of /propofol/ ... injectable emulsion for ICU sedation.|/HUMAN EXPOSURE STUDIES/ Propofol causes dose-related respiratory depression, and transient apnea may occur. The drug may also decrease systemic arterial pressure, and may cause myocardial depression.

2,6 Diisopropylphenol

Trade Name: Diprivan /from table/

All other basic inorganic chemical manufacturing|Phenol, 2,6-bis(1-methylethyl)-: ACTIVE

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients|Animal Drugs -> FDA Approved Animal Drug Products (Green Book) -> Active Ingredients|Pharmaceuticals