Propofol is a short-acting,
intravenouslyIntravenous therapy or IV therapy is the infusion of liquid substances directly into a vein. The word intravenous simply means "within a vein". Therapies administered intravenously are often called specialty pharmaceuticals...
administered
hypnoticHypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...
agent. Its uses include the induction and maintenance of general anesthesia, sedation for
mechanically ventilatedIn medicine, mechanical ventilation is a method to mechanically assist or replace spontaneous breathing. This may involve a machine called a ventilator or the breathing may be assisted by a physician, respiratory therapist or other suitable person compressing a bag or set of bellows...
adults, and
procedural sedationProcedural sedation and analgesia previously referred to as conscious sedation is defined as "a technique of administering sedatives or dissociative agents with or without analgesics to induce a state that allows the patient to tolerate unpleasant procedures while maintaining cardiorespiratory...
. Propofol is also commonly used in
veterinary medicineVeterinary Medicine is the branch of science that deals with the prevention, diagnosis and treatment of disease, disorder and injury in non-human animals...
. Propofol is approved for use in more than 50 countries, and
genericA generic drug is a drug defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use." It has also been defined as a term referring to any drug marketed under its...
versions are available.
Chemically, propofol is unrelated to
barbiturateBarbiturates are drugs that act as central nervous system depressants, and can therefore produce a wide spectrum of effects, from mild sedation to total anesthesia. They are also effective as anxiolytics, as hypnotics, and as anticonvulsants...
s and has largely replaced
sodium thiopentalSodium thiopental, better known as Sodium Pentothal , thiopental, thiopentone sodium, or Trapanal , is a rapid-onset short-acting barbiturate general anaesthetic...
(Pentothal) for induction of anesthesia because recovery from propofol is more rapid and "clear" when compared with thiopental. Propofol is not considered an
analgesicAn analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
, so opioids such as
fentanyl may be combined with propofol to alleviate pain. Propofol has been referred to as "milk of amnesia" (a play on words of
milk of magnesiaMagnesium hydroxide is an inorganic compound with the chemical formula Mg2. As a suspension in water, it is often called milk of magnesia because of its milk-like appearance. The solid mineral form of magnesium hydroxide is known as brucite....
), because of the milk-like appearance of its intravenous preparation.
Medical uses
Propofol is used for induction and maintenance of anesthesia, having largely replaced
sodium thiopentalSodium thiopental, better known as Sodium Pentothal , thiopental, thiopentone sodium, or Trapanal , is a rapid-onset short-acting barbiturate general anaesthetic...
for this indication. Propofol is also used to sedate individuals who are receiving
mechanical ventilationIn medicine, mechanical ventilation is a method to mechanically assist or replace spontaneous breathing. This may involve a machine called a ventilator or the breathing may be assisted by a physician, respiratory therapist or other suitable person compressing a bag or set of bellows...
. In critically ill patients it has been found to be superior to
lorazepamLorazepam is a high-potency short-to-intermediate-acting 3-hydroxy benzodiazepine drug that has all five intrinsic benzodiazepine effects: anxiolytic, amnesic, sedative/hypnotic, anticonvulsant, antiemetic and muscle relaxant...
both in effectiveness as well as overall cost; as a result, the use of propofol for this indication is now encouraged whereas the use of lorazepam for this indication is discouraged. Propofol is also used for sedation, for example, prior to endoscopic procedures, and has been found to have less prolonged sedation and a faster recovery time compared to
midazolamMidazolam is a short-acting drug in the benzodiazepine class developed by Hoffmann-La Roche in the 1970s. The drug is used for treatment of acute seizures, moderate to severe insomnia, and for inducing sedation and amnesia before medical procedures. It possesses profoundly potent anxiolytic,...
.
Adverse effects
Aside from
low blood pressureIn physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
(mainly through
vasodilationVasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When...
) and transient
apneaApnea, apnoea, or apnœa is a term for suspension of external breathing. During apnea there is no movement of the muscles of respiration and the volume of the lungs initially remains unchanged...
following induction doses, one of propofol's most frequent side effects is pain on injection, especially in smaller veins. This pain can be mitigated by pretreatment with
lidocaineLidocaine , Xylocaine, or lignocaine is a common local anesthetic and antiarrhythmic drug. Lidocaine is used topically to relieve itching, burning and pain from skin inflammations, injected as a dental anesthetic or as a local anesthetic for minor surgery.- History :Lidocaine, the first amino...
. Patients show great variability in their response to propofol, at times showing profound sedation with small doses. A more serious but rare side effect is
dystoniaDystonia is a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to...
. Mild myoclonic movements are common, as with other intravenous hypnotic agents. Propofol appears to be safe for use in
porphyriaPorphyrias are a group of inherited or acquired disorders of certain enzymes in the heme bio-synthetic pathway . They are broadly classified as acute porphyrias and cutaneous porphyrias, based on the site of the overproduction and accumulation of the porphyrins...
, and has not been known to trigger malignant hyperpyrexia.
It has been reported that the euphoria caused by propofol is unlike that caused by other sedation agents, "I even remember my first experience using propofol: a young woman who was emerging from a MAC anesthesia looked at me as though I were a masked Brad Pitt and told me that she felt simply wonderful." —C.F. Ward, M.D.
Propofol has reportedly induced
priapismPriapism is a potentially harmful and painful medical condition in which the erect penis or clitoris does not return to its flaccid state, despite the absence of both physical and psychological stimulation, within four hours. There are two types of priapism: low-flow and high-flow. Low-flow...
in some individuals.
Propofol infusion syndrome
Another recently described rare, but serious, side effect is
propofol infusion syndromePropofol infusion syndrome is a rare syndrome first described by Dr. Amit Borah which affects patients undergoing long-term treatment with high doses of the anaesthetic and sedative drug propofol. It can lead to cardiac failure, rhabdomyolysis, metabolic acidosis and renal failure and is often...
. This potentially lethal metabolic derangement has been reported in critically ill patients after a prolonged infusion of high-dose substance in combination with
catecholamineCatecholamines are molecules that have a catechol nucleus consisting of benzene with two hydroxyl side groups and a side-chain amine. They include dopamine, as well as the "fight-or-flight" hormones adrenaline and noradrenaline released by the adrenal medulla of the adrenal glands in response to...
s and/or
corticosteroidCorticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
s.
Chemistry
Propofol was originally developed in the UK by
Imperial Chemical IndustriesImperial Chemical Industries was a British chemical company, taken over by AkzoNobel, a Dutch conglomerate, one of the largest chemical producers in the world. In its heyday, ICI was the largest manufacturing company in the British Empire, and commonly regarded as a "bellwether of the British...
as ICI 35868. Clinical trials followed in 1977, using a form solubilised in
cremophor ELCremophor EL is the registered trademark of BASF Corp. for its version of polyethoxylated castor oil. It is prepared by reacting 35 moles of ethylene oxide with each mole of castor oil...
. However, due to
anaphylactic reactionsAnaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...
to cremophor, this formulation was withdrawn from the market and subsequently reformulated as an
emulsionAn emulsion is a mixture of two or more liquids that are normally immiscible . Emulsions are part of a more general class of two-phase systems of matter called colloids. Although the terms colloid and emulsion are sometimes used interchangeably, emulsion is used when both the dispersed and the...
of a soya oil/propofol mixture in water. The emulsified formulation was relaunched in 1986 by ICI (now
AstraZenecaAstraZeneca plc is a global pharmaceutical and biologics company headquartered in London, United Kingdom. It is the world's seventh-largest pharmaceutical company measured by revenues and has operations in over 100 countries...
) under the brand name
Diprivan (abbreviated version of
diiso
propyl
intra
venous
anesthetic). The currently available preparation is 1% propofol, 10%
soybean oilSoybean oil is a vegetable oil extracted from the seeds of the soybean . It is one of the most widely consumed cooking oils. As a drying oil, processed soybean oil is also used as a base for printing inks and oil paints...
, and 1.2% purified egg phospholipid (emulsifier), with 2.25% of glycerol as a
tonicityTonicity is a measure of the osmotic pressure gradient of two solutions separated by a semipermeable membrane. It is commonly used when describing the response of cells immersed in an external solution...
-adjusting agent, and
sodium hydroxide to adjust the pH. Diprivan contains EDTA, a common chelation agent, that also acts alone (bacteriostatically against some bacteria) and synergistically with some other antimicrobial agents. Newer generic formulations contain
sodium metabisulfiteSodium metabisulfite or sodium pyrosulfite is an inorganic compound of chemical formula Na2S2O5. The substance is sometimes referred to as disodium...
or
benzyl alcoholBenzyl alcohol is an organic compound with the formula C6H5CH2OH. The benzyl group is often abbreviated "Bn", thus benzyl alcohol is denoted as BnOH. Benzyl alcohol is a colorless liquid with a mild pleasant aromatic odor. It is a useful solvent due to its polarity, low toxicity, and low vapor...
as antimicrobial agents. Propofol emulsion is a highly opaque white fluid due to the scattering of light from the tiny (~150 nm) oil droplets that it contains.
A water-soluble
prodrugA prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
form,
fospropofolFospropofol is an intravenous sedative-hypnotic agent. It is currently approved for use in sedation of adult patients undergoing diagnostic or therapeutic procedures such as endoscopy.-Clinical applications:...
, has recently been developed and tested with positive results. Fospropofol is rapidly broken down by the enzyme
alkaline phosphataseAlkaline phosphatase is a hydrolase enzyme responsible for removing phosphate groups from many types of molecules, including nucleotides, proteins, and alkaloids. The process of removing the phosphate group is called dephosphorylation...
to form propofol. Marketed as Lusedra, this new formulation may not produce the pain at injection site that often occurs with the traditional form of the drug. The US Food and Drug Administration approved the product in 2008.
Mechanism of action
Propofol has been proposed to have several mechanisms of action, both through potentiation of
GABAAThe GABAA receptor is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid , the major inhibitory neurotransmitter in the central nervous system. Upon activation, the GABAA receptor selectively conducts Cl- through its pore, resulting in...
receptor activity, thereby slowing the channel-closing time, and also acting as a sodium channel blocker. Recent research has also suggested that the endocannabinoid system may contribute significantly to propofol's anesthetic action and to its unique properties.
Pharmacokinetics
Propofol is highly protein-bound
in vivo and is metabolised by conjugation in the liver.
Its rate of clearance exceeds hepatic blood flow, suggesting an extrahepatic site of elimination as well. The
half life of eliminationThe biological half-life or elimination half-life of a substance is the time it takes for a substance to lose half of its pharmacologic, physiologic, or radiologic activity, as per the MeSH definition...
of propofol has been estimated at between 2 and 24 hours. However, its duration of clinical effect is much shorter, because propofol is rapidly distributed into peripheral tissues. When used for IV sedation, a single dose of propofol typically wears off within minutes. Propofol is versatile; the drug can be given for short or prolonged sedation as well as for general anesthesia. Its use is not associated with nausea as is often seen with opioid medications. These characteristics of rapid onset and recovery along with its amnestic effects have led to its widespread use for sedation and anesthesia.
EEGElectroencephalography is the recording of electrical activity along the scalp. EEG measures voltage fluctuations resulting from ionic current flows within the neurons of the brain...
research upon those undergoing general anesthesia with propofol finds that it causes a prominent reduction in the brain's information integration capacity at
gamma waveA gamma wave is a pattern of neural oscillation in humans with a frequency between 25 to 100 Hz, though 40 Hz is prototypical.According to a popular theory, gamma waves may be implicated in creating the unity of conscious perception...
band frequencies.
Contraindications and interactions
The respiratory effects of propofol are potentiated by other
respiratory depressantIn medicine, hypoventilation occurs when ventilation is inadequate to perform needed gas exchange...
s, including
benzodiazepineA benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
s.
As with any other general anesthetic agent, propofol should be administered only where appropriately trained staff and facilities for monitoring are available, as well as proper airway management, a supply of supplemental oxygen, artificial ventilation and cardiovascular resuscitation.
Recreational use
There are reports of self-administration of propofol for recreational purposes.
Short-term effects include mild euphoria, hallucinations, and disinhibition. Long-term use has been reported to result in addiction. Such use of the drug has been described amongst medical staff, such as anesthetists who have access to the drug. Misuse is reported to be more common among anesthetists on rotations with short rest periods, as recreational users report rousing to a well-rested state. Recreational use of the drug is relatively rare due to its potency and the level of monitoring required to take it safely. Propofol has not yet been scheduled by the US
Drug Enforcement AdministrationThe Drug Enforcement Administration is a federal law enforcement agency under the United States Department of Justice, tasked with combating drug smuggling and use within the United States...
. The steep dose-response curve of the drug makes potential misuse very dangerous without proper monitoring, and at least three deaths from self-administration have been recorded.
Attention to the risks of off-label use of propofol increased in August 2009 due to the Los Angeles County coroner's conclusion that
Michael Jackson diedOn June 25, 2009, American singer Michael Jackson died of acute propofol intoxication after he suffered a respiratory arrest at his home in the Holmby Hills neighborhood in Los Angeles. His personal physician, Conrad Murray, said he found Jackson in his room, not breathing, but with a faint pulse,...
from a mixture of propofol and the
benzodiazepineA benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
drugs
lorazepamLorazepam is a high-potency short-to-intermediate-acting 3-hydroxy benzodiazepine drug that has all five intrinsic benzodiazepine effects: anxiolytic, amnesic, sedative/hypnotic, anticonvulsant, antiemetic and muscle relaxant...
on top of
diazepamDiazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
ingested earlier. According to a 22 July 2009, search warrant affidavit unsealed by the district court of Harris County, Texas, Jackson's personal physician, Conrad Murray, administered 25 milligrams of propofol diluted with
lidocaineLidocaine , Xylocaine, or lignocaine is a common local anesthetic and antiarrhythmic drug. Lidocaine is used topically to relieve itching, burning and pain from skin inflammations, injected as a dental anesthetic or as a local anesthetic for minor surgery.- History :Lidocaine, the first amino...
shortly before Jackson's death. Propofol is at the centre of the current case People of the State of California v. Conrad Robert Murray.. On 7 November 2011, jurors found Murray guilty of involuntary manslaughter in Jackson's death. Sentencing was set for 29 November 2011, and Murray was sentenced to four years in Los Angeles county jail with no probation.
Supply issues
On 4 June 2010
Teva Pharmaceutical IndustriesTeva Pharmaceutical Industries Ltd. , is an international pharmaceutical company headquartered in Petah Tikva, Israel. It specializes in generic and proprietary pharmaceuticals and active pharmaceutical ingredients...
Ltd., an Israel-based pharmaceutical firm, and major supplier of the drug, announced that they would no longer manufacture it. This aggravates an already existing shortage, caused by manufacturing difficulties at Teva and
HospiraHospira, Inc. is a U.S.-based global pharmaceutical and medical device company with headquarters in Lake Forest, Illinois. It has approximately 14,000 employees. Hospira is the world's largest producer of generic injectable pharmaceuticals, manufacturing generic acute-care and oncology...
. (AstraZeneca has not made propofol in some time.) A Teva spokesperson attributed the halt to ongoing process difficulties, and a number of pending lawsuits related to the drug.
External links
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