![7
Other Use:
Executions:
The Missouri Supreme Court decided to allow the use of propofol to execute prisoners
condemned to death. However, the first execution by administration of a lethal dose of propofol
was halted on 11 October 2013 by governor Jay Nixonfollowing threats from the European
Union to limit the drug's export if it were used for that purpose. The United Kingdom had
already banned the export of medicines or veterinary medicines containing propofol to the
United States.
Recreationaluse:
Recreational use of the drug via self-administration has been reported (including among medical
professionals, see below), but is relatively rare due to its potency and the level of monitoring
required for safe use. Critically, the steep dose-response curve of the drug makes potential
misuse very dangerous without proper monitoring, and deaths from self-administration continue
to be reported. The short-term effects sought via recreational use include mild euphoria,
hallucinations, and disinhibition. The euphoria caused by propofol has been reported to be unlike
that caused by other sedation agents; as one anesthetist reported, "I... remember my first
experience using [administering] propofol: a young woman... emerging from a MAC
anesthesia looked at me as though I were a masked Brad Pitt and told me that she felt simply
wonderful."
Recreational use of the drug has been described among medical staff, such as anesthetists who
have access to the drug, and is reportedly more common among anesthetists on rotations with
short rest periods (as rousing is to a well-rested state). Long-term use has been reported to result
in addiction.
Attention to the risks of off-label use of propofol increased in August 2009 due to the Los
Angeles County coroner's conclusion that music icon Michael Jackson diedfrom a mixture of
propofol and the benzodiazepine drugs lorazepam, midazolam and diazepam on June 25, 2009.
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](https://image.slidesharecdn.com/propofolassignment-170820180711/85/Propofol-assignment-7-320.jpg)
Propofol assignment
- 1. 1 Serial no Topic Page no 01 Definition 02 02 Introduction 02 03 Common side effects 03 04 Case presentation 04 05 Discussion 05 06 Medical uses 06 07 Other Use 07 08 Side effects 08 09 Propofol infusion syndrome 09 10 Mechanism of action 09 11 Chemistry 10 12 Recent Development 11 13 Conclusion 11
- 2. 2 “A Case Study on Propofol” Definition: Propofol, marketed as Diprivan among others, is a short-acting medication that results in a decreased level of consciousness and lack of memory for events. Its uses include the starting and maintenance of general anesthesia, sedation for mechanically ventilated adults, and procedural sedation. It is also used for status epileptics if other medications have not worked. It is given intravenously. Maximum effect takes about two minutes to occur and it typically lasts five to ten minutes. Introduction: Propofol is an intravenous agent used for sedation or induction of general anaesthesia. Short acting time, fast recovery, few side-effects and amnestic properties are the advantages of the drug in clinical practice. Unconciousness occurs at 30 s after the injection of 1.5–2.5-mg kg−1 propofol and lasts up to 5–10 min. Propofol has many clinical uses outside of the operating room such as to treat seizure, migraine, tension headache and alcohol abstinence or to sedate the patients while performing electroconvulsive therapy, gastrointestinal or any other unpleasant procedures. The increasing usage of the drug for different procedures results in an increasing number of human exposure. Patients who are medical professionals or lay persons reported pleasant and euphoric effects without any residual effects and high satisfaction rates after usage. In light of the above-mentioned information, medical professionals thought that the drug may have abuse potential; this hypothesis was supported with several case reports. The most remarkable report was the case of Michael Jackson. However, the drug is not regulated as a controlled substance in any country, except South Korea. Hence, propofol dependence case reports still preserve value to demand attention toward its potential abuse. Particularly, addiction
- 3. 3 case reports rather than death reports with propofol increase the knowledge regarding psychiatric management of propofol addiction. Therefore, we report a propofol-dependent emergency medicine doctor who gave up our psychiatric therapy on his own will; after sometime, he was found dead in his emergency service due to suspected propofol overdose. Common side effects: include an irregular heart rate, low blood pressure, burning sensation at the site of injection, and the stopping of breathing. Other serious side effects may include seizures, infections with improper use, addiction, and propofol infusion syndrome with long-term use. It appears to be safe for using during pregnancy but has not been well studied in this group. However, it is not recommended during cesarean section. Propofol is not a pain medication, soopioids such as morphine may also be used. Whether or not they are always needed is unclear. Propofol is believed to work at least partly via the receptor for GABA. Propofol was discovered in 1977. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. It is available as a generic medication. The wholesale price in the developing world is between 0.61 and 8.50 USD per vial. It has been referred to as milk of amnesia (a play on milk of magnesia) because of the milk-like appearance of the intravenous preparation. Propofol is also used in veterinary medicine. Case presentation: The patient was a 29-year-old male emergency medicine doctor who was admitted to the psychiatry clinic on his own will because of his propofol addiction that continued for 2 years. During these 2 years, he stopped using propofol for 2 months on his own will on account of his marriage. However, he started abusing propofol again. After his unsuccessful efforts, he was convinced to attend a psychiatric rehabilitation program. He was hospitalised after his first evaluation. He had started to use propofol repeatedly for relieving pain caused by nephrolithiasis. He did not have a history of any drug abuse, except a history of smoking. After repeated drug exposures for pain relief, he started to use it for recreational purposes because of its pleasant effects. He reported that his energy and courage increased, and that he felt happier and relaxed after propofol
- 4. 4 use. He did not report any unpleasant residual effects or withdrawal symptoms. When he visited for therapy, he was using approximately up to 40–50-mg propofol per injection and a total of 200–300-mg propofol per day intravenously. Tolerance for the desired effects did not occur. He reported that he had obtained the drug from the hospital easily. The most important reason for craving the drug was the feeling of euphoria and relaxation. After his first examination, it was found that his general physical status and appearance was compatible with his age and socioeconomic status. His attention and concentration was disoriented. His mood was depressed, thoughts were rational and objective and speaking tone as well as speaking speed were low. Blood and urine analyses were normal; no psychoactive substance was determined in urine. In pharmacological treatment, diazepam, quetiapine and sertraline were used. Diazepam was ceased in a week by gradually decreasing the dose. Supportive and cognitive psychotherapy interviews were conducted with the patient, and the patient was asked to participate in the group therapies for addicted patients that were performed for 4 days per week. He did not show any withdrawal symptoms. However, after 14 days, he refused to participate in therapies any further and left the hospital. After 2 years, it was learnt that the patient was found dead in his study room at the hospital’s emergency department due to suspected propofol overdose. Because of legal difficulties, we cannot report the post-mortem examination. Written informed consent was provided from the patient’s next of kin for this case report. Discussion: This case was the first propofol addiction reported in Turkey, and this study is the first case report in the literature of an emergency medicine doctor who became dependent on propofol. Since 1992, propofol has been discussed with regard to its abuse potential after the first propofol addiction case report. Propofol has several desirable properties superior to those of other sedatives such as easy access, rapid onset of action, and short duration of action and minimal or no residual side-effects. These properties may be the major factor for the increase in the number of addiction cases. The first propofol addiction case report documented a patient who preferred propofol to midazolam and fentanyl because of its advantages, as described above. In addition to the above-mentioned advantages, this patient started using propofol for stress relief, which was
- 5. 5 eventually followed by craving. In several reports, most cases of propofol dependence were not after propofol anaesthesia for an operation. Although they may experience the same effects, these patients do not know as to which drug is used for anaesthesia. Therefore, authors thought that these patients are not under the risk of propofol addiction. A majority of propofol abusers use the drug for non-anaesthetic purposes such as stress relief, insomnia relief, pain relief and euphoria. Headache treatments, gastrointestinal endoscopic procedures or nephrolithiasis pain relief such as the case of our patient are some methods to meet and experience propofol effects. These procedures are mostly performed by healthcare providers who are not anaesthesiologists and who are not well learned regarding the pleasant effects of propofol and its abuse potential. However, because of its easy access and lack of sufficient information regarding its routine use in medical textbooks, some anesthesiologists also may not be aware of its abuse potential. Thus, case reports regarding propofol dependence are important to improve the knowledge of the healthcare providers. Healthcare providers who use propofol may know its pleasant effects and may abuse the drug without any personal experience. A review examined propofol abuse or dependence cases between 1992 and 2007 and reported that propofol dependence resulted in the death of 38 patients. Nine of them were anaesthesiologists and three were other medical professionals. According to this data, propofol dependence is a very dangerous addiction because of its high mortality rate owing to unconsciousness and apnoea even with low doses. We know that propofol causes euphoria, stress relief, sexual fantasies and dreams as well as sexual disinhibition; thus, psychological dependence is more common than physical dependence. Studies regarding the subjective effects of propofol reported that drug evokes positive feelings, such as happiness, after injections. it has a very high Morphine–Benzedrine Group (MBG) Scale, which is used as an index of euphoria scores, similar to that for morphine or marijuana that are highly abused drugs. Our patient’s dependence pattern is compatible with this data similar to that of patients in other case reports. For the patient, euphoria was the most important reason for craving the drug. Including drug-craving behaviour, our patient showed other strong dependence symptoms such as loss of control, continued use of the drug despite social life disruption and incompatibility with psychiatric treatments. In addition, this case shows the failure of usual addiction psychotherapy for propofol addiction. Under these conditions, we thought that
- 6. 6 reporting propofol-dependent patients who are followed up by a psychiatrist is more important than reporting deaths caused by propofol to provide improvement in the knowledge of propofol addiction treatment. Similar to all other countries worldwide, except South Korea, propofol dispensing is not restricted and not under control in our country. Strict control may not eradicate propofol abuse but easy access conditions may continue to increase propofol abuse. Hence, it should not be ignored that it is essential for the ministries of health to take precautions regarding propofol dispensing. MEDICAL USE: Anesthesia: Propofol is used for induction and maintenance (in some cases) of anesthesia, having largely replaced sodium thiopental. It can also be administered as part of an anaesthesia maintenance technique called total intravenous anesthesia using either manually-programmed infusion pumps or computer-controlled infusion pumps in a process called target controlled infusion or TCI. Propofol is also used to sedate individuals who are receiving mechanical ventilation but are not undergoing surgery, such as patients in the intensive care unit. In critically ill patients, propofol has been found to be superior to lorazepam both in effectiveness and overall cost. Propofol is often used instead of sodium thiopental for starting anesthesia because recovery from propofol is more rapid and "clear." Proceduralsedation: Propofol is also used for procedural sedation. Its use in these settings results in a faster recovery compared tomidazolam. It can also be combined with opioids or benzodiazepines. Because of its fast induction and recovery time, propofol is also widely used for sedation of infants and children undergoing MRI. It is also often used in combination with ketamine as the two together have lower rates of side effects.
- 7. 7 Other Use: Executions: The Missouri Supreme Court decided to allow the use of propofol to execute prisoners condemned to death. However, the first execution by administration of a lethal dose of propofol was halted on 11 October 2013 by governor Jay Nixonfollowing threats from the European Union to limit the drug's export if it were used for that purpose. The United Kingdom had already banned the export of medicines or veterinary medicines containing propofol to the United States. Recreationaluse: Recreational use of the drug via self-administration has been reported (including among medical professionals, see below), but is relatively rare due to its potency and the level of monitoring required for safe use. Critically, the steep dose-response curve of the drug makes potential misuse very dangerous without proper monitoring, and deaths from self-administration continue to be reported. The short-term effects sought via recreational use include mild euphoria, hallucinations, and disinhibition. The euphoria caused by propofol has been reported to be unlike that caused by other sedation agents; as one anesthetist reported, "I... remember my first experience using [administering] propofol: a young woman... emerging from a MAC anesthesia looked at me as though I were a masked Brad Pitt and told me that she felt simply wonderful." Recreational use of the drug has been described among medical staff, such as anesthetists who have access to the drug, and is reportedly more common among anesthetists on rotations with short rest periods (as rousing is to a well-rested state). Long-term use has been reported to result in addiction. Attention to the risks of off-label use of propofol increased in August 2009 due to the Los Angeles County coroner's conclusion that music icon Michael Jackson diedfrom a mixture of propofol and the benzodiazepine drugs lorazepam, midazolam and diazepam on June 25, 2009. 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
- 8. 8 propofol diluted with lidocaine shortly before Jackson's death. Even so, as of 2016 propofol was not on a U.S Drug Enforcement Administration schedule. SIDE EFFECTS: One of propofol's most frequent side effects is pain on injection, especially in smaller veins. This pain arises from activation of the pain receptor, TRPA1, found on sensory nerves and can be mitigated by pretreatment with lidocaine. Less pain is experienced when infused at a slower rate in a large vein (antecubital fossa). Patients show great variability in their response to propofol, at times showing profound sedation with small doses. Additional side effects include low blood pressure related to vasodilation, transient apnea following induction doses, and cerebrovascular effects. Propofol has more pronounced hemodynamic effects relative to many intravenous anesthetic agents. Reports of blood pressure drops of 30% or more are thought to be at least partially due to inhibition of sympathetic nerve activity. This effect is related to dose and rate of propofol administration. It may also be potentiated by opioid analgesics. Propofol can also cause decreased systemic vascular resistance, myocardial blood flow, and oxygen consumption, possibly through direct vasodilation. There are also reports that it may cause green discolouration of the urine. As a respiratory depressant, propofol frequently produces apnea. The persistence of apnea can depend on factors such as premedication, dose administered, and rate of administration, and may sometimes persist for longer than 60 seconds. Possibly as the result of depression of the central inspiratory drive, propofol may produce significant decreases in respiratory rate, minute volume, tidal volume, mean inspiratory flow rate, and functional residual capacity. Diminishing cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure are also characteristics of propofol administration. In addition, propofol may decrease intraocular pressure by as much as 50% in patients with normal intraocular pressure. A more serious but rare side effect is dystonia. Mild myoclonic movements are common, as with other intravenous hypnotic agents. Propofol appears to be safe for use in porphyria, and has not been known to trigger malignant hyperpyrexia.
- 9. 9 Propofol is also reported to induce priapism in some individuals, and has been observed to suppress REM sleep stage and to worsen the poor sleep quality in some patients. 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. Propofolinfusion syndrome: Another recently described rare, but serious, side effect is propofol infusion syndrome. This potentially lethal metabolic derangement has been reported in criticall ill patients after a prolonged infusion of high-dose substance in combination with catecholamine’s and/or corticosteroids. CBS genetic defects: People with this gene have trouble processing sulphites (one of the potential ingredients), and should discuss use of this drug with their specialist. Interaction: The respiratory effects of propofol are increased if given with other respiratory depressants, including benzodiazepines. Mechanismof action: Propofol has been proposed to have several mechanisms of action, both through potentiation of GABAA 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. EEG research upon those undergoing general anesthesia with propofol finds that it causes a prominent reduction in the brain's information integration capacity at gamma wave band frequencies. Researchers have identified the site where propofol binds to GABAA receptors in the brain, on the second transmembrane domain of the beta subunit of the GABA Areceptor.
- 10. 10 Pharmacokinetics: Propofol is highly protein-bound in vivo and is metabolised by conjugation in the liver. The half- life of elimination of propofol has been estimated to be 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 amnesticeffects have led to its widespread use for sedation and anesthesia. Chemistry: A 20-ml ampoule of 1% propofol emulsion, as sold in Australia bySandoz Propofol was originally developed in the UK by Imperial Chemical Industries as ICI 35868. Clinical trials followed in 1977, using a form solubilised in cremophor EL. However, due to anaphylactic reactions to cremophor, this formulation was withdrawn from the market and subsequently reformulated as an emulsion of a soya oil/propofol mixture in water. The emulsified formulation was relaunched in 1986 by ICI (now AstraZeneca) under the brand name Diprivan. The currently available preparation is 1% propofol, 10% soybean oil, and 1.2% purified egg phospholipid as an emulsifier, with 2.25%glycerol as a tonicity-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
- 11. 11 antimicrobial agents. Newer generic formulations contain sodium metabisulfite or benzyl alcohol as antimicrobial agents. Propofol emulsion is a highly opaque white fluid due to the scattering of light from the tiny (about 150-nm) oil droplets it contains. A water-soluble prodrug form, fospropofol, has recently been developed and tested with positive results. Fospropofol is rapidly broken down by the enzyme alkaline phosphatase 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. However fospropofol is a Schedule IV controlled substance with the DEAACSCN of 2138 in the United States unlike propofol. RecentDevelopment: By incorporation of an azobenzene unit, a photoswitchable version of propofol (AP2) was developed in 2012 that allows for optical control of GABAA receptors with light. In 2013, a propofol binding site on mammalian GABAA receptors has been identified by photolabeling using a Diazirine derivative. Additionally, it was shown that the hyaluronan polymer present in the synovia can be protected from free-radical synovia by propofol. Propofol is one of the chemicals used in the manufacture of Avasamibe (ACAT inhibitor). Conclusion: The above-mentioned case reports and clinical studies show that propofol has a serious abuse potential because of its pleasant subjective effects and inconsiderable residual effects that cause social life disruptions or death of lay persons or medical professionals. Easy drug access and insufficient knowledge of healthcare providers are contributing factors for its increased abuse frequency. Here, we have attempted to highlight the potential danger regarding increase in propofol dependence as well as to highlight the importance of the knowledge of clinicians and for taking appropriate precautions for its dispensing.