Propofol (2, 6 dissopropylphenol) is a short-acting, general anaesthetic administered intravenously, for induction and maintenance of general anaesthesia. The analgesic effect of Propofol is caused by the potentiation of GABA, which results in increased chloride ion conductance. Benzodiazepines are often prescribed for its anxiolytic and hypnotic properties. They selectively bind to a specific benzodiazepine receptor which is part of the GABA/Benzodiazepine/Chloride complex, which increases the membrane's permeability to chloride ions induced by GABA. Despite the many side-effects, the synergistic interactions between Benzodiazepines and Propofol are known to produce some beneficial effects in clinical settings through augmentation of the speed that anaesthesia is induced and the reduction in arousal time in patients' anaesthetized. It is recommended that due to the nature of side-effects, Propofol should not be administered outside a hospital setting; advise which was not followed in the case of Michael Jackson.
Introduction
GABA (Gamma-aminobutyric acid) is the principal inhibitory neurotransmitter in the Central Nervous System. GABA has two receptor sites located on the extracellular domains of the beta sub-unit on the neurotransmitter-gated ion channels (Tanelian et al, 1993). GABA expresses its inhibitory effect by hyperpolarizing the neuron, to increase the neural membrane's permeability to chloride ions; contributing towards subsequent desensitization (Pritchett et al, 1989). The GABA type A receptor (GABAA) is one of three receptors GABA acts on (Pritchett et al, 1989). The GABAA receptor is an ionotropic macromolecular complex consisting of five sub-units arranged centrally to an intrinsic ion channel (Yamakura et al, 2001). More permeable to chloride ions than bromide ions, it is the pharmaceutical target (Bali and Akabas, 2003) of many anticonvulsants, anxiolytics and general anaesthetics, which acquire an alternative binding site to GABA (Tanelian et al, 1993). This paper, presents a review of scientific literature on the augmentation of GABAA receptor activity caused by modulation of the anaesthetic Propofol and anxiolytic Benzodiazepines concentrations. Recently, there has been considerable scientific and public concern regarding the increasingly common medical problems of anaesthetic misuse and abuse that could be expected from prolonged sub-anaesthetic dosage. This public and medical interest stems from the publication of Michael Jackson's autopsy report which revealed death as a result of respiratory depression. The anatomical findings of the toxicology report ascribed death to acute Propofol Intoxication and the synergic interaction of the Benzodiazepines (Lorazepam, Diazepam and Midazolam); both found present at high concentrations in the blood at the time of death (The Smoking Gun, 2009).
Basic Pharmacology
Propofol (2,6 dissopropylphenol) is a short-acting, intravenous general anaesthetic (Skues and Prys~Roberts,1989) commonly used for the initiation and/or maintenance of anaesthesia during surgical procedures (Wischmeyer et al, 2007) with a quick return to normal psychomotor performance (Zacny et al, 1992). At the sub-anaestheic concentration of 0.5M (Bali and Akabas, 2003), Propofol is unable to induce channel opening through direct activation of the GABAA receptors, but achieves this effect by potentiating currents produced by submaximal GABA concentrations (Bali and Akabas, 2003). At concentrations >10M, Propofol can directly activate the GABA receptor, stimulating the conformational change of the channel in the absence of the GABA neurotransmitter (Bali and Akabas, 2003).
Benzodiazepines are a class of anxiolytics that potentiates currents produced by low GABA concentrations (Longo and Johnson, 2000; Pritchett et al, 1989), to reduce neural communication and lower the activity of the brain (Tanelian et al, 1993). This action is used to help diminish hyperactivity within the brain associated with anxiety disorders, insomnia, muscle spasm, and epilepsy (Longo and Johnson, 2000). Modulation of GABA efficacy is achieved by Benzodiazepines highly selective activation of their receptors which are closely associated to the GABA receptors (Argyropoulos and Nutt, 1999). It is responsible for enhancing the affinity of GABA to its binding receptors, therefore reducing the GABA concentration (KD) required, to activate a conformational change of the gated chloride ion channel, inducing more frequent opening of the ion channel to make the neuron less excitable (Argyropoulos and Nutt, 1999). This mechanism however, occurs only in the presence of GABA on the GABAA receptor, as Benzodiazepines do not activate the GABAA receptors directly but act on the gamma2 component (Argyropoulos and Nutt, 1999; Pritchett et al, 1989), contributing towards its sedative properties and toxicity (Tanelian et al, 1993).
Dosage and Administration
Propofol undergoes oxidative degradation, in the presence of oxygen (Medscape, 2009), therefore is a fast-acting and rapidly metabolising anaesthetic agent. It has an average half-life of elimination between 30 to 60 minutes (Iwersen-Bergmann et al, 1999). Propofol administration often results in swelling and pain at the injection site, the local anaesthetic; Lidocaine is often mixed with Propofol at a maximal ratio of 1:10 respectively to help alleviate symptoms (Medscape, 2009; Tan and Hwang, 2003). The concentration of Propofol in the blood is directly proportional to its rate of infusion (Iwersen-Bergmann et al, 1999), at higher blood concentrations there is an increased contingency of side-effects occurring such as hypotension, cardio-respiratory depression and Apnoea; which can persist for up to 3 minutes (Medscape, 2009).
The induction of General Anaesthesia in healthy adults less than 55 years of age can be achieved through 40mg of repeated boluses every 10 seconds until induction of anaesthesia (Rxlist, 2008). Once induced, the state of Anaesthesia is maintained by continuous Propofol infusion between 6 to 12 mg/kg/h and it is therefore vital to ensure infusions remain within this range (Rxlist, 2008). Additional intermittent boluses between 20 to 50 mg may further by required if discrepancies result, indicating the patient's response to surgical pain (Rxlist, 2008). Caution must be taken when awakening a patient from the state of anaesthesia to prevent possible withdrawal symptoms and unwanted cardio-respiratory effect manifesting (Rxlist, 2008); it is therefore vital awakening of patient is done so slowly. Firstly, through the induction of sedation by reducing Propofol doses to 6 to 9 mg/kg/h for a 3 to 5 minute interval (Rxlist, 2008). This is then followed by an additional reduction in dosage to 1.5 to 4.5 mg/kg/h (also known as the therapeutic range) (Rxlist, 2008). Propofol has a fast recovery time; 8-10 minutes after up to 2 hours infusion (Gordon, 2000), with little chance of post-operative nausea or vomiting, and rapid extubation (Rxlist, 2008). Propofol solutions provide an ideal environment for bacterial growth, so it is important attention is paid to antisepsis and that vials and syringes are discarded with 12 hours of use and/or opening (Rxlist, 2008; Wachowski et al, 1999).
Benzodiazepines are amongst the most frequently prescribed drugs used for treatment in a broad spectrum of conditions, particularly anxiety and insomnia (Lader, 1999). They are metabolised in the liver by hepatic microsomal oxidation and glucuronide conjugation (Gordon, 2000). This is a degenerative process that becomes impaired with age, liver disease and the co-administration of synergistically-acting drugs, which results in prolonged Benzodiazepine half-lives as a result of slower clearance due to decreased hepatic metabolism (Gordon, 2000). Regular alcohol consumption however, is known to increase the clearance of some Benzodiazepines. Elderly patients require lower dosages to that of younger adults as they are particularly sensitive to the CNS effects of benzodiazepines (Gordon, 2000).
Diazepam is a long-acting Benzodiazepine, with a half-life of 20-100 hours (Ashton, 2002); Benzodiazepine effect is a consequence of its break-down in the liver into two metabolites. Similar to the majority of Benzodiazepines, it is often used for short-durations (2 to 4 weeks), to provide relief from severe anxiety or insomnia (Lader, 1999). The lowest effective dose which provides beneficial effect should be used to treat symptoms, it is required that dosage is continually reassessed due to the potential development of tolerance and dependency, indicatory for the reason long-term usage is also not recommended (Ashton, 1995; Longo and Johnson, 2000). The usual dose of Diazepam, used for treatment of anxiety in adults is 2mg three times per day with a maximal dosage of 30mg which must be taken daily in spilt doses modified for individual suitability (Lader, 1999). Administration required for treatment of insomnia is 5 to 15mg before sleeping (Lader, 1999).
Abuse Potential of Propofol: Could Michael Jackson have administered Propofol himself?
Incidences of death as a result of acute Propofol intoxication through self-administration are rare (Iwersen-Bergmann et al, 2001), primarily due to the low availability of Propofol for commercial use. Abuse of Propofol is therefore usually limited to amongst medical professionals with a handful of non-medical professionals being able to gain access, in which, there is 28% mortality amongst abusers (Longo and Johnson, 2000). Commercial ampoules of 20ml contain 200mg Propofol (Iwersen-Bergmann et al, 2001), a dose that is equivalent to 2-2.5 mg/kg body weight (Iwersen-Bergmann et al, 2001). If a dose as such was injected, general anaesthesia would be induced within 1 to 2 minutes of administration with signs of awakening occurring 5-10 minutes after (Iwersen-Bergmann et al, 2001). In the case of Michael Jackson, who had been administered 50 mg of Propofol every night before retiring by his doctor (Telegraph, 2009), it is highly doubted that the lethal overdose of Propofol could have been self-administered, before he lost consciousness. The IV set-up configured of an IV catheter that was placed in his left leg, with its injection port 13.5cm away from the tip of the catheter, suggests that he would have to sit up or bend his knee if he were to reach the injection port for self-administration. An uncomfortable stance, particularly since the primary aim was to achieve a state of unconsciousness to help treat insomnia (The Smoking Gun, 2009). Furthermore continuous boluses would need to be administered to maintain the state of unconsciousness (Iwersen-Bergmann et al, 2001), demonstrating that a medical professional would indeed have been presence, therefore the possible injection of a greater amount of Propofol to deepen sleep would not be possible due to Propofol's rapid narcotic effect (Iwersen-Bergmann et al, 2001).
Abuse Potential of Benzodiazepines
Fatal overdose from Benzodiazepine use alone is unusual (Longo and Johnson, 2000). Death from acute toxicity often occurs, in 80% of cases, due to the synergistic interactions from co-administration with alcohol with or without opiates (Longo and Johnson, 2000), which augments the toxic effects and pharmacokinetic drug interactions of Benzodiazepines. Careful monitoring of Benzodiazepines prescription is required as therapeutic dosage has the tendency to develop into physiological and psychological tolerance and dependence (Donaldson, 2006; Ashton, 1995) based on the strength of dosage, duration of therapy and effectiveness of the drug (Ashton, 1995). The abuse potential of Benzodiazepines is especially high because of the relative ease of access to prescription (Ashton, 1995). In 1990, a study based in the US illustrated that approximately 11% of the population surveyed had reported Benzodiazepine use. With a further 2% of the adult population indicating prolonged usage of 5 to 10 years, results which correlated with its use in UK, European and Asian populations (Ashton, 1995). Addictionologists have observed short-term withdrawal symptoms from therapeutic dosages of benzodiazepines, known to include autonomic instability, insomnia and most commonly symptoms of anxiety (Donaldson, 2006; Ashton, 1995). However, termination of usage in individuals who suffer from Benzodiazepine addiction may stimulate onset of the more severe; protracted abstinence syndrome. It is therefore usual that addiction recovery is controlled through dose tapering to prevent the likelihood of such undesirable effects occurring (Longo and Johnson, 2000).
Conclusion
Despite the numerous transpositions of Benzodiazepines, they are still generally regarded as a safe and effective short-term treatment for patients suffering from anxiety and insomnia disorders. The benefits however from long-term usage remain disputable; research suggests that the potential of adverse effects occurring increases with prolonged usage. Pharmaceutical dependence or addiction manifest itself in withdrawal symptoms upon sudden discontinuation or reduction in dosage intake of the medication, this may arise in patients on prescribed therapeutic doses. Benzodiazepines efficacy reduces as tolerance develops, enhancing the risk of abuse. The body naturally becomes accustomed to having the drug in the system where a gradual increase in dosage would eventually be required to reach the same level of effectiveness that was previously possible at a lower concentration. Benzodiazepines act synergistically with Propofol enhancing their adverse effects; generally causing increased depression of the CNS. Benzodiazepines are a secondary drug of abuse, used principally to complement the effect received from another drug, through their synergic interactions, as shown in the case of Michael Jackson. It is a rare occurrence that addiction arises solely from the legitimate use of Benzodiazepines; usually those addicted have underlying substance abuse problems.
Clinical trials have demonstrated Propofol as a potent intravenous anaesthetic well-suited for the induction of sedation and/or unconsciousness. Studies confirm Propofol undoubtedly has addictive properties, it is rapidly metabolised by the liver to produce a quick return to normal psychomotor performance with minimal postoperative side effects. The short duration of the narcotic effect, means it is difficult to detect misuse. There is a high mortality rate amongst Propofol abusers, usually the result of rapid bolus administration opposed to chronic Propofol abuse. Apnoea and hypotension commonly occur upon administration; this effect is potentiated further by bolus injections, which can potentially cause cardio-respiratory depression. Therefore, due to the extent of caution required during administration, it is strongly advised that Propofol should only be given in a hospital setting, under full observation by an anaesthesiologist with the recommended equipment for patient monitoring and precision dosing in place.
