DEVELOPMENT OF TOLERANCE AND DEPENDENCE IN BARBITURATE USE: A SYSTEMS MODELING APPROACH

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1 DEVELOPMENT OF TOLERANCE AND DEPENDENCE IN BARBITURATE USE: A SYSTEMS MODELING APPROACH by Ali Osman Konuray B.S., Chemical Engineering, Istanbul Technical University, 25 Submitted to the Institute for Graduate Studies in Science and Engineering in partial fulfillment of the requirements for the degree of Master of Science Graduate Program in Industrial Engineering Boaziçi University 28

2 ii DEVELOPMENT OF TOLERANCE AND DEPENDENCE IN BARBITURATE USE: A SYSTEMS MODELING APPROACH APPROVED BY: Prof. Yaman Barlas (Thesis Supervisor) Assist. Prof. Aybek Korugan... Assoc. Prof. Cengizhan Öztürk... DATE OF APPROVAL:

3 iii ACKNOWLEDGEMENTS I am deeply grateful to Professor Yaman Barlas, my thesis supervisor, for being a great example of an enthusiastic scientist. Without him, I would never indulge the field of System Dynamics which seemed, at first, very distinct from my scientific background. His contribution to my studies in recent years is invaluable. I would like to thank Assist. Prof. Aybek Korugan and Assoc. Prof. Cengizhan Öztürk for taking part in my thesis jury and providing valuable feedback. I would like to thank Ceyhun Eksin and Genco Fas for their company, during and after intense academic moments. I would also like to thank members of SESDYN Research Group for their support and friendship, and all the bright people in the department for contributing to my academic development. years. I would like to thank Süheyla Ayar for sharing her life with me in the last couple of I would like to express my deepest gratitude to my mother Gülsün Konuray for inspiring me with her artistic personality. Her wisdom is my guiding light. Lastly, I would like to thank my late father Dr. M. Mehmet Konuray for installing in me an unfailing respect for science.

4 iv ABSTRACT DEVELOPMENT OF TOLERANCE AND DEPENDENCE IN BARBITURATE USE: A SYSTEMS MODELING APPROACH A system dynamics model is constructed to study the development of tolerance and dependence to phenobarbital in prolonged use. Phenobarbital is a sedative barbiturate drug whose target of action is the brain. Although its use has decreased over the years, phenobarbital is still being prescribed to many patients. As a side effect, phenobarbital enhances the synthesis of its own metabolic enzymes in the liver. This enzyme induction problem causes increased tolerance to phenobarbital over time. Moreover, the brain adapts to the presence of the drug and its sensitivity decreases with time. The resulting decrease in drug effectiveness urges the drug user to increase the dose. A feedback loop results, as the increased dose in turn leads to more metabolic induction and neuroadaptation. Furthermore, the brain s adaptation to the drug plays a major role in rendering the user dependent on the drug hence complicating withdrawal from the drug. Because adaptive changes persist even after drug intake stops, upon abrupt discontinuation to the drug, the user experiences unwanted rebound effects. The model incorporates phenobarbital absorption, distribution, metabolism, and elimination processes with enzyme induction and neuroadaptation related structures. We start with validating the model by assuming a normal person. We then consider three scenarios: An epilepsy patient, a normal person taking an enzyme inhibitor drug concurrently with phenobarbital, and a normal person adopting different dosing schemes. We finally search for dosing regimens that facilitate gradual withdrawal from the drug so that rebound effects are avoided. Results show that an epilepsy patient is more prone to developing tolerance and dependence. Also, it is shown that concurrent intake of an enzyme inhibitor drug weakens rebound effects after sudden discontinuation since phenobarbital is cleared slower. Experiments with dosing frequencies show that the patient is more prone to tolerance and dependence development if dosing frequency is decreased. Finally, experiments confirm that in order to withdraw from the drug safely, doses should be reduced gradually.

5 v ÖZET BARBTURAT KULLANIMINDA TOLERANS VE BAIMLILIK OLUUMU: BR SSTEM MODELLEMES Sürekli fenobarbital kullanımında tolerans ve baımlılık oluumunu aratırmak için bir sistem dinamii modeli kurulmutur. Fenobarbital, beyni etkileyen sedatif (sakinletirici) bir ilaçtır. Geçmi yıllara kıyasla kullanımı azalmı olmasına ramen bir çok insan halen fenobarbital kullanmaktadır. Fenobarbital bir yan etki olarak kendini metabolize eden karacier enzimlerinin sayısını arttırır. Bu enzim artıı ilaca tolerans oluumuna neden olur. Bunun yanında, zamanla beyin ilaca adapte olur ve dolayısıyla ilaca karı hassasiyeti azalır. Bu iki faktör, ilacın etkinliini azalttıından kullanıcının aynı etkiyi hissedebilmesi için dozu arttırması gerekir. Artan dozlar metabolizma ve nöroadaptasyon etkilerini güçlendirerek kısır bir geri bildirim döngüsü oluturur. Nöroadaptasyon, kullanıcıyı ilaca baımlı kılarak ilacın bırakılmasını zorlatırır. laç alımı kesilmesine ramen adaptif deiimler hemen yokolmaz ve dolayısıyla kullanıcı ilacı bıraktıktan kısa bir süre sonra yoksunluk sendromu yaar. Kurulan model, fenobarbital ilacının emilimi, daılımı, metabolizması ve atılımı süreçlerini içermektedir. Enzim artıı ve nöroadaptasyon mekanizmaları da modele eklenmitir. Tezde öncelikle normal bir insan ele alınmakta ve model empirik veriler kullanılarak gerçeklenmektedir. Bunun ardından, bir epilepsi hastasının, bir enzim inhibitörüyle birlikte fenobarbital kullanan bir insanın, ve normal bir insanın uyguladıı farklı doz uygulamalarının modellendii üç ayrı senaryo incelenmitir. Son olarak yoksunluk sendromunu engelleyebilecek doz stratejileri ile deneyler yapılmıtır. Sonuçlar epilepsi hastalarının tolerans ve baımlılık geliimine daha hassas olduklarını göstermitir. Dier taraftan, fenobarbital ile beraber enzim inhibitörü bir ilaç alınırsa, fenobarbital vücuttan daha yava atılmakta, dolayısıyla da fenobarbital alımı aniden kesildiinde ortaya çıkan yoksunluk sendromunun iddeti daha az olmaktadır. Farklı doz stratejileriyle yapılan deneylerde, doz alım sıklıı azaldıkça tolerans ve baımlılık geliiminin hızlandıı görülmütür. Son olarak, yoksunluk sendromundan kaçınmak için, dozun kademeli bir ekilde azaltılması gerektii gösterilmitir.

6 vi TABLE OF CONTENTS ACKNOWLEDGEMENTS... iii ABSTRACT... iv ÖZET... v LIST OF FIGURES... viii LIST OF TABLES... xi LIST OF ABBREVIATIONS... xii 1. INTRODUCTION Neurotransmission in the Central Nervous System Definition of Pharmacokinetics Pharmacokinetics of Barbiturates Action mechanism of barbiturates Development of Tolerance and Dependence to Barbiturates RESEARCH OBJECTIVE AND DYNAMIC HYPOTHESIS METHODOLOGY MODEL DESCRIPTION Pharmacokinetics Sector Fundamental Approach and Assumptions Description of the Structure Central Nervous System Sector Fundamental Approach and Assumptions Description of the Structure Dose Sector Fundamental Approach and Assumptions Description of the Structure Model Parameters VALIDATION OF THE MODEL Simulation Results Single Dose Continuous Drug Intake with Constant Dose... 4

7 vii Continuous Drug Intake with Dose Increase as a Result of Feedback Drug Treatment for Seven Days Drug Treatment for 2 Days Drug Treatment for 6 Days Model Validity Discussion SCENARIO ANALYSES Epilepsy Patient Co-administration of a Drug That Causes Enzyme Inhibition Different Dosing Frequencies ANALYSIS OF WITHDRAWAL POLICIES Withdrawal after 2 days of treatment An unsuccessful regimen A successful regimen Withdrawal after 6 days of treatment An unsuccessful regimen A Successful Regimen CONCLUSIONS AND FUTURE RESEARCH DIRECTIONS APPENDIX. EQUATIONS OF THE MODEL... 8 REFERENCES... 89

8 viii LIST OF FIGURES Figure 1.1. Relative safety of barbiturates and benzodiazepines... 1 Figure 1.2. Frequency of barbiturate use among twelfth grade high school students... 2 Figure 1.3. Different types of synapses (top). A schematic representation of neurotransmission (bottom)... 5 Figure 1.4. Steps in excitatory and inhibitory neurotransmission... 6 Figure 1.5. Blood plasma concentration time data for a single IV dose of thiopental... 8 Figure 1.6. GABA A receptor-chloride channel complex... 9 Figure 1.7. Pre- and post-synaptic neuroinhibition by barbiturates... 1 Figure 1.8. Proposed mechanism of enzyme induction by phenobarbital Figure 1.9. Administered doses of PB Figure 1.1. Change in the intensity of rebound behavior with time Figure The Himmelsbach hypothesis Figure 2.1. Causal loop diagram for tolerance and dependence development Figure 4.1. Stock-flow structure of the pharmacokinetics sector Figure 4.2. Saturability of enzyme induction Figure 4.3. Concentration-response data for phenobarbital Figure 4.4. Stock-flow structure of the CNS sector Figure 4.5. Graphical function for IndAdptnRate Figure 4.6. Graphical function for EffSatur... 3 Figure 4.7. Graphical function for EffAdptnOnNormClCur Figure 4.8. Graphical function for EffPBOnReadptn Figure 4.9. Stock-flow structure for the Dose Sector Figure 5.1. Absorption and distribution of a single dose Figure 5.2. Increasing chloride current in the brain after a single dose Figure 5.3. Dynamics of enzyme induction and neuroadaptation for a single dose... 4 Figure 5.4. Constant doses (a) and drug profiles in the brain (b) in both a seven day and a 2 day treatment Figure 5.5. Enzyme induction and neuroadaptation and the resulting chloride current profile when the user takes constant doses (for seven and 2 days)... 42

9 ix Figure 5.6. Dose profile (a) and drug amount in the brain (b) in the seven day drug treatment followed by abrupt withdrawal Figure 5.7. Enzyme and neuroadaptation dynamics in the seven day drug treatment followed by abrupt withdrawal Figure 5.8. Behavior of chloride current in the seven day drug treatment Figure 5.9. Dose profile (a) and drug amount in the brain (b) in the 2 day drug treatment followed by abrupt withdrawal Figure 5.1. Enzyme and neuroadaptation dynamics in the 2 day drug treatment followed by abrupt withdrawal Figure Behavior of chloride current in the 2 day drug treatment Figure Dose profile (a) and drug amount in the brain (b) in the 6 day drug treatment followed by abrupt withdrawal... 5 Figure Enzyme and neuroadaptation dynamics in the 6 day drug treatment followed by abrupt withdrawal Figure Behavior of chloride current in the 6 day drug treatment Figure Progression of enzyme induction in 2 days of continuous PB use Figure Comparison of tolerance dynamics generated by the model (a) against real data (b) from Gay et al (1983) Figure Tolerance and dependence indicators for 6 days of continuous PB intake, (a) Model output, (b) Real data Figure Differences in withdrawal dynamics between a partially dependent (2 day user) and a completely dependent (6 day user) Figure 6.1. Dose profiles (a) and drug profiles in brain tissue (b) of both a healthy and an epileptic individual in 2 days of continuous PB use Figure 6.2. Enzyme and neuroadaptation dynamics in both a healthy and an epileptic individual taking PB for the last 6 days Figure 6.3. Chloride current in a healthy and an epileptic individual) Figure 6.4. Flurbiprofen average clearance as influenced by fluconazole pre-treatment Figure 6.5. Dose profiles (a) and drug amounts in the brain (b) with and without fluconazole pre-treatment Figure 6.6. Enzyme and neuroadaptation dynamics with and without fluconazole pre-

10 x treatment Figure 6.7. Enzyme and neuroadaptation dynamics in different dosing schemes (No feedback to increase the doses) Figure 6.8. Comparative behavior of chloride current (No feedback to increase the doses) Figure 6.9. Difference in the extent of tolerance development w.r.t dosing schemes (Feedback allowed to increase doses) Figure 6.1. Neuroadaptation dynamics for different dosing schemes (Feedback allowed to increase doses) Figure Dependence dynamics for different dosing schemes (Feedback allowed to increase doses) Figure Behavior of chloride current in different dosing schemes (Feedback allowed to increase doses) Figure 7.1. Dynamics of an unsuccessful withdrawal regimen after partial dependence Figure 7.2. Severity of withdrawal signs after an unsuccessful dosing strategy in partial dependence Figure 7.3. Dynamics in a successful withdrawal regimen after partial dependence Figure 7.4. Severity of withdrawal signs after a successful dosing strategy in partial dependence Figure 7.5. Results for an unsuccessful withdrawal regimen after complete dependence Figure 7.6. Severity of withdrawal signs after an unsuccessful dosing strategy in complete dependence Figure 7.7. Results for a gradual withdrawal regimen of 3 days following a 6 day drug treatment Figure 7.8. Severity of withdrawal signs after a successful dosing strategy in complete dependence... 77

11 xi LIST OF TABLES Table 1.1. Classification and properties of barbiturates... 3 Table 4.1. Main pharmacokinetic parameters used in the model Table 4.2. Other pharmacokinetic parameters Table 5.1. Initial values for the stocks... 37

12 xii LIST OF ABBREVIATIONS Adptn Arterial Braincapil Braintis C ClCur ClCurWOP B CNS CYP Eff GABA GI Ind Induc M Norm P PB Q Readptn Real ThresholdSedat V Venous Adaptation Arterial Blood Brain Capillary Brain Tissue Concentration (of phenobarbital in) Chloride Current Chloride Current Without Phenobarbital Central Nervous System Cytochrome P Effect Gamma Amino Butyric Acid Gastrointestinal Indicated Induction Amount (of phenobarbital in) Normal Tissue-Blood Partitition Coefficient (of phenobarbital in) Phenobarbital Blood Volumetric Flow Rate (through) Re-adaptation Realized Sedation Threshold Volume (of) Venous Blood

13 1 1. INTRODUCTION Barbiturates are classified as central nervous system (CNS) depressants. They act generally on the CNS. In low doses, they cause sedation and as the dose is increased, the user experiences hypnosis (i.e. sleep). Further increase in the dose results in anesthesia and finally coma. Overdose of barbiturates causes severe respiratory depression and may lead to death. For instance, Jimi Hendrix, the famous rock artist, died of barbiturate overdose in the year 197. Because of having high abuse potential, they are being replaced by the safer benzodiazepines. Figure 1.1 gives an idea about the relative safety of barbiturates and benzodiazepines. Figure 1.1. Relative safety of barbiturates and benzodiazepines (Katzung 24) The dose-effect relationship of barbiturates is rather linear and lethal overdoses are more likely. On the other hand, this relationship is saturable for benzodiazepines. At high doses, as the dose is further increased, CNS depression stays almost constant. This enables a wider margin of safety.

14 2 Despite their high abuse potential, barbiturates are still being used as anticonvulsants (i.e. anti-epileptic drugs), intravenous anesthetics, and death inducing agents (Hardman and Limbird, 21). Furthermore, a lot of people still use barbiturates for sedation or to fall asleep. Alarmingly, a statistical study revealed that the frequency of barbiturate use among twelfth grade high school students in the U.S. has increased slightly over the last few years (See Figure 1.2 below). Figure 1.2. Frequency of barbiturate use among twelfth grade high school students (From Barbiturates are classified with respect to their onset and duration of action. However, the action mechanism is the same for all barbiturates. Different barbiturate classes are tabulated in Table 1.1.

15 3 Table 1.1. Classification and properties of barbiturates (Hardman and Limbird, 21) CLASS Ultra-shortacting Short-acting Intermediateacting Long-acting COMPOUND (TRADE NAMES) Methohexital (BREVITAL) Thiopental (PENTHOTAL) Pentobarbital (NEMBUTAL) Secobarbital (SECONAL) Amobarbital (AMYTAL) Aprobarbital (ALURATE) Butabarbital (BUTISOL, others) ROUTES OF ADMINISTRATION HALF- LIFE, HOURS THERAPEUTIC USES I.V. 3-5 * Induction and/or maintenance of anesthesia I.V., rectal 8-1 * Induction and/or maintenance of anesthesia, preoperative sedation, emergency management of seizures Oral, I.M., I.V., rectal 15-5 Insomnia, preoperative sedation, emergency management of seizures Oral, I.M., I.V., rectal 15-4 Insomnia, preoperative sedation, emergency management of seizures Oral, I.M., I.V. 1-4 Insomnia, preoperative sedation, emergency management of seizures Oral Insomnia Oral 35-5 Insomnia, preoperative sedation Butalbital Oral Marketed in combination with analgesic agents Mephobarbital (MEBARAL) Phenobarbital (LUMINAL, others) Oral 1-7 Seizure disorders, daytime sedation Oral, I.M., I.V Seizure disorders, status epilepticus, daytime sedation I.M.: intramuscular injection, I.V.: intravenous administration * Value represents terminal half-life due to metabolism by liver; redistribution following intravenous administration produces effects lasting only a few minutes

16 4 Other than the therapeutic uses mentioned in Table 1.1, some barbiturates have had different uses. For example, other than its common use as an inducer of anesthesia, the ultra-short acting thiopental is used in large doses in the United States to execute prisoners on death row. In lower doses, it is sometimes used as a truth serum. The drug does not itself force people to tell the truth, but is thought to make subjects more likely to be caught off guard when questioned (Stevens and Bannon, 27). Barbiturate use can cause dependence. This dependence may be psychological in the initial stages of barbiturate treatment. However, as treatment continues, tolerance and then physical dependence develops. As people develop tolerance for barbiturates, they may need more of the drug to get the desired effect. This can lead to an overdose. As Weil and Rosen (24) point out in From Chocolate to Morphine, People who get in the habit of taking sleeping pills every night to fall asleep might start out with one a night, progress to two, and then graduate to four to get the same effect. One night the dose they need to fall asleep might also be the dose that stops their breathing." Overdoses occur because tolerance to the lethal effects of the drug is less than tolerance to its therapeutic effects (e.g. sedation). In physical dependence, the user experiences difficulties in stopping drug treatment. Upon discontinuation of the drug, the user experiences a withdrawal syndrome in which he/she goes through a state of rebound hyperexcitability manifested as excessive nightmarish dreaming, restlessness, irritability, and convulsions (Liska, 21). Although their use is decreasing, mechanism of action of barbiturates is just recently being clarified. Before reviewing the mechanism, it would be useful to briefly overview first the subject of neurotransmission and then pharmacokinetics Neurotransmission in the Central Nervous System Neurotransmission means the communication of nerve cells (i.e. neurons). This is accomplished by billions of interconnected neurons. The point where two neurons meet is called a synapse. Different types of synapses exist and these are shown in Figure 1.3.

17 5 Figure 1.3. Different types of synapses (top). A schematic representation of neurotransmission (bottom) (From The message between two neurons is conveyed through synapses via substances called neurotransmitters. Neurotransmitters are stored in specialized sacs (i.e. vesicles) inside the presynaptic nerve endings (i.e. nerve terminals). When a reversal of electrical charge is experienced in the nerve terminal, the vesicles translocate and bind to the neuronal membrane. This process is called docking. The reversal of charge is called the action potential. It is accomplished through an influx of sodium ions and efflux of potassium ions through specialized ion channels located on the axon of the presynaptic neuron. This depolarization is conveyed to the nerve ending and causes ion channels to open and allow an influx of calcium. The influx of calcium ions induces the release of the neurotransmitter to the synaptic cleft by exocytosis of the docked vesicles. The neurotransmitter then travels to the postsynaptic neuron and binds to specific receptor proteins on its membrane and changes the membrane electrical potential. If the neurotransmitter is excitatory, an influx of sodium ions to the postsynaptic neuron causes depolarization and this initiates an action potential in the neuron. However, if the

18 6 neurotransmitter is inhibitory, an influx of chloride and potassium ions occurs which hyperpolarizes the membrane and thus an action potential is inhibited (Hardman and Limbird, 21). In figure 1.4, inhibitory and excitatory neurotransmission are summarized. Figure 1.4. Steps in excitatory and inhibitory neurotransmission (Hardman and Limbird, 21) The most widespread excitatory and inhibitory transmitters in the CNS are glutamate and gamma-aminobutyric acid (GABA), respectively (Powis and Bunn, 1995). As mentioned previously, there exist receptors on neuronal membranes that are specialized to bind neurotransmitters. Each receptor is specialized to bind a specific type of neurotransmitter. Furthermore, there are many sub-types of a receptor for a specific

19 7 neurotransmitter and functions of each of these subunits are modulated by different mechanisms (Hardman and Limbird, 21) Definition of Pharmacokinetics There are several phases before an administered drug causes a response. After administration, the drug goes through many phases during which it may lose effectiveness. After oral administration, the drug must dissolve in stomach fluids, and it must be absorbed from the gastrointestinal tract. Once absorbed, it is directly transported to the liver via the hepatic portal vein. The metabolism in liver at this stage is referred to as first-pass metabolism. In drug development, it is aimed to design drugs that have little first-pass metabolism since it has a negative impact on drug efficacy. Furthermore, a drug may also undergo elimination in different regions such as the gastrointestinal wall which too is an undesired property. After first-pass metabolism, the remaining drug enters blood circulation and reaches the target organ. There, it binds its receptor to exert its effect. While in blood circulation, the drug is transported to the liver once more and it undergoes further elimination. Also while in circulation, it may bind to blood plasma proteins or tissues of different organs. Once bound, a drug molecule is ineffective. This process of drug delivery in the body is referred to as pharmacokinetics Pharmacokinetics of Barbiturates Most barbiturates are rapidly absorbed into the blood following oral intake. The most important factor that plays a role in the entrance of a barbiturate into the brain is its lipid solubility. To exemplify the differences in pharmacokinetic profiles of barbiturates, we consider two barbiturates: ultra-short acting thiopental and long acting phenobarbital (See Table 1.1). Due to its high lipid solubility, the ultra-short acting thiopental has a very rapid onset of effects in the CNS. In comparison, the long acting phenobarbital has low lipid solubility and thus penetrates into the brain slower.

20 8 In order to be cleared from the body, barbiturates must be transformed into more water-soluble forms so that they can be filtered in the kidneys. Only insignificant quantities (less than 1per cent) of thiopental are excreted unchanged in the urine. Unlike thiopental, 2 to 3 percent of the administered dose of phenobarbital is excreted unchanged. The elimination-half life of phenobarbital is 4 to 5 days. For thiopental, the situation is much more complex. Upon intravenous administration, thiopental rapidly penetrates into the brain due to its very high lipid solubility and if the dose is sufficient, produces loss of consciousness in one circulation time. The blood plasma-brain equilibrium is reached in less than a minute. After that, thiopental diffuses out of the brain and out of other tissues that receive high blood supply and is redistributed to all the remaining less perfused tissues such as muscle and fat. It is because of this rapid redistribution that a single dose of thiopental is very short acting (Katzung, 24). The redistribution phenomenon causes the half-life of thiopental to be time dependent. Initially, the fall in plasma concentration is very rapid corresponding to a half-life of less than ten minutes. It is denoted as t 1/2α in Figure 1.5 below. After redistribution to less perfused areas, the fall of concentration slows down. The half-life increases to more than ten hours. This half-life is denoted as t 1/2β in the figure. Figure 1.5. Blood plasma concentration time data for a single IV dose of thiopental (From

21 Action mechanism of barbiturates It was shown that barbiturates exert their CNS-depressant effects by both potentiating the inhibitory effects of GABA and suppressing excitatory effects of glutamate. However, suppression of excitatory neurotransmission does not contribute to their sedative/hypnotic effects (Powis and Bunn, 1995; Joo et al., 1999). At low to moderate concentrations, barbiturates bind to the GABA A receptor. The GABA A receptor is a sub-type of GABA receptors which is classified as a ligand-gated ion channel meaning that the binding of a ligand (a molecule) to the receptor causes the ion channel to open. The GABA A receptor is composed of different sub-units. The distribution of these sub-units in the CNS is widespread and heterogeneous and this heterogeneity has yet to be fully defined (Hardman and Limbird, 21). Schematically, the GABA A receptorion channel complex is as in Figure 1.6. Figure 1.6. GABA A receptor-chloride channel complex. There are five binding sites (subunits) on the complex (From By binding to its specific site, barbiturates enhance the inhibitory chloride ion currents mediated by GABA. Essentially, barbiturates increase the time for which GABAactivated channels are open. At higher concentrations, they activate the chloride channels even in the absence of GABA. This action is regarded as postsynaptic inhibition. In

22 1 addition to postsynaptic effects, barbiturates induce GABA-mediated presynaptic inhibition as well. This takes place in axo-axonic synapses (See Figure 1.3). GABA released from the ending of the inhibitory neuron binds to GABA receptors on the terminal of the excitatory neuron and causes a modest depolarization which decreases excitatory neurotransmitter release. It was also shown that especially at higher concentrations, barbiturates directly suppress excitatory transmission mediated by glutamate. The postand pre-synaptic inhibition effects of barbiturates are shown in Figure 1.7. Figure 1.7. Pre- and post-synaptic neuroinhibition by barbiturates (Powis and Bunn, 1995) Also, at anesthetic concentrations, barbiturates inhibit calcium influx to the presynaptic nerve ending and thus reduce transmitter release. In addition to these, barbiturates reduce axonal conduction through ion channels and thus increase the threshold for electrical excitability and decrease the rate of rise of the action potential. However, these

23 11 effects are realized at very high concentrations which are practically irrelevant (Powis and Bunn, 1995) Development of Tolerance and Dependence to Barbiturates Barbiturates have been shown to cause the phenomenon of enzyme induction. In the liver, there exists a system of enzymes that are responsible for converting many endogenous and exogenous substances into active and/or inactive forms. The so-called cytochrome P45 family of enzymes constitutes the majority of the enzyme population in the liver (Hardman and Limbird, 21). By convention, cytochrome enzymes have the prefix CYP. The CYP enzymes catalyze various destructive reactions such as oxidation. The inducing effect of barbiturates causes more enzymes to be synthesized and thus a faster metabolism of the substrates of these enzymes. When the set of substrates include the drug itself, this is called autoinduction. In time, a tolerance to the barbiturate occurs and higher doses are required to induce the same drug effect. Among barbiturates, phenobarbital (will be denoted by PB hereafter) is the most potent inducer of CYP2C subfamily of enzymes. Since PB itself is mostly metabolized by this subfamily of enzymes (Tanaka, 1999), it has autoinduction properties. This was also reported by Magnusson (27). Induction of enzymes by PB in rats is studied by Magnusson et al. (26). Their purpose is to characterize the magnitude, time course, and specificity of PB mediated enzyme induction, and to develop an integrated pharmacokinetic model that represents the change in the activities of different CYP enzymes. In another study, Raucy et al. (22) work with human liver cells in vitro to investigate the extent of induction of CYP2C enzymes by several inducers including PB. The mechanism of induction is not fully understood. Nevertheless, there is progress. A variety of drugs and xenobiotics cause enzyme induction and each is believed to have its own mechanism. It is believed that inside liver cells, there exist several receptors that respond to different types of chemicals. These receptors are called nuclear receptors. An excellent review on the topic is provided by Handschin and Meyer (23). It is believed

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