PHAR 100 Module 03 Companion Guide PDF - Central Nervous System Pharmacology

PHAR 100 INTRODUCTORY PHARMACOLOGY MODULE 03 CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS Please note: This course was designed to be interacted and engaged with using the online modules. This Module Companion Guide is a resource created to complement the online slides. If there is a discrepancy between this guide and the online module, please refer to the module. How can you help protect the integrity and quality of your Queen’s University course? Do not distribute this Module Companion Guide to any students who are not enrolled in PHAR 100 as it is a direct violation of the Academic Integrity Policy of Queen’s University. Students found in violation can face sanctions. For more information, please visit https://www.queensu.ca/academic- calendar/health-sciences/bhsc/ MODULE 03 COMPANION GUIDE PHAR 100 TABLE OF CONTENTS INTRODUCTION..................................................................................................................................................... 3 SECTION 01: Sedative-Hypnotics......................................................................................................................... 5 SECTION 02: Alcohol............................................................................................................................................18 SECTION 03: Cannabis........................................................................................................................................32 SECTION 04: Opioids...........................................................................................................................................42 CONCLUSION.......................................................................................................................................................52 CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 2 MODULE 03 COMPANION GUIDE PHAR 100 INTRODUCTION Module 03 covers the mechanism of action, therapeutic effects, and adverse effects of classes of drugs that depress the central nervous system (C N S) or inhibit pain. These include sedative-hypnotics, alcohol, cannabis, and opioids. For each of these drugs, you will learn about their potential for misuse and substance use disorder (S U D), focusing on tolerance, withdrawal, and addiction. The information presented in this module will help you complete Assessment 2. Watch the video for an introduction to Module 03 from Mandy Turner, P h D (1:48). Start of Video Transcript: Welcome to Module 03 of Introductory Pharmacology. This module connects the basic principles of pharmacology you learned in Module 01 with the framework of SUD and drug misuse you learned in Module 02 and applies these to common central nervous system depressants. The module starts with a class of drugs called sedative-hypnotics. This class of drug consists of benzodiazepines, barbiturates, and benzodiazepine-like drugs. While you may or may not recognize these names, these drugs are some of the most widely prescribed in the world. Their therapeutic effects can range from anti-anxiety all the way to general anesthesia. Next, you will learn about alcohol. You will learn how it works (its mechanism of action) and also why some can tolerate more alcohol than others due to differences in pharmacokinetics. The module will cover the effects of both short-term and chronic alcohol consumption, and the dangers of combining alcohol with other drugs. In the third section, you will learn about cannabis. Since its legalization in Canada in 2019, there has been increased interest in how it works and its potential therapeutic uses. The fourth and final section of this module will cover opioids. You will learn the difference between natural opioids like morphine and synthetic opioids like fentanyl. The module will cover how opioids block the pain pathways, and how this mechanism of action relates opioid overdose and the opioid crisis. I hope this module empowers you with the knowledge of pharmacology, and you realize how a bit of understanding of basic drug principles will allow you to better contextualize these drugs you hear and see about on the news. End of Video Transcript. Module Learning Outcomes By the end of Module 03, you should be able to: 1. Compare and contrast the classes of sedative-hypnotics in terms of beneficial and adverse effects and therapeutic uses. 2. Describe the effect of short-term and long-term use of alcohol and cannabis on human health. CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 3 MODULE 03 COMPANION GUIDE PHAR 100 3. Summarize the social and legal issues associated with the use of C N S depressant drugs. 4. Explain the mechanism of action and adverse effects of opioid analgesics. Module Assessments These assessment(s) are associated with Module 03. View the details of the assessment. ASSESSMENT 2: Individual Written Report The purpose of this assessment is to apply information learned in Modules 01-04 by answering the posed questions. For specific details about this assessment, visit the assessment page in your online learning environment. Activities Throughout the Module Note that text responses and interactions within the learning module will not be graded unless otherwise noted. However, your responses to these interactions are recorded in the module and viewable by your instructor(s). This includes the short quizzes at the end of each section. These questions are included to prepare you for the types of questions you will see on the midterm and final exam. Module Outline Section 01: Sedative-Hypnotics Section 02: Alcohol Section 03: Cannabis Section 04: Opioids Page Link: https://player.vimeo.com/video/605902652?h=91dadc6440 End of INTRODUCTION CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 4 MODULE 03 COMPANION GUIDE PHAR 100 SECTION 01: SEDATIVE-HYPNOTICS Introduction to Sedative-Hypnotic Agents Sedative-hypnotic agents are C N S depressants. The magnitude of C N S depression produced by a drug at a particular dose determines what effect the agent produces. Learn about the different magnitudes of C N S depression. Low Dose to High Dose Anti-Anxiety Used to treat anxiety disorders, such as generalized anxiety disorder and obsessive compulsive disorder. Sedation Used to relieve anxiety, decrease activity, moderate excitement, and generally calm the individual. Hypnosis (sleep) Used to produce drowsiness and aid in the onset and maintenance of sleep. General Anesthesia Used to induce general anesthesia, which is a state of unconsciousness with an absence of pain sensation. Note: The interaction between sedative-hypnotic agents with other C N S depressants (e.g., alcohol, some antihistamines) are clinically important and can be dangerous. Mechanism of Action of Sedative-Hypnotics Recall from Module 01 that the major excitatory neurotransmitter in the brain is glutamate. When a person is anxious or having difficulty sleeping, some therapies aim to depress overall brain activity, by decreasing glutamate-induced nerve firing. This can be accomplished by increasing inhibitory signalling in the brain. Most of the sedative-hypnotic drug classes work in this manner. Learn how C N S excitation is controlled by comparing neuronal activity with and without sedative-hypnotics. Without Sedative-Hypnotics Most brain activity involves excitatory neurons. These excitatory neurons release the neurotransmitter glutamate. Neurons “fire” when the excitatory inputs exceed inhibitory inputs. CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 5 MODULE 03 COMPANION GUIDE PHAR 100 With Sedative-Hypnotics Inhibitory signals from GABA neurons increase with most sedative-hypnotics, resulting in decreased glutamate nerve firing. Video: GABA Signalling To understand how sedative-hypnotics work, you have to first understand GABA signalling. Recall from Module 01 that GABA is the primary inhibitory neurotransmitter in the C N S. It causes inhibition by binding to and selectively opening chloride channels. These chloride channels are built of multiple subunits that span the neuronal cell membrane, allowing chloride ions to flow into the cell when signalled to open. When GABA binds to and opens the chloride channel, chloride ions flow into the postsynaptic neuron. The influx of chloride ions makes it harder for the postsynaptic neuron to transmit incoming messages to other neurons, thereby depressing C N S neuronal signalling. Watch the video to see the interaction of GABA with the chloride channel (0:46). Note: This video does not have any audio. Start of Video Description: Each G A B A A receptor subunit has four transmembrane-spanning regions. The receptor itself is a pentamer, with two alpha subunits, two beta subunits, and one gamma subunit. When there is nothing bound to the G A B A binding site, the channel is closed. When a drug (such as a sedative-hypnotic) binds to the G A B A binding site, the channel opens and allows an influx of chloride ions into the neuron. End of Video Description. CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 6 MODULE 03 COMPANION GUIDE PHAR 100 Drugs That Bind to the Chloride Channel Most sedative-hypnotics modulate the chloride ion channel in the brain and spinal cord, but each bind to a different site on the chloride channel, as indicated in the diagram. The result is an increase in synaptic inhibition and, thus, a dampening of neuronal responses. In essence, they enhance the inhibitory effect of GABA. Throughout the rest of this section, you will learn about the mechanism of action and therapeutic uses of benzodiazepines, barbiturates, and benzodiazepine-like drugs. You will discuss alcohol and its influence on the chloride channel in Section 02 of this module. Benzodiazepines Benzodiazepines are among the most widely prescribed drugs in the world, with 5-10% of Canadians being prescribed this class of drugs. Many different types of benzodiazepines exist, and their therapeutic effects and duration of action differ, however, their mechanism of action is the same. Learn about the characteristics of benzodiazepines. Routes of Administration Benzodiazepines are usually taken as a capsule or tablet, but some are available for intravenous or intranasal use. Mechanism of Action Activation of the benzodiazepine receptor increases the frequency of the opening of the chloride channel. Therapeutic Effects The therapeutic or desirable effects of benzodiazepines are relaxation, calmness (i.e., they can decrease aggression), and relief from anxiety or tension. They also produce skeletal muscle relaxation and have anticonvulsant effects. Some benzodiazepines are effective hypnotics. Benzodiazepines also have minimal suppression of REM-type sleep. Reference: Campbell, T. J., Men, S., Shearer, D., Ebejer, T., Joosse, M., Quercia, J., Sanders, J., Tadrous, M., Antoniou, T., Gomes, T., & Ontario Drug Policy Research Network Citizens’ Panel (2023). The epidemiology of benzodiazepine-related toxicity in Ontario, Canada: a population-based descriptive study. Canadian CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 7 MODULE 03 COMPANION GUIDE PHAR 100 journal of public health = Revue canadienne de sante publique, 114(6), 956-966. Retrieved August 2024, from: https://doi.org/10.17269/s41997-023-00784-3 Esposito, E., Barbui, C., & Patten, S. B. (2009). Patterns of benzodiazepine use in a Canadian population sample. Epidemiologia e psichiatria sociale, 18(3), 248–254. Retrieved July 2021, from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10267543/ CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 8 MODULE 03 COMPANION GUIDE PHAR 100 Lethality of Benzodiazepines The benzodiazepines are among the drugs most commonly involved in overdose. Fortunately, they have a very high therapeutic index and, therefore, a wide margin of safety which means that deaths from overdose are very rare. Death has occurred following ingestion of enormous doses, rapid intravenous injection of a large dose, or when taken in combination with other sedating drugs (e.g., alcohol). Learn about the antidote for benzodiazepines. Antidote for Benzodiazepines A key benefit of the benzodiazepines is that an antidote exists to reverse its effects in the event of an overdose. The antidote is called flumazenil, a benzodiazepine receptor antagonist that blocks the effects of benzodiazepines. When benzodiazepines are taken in overdose, flumazenil can be administered as an antidote. Adverse Effects of Benzodiazepine Use Benzodiazepines are also associated with adverse effects. Learn about the adverse effects of short-term and long-term benzodiazepine use, as well as the adverse effects for special populations. Adverse Effects of Short-Term Benzodiazepine Use Following short-term use, benzodiazepines affect the C N S, lungs, and motor coordination. Learn how these systems are affected. CNS Adverse effects may include drowsiness, lethargy, fatigue, and impairment of thinking and memory. For C N S depression, what is considered an adverse effect depends on the targeted therapeutic effect. For example, if the therapeutic goal is anti-anxiety, drowsiness may be an adverse effect, however, it would be considered a therapeutic effect if the goal is sedation. Breathing Respiratory depression has been observed following rapid intravenous administration of benzodiazepines. Motor Coordination Moderate doses of all benzodiazepines can impair motor coordination and driving. Patients taking these drugs during the day should refrain from driving or operating dangerous machinery. These responses are exaggerated as the dose is increased. CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 9 MODULE 03 COMPANION GUIDE PHAR 100 Adverse Effects of Long-Term Benzodiazepine Use The effects of long-term use vary between individuals. Some individuals can take large amounts of benzodiazepines for long periods of time without any major evidence of intoxication. Others will demonstrate the symptoms of chronic sedative-hypnotic intoxication, such as impaired thinking, poor memory and judgement, disorientation, incoordination, and slurred speech. Benzodiazepine Use in Special Populations The effects of benzodiazepine use should be particularly considered for pregnant people and older adults. Pregnant/Chestfeeding Benzodiazepines cross the placenta and distribute into the fetus. If they are administered in the first trimester, they result in a small but significant risk for fetal abnormalities. Benzodiazepines are secreted into the milk, exposing nursing infants to therapeutic or toxic doses of the drug, and can result in sedation or death. Older Adults Benzodiazepines can produce cognitive dysfunction in older adults and, as a result, should be used with caution, if at all, in this age group. Benzodiazepines are metabolized more slowly in older adults than in young adults, often leading to over-sedation, falls, and injury. Benzodiazepines: Potential for Misuse and S U D Benzodiazepine use can result in tolerance, withdrawal, and addiction. Misuse of benzodiazepines for recreation purposes does occur, typically in combination with alcohol to enhance the C N S depression effects of both. Learn about the potential for misuse and S U D of benzodiazepines. Misuse Potential Benzodiazepines have weaker reinforcing properties than other drugs you will learn about in this module, including barbiturates, alcohol, opioids, and stimulants. The inherent harmfulness is also low, as it does not depress respiration at therapeutic doses and does not often lead to death on its own. Tolerance Tolerance can develop to the sedative effects and impairment of coordination, the anxiolytic effect (less common) or the euphoric effects (occasionally). However, the magnitude of tolerance that develops to benzodiazepines does not produce clinical concerns. A high degree of cross- tolerance occurs among the benzodiazepines and other sedative-hypnotic drugs, such as barbiturates and alcohol, as they all modulate the chloride channel in the C N S. Withdrawal A mild but distinct withdrawal can occur after therapeutic use, exhibiting anxiety, headache, and insomnia. Following chronic use (i.e., one year or more) sudden discontinuation may lead to more pronounced withdrawal symptoms, such as agitation, paranoia, seizures, and delirium. These extreme symptoms occur much less frequently than with barbiturates. CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 10 MODULE 03 COMPANION GUIDE PHAR 100 Addiction Addiction may develop in some individuals, but not all, and depends on a multitude of factors including genetics and the environment. Benzodiazepine in Sports Recall from Module 02 that benzodiazepines are sometimes used by athletes to reduce anxiety during competition. Answer the question using what you know about how benzodiazepines work. 1 of 1: How do benzodiazepines reduce an athlete’s anxiety? Feedback: Benzodiazepines increase C N S depression in a dose-dependent manner. Therefore, at low doses, they act as anti-anxiety agents. Barbiturates Another class of sedative-hypnotics are barbiturates. These drugs are classified according to their duration of action, and can be long-acting (1-2 days), short-acting (3-8 hours), and ultra-short acting (20 minutes). Barbiturates are an older class of drugs that have generally been replaced by safer, more effective sedative-hypnotics. Barbituric acid, the basic structure of all barbiturates. Note: The chemical structure is included for your interest only Learn about properties of barbiturates. Routes of Administration Barbiturates are administered in different ways depending on what they are being used to treat. For epilepsy, barbiturates are administered orally. For anesthesia, they are administered intravenously. Mechanism of Action Activation of the barbiturate receptor increases the duration of the opening of the chloride channel. They demonstrate the full spectrum of dose-dependent C N S depression that you learned about earlier in this section: Anti-Anxiety → Sedation → Hypnosis → General Anesthesia → Death Therapeutic Uses In low doses, barbiturates usually result in the beneficial effects of tranquility and relaxation. They will also induce sleep if the dose is sufficient. CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 11 MODULE 03 COMPANION GUIDE PHAR 100 Clinical uses of barbiturates are limited. Ultra-short acting and short-acting barbiturates can be used to induce anesthesia. Some long-acting agents can be used as antiepileptics. Lethality Barbiturates have been replaced for the most part by newer and safer drugs because of their low therapeutic index and potential for lethality. Lethality due to depression of respiration is common, especially when combined with alcohol. The While respiratory depression is dose-dependent, the lethal dose of barbiturates varies between individuals. In addition, a specific antidote for barbiturate poisoning does not exist. Death can also occur during barbiturate withdrawal. Adverse Effects of Barbiturate Use Unfortunately, barbiturates also have numerous adverse effects. In general, they suppress R E M-type sleep. Learn the adverse effects of both short- and long-term barbiturate use. Short-Term Use Following short-term use, barbiturates: In low doses, usually result in mild euphoria and reduced interest in one’s surroundings. May cause dizziness and mild impairment of motor coordination (especially fine motor dexterity). May cause a pleasurable state of intoxication and euphoria as the dose of drug is increased. In high doses, depress the cardiovascular system, slowing the heart and lowering blood pressure. Long-Term Use The term that best describes long-term use of barbiturates is chronic inebriation. Memory, judgement, and thinking are all impaired. Individuals often exhibits hostility and mood swings, including depression. Barbiturates: Potential for Misuse and S U D Barbiturates are prescribed much less frequently now than they were 40 years ago, but illicit use continues to be a problem. They are also sometimes combined with other drugs such as opioids, amphetamines, and alcohol. Potential for Misuse Barbiturates should be avoided, as the potential for misuse is equal to or greater than alcohol. The pleasurable effects of some of barbiturates give significant degree of reinforcement. Barbiturates are sometimes injected to obtain a “rush effect”. The inherent harmfulness is very high due to the risk of death from respiratory depression or from withdrawal. Tolerance Tolerance to barbiturates can develop. A high degree of cross-tolerance occurs between barbiturates and other sedatives (e.g., benzodiazepines). Withdrawal CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 12 MODULE 03 COMPANION GUIDE PHAR 100 Withdrawal occurs after discontinuation of chronic use. Symptoms initially appear as tremors, anxiety, weakness, and insomnia, as well as postural hypotension. These symptoms may progress to include seizures, delirium, visual hallucinations, and a high body temperature. Barbiturates must be withdrawn slowly under medical supervision. Addiction Addiction can result from regular use, irrespective of the dose. Those with addiction will crave the drug and a feeling of panic may occur if they cannot get an adequate supply. Craving often persists long after use has stopped. Comparison: Benzodiazepines vs Barbiturates Benzodiazepines and barbiturates are two classes of sedative-hypnotics with similarities and some key differences. Compare and contrast benzodiazepines and barbiturates. Benzodiazepines Barbiturates Mechanism of Increases the frequency of Increases the duration of the Action opening of the chloride channel. opening of the chloride channel. Therapeutic Acute anxiety states Tonic-clonic (i.e., grand mal) Uses Sedation for minor surgical seizures, partial seizures procedures Insomnia Absence seizures, status epilepticus Skeletal muscle spasms Alcohol withdrawal Pharmacology Very high therapeutic index Low therapeutic index Minimal suppression of REM Suppress REM sleep sleep Cause dose-dependent respiratory Decreased aggression, skeletal and cardiovascular depression muscle relaxation Lethality common, especially with Have an antidote: flumazenil alcohol No antidote Misuse Low misuse potential and Misuse potential equal to or greater inherent harmfulness than alcohol, high inherent Tolerance: Yes, develops to harmfulness desired effects but not a problem Tolerance: Yes clinically Withdrawal: Yes Withdrawal: Yes, less common Addiction: Yes than with barbiturates Addiction: Yes, in some Zopiclone and the Benzodiazepine-Like Drugs Benzodiazepine-like drugs are another class of sedative-hypnotics used to treat problems like anxiety or difficulty sleeping. Benzodiazepine-like drugs, such as zopiclone and zolpidem, bind to a subset of the GABA receptors and cause sedation. CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 13 MODULE 03 COMPANION GUIDE PHAR 100 This class of drugs acts similarly to the benzodiazepines, however, has an advantages over the benzodiazepines as a hypnotic, as they disturb sleep patterns (REM sleep) even less than the benzodiazepines. Benzodiazepine-like drugs appear to have more sedative effects as compared to anxiolytic effects. As with benzodiazepines, these drugs should be used with caution in older adults. Zopiclone and Zolpidem are two types of Benzodiazepine-like drugs. Note: Chemical structures are included for your interest only. Video: Drugs That Bind to the Chloride Channel Watch the video for a review of how drugs that bind to the chloride channel work (1:19). Start of Video Transcript: This diagram depicts the GABA receptor, which is a chloride ion channel, with its several subunits. The chloride channel depending on location in the body may be comprised of different subunits, which may in turn give different drug responses. The channel is controlled by GABA. When GABA binds to its receptor, the GABAA receptor, it opens the chloride channel, chloride moves inward, and there is inhibition of the neuronal activity. The benzodiazepines, by binding to benzodiazepine receptors, facilitate the actions of GABA. They enhance GABA receptor mediated opening of the chloride channel causing increased inhibition. The Barbiturates have separate and distinct binding sites on the chloride channel from the benzodiazepines. Unlike the benzodiazepines, the barbiturates do not act by enhancing GABA but rather bind to the GABAA receptor directly opening the chloride channel. Similarly, Zolpidem has a discrete binding site on the chloride channel. Like the benzodiazepines, it increases chloride channel opening induced by GABA. Finally, we see Flumazenil is a benzodiazepine receptor antagonist. It will block the enhanced GABA responses produced by the benzodiazepines. End of Video Transcript. CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 14 MODULE 03 COMPANION GUIDE PHAR 100 As you watch, pay attention to how drugs affect the GABA receptor in different ways. Activity: Therapeutic Uses of Sedative-Hypnotics Match the sedative-hypnotic with its most likely therapeutic use. Options: Anti-Epileptic, Anti-Anxiety, Hypnotic, Antidote for Benzodiazapine Overdose Sedative-Hypnotic Therapeutic Use Barbiturates Benzodiazepines Benzodiazepine-like drugs Flumazenil Feedback: Sedative-Hypnotic Therapeutic Use Barbiturates Anti-Epileptic Benzodiazepines Anti-Anxiety Benzodiazepine-like drugs Hypnotic Flumazenil Antidote for Benzodiazapine Overdose Buspirone Buspirone is an interesting anxiolytic as it does not act on the GABA receptor, but rather at the serotonin receptor. It is used in generalized anxiety states and may have an advantage over other sedatives in that it does not appear to have additive effects with other sedative-hypnotic drugs. As such, this drug may be prescribed instead of a benzodiazepine or benzodiazepine-like drug when the individual is already taking other C N S depressant drugs and there is a concern of additive effects. Buspirone is sold under the brand name Buspar. End of Section 01 Practice Quiz (1 of 2) Answer the question based on what you have learned in this section. 1 of 2: Which one of the statements listed correctly applies to sedative-hypnotics? a) Flumazenil is a GABA receptor agonist. b) Zopiclone, a benzodiazepine-like drug, which has minimal effects on sleep patterns. CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 15 MODULE 03 COMPANION GUIDE PHAR 100 c) Benzodiazepines act on serotonin receptors. d) Barbiturates are rarely, if ever, associated with lethality. Feedback: The correct answer is B. Zopiclone and the other benzodiazepine-like drugs have been shown to disturb sleep patterns even less than the benzodiazepines. End of Section 01 Practice Quiz (2 of 2) Answer the question based on what you have learned in this section. 2 of 2: Which one of the options listed is a pharmacological property of the benzodiazepines? a) The benzodiazepines often causes lethality. b) The benzodiazepines do not exhibit cross-tolerance with barbiturates. c) Tolerance occurs to the sedative and hypnotic effects of the benzodiazepines. d) Addiction does not develop to the benzodiazepines. Feedback: The correct answer is C. Tolerance does not appear to be a problem for the clinical use of benzodiazepines, however, it can develop to the sedative effects and impairment of coordination, the anxiolytic effects, or the euphoric effects. Section 01: Summary In this section, you learned about sedative-hypnotic agents. This class of drugs are C N S depressants that function by dampening the neuronal response. Sedative-hypnotic drugs primarily have four effects depending on the dose: anti-anxiety, sedation, hypnosis, and general anesthesia. Specifically, you learned about sedative-hypnotic agents that bind to the chloride ion channel, including benzodiazepines, barbiturates, and benzodiazepine-like drugs. You learned about their administration, mechanism of action, therapeutic use, short- and long-term effects, and their potential for misuse. Definitions: Drug Classes: A class of drugs is a group of drugs that have the same mechanism of action and similar pharmacological properties. For example, thiopental, secobarbital, and phenobarbital are all drugs that fall under the barbiturate class of drugs. Anxiolytic: A drug, medication, or other intervention that reduces anxiety. Postural Hypotension: A form of low blood pressure in which a person's blood pressure falls when suddenly standing up or stretching. Page Links: https://www.youtube.com/watch?v=ne-YWfTCxLk https://player.vimeo.com/video/183317420 CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 16 MODULE 03 COMPANION GUIDE PHAR 100 References: Esposito, E., Barbui, C., & Patten, S. B. (2009). Patterns of benzodiazepine use in a Canadian population sample. Epidemiologia e psichiatria sociale, 18(3), 248–254. Retrieved July 2021, from: https://pubmed.ncbi.nlm.nih.gov/20034203/ Each G A B A A receptor subunit has four transmembrane-spanning regions. The receptor itself is a pentamer, with two alpha subunits, two beta subunits, and one gamma subunit. When there is nothing bound to the G A B A binding site, the channel is closed. When a drug (such as a sedative-hypnotic) binds to the G A B A binding site, the channel opens and allows an influx of chloride ions into the neuron. Adapted from: Chapter 22 Sedative-Hypnotic Drugs, Katzung BG. Basic & Clinical Pharmacology, 14e; 2017. Retrieved July 2021, from: https://proxy.queensu.ca/login?url=https://accessmedicine.mhmedical.com/ViewLarge.aspx?figid=1752 18813&gbosContainerID=0&gbosid=0&groupID=0&sectionId=175218773&multimediaId=undefined The Poison Review. (n.d.). Flumazenil [Digital image]. Retrieved July 2021, from: http://www.thepoisonreview.com/wp-content/uploads/Flumazenil.jpg Servier Medical Art. (n.d.). [Image]. Retrieved July 2021, from: https://smart.servier.com/ Adobe Stock image. File #443711085. Direct link: https://stock.adobe.com/images/frustration-swirl-as- dizzy-mental-feeling-problem-crisis-tiny-person-concept-work-overload-pressure-caused-depression- and-emotional-state-vector-illustration-psychological-tension-and- disorientation/443711085?prev_url=detail Manuel Almagro Rivas, CC BY-SA 4.0 , via Wikimedia Commons. Retrieved July 2021, from: https://commons.wikimedia.org/wiki/File:Barbituric-acid- structural.svg Adobe Stock Image. File #: 184277976. Direct link: https://stock.adobe.com/ca/images/zopiclone- insomnia-drug-sleeping-pill-z-drug-molecule-skeletal-formula/184277976?prev_url=detail Adobe Stock Image. File #: 184277982. Direct link: https://stock.adobe.com/ca/images/zolpidem- insomnia-drug-sleeping-pill-molecule-skeletal-formula/184277982?prev_url=detail Adapted from: Chapter 22 Sedative-Hypnotic Drugs, Katzung BG. Basic & Clinical Pharmacology, 14e; 2017. Retrieved July 2021, from: https://proxy.queensu.ca/login?url=https://accessmedicine.mhmedical.com/ViewLarge.aspx?figid=1752 18813&gbosContainerID=0&gbosid=0&groupID=0&sectionId=175218773&multimediaId=undefined Editor182, Public domain, via Wikimedia Commons. Retrieved July 2021, from: https://commons.wikimedia.org/wiki/File:Buspar.jpg End of Section 01 CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 17 MODULE 03 COMPANION GUIDE PHAR 100 SECTION 02: ALCOHOL Introduction to Alcohol Alcohol (ethanol) is one of the three most used non-medical drugs in Canada, alongside caffeine and nicotine, which you learned about in Module 02. While alcohol consumption has decreased in the past decade, alcohol still produces more health problems and deaths than all illicit drugs combined, resulting in enormous healthcare and social costs. The major reason for the extensive use and misuse of alcohol is its ready availability and the permissive attitudes of society. However, societal attitudes to the misuse of alcohol, at least to drinking and driving, have undergone substantive changes since 1970. A D M E of Alcohol Alcohol is a C N S depressant that works by slowing down brain functioning and neural activity. Ethanol is the only type of alcohol that can be safely consumed - these terms will be used interchangeably throughout this section. Learn about the pharmacokinetics of ethanol. 1. Absorption of Ethanol Ethanol is absorbed rapidly from the stomach (where 20% is absorbed) and the upper small intestine (where 80% is absorbed). The overall absorption rate for a given dose of ethanol is affected by: Stomach-emptying time, or the time required for the alcohol to reach the small intestine. Ethanol concentration in the gastrointestinal (G I) tract and the presence of food. The time from the last drink to the maximal blood alcohol concentration ranges from 30 to 90 minutes. 2. Distribution of Ethanol Ethanol distributes throughout the total body water and readily gains access to the brain. Ethanol can also readily transfer across the placenta and distribute throughout a developing fetus. CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 18 MODULE 03 COMPANION GUIDE PHAR 100 3. Metabolism of Ethanol The metabolism of alcohol has four main steps. Learn about the metabolism of alcohol. Alcohol Dehydrogenase Ethanol is converted to acetaldehyde by the enzyme alcohol dehydrogenase (A D H). This is the rate-limiting step in alcohol metabolism, meaning the speed of this conversion typically sets the pace for the rest of the metabolism. MEOS A second, although less important pathway of ethanol metabolism is the microsomal ethanol oxidizing system (M E O S), which is part of the cytochrome P450 system. The M E O S contributes to the metabolism of ethanol, breaking it down to acetaldehyde, especially at high doses when alcohol dehydrogenase is running at full capacity (i.e., is saturated). Aldehyde Dehydrogenase Acetaldehyde is then converted to acetate by the enzyme aldehyde dehydrogenase (A L D H). Acetate Acetate (or acetic acid) is further metabolized by a number of tissues into carbon dioxide and water. CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 19 MODULE 03 COMPANION GUIDE PHAR 100 Genetic Variability in Ethanol Metabolism Genetic variants in the gene that codes for alcohol dehydrogenase (A D H) exist. Some individuals rapidly convert alcohol to acetaldehyde, causing an accumulation of acetaldehyde in the body. This is considered protective against alcoholism since accumulated acetaldehyde produces unpleasant side effects, such as a flushed face. The second enzyme in the pathway, aldehyde dehydrogenase (A L D H), also exhibits genetic variability in a population. Rate of Ethanol Metabolism The metabolism of alcohol is unusual, in that it occurs at a constant rate, irrespective of the blood alcohol concentration (B A C). This is because alcohol dehydrogenase (A D H) becomes rate-limiting, or saturated. Therefore, the body rate of ethanol metabolism is about 120 m g ethanol/k g body weight/hour. 4. Excretion of Ethanol Over 95% of ethanol in the body is eliminated by biotransformation, primarily in the liver. The remaining 5% is excreted in the breath, urine, and sweat. Breathalyzers are used to measure the level of intoxication via excretion of ethanol in the breath. CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 20 MODULE 03 COMPANION GUIDE PHAR 100 Video: Summary of Metabolism of Ethanol Recall that alcohol is primarily metabolized by the enzyme alcohol dehydrogenase. Watch the video for an overview of ethanol metabolism (1:46). Start of Video Transcript: Alcohol, or ethanol, is primarily metabolized by the enzyme alcohol dehydrogenase into acetaldehyde. Alcohol dehydrogenase is located mainly in the liver, but there is also some in the stomach. Predominantly, alcohol is metabolized in the liver. However, in men, some alcohol metabolism also occurs in the stomach, but less alcohol metabolism occurs in the stomachs of women. Alcohol converted to acetaldehyde by alcohol dehydrogenase is the primary mechanism of alcohol metabolism. However, once the blood alcohol concentration reaches 100mg/dL, which is equivalent to a 0.1% blood alcohol concentration, then the liver runs out of the cofactor NAD+, inhibiting this reaction from occurring. To compensate for this, the body has an alternative method to metabolize alcohol, which involves the microsomal ethanol oxidizing system, which consists of some enzymes from the cytochrome P450 family. So, during chronic alcohol consumption, or when the blood alcohol concentration is 0.1% or greater, the microsomal ethanol oxidizing system is induced, converting alcohol to acetaldehyde. Acetaldehyde is then oxidized in the liver to acetate by the enzyme aldehyde dehydrogenase. Acetate can be further metabolized into carbon dioxide and water, or acetate can be used to form acetyl-CoA. Interestingly, it is the buildup of acetaldehyde in your body that causes the unpleasant reaction of facial flushing, nausea, vomiting, dizziness, and headache that you experience during a hangover. End of Video Transcript. Activity: Metabolism of Ethanol Complete the activity by selecting whether each statement is true or false. Statement True False The rate limiting step in the metabolism of ethanol involves the enzyme aldehyde dehydrogenase. Alcohol dehydrogenase converts ethanol to acetaldehyde. The minor pathway pathway of ethanol metabolism is the microsomal ethanol oxidizing system (MEOS), which contributes to ethanol metabolism at low doses. Ethanol is first converted to acetaldehyde then to acetate. Ethanol metabolism results in the production of carbon dioxide and water. Feedback: Statement True False The rate limiting step in the metabolism of ethanol involves the enzyme aldehyde X dehydrogenase. Alcohol dehydrogenase converts ethanol to acetaldehyde. X The minor pathway pathway of ethanol metabolism is the microsomal ethanol X oxidizing system (MEOS), which contributes to ethanol metabolism at low doses. Ethanol is first converted to acetaldehyde then to acetate. X Ethanol metabolism results in the production of carbon dioxide and water. X CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 21 MODULE 03 COMPANION GUIDE PHAR 100 The rate limiting step in ethanol metabolism is the first step in which alcohol dehydrogenase converts ethanol to acetaldehyde. Additionally, the M E O S pathway contributes to ethanol metabolism when there are high levels of ethanol in the body and alcohol dehydrogenase is saturated. Medical Uses of Ethanol Very few medical uses for ethanol exist. Some of the current uses are: Alcohol sponges applied topically to treat fever. As a skin disinfectant. As an antidote in the treatment of methanol (wood alcohol) poisoning. As a hand sanitizer, particularly since the SARS epidemic. More recently, hand sanitizers have been widely used to reduce the risk of infection during the COVID-19 pandemic. C N S Effects of Ethanol Ethanol is classified as a general C N S depressant. The C N S effects of ethanol are proportional to the blood alcohol concentration (B A C), shown in the table. To convert B A C in m g/d L to a B A C represented as a percentage of weight/volume, you simply move the decimal place three places to the left. For example, a B A C of 100 m g/d L is equal to 0.1 g per 100 m L of blood or 0.1% (weight/volume). B A C and Clinical Effects in Non-Tolerant Individuals B A C (m g/d L) B A C (weight/volume) Clinical Effect 50–100 0.05-0.1% Sedation, subjective “high,” slower reaction times 100–200 0.1-0.2% Impaired motor function, slurred speech, ataxia 200–300 0.2-0.3% Emesis, stupor 300–400 0.3-0.4% Coma >400 >0.4% Respiratory depression, death B A C and Driving The risk for a driver getting in an accident increases exponentially in relation to their B A C, as shown in the graph on this slide. In 2014, approximately 29% of all fatal car accidents in Canada were associated with alcohol, or alcohol and drugs combined. In Canada, for new drivers and drivers under the age of 22, a zero tolerance BAC applies. For all other drivers, having a B A C of 0.05% is a provincial offence, and having a B A C of 0.08% is a criminal offence. Many B A C calculators are available and free to use online. For your interest, access a B A C calculator. CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 22 MODULE 03 COMPANION GUIDE PHAR 100 B A C and relative accident risk have a positive correlation Mechanism of Action of Alcohol Alcohol affects a large number of membrane proteins that participate in signalling pathways. However, it is thought that alcohol works through one main mechanism - by binding to the chloride ion channel and augmenting GABA- mediated neuronal inhibition. The binding site for alcohol is different from the other GABA agonists you learned about in Section 01. The interaction of alcohol with the chloride ion channels on dopaminergic neurons in the reward areas of the brain may explain the reinforcing effects of the drug. Effects of Short-Term Use of Alcohol Besides the C N S, alcohol also affects other systems and organs in the body such as the cardiovascular system, the stomach, and the liver. Compare the effects of short-term alcohol use at low and high doses. Low Doses (1-3 drinks) High Doses (>5 drinks) Cardiovascular Low doses of alcohol can High doses of alcohol will create vasodilation (flushing) of depress the cardiovascular the vessels to the skin, system, which can lead to resulting in a feeling of warmth. alterations in the normal rhythm of the heart. CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 23 MODULE 03 COMPANION GUIDE PHAR 100 Stomach Low doses of alcohol lead to High doses of alcohol will increased gastric secretion. irritate the lining of the stomach, causing inflammation and erosion (known as gastritis). This condition causes vomiting and abdominal pain. Ulcers may be aggravated, often leading to a serious gastrointestinal bleed. Liver Occasional use of low doses of Acute high doses of alcohol alcohol does not appear to (alcohol binge) will inhibit have significant adverse effects glucose production, and in on the liver. association with fasting, can lead to hypoglycemia (low blood sugar). Adverse Effects of Short-Term High Dose Alcohol Use Short-term high dose drinking, otherwise known as binge-drinking, has several additional adverse effects to the ones you just explored. Learn about the adverse effects of short-term high-dose alcohol consumption. Memory Loss This is the phenomenon where the individual does not remember events while under the influence of alcohol. This can be very frightening and may result in the individual seeking help. Psychiatric Effects Heavy drinking often leads to depression, irritability, and over-sedation. The negative mood states, in concert with impaired judgement and impulsiveness, may lead to self-harm or acts of violence. Overdose Excessive short-term alcohol consumption can also result in overdose, which is characterized by respiratory depression, coma, and death. A number of comatose drinkers die each year after aspirating their own vomit. Adverse Effects of Chronic High Dose Alcohol Use Chronic high dose use of alcohol has a number of detrimental effects on the body. CNS A number of neurological and mental disorders are associated with chronic alcohol misuse. One such disorder is alcoholic dementia, which is a decrease in cognitive functioning affecting memory, judgement, and thinking. Alcohol damages axons of neurons within the brain, resulting in fewer connections between neurons. Cardiovascular High chronic doses of alcohol can lead to alcoholic cardiomyopathy. An increased incidence of hypertension and stroke is also apparent. Liver CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 24 MODULE 03 COMPANION GUIDE PHAR 100 Chronic high doses of alcohol leads to alcoholic liver disease, a major cause of hospitalization and deaths in North America. At early stages, this can be reversible with alcohol abstinence, but at later stages it is irreversible and liver function is severely impaired. Effects of Alcohol Use During Pregnancy Chronic use of high-dose ethanol throughout pregnancy can produce teratogenic effects in the embryo/fetus, which can manifest postnatally as Fetal Alcohol Spectrum Disorder (F A S D). The incidence of F A S D in Canada is 1 per 1000 live births. A safe dose of ethanol in pregnancy has not been established. Therefore, alcohol abstinence during pregnancy is recommended. Individuals with F A S D tend to have certain distinctive facial features. Reference: The Alcohol Pharmacology Education Partnership. (n.d.). Facial abnormalities associated with Fas and Arbd. Content: What Are Fetal Alcohol Spectrum Disorders? Retrieved July 2021, from: https://sites.duke.edu/apep/module-5-alcohol-and-babies/content-what-are-fetal-alcohol-spectrum- disorders/. Palmeter, S., Probert, A., Lagacé, C. (2021). At-a-glance - FASD prevalence among children and youth: results from the 2019 Canadian Health Survey on Children and Youth. Health Promotion and Chronic Disease Prevention Branch, Public Health Agenda of Canada, 41(9):272-6. Retrieved August 2024, from:https://doi.org/10.24095/hpcdp.41.9.05 Alcohol and Drug Interactions Drug-drug interactions with alcohol can occur in two ways depending on whether the drug and alcohol are in the body at the same time or not. Explore the two types of drug-drug interactions. Alcohol Use During Drug Therapy CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 25 MODULE 03 COMPANION GUIDE PHAR 100 The effects of having a drug and ethanol in the body at the same time include: Ingestion of ethanol and other C N S depressants leads to an additive or synergistic effect of C N S depression. Inhibition of metabolism of certain drugs (e.g., sedative-hypnotics). Chronic Alcohol Use Before Drug Therapy The effects of chronically drinking alcohol but abstaining during drug therapy: Only occurs if there is no co-existing ethanol-induced liver injury. Increases the activity of metabolizing enzymes in the liver, resulting in increased metabolism of certain drugs (e.g., sedative-hypnotics). Alcohol: Potential for Misuse and S U D Alcohol produces both reinforcing and sedating effects in the C N S, which contributes to its potential for misuse and S U D. Learn about the potential for misuse and S U D with alcohol. Potential for Misuse Ethanol has significant reinforcing properties, and as a result, the misuse potential is moderate. The ease of availability and social and legal acceptance contributes to ethanol’s misuse potential. The inherent harmfulness of alcohol is moderate. Death can occur from high dose acute ethanol ingestion and chronic ingestion can have long-term effects on health. Ethanol is less inherently harmful than methanol. Tolerance Tolerance to chronic consumption of ethanol does occur. Individuals can develop tolerance more rapidly to the ethanol-induced impairment of performance of a task when they perform that task repeatedly under the influence of ethanol. Cross-Tolerance Cross-tolerance occurs between ethanol and: 1. Sedative-Hypnotics: A higher dose of a sedative-hypnotic drug is required for the desired therapeutic effect. 2. General Anesthetics: A higher dose of anesthetic agent is required for surgical anesthesia in someone who has developed tolerance to alcohol. Withdrawal Withdrawal from ethanol produces compensatory excitation of the C N S (e.g., arousal, stimulation). In severe cases of ethanol withdrawal, delirium tremens (DTs) may occur, which can involve convulsions, coma, and possibly death. CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 26 MODULE 03 COMPANION GUIDE PHAR 100 The different symptoms and stages of alcohol withdrawal. Addiction A compulsive desire to seek, obtain, and drink ethanol exists. Addiction could be the most powerful factor in chronic use of ethanol, contributing to S U D. Treatment of Alcohol Withdrawal Initial therapy of alcohol withdrawal syndrome is to maintain fluid and electrolyte balance, and to prevent seizures. More severe alcohol withdrawal can be treated effectively by oral administration of diazepam, a benzodiazepine. Answer the question using what you have learned about withdrawal, alcohol, and benzodiazepines. 1 of 1: What do you think is the pharmacological basis for using benzodiazepines to treat alcohol withdrawal symptoms? Feedback: The withdrawal syndrome following cessation of use of a particular drug is suppressed by administration of a second drug of similar mechanism of action. Following successful withdrawal of the patient from ethanol, the dose of diazepam is decreased gradually over the course of several days to weeks. Drugs Used to Treat Alcohol Use Disorder A number of drugs can be used to treat alcohol use disorder. These drugs are used as pharmacological adjuncts to psychotherapy or group therapy, and are referred to as alcohol-deterrent or alcohol- sensitizing drugs. Learn about an example of a drug used to treat alcohol use disorder. Naltrexone Naltrexone (an opioid antagonist) is effective in the treatment of alcohol addiction. It diminishes the craving for ethanol, and assists in the maintenance of abstinence. It blocks the activation of dopaminergic reward pathways in the brain. Summary: Alcohol Alcohol CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 27 MODULE 03 COMPANION GUIDE PHAR 100 ADME Absorption: Absorbed primarily from the small intestine Distribution: Throughout total body water, to brain, placenta, and fetus Metabolism: 95% of biotransformation occurs in the liver Ethanol → acetaldehyde → acetic acid Alcohol dehydrogenase conversion to acetaldehyde is rate-limiting step Occurs at a constant rate Excretion: Mainly through urine, with 5% excreted in the breath Mechanism of Action Alcohol binds to the chloride ion channel and augments inhibitory GABA signalling. Effects Alcohol is a dose-dependent C N S depressant. Short-Term Use Effects C N S: Disinhibition Cardiovascular System: Vasodilation G I: Gastric secretion, inflammation Liver: Inhibition of glucose production Chronic High Dose Effects C N S: Alcoholic dementia Cardiovascular System: Alcoholic cardiomyopathy Liver: Alcoholic liver disease Misuse and Alcohol Use Misuse: Alcohol carries a significant potential for misuse. Disorder Tolerance: Yes, cross-tolerance between sedative-hypnotics and general anesthetics occur. Withdrawal: Yes, withdrawal symptoms are severe. Addiction: Yes. Alcohol use disorder can be treated with: Benzodiazepines to manage withdrawal symptoms Naltrexone to decrease the reinforcement of alcohol End of Section 02 Practice Quiz (1 of 2) Answer the question based on what you have learned in this section. 1 of 2: One pharmacological property of alcohol is that it is: a) Classified as a C N S stimulant. b) Transferred across the placenta with some difficulty. c) Rapidly absorbed from the stomach and intestine. d) Able to produce tolerance but not withdrawal. Feedback: The correct answer is: C. Alcohol is rapidly absorbed from the stomach (20%) and intestine (80%). End of Section 02 Practice Quiz (2 of 2) Answer the question based on what you have learned in this section. 2 of 2: Which step of alcohol metabolism is considered rate-limiting? a) Conversion of alcohol to acetaldehyde by alcohol dehydrogenase. CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 28 MODULE 03 COMPANION GUIDE PHAR 100 b) Conversion of alcohol to acetaldehyde by the M E O S. c) Conversion of acetaldehyde to acetate by aldehyde dehydrogenase. d) Conversion of acetate to carbon dioxide and water by a number of tissues. Feedback: The correct answer is: A. Alcohol dehydrogenase is the rate-limiting step in alcohol metabolism. Section 02: Summary In this section, you learned about alcohol, one of the three most used non-medical drugs in Canada. Alcohol is a C N S depressant; ethanol specifically is the only type of alcohol that can be safely consumed. You explored the pharmacokinetics of ethanol, including it’s absorption, distribution, metabolism (including why some people metabolize alcohol faster than others), and excretion. You were introduced to the short- and long-term effects of chronic alcohol use, the dangers of drinking alcohol when pregnant, and how it produces different effects when in combination with other drugs. You finished off the section by learning about the potential for misuse with alcohol. Definitions: Constant Rate: In other words, a constant amount of alcohol is metabolized each hour. 120 m g Ethanol/kg Body Weight/Hour: That is, a 70 k g person metabolizes one drink per hour. Cardiomyopathy: The destruction of, or poor heart muscle. Fetal Alcohol Spectrum Disorder: A group of conditions that can occur in a person whose mother drank alcohol during pregnancy, including fetal alcohol syndrome (F A S). Page Links: https://player.vimeo.com/video/183318616 https://www.smartserve.ca/index.php/bac-chart/ References: Trevor A.J. (2017). The alcohols. Katzung B.G.(Ed.), Basic & Clinical Pharmacology, 14e. McGraw Hill. Retrieved July 2021, from: https://accessmedicine-mhmedical- com.proxy.queensu.ca/content.aspx?bookid=2249&sectionid=175218881 Statistics. MADD Canada. (n.d.). Retrieved July 2021, from: https://madd.ca/pages/impaired- driving/overview/statistics/. Free Adobe Stock Image. File #: 138899983. Direct link: https://stock.adobe.com/ca/images/glasses-of- wine-and-spirits-on-light-background/138899983?prev_url=detail&asset_id=138899983 Servier Medical Art. (n.d.). [Image]. Retrieved July 2021, from: https://smart.servier.com/ CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 29 MODULE 03 COMPANION GUIDE PHAR 100 Adapted from Servier Medical Art. (n.d.). [Image]. Retrieved July 2021, from: https://smart.servier.com/ Adobe Stock Image. File #: 437172485. Direct Link: https://stock.adobe.com/ca/images/central-organ- of-human-nervous-system-brain-anatomy/437172485?prev_url=detail Adobe Stock Image. File #: 231817302. Direct Link: https://stock.adobe.com/ca/images/fetus-baby-in- womb/231817302?prev_url=detail Adapted from: Servier Medical Art. (n.d.). [Image]. Retrieved July 2021, from: https://smart.servier.com/ Rsheram, CC BY-SA 3.0 , via Wikimedia Commons. Retrieved July 2021, from: https://commons.wikimedia.org/wiki/File:Guardian_Interlock_AMS2000_1.jpg Simon James, CC BY-SA 2.0 , via Wikimedia Commons. Retrieved July 2021, from: https://commons.wikimedia.org/wiki/File:Hand_sanitiser.jpg James Heilman, MD, CC BY-SA 3.0 , via Wikimedia Commons. Retrieved July 2021, from: https://commons.wikimedia.org/wiki/File:Relative_risk_of_an_accident_based_on_blood_alcohol_levels. png Adapted from: Chapter 22 Sedative-Hypnotic Drugs, Katzung BG. Basic & Clinical Pharmacology, 14e; 2017. Retrieved July 2021, from: https://proxy.queensu.ca/login?url=https://accessmedicine.mhmedical.com/ViewLarge.aspx?figid=1752 18813&gbosContainerID=0&gbosid=0&groupID=0&sectionId=175218773&multimediaId=undefined Servier Medical Art. (n.d.). [Image]. Retrieved July 2021, from: https://smart.servier.com/ Adobe Stock Image. File #: 238559346. Direct link: https://stock.adobe.com/ca/images/african- american-man-with-headache-taking-pill-at- home/238559346?prev_url=detail&content_id=238559346&asset_id=238559346 Adobe Stock Image. File #: 415198921. Direct link: https://stock.adobe.com/ca/images/young-woman- with-a-bottle-of-vodka-at-home/415198921?prev_url=detail&asset_id=415198921 Adobe Stock Image. File #: 210644733. Direct link: https://stock.adobe.com/ca/images/businessman- passed-out-on-the-couch/44581661?prev_url=detail Servier Medical Art. (n.d.). [Image]. Retrieved July 2021, from: https://smart.servier.com/ The Alcohol Pharmacology Education Partnership. (n.d.). Facial abnormalities associated with Fas and Arbd. Content: What Are Fetal Alcohol Spectrum Disorders? Retrieved July 2021, from: https://sites.duke.edu/apep/module-5-alcohol-and-babies/content-what-are-fetal-alcohol-spectrum- disorders/. Adapted from: Chapter 23 The Alcohols, Katzung BG. Basic & Clinical Pharmacology, 14e; 2017. Retrieved July 2021, from: https://accessmedicine-mhmedical- com.proxy.queensu.ca/content.aspx?bookid=2249&sectionid=175218881 CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 30 MODULE 03 COMPANION GUIDE PHAR 100 End of Section 02 CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 31 MODULE 03 COMPANION GUIDE PHAR 100 SECTION 03: CANNABIS Introduction to Cannabis The term cannabis refers to the drug-containing forms of the hemp plant, Cannabis sativa, which is an herbaceous annual. 60 chemical compounds are found only in Cannabis sativa, and these compounds are referred to as cannabinoids (C B). Of these compounds, l-trans-Δ9- tetrahydrocannabinol (T H C), is the most potent psychoactive agent in cannabis and accounts for most, but not all, of the psychoactive effects. Note: Cannabis and T H C are used interchangeably in this section. The Cannabis sativa plant. History of Cannabis Throughout history, cannabis has been used in a variety of ways. Gain an understanding of the history and controversy surrounding cannabis use in society. 2700 B C E-1800 C E Cannabis plants were used for manufacturing rope. Cannabis was used for its mild intoxicating effects. 1920s Public concern was raised over the effects of cannabis on individuals and society. Legislation was enacted to outlaw the use of cannabis, which was considered a narcotic. 1960s Throughout the 1960s, use of cannabis increased. This is purported to be driven by the cold war and the changing political and cultural climate. 1978 A U S A-sponsored project using the herbicide paraquat was initiated in an attempt to destroy cannabis crops in Mexico. It failed. U S A citizens were smoking cannabis products containing paraquat, which can produce lung toxicity. 1997 An Ontario court dismissed charges related to possession and cultivation of cannabis on the basis that the individual was using it to control epilepsy that was not controlled by conventional drug therapy. Canada changed the law to allow the cultivation of some varieties of cannabis that contain very small amounts of T H C for use in the manufacture of rope, clothing, and other hemp products. Farmers must obtain a special license to grow hemp. 2005 CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 32 MODULE 03 COMPANION GUIDE PHAR 100 Health Canada supported trials on the medical use of cannabis. 2012 Recreational use of cannabis was legalized in Washington. 2018 In the fall of 2018, recreational cannabis became legal in Canada. Classification of Cannabis Cannabis can be classified legally and pharmacologically. Explore these two classifications. Pharmacological Cannabis is classified as a C N S depressant, euphoriant, and hallucinogen (although the hallucinogenic properties only occur at high doses). Legal As of October 17, 2018, cannabis became legal in Canada. For your interest, visit the Government of Ontario website for an overview of what legalization of cannabis means in Ontario. Cannabis - Government of Ontario Administration of Cannabis Cannabis is a dried flowering plant that is typically smoked or inhaled. Extracts containing concentrated amounts of cannabinoids, typically in oil, can be administered by vaping or through oral consumption. Video: Mechanism of Action of Cannabis The mechanism of action of cannabis is not fully understood. It is known that THC binds specifically to receptors located in the brain and spinal cord called type 1 cannabinoid receptors (CB1). Anandamide is an endogenous ligand for C B receptors involved in learning and memory processes. The C B1 receptor, when activated by anandamide or T H C, inhibits the release of excitatory neurotransmitters. This explains the reduction in cognitive function and C N S depressant effects seen with T H C. Watch the video to learn about the mechanism of action of cannabis (0:59). Start of Video Transcript: The mechanism of action of cannabis, and of the endogenous cannabinoid, anandamide, is unique. Anandamide is considered a retrograde transmitter, meaning that it is released from the postsynaptic neuron and influences the presynaptic neuron, which is opposite to the way most transmitters work. Remember, most transmitters are released from the presynaptic neuron and bind to receptors on the postsynaptic neuron. Anandamide is released from the postsynaptic neuron, diffuses across the CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 33 MODULE 03 COMPANION GUIDE PHAR 100 synaptic cleft, and binds to the type 1 cannabinoid, or C B1 for short, receptors. Activating the C B1 receptors inhibits the release of excitatory neurotransmitters, such as glutamate, into the synaptic cleft. Cannabis works in the same way, by binding to C B1 receptors on the presynaptic neuron, and thereby inhibiting the release of excitatory neurotransmitters. The overall effect is depression of the central nervous system. End of Video Transcript. Cannabinoid Receptors Two types of cannabinoid receptors exist and they are found in specific locations in the body. Learn where the C B receptors are located and what their effects are. C B1 Receptors A large number of C B1 receptors are in the brain, more than any other receptor. T H C is not a very effective agonist, but as a large number of receptors exist, it does produce a response. C B1 receptors in the cerebral cortex mediate the distortions of time, colour, sound, and taste. They also mediate the decrease in cognitive function and concentration. C B1 receptors in the hippocampus may account for changes in memory and learning. No CB1 receptors are present in the brain stem, thus, cannabinoids do not depress respiration, explaining the relative non-lethality of the drug. C B2 Receptors C B2 receptors are only found outside the C N S. They do not appear to be involved in the psychoactive effects of THC, but they may be involved in inflammation. The binding of T H C to C B2 receptors on lymphocytes is thought to be responsible for the immunosuppressive properties of T H C. A D M E of T H C T H C is the primary component in cannabis causing psychoactive effects. Learn about the pharmacokinetics of T H C. 1. Absorption T H C is commonly inhaled or ingested. The method of administration influences its absorption: Inhaled: The absorption of T H C from cannabis smoke is rapid and the onset of action is almost immediate. The effect lasts three to four hours. CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 34 MODULE 03 COMPANION GUIDE PHAR 100 Ingested: When T H C is absorbed after oral administration, the absorption occurs slowly and is incomplete. The onset of action will be is delayed 30 to 60 minutes. The effect is less than that from smoking cannabis. 2. Distribution Following inhalation, T H C rapidly distributes throughout the body, especially to tissues with high blood perfusion such as the lung, heart, brain, and liver. T H C also rapidly crosses the placenta. These processes are much slower following oral ingestion given the slow absorption of this route of administration. T H C is highly lipid soluble and over time will be stored in adipose tissues. 3. Metabolism T H C is metabolized slowly. The metabolites of T H C can be measured in drug tests, so those consuming cannabis chronically may test positive for the metabolites weeks after use has stopped. 4. Excretion: T H C has a half-life of approximately 30 hours. However, the elimination of T H C from adipose tissue may take longer. Effects of Short-Term Cannabis Use The short-term effects of cannabis are primarily observed in the C N S, the cardiovascular system, and the GI tract. Learn about some of the short-term effects of cannabis. CNS Early effects of cannabis on the C N S will be seen as: o Relaxation and drowsiness. o A feeling of well-being and euphoria. o Impaired motor coordination. o Increased appetite. As the dose is increased, a person may experience pseudo-hallucinations, a running together of senses, and impaired judgement and coordination. In some cases, a toxic psychotic reaction may occur. Cardiovascular System Short-term effects of cannabis use on the cardiovascular system include: o Increased heart rate. o Increased blood flow to the extremities. o Postural hypotension (may occur). G I Tract Short-term effects of cannabis use on the G I tract include: o Increased appetite. o Dryness of the mouth and throat. CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 35 MODULE 03 COMPANION GUIDE PHAR 100 Other Other short-term effects of cannabis use include: o Reduction of sex drive in males, as T H C may reduce testosterone levels. o Disruption of the ovarian cycle by T H C in females. o A hangover, similar to that with alcohol, when the drug wears off. Question: Short-Term Effects of Cannabis on Driving Answer the question using what you have learned about the short-term effects of cannabis. 1 of 1: What short-term effects of T H C on the body would interfere with driving a vehicle? Feedback: Motor coordination, tracking, perception, and vigilance are all impaired under the influence of T H C and interfere with the safe functioning of a vehicle. Driving while impaired is illegal and dangerous. Performance on the road is impaired when driving under the influence of T H C and the degree of disruption is dose-dependent. Alcohol and T H C, used simultaneously, will intensify the adverse effects of each other on driving performance. Effects of Long-Term Cannabis Use Long-term effects of cannabis involve multiple body systems and range from easily reversible to serious. Learn about the long-term effects of cannabis. Psychological Occasional low dose: Does not appear to be associated with harmful psychological effects. High Doses: Significant psychological problems occur over time such as loss of short-term memory, lack of concentration, and loss of ability in abstract thinking. Amotivational syndrome is characterized by these psychological problems, as well as loss of ambition and emotional flatness. This syndrome usually disappears upon cessation of drug use, suggesting that it represents chronic intoxication. Permanent Effects: The permanent effects of long-term cannabis use are currently unknown. Some data suggests that structural changes do occur in the brain that may be associated with impairment of memory and learning. Cardiovascular Cardiovascular effects of cannabis are usually reversible. Changes in blood pressure do not appear to be serious, but an increase in heart rate can be a potential problem for those with heart disease. Respiratory CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 36 MODULE 03 COMPANION GUIDE PHAR 100 A number of respiratory symptoms are associated with smoking cannabis. Symptoms include bronchitis, asthma, sore throat, and chronic irritation of and damage to membranes of the respiratory tract. These symptoms are additive with the simultaneous use of tobacco and cannabis. Smoking cannabis can be damaging in the long-term because of the higher concentrations of tars and carcinogens present in cannabis smoke compared to tobacco smoke. Cannabis is typically inhaled deeply and held in the lungs in order to maximize the absorption of T H C and other cannabinoids. This also enhances the amount of tars and carcinogens absorbed. The incidence of lung cancer and chronic obstructive pulmonary disease (C O P D) are both increased with long-term use of smoked cannabis. These are the most serious effects of long-term use. Fertility Long-term cannabis use can also have effects on fertility and pregnancy: o Males: Long-term cannabis use can lead to decreased sperm count. o Females: Long-term cannabis use can cause follicle stimulating hormone and luteinizing hormone to be reduced, and cycles can potentially occur without ovulation (i.e., no release of an egg from the ovary). o Pregnancy: T H C freely crosses the placenta and can cause developmental delays leading to cognitive deficits, impulsiveness and inattention, and hyperactivity. It is difficult to distinguish the effects of T H C from those of concurrent drug use, diet, and overall poor prenatal care. The drug should be avoided in pregnancy. Question: What About Vaping? Answer the question using what you have learned about the respiratory effects of cannabis use. 1 of 1: Do you think vaping is a safe way to consume cannabis without risking damage to your respiratory system? Feedback: No, vaping is associated with respiratory risks as well. Electronic cigarette (e-cigarette) use and vaping have significantly increased in recent years. In 2019, e-cigarette or vaping product use-associated lung injury (E V A L I) was recognized as a unique disease entity. The rapid rise of individuals with E V A L I has resulted in it being labeled a public health crisis, with over 2800 cases of hospitalizations and 68 deaths as of March 2020. Medical Uses of Cannabis As more information is obtained on the functions of anandamide and its receptors, it is likely that drugs that bind to the C B1 and C B2 receptors will be developed that are more effective and less toxic than T H C. The challenge for pharmacological use is to separate the beneficial effects (e.g., analgesia) from the psychotropic effects. Learn about an example of when cannabis use may be authorized by a health care practitioner. CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 37 MODULE 03 COMPANION GUIDE PHAR 100 Cannabis is not a Health Canada approved therapeutic product. However, healthcare practitioners may authorize the use of cannabis for the relief of a number of symptoms which have not responded to conventional medical treatments. For example, medical marijuana can be prescribed for the prevention of nausea and vomiting associated with anticancer drugs. That being said, synthetic THC derivatives are generally more selective than cannabis in treating nausea. Therefore, these, and other more effective anti-nausea medications, are generally used instead of cannabis. Cannabis: Potential for Misuse and S U D The misuse potential of cannabis products is low to moderate, as euphoria and reinforcement is less compared to some other drugs (e.g., cocaine). The inherent harmfulness of cannabis is also low, especially with infrequent use. The greatest concerns may be automobile accidents, accidental exposure of cannabis to children, and the lung effects associated with smoking and vaping. Learn about components of cannabis use disorder. Tolerance Tolerance occurs to: o The psychoactive properties of T H C. o The effects on the cardiovascular system. o The impairment of performance and cognitive function. Withdrawal Upon termination of long-term high dose use, a mild withdrawal syndrome occurs. Withdrawal is characterized by: o Sleep disturbances o Irritability o Loss of appetite o Nervousness o Mild agitation o Upset stomach o Sweating Addiction Addiction develops as a persistent craving for the drug. The risk of addiction is more evident in those who use cannabis to control psychological stress. Summary: Cannabis Cannabis is a C N S depressant, euphoriant, and hallucinogen. Research is still underway to determine its specific mechanism of action and identify all of its long-term effects. Review a summary of what you have learned about cannabis. Mechanism of Action CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 38 MODULE 03 COMPANION GUIDE PHAR 100 Receptor Location Function C B1 Found in high concentrations in the brain Responsible for cognitive alterations C B2 Found in the periphery Responsible for immunosuppressive qualities Effects C N S Effects Fertility Effects Respiratory Effects Euphoria, relaxation Potential adverse effects in Potential serious adverse Distortions of time, colour, males and females effects if smoked (e.g., sound, taste Should be avoided in COPD, lung cancer) Decrease in cognitive pregnancy function and concentration Impaired motor coordination Misuse Misuse Tolerance Withdrawal Addiction Low. Yes. Can occur with long- Can occur, particularly Car accidents may be Occurs to most effects. term high dose use. if using drug to deal greatest risk. with stress. End of Section 03 Practice Quiz (1 of 2) Answer the question based on what you have learned in this section. 1 of 2: The mechanism of action of cannabis is best described as? a) Cannabis binds to C B2 receptors on postsynaptic neuronal membranes in the brain. b) Cannabis binds to C B1 receptors on postsynaptic neuronal membranes in the periphery. c) Cannabis binds to C B1 receptors on presynaptic neuronal membranes in the brain. d) Cannabis binds to C B2 receptors on presynaptic neuronal membranes in the brainstem. Feedback: The correct answer is: C. The mechanism of action of cannabis involves C B1 receptors on presynaptic neuronal membranes. End of Section 03 Practice Quiz (2 of 2) Answer the question based on what you have learned in this section. 2 of 2: Which receptor does T H C bind to? a) Dopamine b) Cannabinoid c) Alpha d) Beta Feedback: The correct answer is: B. T H C binds to cannabinoid receptors. CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 39 MODULE 03 COMPANION GUIDE PHAR 100 Section 03: Summary In this section, you learned about cannabis, a C N S depressant, euphoriant, and hallucinogen. You explored a timeline of cannabis use throughout history, as well as its current pharmacological and legal classification. You were introduced to T H C and the location of the cannabinoid receptors in the body. You learned about the pharmacokinetic properties of T H C, its short- and long-term effects, and its medical uses. You finished this section by learning about the potential for misuse and S U D with cannabis. Definitions: Narcotic: A drug that affects behaviour or mood consumed for non-medical reasons. Vaping: Inhalation of aerosolized extracts, usually containing other chemicals, that have been heated via an electronic device (i.e., e-cigarette). Lymphocytes: A type of white blood cell. Pseudo-Hallucinations: The person knows that it is a hallucination. Postural Hypotension: Acute low blood pressure when standing or sitting up which can cause dizziness or fainting. Analgesia: A loss of sensation of pain due to an interruption of nervous system pathways between sense organs and the brain. Page Link: https://player.vimeo.com/video/183318910 References: Zoau, S., & Kumar, U. (2018). Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System. International Journal of Molecular Sciences, 19(3), 833. Retrieved July, 2021 from: https://doi.org/10.3390/ijms19030833 Huestis M. A. (2007). Human cannabinoid pharmacokinetics. Chemistry & biodiversity, 4(8), 1770–1804. Retrieved July 2021, from: https://doi.org/10.1002/cbdv.200790152 Government of Ontario. (2021, May 20). Cannabis and driving. ontario.ca. Retrieved July 2021, from: https://www.ontario.ca/page/cannabis-and- driving#:~:text=Driving%20a%20vehicle%20while%20you,of%20being%20in%20a%20collision Hartman, R. L., Brown, T. L., Milavetz, G., Spurgin, A., Pierce, R. S., Gorelick, D. A., Gaffney, G., & Huestis, M. A. (2016). Cannabis effects on driving longitudinal control with and without alcohol. Journal of Applied Toxicology, 36(11), 1418–1429. Retrieved July 2021, from: https://doi.org/10.1002/jat.3295 Lenné, M. G., Dietze, P. M., Triggs, T. J., Walmsley, S., Murphy, B., & Redman, J. R. (2010). The effects of cannabis and alcohol on simulated arterial driving: Influences of driving experience and task demand. CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 40 MODULE 03 COMPANION GUIDE PHAR 100 Accident Analysis & Prevention, 42(3), 859–866. Retrieved July 2021, from: https://doi.org/10.1016/j.aap.2009.04.021 Hartman, R. L., & Huestis, M. A. (2013). Cannabis Effects on Driving Skills. Clinical Chemistry, 59(3), 478– 492. Retrieved July 2021, from: https://doi.org/10.1373/clinchem.2012.194381 Health Nexus. (2019). Risks of Cannabis on Fertility, Pregnancy, Breastfeeding and Parenting. Best Start. Retrieved July 2021, from: https://resources.beststart.org/product/a30e-risks-of-cannabis-booklet/ Alexander, L. E., Bellinghausen, A. L., & Eakin, M. N. (2020). What are the mechanisms underlying vaping-induced lung injury? Journal of Clinical Investigation, 130(6), 2754–2756. Retrieved July 2021, from: https://doi.org/10.1172/jci138644 Thayne Tuason, CC BY-SA 4.0 , via Wikimedia Commons. Retrieved July 2021, from: https://commons.wikimedia.org/wiki/File:Cannabis_sativa_2.jpg Icon by Smashicons from flaticon.com. Retrieved July 2021, from: https://www.flaticon.com/free- icon/marijuana_2160354?term=cannabis&page=1&position=18&page=1&position=18&related_id=2160 354&origin=search No attribution required. Direct link: https://pixabay.com/photos/marijuana-cannabis-weed-bud-green- 2174302/#comments No attribution required. Direct link: https://pixabay.com/photos/weed-cannabis-marijuana-dank-ganja- 3815114/ Adapted from: Psychology. Authored by: OpenStax College. CC 4.0. Retrieved July 2021, from: https://courses.lumenlearning.com/wsu-sandbox/chapter/parts-of-the-nervous-system/ Servier Medical Art. (n.d.). [Image]. Retrieved July 2021, from: https://smart.servier.com/ Adobe Stock Image. File #: 238559346. Direct link: https://stock.adobe.com/ca/images/no-drug-for- driving/138439309?prev_url=detail Adobe Stock image. File #231355746. Direct link: https://stock.adobe.com/ca/images/doctor-hand- hold-and-offer-to-patient-medical-marijuana-and-oil-cannabis-recipe-for-personal-use-legal-light- drugs-prescribe-alternative-remedy-or-medication-medicine-concept/231355746?prev_url=detail End of Section 03 CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 41 MODULE 03 COMPANION GUIDE PHAR 100 SECTION 04: OPIOIDS Introduction to Opioids Opioids are a class of drugs naturally found within the opium poppy plant, Papaver somniferum. Drugs obtained from Papaver somniferum have been used for millennia. Initially, opium was used as a crude extract, but for the last 200 years it has been used as purified substances, producing clinically used drugs such as morphine and codeine. Morphine is one of the most useful drugs known to pharmacologists. Unfortunately, it is renowned for causing opioid use disorder (O U D). Papaver somniferum. Classes of Opioids An opioid is any natural or synthetic substance which exerts actions on the body through binding to the opioid receptors. Many different types of opioids exist. Most opioids are analgesics and have high potential for misuse and O U D. Learn about different types of opioids. Endogenous Opioids Endogenous opioids are not administered drugs, but are opioids made in the body that bind to opioid receptors and exert analgesic effects. The three families of endogenous opioids are enkephalins, dynorphins, and beta-endorphins (also known as endorphins). Endogenous opioids affect the perception of pain and the emotional response to pain. They may also influence mood and are associated with the reward pathways in the brain. When you exercise, your body releases endorphins CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 42 MODULE 03 COMPANION GUIDE PHAR 100 Natural Opioids Natural opioids are not made by the human body, but are derived from the opium poppy plant. They include morphine and codeine. Learn more about these two natural opioids. Morphine Morphine binds directly to opioid receptors. It is used clinically to treat severe acute and chronic pain, and can cause euphoria. Codeine Codeine is converted to morphine in the body by liver enzymes. Morphine is approximately 10 times more potent than codeine. A commonly prescribed drug you may be familiar with that contains codeine is Tylenol 3®, a combination of codeine, acetaminophen (which you will learn about in Module 04), and caffeine (which you learned about in Module 02). Semi-Synthetic Opioids Semi-synthetic opioids are slightly altered versions of morphine that are chemically changed to obtain different pharmacological properties (e.g., potency, duration of action, distribution), but typically maintain a very similar effect profile. Examples of semi-synthetic opioids you may be familiar with. Hydromorphone Hydromorphone is clinically used for analgesia. It is five times more potent than morphine. Diacetylmorphine Diacetylmorphine (brand name heroin) is used as part of injectable opioid agonist therapy (i O A T) to manage O U D. There are limited other clinical uses of diacetylmorphine, therefore, it is most often synthesized for illicit use. It is two to five times more potent than morphine. Synthetic Opioids Synthetic opioids are not derived from morphine, but are chemically synthesized to bind to the opioid receptor. These drugs may be designed to elicit similar pharmacological responses to morphine (i.e., analgesia, euphoria), or be used for other clinical purposes that are related to the other functions of opioid receptors. Learn more about synthetic opioids. Fentanyl and Related Compounds Fentanyl is approximately 100 times more potent than morphine and was designed for treatment of severe acute and chronic pain. Illicit synthesis and use of fentanyl, and other new, related, and more potent compounds (i.e., carfentanyl, furafentanyl) contribute to the O U D crisis you learned about in Module 02. Loperamide Loperamide is an over the counter drug that leverages a common side effect of opioids, constipation, and is used to treat diarrhea. The chemical structure of the drug is such that very CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 43 MODULE 03 COMPANION GUIDE PHAR 100 little enters and remains in the circulation, but instead stays in the intestine or is quickly metabolized. This prevents illicit use as it does not cause substantial analgesia or euphoria. You will learn about loperamide in Module 05. Methadone Methadone is used for analgesia and can be used in the treatment of O U D. When used to treat O U D, it prevents withdrawal symptoms, however, does not cause euphoria in a stabilized patient. You will learn more about methadone later in this section. Opioid Receptors Opioid receptors are located in both the central and peripheral nervous systems. These receptors are also located in the gastrointestinal tract and are responsible for the constipation caused by opioids. Compare the three types of opioid receptors. Mu Mu (μ) receptors are present in all structures of the brain and spinal cord. They mediate analgesia and are responsible for morphine-mediated depression of respiration in the brain stem. Because the same receptor is responsible for both effects, it is difficult to obtain drugs with a separation between the two responses. These receptors are also involved in the compulsive misuse of opioids. Kappa Kappa (κ) receptors are involved in analgesia, dysphoria, and miosis. Delta Delta (δ) receptors are involved in analgesia at the level of the spinal cord and brain. They may also modulate the emotional response to opioids. Mechanism of Action of Opioids Morphine and other opioids will block pain pathways in the spinal cord and brain. This effect is primarily exerted through activation of mu opioid receptors. Learn about how opioids inhibit pain impulses. Reduce Neurotransmitter Release Opioids prevent pain signals from travelling by reducing neurotransmitter release from presynaptic neurons and reducing the effect on postsynaptic neurons. Reduce Emotional Reaction Opioids reduce the emotional reaction to pain through modulation of the limbic system. Short-Term Effects of Opioids Morphine may be taken orally in tablet form, administered intravenously, smoked, or sniffed to produce its effects. CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 44 MODULE 03 COMPANION GUIDE PHAR 100 Learn the short-term effects of opioids. Analgesia Opioids, including morphine, produce analgesia and indifference to pain, reducing the intensity of pain and the perception or reaction to pain. There is no ceiling to the intensity of pain which can be relieved. Respiratory depression is the limiting factor. Sedation and Hypnosis Opioids produce sedation and hypnosis, but not as intense as that produced by the C N S depressants. Usually, the patient can be aroused but may experience a drowsy, dreamy, mild dozing state. All opioid analgesics produce sedation. Suppression of Cough Centre Relief or prevention of cough occurs through suppression of the cough centre in the medulla. Respiratory Depression Opioids suppress the respiratory centre in the brain stem. In particular, the response to respiratory drive by carbon dioxide is blunted. The receptors that mediate this effect are mu and delta opioid receptors. Depression of respiration is the single most important side effect of the opioids, and is usually the cause of death in overdose. Endocrine Effects Opioids reduce the release of the hormone that is responsible for regulating the release of sex hormones from the hypothalamus. This results in a reduction in the production of testosterone, estrogens, and progesterone. The overall result is a drop in libido in men. Miosis Opioids cause constriction of the pupils of the eyes, or miosis. All opioids that gain access to the C N S will cause pinpoint pupils. This can indicate that someone has an opioid in their system. Heart Rate and Thermoregulation With high doses of opioids, the heart rate is irregular, body temperature is low, and the skin is cold and clammy. Decreased Intestinal Motility All individuals taking opioids will experience constipation as an adverse effect. Long-Term Use: Marked physiological deterioration or psychological impairment does not seem to occur with long-term use of opioids. Therapeutic Uses of Opioids Opioids have three main therapeutic uses. These three therapeutic uses apply to morphine and most of the other opioids. Relief of Severe Pain Analgesia is the major use of the opioids. For example, opioids may be used to mitigate post- surgical pain and pain experienced by some terminally ill patients. Treatment of Diarrhea Loperamide is an over-the-counter opioid that is not an analgesic and does not produce withdrawal, but it is useful in controlling diarrhea. You will learn more about this drug in Module 05. Cough Suppression CENTRAL NERVOUS SYSTEM DEPRESSANTS AND OPIOIDS | PHAR 100 M03 PAGE 45 MODULE 03 COMPANION GUIDE PHAR 100 All opioids are effective cough suppressants, however, better alternatives with lower misuse potential are available. Opioids: Potential for Misuse Opioids, such as morphine, are usually taken alone but may be found in combination with other drugs such as cocaine and methamphetamine. The misuse potential described on this slide is for opioids alone. Learn about the misuse potential of opioids. Misuse Potential Most opioids have powerful euphoric effects, which means there’s a large

PHAR 100 Module 03 Companion Guide PDF - Central Nervous System Pharmacology

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