Drugs of Abuse pt.1.pdf

Drugs of Abuse – Part 1 Presented by: Karishma Jeeboo, RPh., PharmD. Case Study A 15-year-old high school student was brought to the emergency department after his parents found him in his room staring at the ceiling and visibly frightened. Earlier that evening, he attended a party but was...

Drugs of Abuse – Part 1 Presented by: Karishma Jeeboo, RPh., PharmD. Case Study A 15-year-old high school student was brought to the emergency department after his parents found him in his room staring at the ceiling and visibly frightened. Earlier that evening, he attended a party but was depressed because his girlfriend just broke up with him. His parents are also worried about a change in his behaviour over the last few months. He is failing this year at school and has stopped playing soccer. He has lost interest in school, at times seems depressed, and tells his parents that his pocket money is not sufficient. When questioned by the intern, he reports that space cookies were served at the party. He also says that smoking marijuana has become a habit (three to four joints a week) but denies consumption of alcohol and other drugs. Case Study How do you explain the state in which he was found? What is the difference between hashish and marijuana? What may be the link to his poor performance at school? Do all drug users necessarily use several drugs? Introduction Drugs are abused (used in ways that are not medically approved) because they cause intense feelings of euphoria. repetitive exposure induces widespread adaptive changes in the brain; therefore, drug use may become compulsive—the hallmark of addiction. Dependence – previously known as physical dependence Addiction – psychological dependence Addictive drugs - all induce strong feelings of euphoria and reward; induce adaptive changes such as tolerance Withdrawal effects once the drug is no longer used – a combination of such signs is referred to as withdrawal syndrome and defines dependence. Introduction The mesolimbic dopamine system is the prime target of addictive drugs. Activation of dopamine neurons and dopamine release; large quantities of dopamine are released in the nucleus accumbens and the prefrontal cortex. Result in strong reinforcement established the central role of the mesolimbic dopamine system in reward processing. This elicits adaptive behavioural changes typically observed with addictive drugs. Introduction Regardless of the many roles of dopamine under physiologic conditions, all addictive drugs significantly increase its concentration in target structures of the mesolimbic areas. This suggests that high levels of dopamine may actually be at the origin of the adaptive changes that underlie dependence and addiction. Dependence: Tolerance and Withdrawal Chronic exposure to addictive drugs - the brain shows signs of adaptation Morphine – usually used at short intervals, and the drug has to be progressively increased over several days to maintain rewarding or analgesic effects. This is tolerance Tolerance to a drug may lead to overdose-related fatalities. Mechanism: may be due to a reduction of the concentration of a drug or a shorter duration of action in a target system (pharmacokinetic tolerance) Alternatively, it may involve changes in μopioid receptor function (pharmacodynamic tolerance)  Dependence: Tolerance and Withdrawal Other agonists that drive receptor internalization very efficiently induce only modest tolerance. Based on these observations, it has been hypothesized that desensitization and receptor internalization protect the cell from overstimulation. Adaptive changes become fully apparent once drug exposure is terminated. This state is called withdrawal and is observed to varying degrees after chronic exposure to most drugs of abuse. Withdrawal from opioids in humans is particularly strong. Addiction This is characterized by a high motivation to obtain and use a drug despite negative consequences. With time, drug use becomes compulsive (“wanting without liking”). Addiction is a recalcitrant, chronic, and stubbornly relapsing disease that is very difficult to treat. even after successful withdrawal and prolonged drugfree periods, addicted individuals have a high risk of relapsing Relapse is typically triggered by three conditions: reexposure to the addictive drug, stress, or a context that recalls prior drug use Addiction Nonsubstanced-dependent disorders, such as pathologic gambling and compulsive shopping, share many clinical features of addiction. Large individual differences also exist in vulnerability to substance-related. One person may become “hooked” after a few doses, whereas others may be able to use a drug occasionally during their entire lives without ever having difficulty stopping. Some drugs of abuse do not lead to addiction. Substances that alter perception without causing sensations of reward and euphoria, such as psychedelics and dissociative anaesthetics. Unlike addictive drugs, which primarily target the mesolimbic dopamine system, these agents primarily target cortical and thalamic circuits. Lysergic acid diethylamide (LSD), for example, activates the serotonin 5HT2A receptor in the prefrontal cortex, acutely enhancing glutamatergic transmission onto pyramidal neurons for the duration of the presence of the drug. Nicotine In terms of numbers affected, addiction to nicotine exceeds all other forms of addiction, touching more than 50% of all adults in some countries. Occurs primarily through smoking tobacco, which causes associated diseases that are responsible for many preventable deaths. The chronic use of chewing tobacco and snuff tobacco is also addictive. Nicotine is a selective agonist of the nicotinic acetylcholine receptor (nAChR) that is typically activated by acetylcholine. When nicotine excites projection neurons, dopamine is released in the nucleus accumbens and the prefrontal cortex, thus fulfilling the dopamine requirement of addictive drugs Nicotine Nicotine withdrawal is mild compared with opioid withdrawal and involves irritability and problems sleeping. However, nicotine is among the most addictive drugs (relative risk 4), and relapse after attempted cessation is very common. Treatments for nicotine addiction include nicotine itself in forms that are slowly absorbed and several other drugs. Nicotine that is chewed, inhaled, or transdermally delivered can be substituted for the nicotine in cigarettes Nicotine Slows the pharmacokinetics and eliminates the many complications associated with the toxic substances found in tobacco smoke. two partial agonists of α4β2containing nAChRs have been characterised: the plant extract cytisine and its synthetic derivative varenicline. Both work by occupying nAChRs on dopamine neurons of the VTA, thus preventing nicotine from exerting its action. Varenicline may impair the capacity to drive and has been associated with suicidal ideation. The antidepressant bupropion is approved for nicotine cessation therapy. It is most effective when combined with behavioural therapies. Cocaine Cocaine is highly addictive (relative risk = 5), and its use is associated with a number of complications. Cocaine is an alkaloid found in the leaves of Erythroxylum coca, a shrub indigenous to the Andes. For more than 100 years, it has been extracted and used in clinical medicine, mainly as a local anaesthetic and to dilate pupils in ophthalmology. Sigmund Freud famously proposed its use to treat depression and alcohol dependence, but addiction quickly brought an end to these ideas. Cocaine Cocaine hydrochloride is a water-soluble salt that can be injected or absorbed by any mucosal membrane (e.g., nasal snorting). When heated in an alkaline solution, it is transformed into the free base, “crack cocaine,” which can then be smoked. Inhaled crack cocaine is rapidly absorbed in the lungs and penetrates swiftly into the brain, producing an almost instantaneous “rush.”  Cocaine In the peripheral nervous system, cocaine inhibits voltage-gated sodium channels, thus blocking the initiation and conduction of action potentials. This mechanism, underlying its effect as a local anaesthetic, seems responsible for neither the acute reward nor the addictive effects. In the central nervous system, cocaine blocks the uptake of dopamine, noradrenaline, and serotonin through their respective transporters. Cocaine and Amphetamine - MOA Cocaine Susceptible individuals may become dependent and addicted after only a few exposures to cocaine. Withdrawal syndrome is not as strong as that observed with opioids. Tolerance may develop; Some users develop reverse tolerance, where they become sensitized to small doses of cocaine. This behavioural sensitization is context-dependent, in part. Cravings are very strong and underlie the very high addiction liability of cocaine. No specific antagonist is available, and the management of intoxication remains supportive. Developing a pharmacologic treatment for cocaine addiction is a top priority.