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Lect. 9 Brain Reward Circuit and Drugs of Abuse

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Lect. 9 Brain Reward Circuit and Drugs of Abuse

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Lect. 9 Brain Reward Circuit and Drugs of Abuse

  1. 1. DRUGS USED IN DISORDERS OF THE CENTRAL NERVOUS SYSTEM AND TREATMENT OF PAIN Lecture 9: Brain Reward Circuit and Drugs of Abuse Marc Imhotep Cray, M.D.
  2. 2. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Learning Objectives: 2 DRUGS OF ABUSE AND DRUG DEPENDENCY 1. The underlying biological basis of addiction as a disease. 2. The differential diagnostic criteria for drug abuse vs dependence and the difference between them 3. The MOA within the central nervous system of the major drugs of abuse 4. The signs and symptoms of overdose caused by the major drugs of abuse including alcohol, heroin and cocaine. 5. The signs and symptoms of opioid withdrawal 6. The pharmacotherapeutic options for the treatment of opioid abuse and dependence and their relative benefits and side effects. 7. The signs and symptoms of alcohol withdrawal 8. The pharmacotherapeutic options for the treatment of alcohol abuse and their relative benefits and side effects.
  3. 3. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Drugs of Abuse (select): Topical Outline 3 I. Brain Reward Circuit II. General Features of Substance Abuse  Drug abuse (addiction) terms and concepts III. Sedative-Hypnotics  Ethanol: Deleterious Effects  Ethanol Abuse: Treatment  Withdrawal: Opioids, Benzodiazepines, and Barbiturates IV. Cigarettes V. CNS Stimulants (sympathomimetics)  Cocaine  Khat & Synthetic Cathinones VI. Hallucinogens (psychotomimetics)  marijuana (cannabis)  dronabinol (marinol)
  4. 4. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 I. Brain Reward Circuit 4 Drug abuse involves 2 components:  psychosocial (e.g., family situation, peer pressure) and  endogenous (e.g., genetics, enzyme levels)  Pharmacologic mechanisms of drug abuse involve CNS neurotransmitter systems that operate for therapeutic drug effects  An endogenous pleasure or reward pathway in the brain is important for motivation and learning (survival) and is thought to be excessively active—because of genetics, overuse, or other factors—in drug abuse
  5. 5. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 I. Brain Reward Circuit (2) 5  Brain reward circuit consists of neuronal pathways, cortical sites, and subcortical nuclei, especially within limbic region  Primary among these are dopaminergic neurons in the ventral tegmentum that project to the nucleus accumbens and then to the cortex and other centers  Also, norepinephrine-containing neurons from the locus ceruleus project to the ventral tegmentum  Stimulation or disinhibition of dopaminergic neurons within the ventral tegmentum may be common to abuse of different substances
  6. 6. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 6 Brain reward circuits
  7. 7. 7 Potential sites of drug action
  8. 8. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 II. General Features of Substance Abuse 8  Drug abuse (addiction) is a multifaceted problem, involving a complex combination of biological and psychosocial contributing factors  Hereditary predisposition is also suspected to play a role in some cases  Many, perhaps most, drug addicts abuse more than 1 drug  Hence, list of abused drugs is extensive and includes some substances that are thought of primarily as mood or physique enhancers or as “recreational” drugs (e.g., anabolic steroids, mushrooms, designer drugs, hallucinogens, inhalants, marijuana, nicotine)  This presentation focuses on some of the major classes of therapeutic and non-therapeutic drugs that are abused
  9. 9. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Drug abuse (dependence and addiction) 9  Abuse is misuse of a drug (e.g., taking it in ways not medically approved)  Abuse of a drug is often, but not always, associated with kinetic, dynamic, homeostatic or learned tolerance o An acute tolerance (with first dose) has been described for ethanol o Cross-tolerance occurs between drugs with same mechanism of action Drugs are abused for a variety of reasons:  To induce a feeling of euphoria  To alter perception  As a means of escape  Due to peer pressure in young people Abusers of drugs usually derive more pleasure from a drug with a rapid onset of action than from a drug with a slow onset of action within same class
  10. 10. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Drug abuse (2) 10  Inappropriate and usually excessive, self-administration of a drug for non-medical purposes  Almost all abused drugs exert their effects in CNS  Drugs with high abuse potential have a tendency to induce compulsive drug-seeking behavior  Preoccupation with procurement and use of drug may be so demanding as to decrease users productivity  Prolonged abuse may cause chronic toxicity
  11. 11. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Physical Dependence: 11 Dependence is physical requirement for a drug due to adaptive physiologic changes (tolerance) after multiple exposures  If drug is not available, abstinent withdrawal syndrome will occur o Symptoms during withdrawal tend to be opposite of effects due to drug administration o Withdrawal from a drug of abuse is usually less severe with long-acting drugs than, with short-acting drugs within same class  This is theoretical basis for replacement therapy (e.g., methadone for heroin addicts)
  12. 12. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Addiction: 12 Addiction is psychological requirement for a drug  It is characterized by compulsive drug use in spite of associated negative social and biological consequences  An addicted person can crave a drug even in absence of physical dependence  Addiction is thought to be caused by an increase in CNS dopamine release and/or a decrease in dopamine reuptake that occurs with use of drug
  13. 13. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Drug tolerance 13 After chronic use, same amount of drug is insufficient to cause desired effect and thus, more drug is used  A compensatory response Acquired Tolerance  Pharmacokinetic or metabolic  Pharmacodynamic or functional  Learned or behavioral Drug Dose Normal Tolerance
  14. 14. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Drug tolerance(2) 14  Metabolic tolerance (pharmacokinetic tolerance):  rate of drug elimination increases with long-term use because of stimulation of its own metabolism (autometabolism)  Cellular tolerance (pharmacodynamic tolerance):  Biochemical adaptation or homeostatic adjustment of cells to continued presence of a drug o development of cellular tolerance may be due to a compensatory change in activity of specific neurotransmitters in CNS caused by a change in their levels, storage, or release o or to changes in number or activity of their receptors
  15. 15. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Cross-tolerance 15 When an individual has become tolerant to a drug and requires higher than normal doses of a second drug to have its effects i.e. Barbiturates  BDZ Amphetamine  Cocaine BARBs  Anesthetics
  16. 16. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Cross-tolerance(2) 16 In general there is cross-dependence and cross-tolerance between drugs of same class, but not between drugs in different classes There is some cross-tolerance btw sedative-hypnotics and volatile intoxicants;  thus a person tolerant to barbiturates will require more anesthesia than a non-tolerant person LSD type drugs (tryptamine group) and phenylethylamines have cross-tolerance for each other but not with other hallucinogens
  17. 17. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Cross-dependence 17 When a drug is administered to achieve same outcome as that of another drug i.e. heroin  methadone  In a heroin user, methadone can be substituted for heroin in preventing withdrawal syndrome
  18. 18. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Co-administration/Co-abuse 18 Drugs of abuse are used in combination with other drugs from one or more categories  Alcohol is used, for example, with almost everything else  Smoking (nicotine intake) is prevalent in patients using other drugs Be aware of possibility of combination of drugs when treating intoxication, withdrawal or overdose, each drug will require a specific treatment
  19. 19. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Important Point: 19 Because of the diverse character of these drugs, there is no “single reason” for their use, nor is there an “addictive personality"  IT IS NOT NECESSARY TO HAVE A PREEXISTING EMOTIONAL OR PSYCHIATRIC PROBLEM TO BECOME DRUG DEPENDENT!!!
  20. 20. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Toxicology of Drugs of Abuse: 20 A) Tissue and organ toxicity  Usual dose vs overdose  Acute use (respiratory depression - narcotics, coma- barbiturates; cardiovascular effects and seizures-cocaine; arrhythmias-volatile intoxicants)  Chronic use (alcohol, tobacco)
  21. 21. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Toxicology of Drugs of Abuse (2) 21 B) Psychic toxicity  Acute use (bad trips, flashbacks - hallucinogens; CNS stimulants)  Chronic use (alcohol, hallucinogens, stimulants => reality distortion)
  22. 22. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Toxicology of Drugs of Abuse (3) 22 C) Behavioral toxicity  Amotivational syndrome, loss of productivity loss of psychomotor control, accidents, violence  Acute use (alcohol, stimulants, PCP)  Chronic use (alcohol, CNS depressants, stimulants, hallucinogens, PCP)
  23. 23. Toxicology of Drugs of Abuse (4) D) Associated Diseases  Infections, AIDS, venereal diseases, tobacco- related fires, toxicity due to bad batches of drug (MPTP, PCP congeners), car accidents, big machinery accidents, other accidents, violent death 23
  24. 24. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Controlled substances: 24  A drug deemed to have abuse liability that is listed on governmental Schedules of Controlled Substances*  Such schedules categorize illicit drugs, control prescribing practices, and mandate penalties for illegal possession, manufacture, and sale of listed drugs (next slide)  Controlled substance schedules are presumed to reflect current attitudes toward substance abuse; therefore, which drugs are regulated depends on a social judgment *An example of such a schedule by US Drug Enforcement Agency (DEA) is shown in next slide. Note that criteria given by an agency do not always reflect actual pharmacologic properties of the drugs.
  25. 25. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Schedule for controlled substances* 25 Schedule Criteria Examples I No medical use; high addiction potential Flunitrazepam, heroin, LSD, mescaline, PCP, MDA, MDMA, STP II Medical use; high addiction potential barbiturates, strong opioids Amphetamines, cocaine, methylphenidate, short acting III Medical use; moderate abuse potential moderate opioid agonists Anabolic steroids, barbiturates, dronabinol, ketamine IV Medical use; low abuse potential Benzodiazepines, chloral hydrate, mild stimulants (e.g., Ritalin), most hypnotics (eg, zaleplon, zolpidem), weak opioids *See http://www.usdoj.gov/dea/pubs/scheduling.html for additional details
  26. 26. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 III: Sedative-Hypnotics: ETHANOL 26 ETHANOL is a commonly abused legal substance 1. Due to high lipid solubility and high water solubility, ethanol distributes in total body water 2. Clearance from the body occurs in liver a. Metabolism by alcohol and aldehyde dehydrogenases follows zero- order kinetics i. Products are acetaldehyde and acetic acid, respectively ii. Two molecules of nicotinamide adenine dinucleotide hydrogenase (NADH) are produced for each molecule of ethanol b. An insignificant amount of ethanol is metabolized by mixed-function oxidases (MFOs), but this can induce the MFOs, particularly in alcoholics
  27. 27. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Sedative-Hypnotics: ETHANOL (2) 27 3. Effects of ethanol are related to blood ethanol concentration a. Legal limit for driving in most states is a 0.08% (80 mg EtOH/100 ml blood) blood alcohol concentration (BAC) b. Death due to respiratory depression occurs in the range of 0.4–0.5% BAC, although this is quite variable c. Treatment of an overdose of ethanol is symptomatic  Support ABCs/vital signs
  28. 28. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Sedative-Hypnotics: ETHANOL (3) 28 4. Acute adverse effects develop after a single exposure to ethanol a. Behavior is changed due to a loss of inhibitions b. Effects of other CNS depressants are enhanced c. Hypothermia results from peripheral vasodilation, which makes person feel warm even though body heat is being lost d. Hangovers are common after drinking ethanol and may represent symptoms of an acute withdrawal e. Acute use of alcohol decreases metabolism of other CNS depressants f. Panic attacks may occur day after alcohol is abused as blood alcohol levels drop 5. A low intake of ethanol (one drink per day) is associated with increased high-density lipoprotein and decreased low-density lipoprotein cholesterol. This may reduce the risk of heart disease
  29. 29. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Sedative-Hypnotics: ETHANOL (4) 29 6. Adverse effects from chronic (repeated) use occur on almost every tissue in body and include: a. Physical and psychological dependence b. Activation of MFOs, which increases metabolism of many other drugs (e.g., phenytoin, warfarin) c. Edema and ascites d. Hypertension e. Cardiomyopathy and arrhythmias f. Liver damage (e.g., cirrhosis, fatty liver) g. Acetaminophen combined with ethanol can cause severe acute liver damage due to production of hepatotoxic metabolites h. Changes in blood glucose due to impaired gluconeogenesis i. Damage to the gastrointestinal tract j. Megaloblastic anemias due to folate or vitamin B12 deficiency, or anemia due to iron deficiency caused by GI bleeding
  30. 30. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Sedative-Hypnotics: ETHANOL (5) 30 Adverse effects cont. k. Malnutrition, especially thiamine deficiency, which leads to Wernicke– l. Korsakoff syndrome (paralysis of extraocular muscles, ataxia, and confusion) m. Psychological sequelae  Depression and Korsakoff’s psychosis (long-term memory loss) n. Fetal alcohol syndrome  Ethanol is a common cause of birth defects and neurologic disorders. o. Impaired visual acuity (blurry vision) p. Immune system effects  Increased inflammation of liver and pancreas and increased risk for oropharynx and liver cancers
  31. 31. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Vitamin B1 (thiamine) and alcoholics 31  Wernicke-Korsakoff syndrome—confusion, ophthalmoplegia, ataxia (classic triad) + confabulation, personality change, memory loss (permanent)  Damage to medial dorsal nucleus of thalamus, mammillary bodies  Dry beriberi —polyneuritis, symmetrical muscle wasting  Wet beriberi —high-output cardiac failure (dilated cardiomyopathy), edema  DEFICIENCY Impaired glucose breakdown ATP depletion worsened by glucose infusion; highly aerobic tissues (e.g., brain, heart) are affected first.  Wernicke-Korsakoff syndrome and beriberi  Seen in malnutrition and alcoholism (2° to malnutrition and malabsorption)  Diagnosis made by in RBC transketolase activity following vitamin B1 administration
  32. 32. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Ethanol: Deleterious Effects 32 Short- and long-term excess ethanol consumption leads to widespread problems for the individual and for society Lifetime prevalence of ethanol dependence is estimated at 10% to 15%, and as many as 30% of male and 10% of female admissions to general hospitals are related to ethanol- associated disorders Ethanol is rapidly absorbed from the GI tract and distributes to all cells in the body  It readily passes into fetal circulation
  33. 33. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Ethanol: Deleterious Effects (2) 33  Low concentrations of ethanol are safely metabolized in a 2-step process: first by alcohol dehydrogenase to acetaldehyde and then by aldehyde dehydrogenase to acetate  High concentrations saturate this pathway and give rise to toxic byproducts of alternative pathways  Because ethanol is so widely distributed throughout body, toxic consequences of excess ethanol consumption involve essentially every organ Modifiedfrom:LippincottIllustratedReviews-PharmacologySixthEdition.2015 The pathway of ethanol metabolism. ADH = alcohol dehydrogenase; ALDH = acetaldehyde dehydrogenase.
  34. 34. 34 Effects of Alcohol on End Organs:
  35. 35. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Organ damage Caused by alcohol 35
  36. 36. 36 Alcoholic Liver Disease: CirrhosisoftheLiver
  37. 37. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Normal vs Cirrhotic Liver: 37 Normal liver, gross Cirrhosis, gross Klatt EC. Robbins and Cotran Atlas of Pathology, 2nd Ed. 2010
  38. 38. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Fetal alcohol spectrum disorder 38  Fetal alcohol spectrum disorder results from maternal abuse of ethanol.  Fetal alcohol syndrome is characterized by retarded growth, microencephaly, poorly developed coordination, mental retardation, and congenital heart abnormalities.  Severe behavioral abnormalities can occur in the absence of dysmorphology. There is also an increased rate of spontaneous abortions.
  39. 39. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Ethanol Abuse: Treatment 39  Abrupt withdrawal from ethanol (in persons with physical dependency) is accompanied by excitatory CNS signs such as delirium tremens and potentially lethal seizures  Medication management in the past was limited to disulfiram, which inhibits aldehyde dehydrogenase  Buildup of acetaldehyde produces an unpleasant reaction when ethanol is consumed and thereby provides a deterrent to excess ethanol use  Naltrexone and acamprosate (in Europe) are newer alternative choices  Naltrexone is an opioid receptor antagonist that seems to have additional (perhaps independent) property of reducing chance of relapse when used in conjunction with psychosocial treatment  Acamprosate seems to enhance abstinence by a modulatory effect on NMDA subtype of glutamate receptor
  40. 40. 40 Alcohol Withdrawal Syndrome:
  41. 41. 41 Alcohol Withdrawal Syndrome(2)
  42. 42. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Methanol (wood alcohol) poisoning 42  Methanol is metabolized by ADH to formaldehyde, which is then oxidized to formic acid, which is toxic  Methanol produces blurred vision and other visual disturbances (“snowstorm”) when poisoning has occurred  In severe poisoning, bradycardia, acidosis, coma, and seizures are common o Treatment of methanol toxicity includes the administration of ethanol to slow the conversion of methanol to formaldehyde (ethanol has a higher affinity for ADH) o In addition to other supportive measures, dialysis is used to remove methanol, and bicarbonate is administered to correct acidosis o Fomepizole, an inhibitor of ADH that reduces the rate of accumulation of formaldehyde, is also used to treat methanol (and ethylene glycol) toxicity
  43. 43. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Withdrawal: Opioids 43 Abrupt discontinuation of drugs used for long-term abuse results in withdrawal signs  In general, these signs are opposite of those induced by drug: o withdrawal from CNS excitatory drugs is inhibitory, and o withdrawal from CNS depressants is excitatory Rate and severity of withdrawal are lessened by tapered cessation of drug use rather than abrupt cessation  Withdrawal that is too rapid, particularly from CNS depressant drugs, such as ethanol and barbiturates, can be life-threatening
  44. 44. 44 Opioid Withdrawal(2)
  45. 45. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Opioid Withdrawal(3) 45
  46. 46. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Withdrawal: Benzodiazepines, and Barbiturates 46
  47. 47. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 IV: Cigarettes: 47 A. NICOTINE is active substance and is responsible for addictive nature of cigarettes 1. Nicotine binds to nicotinic acetylcholine receptors, causing dopamine release in ventral tegmental area of brain 2. Stimulation of CNS induces arousal, relaxation, and mild euphoria 3. Activation of sympathetic nervous system induces vasoconstriction and 4. increase blood pressure B. TARS AND CARBON MONOXIDE inhaled in cigarette smoke increase risk of: 1. Chronic obstructive pulmonary disease (COPD) 2. Cancer 3. Heart disease
  48. 48. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Cigarettes(2) 48 C. PHYSICAL AND PSYCHOLOGICAL DEPENDENCE occurs. Abstinence leads to anxiety, insomnia, and enhanced appetite that can last for several months D. Many approaches are available that increase the probability of successfully abstaining from cigarettes 1. Physicians should follow the five As when counseling smokers a. Ask patients if they smoke b. Advise patients to quit smoking c. Assess patients’ readiness to quit d. Assist patients who would like to quit e. Arrange for follow-up .
  49. 49. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Cigarettes(3) 49 2. Nicotine is available in a patch, in gum, and in an inhaler  These devices release nicotine more slowly compared with smoking 3. Other aids are available for smoking cessation a. Bupropion (Zyban) is an antidepressant b. Varenicline (Chantix) is a nicotinic receptor partial agonist 4. Behavioral modification programs and telephone quit lines are also helpful
  50. 50. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 V: CNS Stimulants: Sympathomimetics 50 A. COCAINE AND AMPHETAMINES are most commonly abused CNS stimulants in Western society B. Magnitude of euphoria depends on speed of onset: 1. Amphetamines can be taken orally, which results in a slow onset  Can also be injected or crushed and snorted, which results in a much faster onset 2. Cocaine can be ingested, chewed, snorted, injected, or smoked a. Crack is free-base form of cocaine HCl  It is formed by heating cocaine HCl in an alkaline solution b. Smoked crack has most rapid onset and the most pleasurable effects
  51. 51. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 CNS Stimulants Mechanism of action 51 1. Cocaine blocks the DA transporter (DAT) also norepinephrine and serotonin transporters(NET and SERT) at higher doses in CNS to inhibit uptake of DA into nerve terminals in mesolimbic pathway that includes “brain reward” center  Blockade of NET also leads to increased sympathomimetic activity 2. Amphetamine increases release of prejunctional neuronal catecholamines, including DA and norepinephrine  Amphetamine also exhibits some direct sympathomimetic action and weakly inhibits MAO
  52. 52. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 CNS Stimulants (3) 52 C. Stimulants produce euphoria with: 1. Enhanced self-confidence and alertness 2. Increased motor activity 3. Little physical dependence  Fatigue is primary physical symptom during withdrawal 4. Strong psychological dependence D. Period of euphoria varies depending on half-life of drug in body 1. Cocaine induces a very short euphoria (approximately 15 minutes), which is followed by a period of marked dysphoria 2. Euphoria from amphetamines has a much longer duration E. Chronic abusers develop paranoid, psychotic-like symptoms
  53. 53. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 CNS Stimulants (4) 53 F. OVERDOSES can be dangerous 1. Sympathomimetic actions can lead to tachycardia and arrhythmias 2. Abusers can become aggressive and experience hallucinations Other dangerous effects include hypertension, hyperthermia, coma, and death. 3. Cocaine can also induce: a. Gangrene, due to peripheral vasoconstriction b. Perforation of nasal septum, due to vasoconstriction in nasal mucosa c. Convulsions, due to local anesthetic effects on brain
  54. 54. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 CNS Stimulants (5) Khat and Synthetic Cathinones 54  Cathinone is the psychoactive component in an evergreen shrub called Khat native to East Africa and the Arabian Peninsula  Synthetic cathinones, also known as “bath salts,” have become increasingly popular products are packaged and labeled in such a way as to circumvent detection, prosecution, and enforcement  These are substances that are sold as something else at large profits with an unstated understanding by seller and buyer that they will produce intoxication  Synthetic cathinones are not easily detected on urine toxicology screens
  55. 55. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 CNS Stimulants (5) Khat and Synthetic Cathinones 55  Methcathinone, butylone, methylene dioxypyrovalerone, and naphyrone are just a few examples of synthetic cathinones  These drugs increase the release and inhibit the reuptake of catecholamines (norepinephrine, epinephrine, and dopamine) in a manner very similar to cocaine and amphetamines  A rapid onset of amphetamine-like stimulation with psychotomimetic effects of variable duration is common with synthetic cathinones
  56. 56. 56 See: Kebede Y. Editorial. Should the Silence on Khat Be Allowed to Continue in Ethiopia? Ethiop. J. Health Biomed Sci., 2009. Vol.2, No.1
  57. 57. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 VI: Hallucinogens (psychotomimetics) Marijuana (cannabis) and dronabinol (marinol) 57  Active ingredient in marijuana is Δ-9 tetrahydrocannabinol (THC)  MOA: it acts prejunctionally as an agonist to inhibit adenylyl cyclase through G-protein-linked cannabinoid receptors  Through disinhibition of DA neurons it inhibits activity of GABA neurons in the ventral tegmentum area (VTA) a. Cannabinol CB1 receptors, which account for most CNS effects, are localized to cognitive and motor areas of the brain b. Cannabinol CB2-receptors are found in immune system among other peripheral organs
  58. 58. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 Cannabinoids 58  Cannabinoids are effective antiemetics and appetite stimulants and have some analgesic actions  Dronabinol is a synthetic, orally active cannabinoid approved for treatment of cachexia in patients with cancer or acquired immunodeficiency syndrome (AIDS) and to treat emesis caused by cancer chemotherapy in patients who do not respond to conventional antiemetics  Many also argue for use of smoked marijuana in treating chronic pain, improving appetite in AIDS patients, and suppressing spasticity in multiple sclerosis and spinal injury
  59. 59. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 THE END 59
  60. 60. Marc Imhotep Cray, M.D. CNS Pharmacology Lecture 9 60 Further study (SDL): MedPharm Digital Guidebook: Unit 3-Drugs Used for CNS Disorders Companion eNotes: CNS- Central Nervous System Pharmacology Textbook Reading: Lüscher C. Drugs of Abuse Ch. 32 In: Katzung BG, ed. Basic & Clinical Pharmacology. 12th ed. Pgs. 565-79 Online resource center: Medical Pharmacology Cloud Folder

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