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Drugs of Abuse and Adaptive Changes I. Introduction

Drugs of Abuse and Adaptive Changes I. Introduction. Dr. A. L. Padjen Department of Pharmacology & Therapeutics McGill University alp@pharma.mcgill.ca http://www.cai.mcgill.ca/meded Basis of Medicine, Unit 8. ante.padjen@mcgill.ca. http://www.cai.mcgill.ca. 1.1. Society and drugs….

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Drugs of Abuse and Adaptive Changes I. Introduction

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  1. Drugs of Abuse and Adaptive ChangesI. Introduction Dr. A. L. Padjen Department of Pharmacology & Therapeutics McGill University alp@pharma.mcgill.cahttp://www.cai.mcgill.ca/meded Basis of Medicine, Unit 8 ante.padjen@mcgill.ca http://www.cai.mcgill.ca BOM U8: Drug Abuse 2002

  2. 1.1. Society and drugs… • Drugs of abuse – mostly used for their mood-altering properties • Evidence of use in early human societies • Natural products: alcohol, morphine, cocaine, etc. • Modern times… 19 century.. • Problem often under-recognized (e.g., cocaine in Coca cola) or misinterpreted (“lack of will power”…) • 20th century… • Increasing problem • Contribution of technology (synthetic, designer drugs…) • Huge impact on society BOM U8: Drug Abuse 2002

  3. 1.2. Impact of drug abuse. • Economic impact of drug abuse • Abuse of legal drugs is more prevalent and more costly than is the abuse of illegal drugs • Cost estimates of drug abuse (USA; 1990): • Indirect costs not included (crime, jail, fire, motor vehicle accidents, etc) BOM U8: Drug Abuse 2002

  4. 1.3. How to understand… • Clinical classifications of drug abuse phenomena • DSM IV • IDC10 vs. • Experimental animal models of drug abuse • Operant behaviour… • Mechanism(s)… • At the cellular or system level BOM U8: Drug Abuse 2002

  5. Key points to understand • Society and drugs • Clarify concepts and terminology • Etiology of drug abuse • Factors affecting drug abuse and adaptive mechanisms. • Short review of drugs liable to be abused • Possible mechanism(s) of pharmacological interventions in addiction(s). • Resources BOM U8: Drug Abuse 2002

  6. 2.1. Concepts & Definitions (1) • dependence • Refers to the state of needing a drug (drugs) to function within normal limits • Often associated with tolerance, sensitization,withdrawal, and addiction • addiction • Term restricted to the extreme or pathophysiological state, i.e. loss of control • e.g. WHO definition: • " behavioral pattern ... compulsive use .. tendency to relapse ... drug use ... controlling the behavior. " Note that these definitions are from DSM IV... BOM U8: Drug Abuse 2002

  7. 2.2. Concepts & Definitions (2) • drug abuse • largely a social definition • cultural factors (e.g., alcohol is omnipresent in Western civilization) • religious factors (e.g., hallucinogens are part of life of Amerindians) • non-medical use • i.e., use of drugs outside of its therapeutic indication • recreational use of a drug hazard dependence • compulsive use • progression from need  mild desire craving  compulsion • cont BOM U8: Drug Abuse 2002

  8. 3. Etiology of drug abuse… • Society and drugs • Clarify concepts and terminology • Etiology of drug abuse • Factors affecting drug abuse and adaptive mechanisms. • Short review of drugs liable to be abused • Possible mechanism(s) of pharmacological interventions in addiction(s). • Resources BOM U8: Drug Abuse 2002

  9. 3.1. Etiological models of drug abuse • Moral Model • Drug abuse considered a “sin” or “crime” • These attitudes and understanding lead to the Prohibition • Largely abandoned in favour of  • Medical Model • drug addiction is a disease requiring medical intervention • Social Learning Model • drug abuse is a learned behaviour (explainable by classical & operant conditioning) BOM U8: Drug Abuse 2002

  10. 4. Factors affecting drug abuse... • Society and drugs • Clarify concepts and terminology • Etiology of drug abuse • Factors affecting drug abuse and adaptive mechanisms. • Short review of drugs liable to be abused • Possible mechanism(s) of pharmacological interventions in addiction(s). • Resources BOM U8: Drug Abuse 2002

  11. 4.1. Three factors.... • Individual • Biological & Genetic factors • Psychological Traits • Drugs • Reinforcing Properties of • Drugsx • Environment • Social Factors BOM U8: Drug Abuse 2002

  12. 4.2. Self-stimulation model • In operant behavior experiments (Skinner box) many drugs of abuse were found to facilitate brain stimulation reward(decreasing threshold or increase the rate of self-stimulation) • This approach is used to identify reinforcing properties of a drug BOM U8: Drug Abuse 2002

  13. 4.3. Acute Drug State BOM U8: Drug Abuse 2002

  14. 4.4. Reinforcement & reward systems BOM U8: Drug Abuse 2002

  15. 4.5. Drugs of abuse: Sites of action Some effects may be indirect.. BOM U8: Drug Abuse 2002

  16. 4.6. Drugs of abuse: Sites of action (2) (compare with the next table) BOM U8: Drug Abuse 2002

  17. 4.7. Neurobiological Substrates... • … for the acute reinforcing effects of drugs of abuse (*compare with the diagram on the previous slide) BOM U8: Drug Abuse 2002

  18. 4.8. Chronic drug state Neuroadaptation see also 4.12. Cellular mechanisms… BOM U8: Drug Abuse 2002

  19. 4.9. Tolerance • Pharmacokinetics chronic use  increased metabolism of a drug, e.g., induction of P450 • Pharmacodynamic • chronic use  decreased response to the same concentration of a drug (NEUROADAPTATION– 4.12. Cellular mechanisms… • IMPORTANT: tolerance does not necessarily develop equally to all effects of a drug • Example: tolerance to opiates • euphoric effect >> respiratory depression • Innate vs. acquired • e.g., difference in isoforms of enzymes (e.g. individual differences in tolerance to anticholinergic drugs, chlorpromazine); or receptors…(GENETIC PREDISPOSITION?? see later) • Cross-tolerance & cross-dependence • e.g. barbiturate & alcohol BOM U8: Drug Abuse 2002

  20. 4.10. Sensitization • long lasting increment in response to a drug • upon repeated presentation • (more likely to occur with intermittent exposure to a drug) • Example: sensitization to repeated use of cocaine BOM U8: Drug Abuse 2002

  21. 4.11. Possible mechanisms... ….of tolerance/physical dependence • System level (see slides 9 – 13, 4.4 – 4.7 ) • locus coeruleus (LC) for opiates • n. acumbens (Nac) for cocainedopaminergic system of reward may be involved in many drug dependence • Cellular & molecular level • see slide 23, 4.13... BOM U8: Drug Abuse 2002

  22. 4.12. Cellular mechanisms… ...of action of drugs of abuse • Activation of receptors (1,2) leads to changes in 2nd messengers (cAMP, 3), protein kinases (4), that may cause short-term changes in neuronal activity (changes in excitability, neurotransmitter responses) (6,7) , or long-term changes (11,12,13) via nuclear events (8,10,14). • = NEUROADAPTATION BOM U8: Drug Abuse 2002

  23. 4.13. Short-term Abstinence BOM U8: Drug Abuse 2002

  24. 4.14. Physical dependence… (1) • characterized by the abstinence syndrome: • (withdrawal reaction) • removal of a drug causes rebound effecte.g. hypnotics: rebound hyperexcitability; amphetamine: rebound depression) • unpleasant - aversive • some syndromes potentially life threatening (e.g., seizures after barbiturates withdrawal) • others syndromes not life threatening (e.g., opiate withdrawal) BOM U8: Drug Abuse 2002

  25. 4.15. Physical dependence… (2) • time factors: • longer exposure to drug, more developed dependence • faster removal of drug more pronounced withdrawal reaction • pharmacokinetic differences among drugs: • basis for substitution treatment:e.g. methadone (for heroin): less positive (euphoric) and negative (withdrawal reaction) effects BOM U8: Drug Abuse 2002

  26. 4.16. Environment... • Individual • Biological & Genetic factors • Psychological Traits • Drugs • Reinforcing Properties of • Drugs • Environment • Social Factors • Legal implications BOM U8: Drug Abuse 2002

  27. 4.17. Social and legal aspects... • Important points for development of a drug policy: • Psychoactive drugs are dangerous • Availability affects consumption • Drug-free society is an unachievable state “Drug policy should strike the right balance between reducing the harm done by drugs and reducing the harm that results from strict legal prohibitions and their enforcement.” BOM U8: Drug Abuse 2002

  28. 4.18 Harm Reduction Model BOM U8: Drug Abuse 2002

  29. 5. List of drugs liable to be abused... • Society and drugs • Clarify concepts and terminology • Etiology of drug abuse • Factors affecting drug abuse and adaptive mechanisms. • Short review of drugs liable to be abused • Possible mechanism(s) of pharmacological interventions in addiction(s). BOM U8: Drug Abuse 2002

  30. CNS Stimulants Cocaine Amphetamines Ecstasy Nicotine Caffeine CNS Depressants Alcohol Benzodiazepines Barbiturate Dissociative anesthetics Phencyclidine Ketamine Some psychoactive drugs, such as phenothiazines, haloperidol, and tricyclic antidepressants are not included in this classification of "psychoactive drugs of abuse" because they are seldom chronically abused. . 5.1.a. Drugs liable to be abused... • Analgesics • Morphine, heroin • Methadone • Cannabinoids • Cannabis, THC • Hallucinogens • LSD, Mescaline • D) Hydrocarbon Solvents • E) Combination Drugs Check 5.2. – 5.4 for details on each group: Reward, Tolerance, Withdrawal and Harmful effects BOM U8: Drug Abuse 2002

  31. 5.1.b. How to use the tables… • The next set of table is prepared as a reference of addictive properties of drug classes - • Reward (5.2) • Tolerance, sensitization, dependence & withdrawal (5.3) • Harmful effects of dependence (5.4) • These tables are the main source of information about: • alcohol, cannabinoids, hallucinogens, solvents • Pharmacology of the following drugs is described in other sections of Unit 8 • cocaine, amphetamines, caffeine, benzodiazepines, barbiturates, ketamine, morphine, nicotine BOM U8: Drug Abuse 2002

  32. 5.2.a. Rewards & mechanisms of drug dependence BOM U8: Drug Abuse 2002

  33. 5.2.b.Rewards & mechanisms of drug dependence BOM U8: Drug Abuse 2002

  34. 5.2.c. Rewards & mechanisms of drug dependence BOM U8: Drug Abuse 2002

  35. 5.3.a. Tolerance, dependence & withdrawal … BOM U8: Drug Abuse 2002

  36. 5.3.b. Tolerance, dependence & withdrawal … BOM U8: Drug Abuse 2002

  37. 5.3.c. Tolerance, dependence & withdrawal… BOM U8: Drug Abuse 2002

  38. 5.4.a. Harmful effects of drugs of dependence BOM U8: Drug Abuse 2002

  39. 5.4.b. Harmful effects of drugs of dependence BOM U8: Drug Abuse 2002

  40. 5.4.c. Harmful effects of drugs of dependence BOM U8: Drug Abuse 2002

  41. 5.4.d. Harmful effects of drugs of dependence BOM U8: Drug Abuse 2002

  42. 6. Treatment of addictions... • Society and drugs • Clarify concepts and terminology • Etiology of drug abuse • Factors affecting drug abuse and adaptive mechanisms. • Short review of drugs liable to be abused • Possible mechanism(s) of pharmacological interventions in addiction(s). • Resources BOM U8: Drug Abuse 2002

  43. 6.1. Principles of therapeutic intervention • Drug addiction is a chronic state (see 6.4) • Multimodality treatment is usually most effective (see 6.4). • Three factors have to be dealt with: • individual • drug reinforcing effects • social factors • Phase I: Detoxification… • Phase II: Dealing with chronic issues... • Major objective:  relapse... BOM U8: Drug Abuse 2002

  44. 6.2 Long-term Abstinence BOM U8: Drug Abuse 2002

  45. 6.3. Pharmacotherapy in drug addiction • Psychopharmacotherapy • (only one component of a complex approach - see the next slide ) • Examples: •  craving ( activation of reward system) • e.g., naltrexone in alcoholism •  positive and/or negative effects(substitution) • methadone • treatment of possible co-morbidity (e.g., depression) • Antidepressants in alcoholism, nicotine addiction BOM U8: Drug Abuse 2002

  46. 6.4. Role of pharmacotherapeutic intervention BOM U8: Drug Abuse 2002

  47. 7. Resources • Katzung • Rang • G&G • Chapters on Drugs of Abuse • Web resources • IBRO Edu • http://www.medicine.mcgill.ca/ibroedu BOM U8: Drug Abuse 2002

  48. Cont. • Alcohol & alcoholism BOM U8: Drug Abuse 2002

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