Drugs of abuse.pptx...............................

............................................................................................

1. Drugs of Abuse and Drug Dependence Dr. ARBINDRA CHANSORIA ASSISTANT PROFESSOR

2. Overview of contents Definitions Neurobiological mechanism of addiction Factors affecting liability to become addicted CNS depressants Psychostimulant drugs Cannabinoids Hallucinogens Dissociative drugs Miscellaneous Anabolic steroids

3. DEFINITIONS Abuse Self-administration of any drug in a culturally disapproved manner that causes adverse consequences. Addiction Behavioral pattern of drug abuse characterized by overwhelming involvement (compulsive use), the securing of its supply, and a high tendency to relapse after discontinuation. Compulsivity Behavior- repetitive, (B) it is nonadaptive or inappropriate , (C) it leads to functional impairment, (D) it is performed in a habitual or stereotyped manner. Dependence Physiological state of adaptation produced by repeated administration of certain drugs such as alcohol, heroin, and benzodiazepines when they are abruptly discontinued, and are associated with physical drug withdrawal changes .

4. Crosstolerance and crossdependence The ability of one drug to suppress the physical dependence produced by another drug and to maintain the physically dependent state. Habit Responses triggered by environmental stimuli regardless of the consequences. conditioned response to a stimulus reinforced by past experience with reward (positive reinforcement) or by the omission of an aversive event (negative reinforcement). Impulsivity Act prematurely without foresight; Result in undesirable consequences; predisposition towards rapid, unplanned responses to internal and external stimuli without regard for the negative consequences. Measured in two domains: the choice of a small, immediate reward over a larger delayed reward, or the inability to inhibit behavior to change the course of action or to stop a response once it is initiated.

5. Rebound The exaggerated expression of the original condition sometimes experienced by patients immediately after cessation of an effective treatment. Reinforcement The tendency of a pleasure-producing drug to lead to repeated self-administration. Relapse The reoccurrence, upon discontinuation of an effective medical treatment, of the original condition from which the patient suffered. Tolerance Tolerance has developed when, after repeated administration, a given dose of a drug produces a decreased effect, or, conversely, when increasingly larger doses must be administered to obtain the effects observed with the original use. Withdrawal The psychologic and physiologic reactions to abrupt cessation of a dependence-producing drug.

6. Neurobiology of addiction

7. Nucleus accumbens

8. MIDBRAIN CORTEX

9. Factors affecting ADDICTIVE liability Agent(drug factors) Availability Purity /potency Mode of administration- Chewing Gastrointestinal Intranasal Subcutaneous and intramuscular Intravenous Inhalational 4. Speed of onset and termination of effects (pharmacokinetics: agent and host factors)

10. Environment factors Access to enforcers Affordability of enforcers Social setting Peer influence Conditioned stimuli Host(user factors) Age at first exposure Heredity (genetic vulnerability vs genetic resilience) Innate tolerance Speed of developing tolerance Likelihood of experiencing intoxication as pleasure Pharmacokinetic properties Prior experiences Propensity for risk taking behavior

11. Diagnostic criteria for substance abuse/ dependence(ASA) Maladaptive pattern of substance use. Use leads to social, professional impairment TOLERANCE defined as- I) increased doses to achieve desired effect ii) diminished effect with same dose Presence of withdrawal Substance taken in larger amounts over time Unable to decrease the dose More time spent to acquire, use and recover from substance Responsibilities abandoned for substance Use continued despite adverse results

12. Types of dependence Psychologic (psychic)- compulsive drug seeking behaviour Physical- regular use necessary to avoid acute withdrawal symptoms

13. Psychological factors in drug dependence Stimuli associated with drug use Environmental- peer group, etc. Discriminative- drug taste, smell, appearance Stimuli associated with drug cessation Non-availability Legal problems Financial problems Drug use REWARD Drug stop WITHDRAWAL SYNDROME POSITIVE REINFORCEMENT NEGATIVE REINFORCEMENT REPEAT USE BECAUSE OF POSITIVE EFFECTS UNPLEASANT EFFECTS DUE TO TERMINATION

14. TOLERANCE Reduced response of the same dose of the drug after repeated administration Acute tolerance- rapid tolerance with repeated use on a single occasion ex- nicotine Reverse tolerance- increase response with repetition of the same dose ex- cocaine, amphetamines Cross tolerance- repeated use of a drug confers tolerance to other drugs of the same category ex- morphine with fentanyl

15. Tolerance Innate Acquired Genetic Nonsusceptibility To Certain Class Of Drugs Pharmacokinetic Pharmcodynamic Learned Acute Reverse Cross

16. Classification of psychoactive substances Class of drugs Substances CNS depressants Alcohol, benzodiazipines , barbiturates, methaqualone, chloral hydrate Psychostimulants Amphetamine, methamphetamine, cocaine, methylphenidate Opioid narcotics Heroin, morphine, methadone, codeine, oxycodone, meperidine Nicotine Tobacco Cannabinoids Bhang, Marijuana, tetrahydrocannabinol Hallucinogens/ psychedelics/ psychomimetics / psychodysleptics LSD, Psilocybin, phencyclidine, ketamine Miscellaneous Caffeine- coffee, tea Inhalants- gasoline, sprays, paints, acetone Amyl nitrite, nitrous oxide

17. Classification-based upon dependence Strong psychic and physical dependence- CNS depressants, opioid narcotics Strong psychic + mild psychological- tobacco, cocaine, amphetamine Only psychic- hallucinogens, cannabinoids, caffeine

18. Features of psychoactive substances Rapid delivery to brain Positive psychoactive effects Tolerance Withdrawal syndrome

19. CNS depressants 1 . Alcohol (ethanol) Safe drinking- 20-40g alcohol/day Ex- 400ml beer, 150ml wine, 50ml spirits Preparation Alcohol content Beer 3% Wine 10-15% Strong spirits 50% Rum, whisky, gin, brandy, vodka 40-55%

20. Pharmacokinetics Absorption- rapid orally Reduced by high lipid diet Metabolism- rapid gastric first pass metabolism (alcohol dehydrogenase – gastric wall) Follows first order kinetics- plasma concentration <10mg/dl Further increase saturates alcohol dehydrogenase and follows zero order kinetics Hepatic enzyme inducer- tolerance in habitual users Site of metabolism- 90-98% liver 2-10% excreted unchanged in urine, expired air and sweat Alcohol dehydrogenase Acetaldehyde dehydrogenase Causes organ damage

21. Pathological drinking and dependence Conditions Adverse effects Medical Gastritis, alcoholic liver disease, pancreatitis, peripheral neuritis, Wernicke’s encephalopathy, Korsakoff’s psychosis, nicotinic acid deficiency Psychiatric Anxiety, depression, lack of memory Dependence Psychological- severe Physical- chronic heavy use

22. PLASMA Concentration Nature of effect <50mg/dl Increased sense of well being 50-100mg/dl Lack of concentration, disturbed gait 100-150mg/dl Ataxia, impaired motor skills, slurred speech 200mg/dl No response to sensory stimuli, stupor, emesis 250mg/dl Coma 400-500mg/dl Respiratory depression, death Withdrawal reaction Symptoms- craving, nausea, sleep disturbance, sweating, seizures Treatment- Diazepam/oxazepam (reduce excitability) Atenolol ( as adjunctive) HR >50BPM

23. Disulfiram in chronic alcoholism Causes immediate unpleasantness Effects are due to 5-10 times increase in acetaldehyde ( toxic ). Alcohol administration after disulfiram leads to- Vasodilatation, pulsating headache, nausea, vomiting, severe thirst, respiratory difficulty, syncope Disulfiram-ethanol reaction- respiratory depression, cardiovascular collapse, myocardial infarction, convulsions and sudden death.

24. Benzodiazipines and barbiturates Physical dependence- severe Tolerance- less than morphine No cross tolerance with alcohol Prescription drugs Pseudo-withdrawal- fear from the idea of withdrawal Signs of withdrawal Neuropsychiatric- ataxia, depression, fasciculations, headache, tremors Hyperexcitability- agitation, anxiety, diarrhoea, nausea, urinary urgency Flunitazepam - rapid onset drug, prevents memory storage

25. Pharmacokinetics of benzodiazipines Absorption- high oral bioavailability Distribution- lipophilic molecules- easily cross BBB Cross placenta, breast milk Metabolism- CYP3A4, glucuronidation- Hepatic metabolism Excretion- soluble metabolites, renal excretion Examples- diazepam, oxazepam, midazolam, lorazepam, flunitrazepam

26. Methaquolone - Indian sedative hypnotic Known as street drug of choice More dangerous in combination with diphenhydramine MOA- GABA agonist Can cause physical dependance Widespread use as recreational drug. Increases fatality when combined with other CNS depressants Choral hydrate Intoxicate drinks Used for criminal use

27. Psychostimulants Amphetamine and methamphetamine Psychological dependence- severe Physical dependence- mild Tolerance- seen ROA- IV (run) Crystals of meth are smoked (ice smoking)

28. Cocaine Psychological dependence- severe Physical dependence- slight Tolerance- mild 3 ways of administration A. snuff(snort)- paper sniffing/ insufflation B. smoking after heating in pipe- crack or rock C. I.V. --- i ] shooting/ mainlining- mixed with water and injected i.v. ii] kicking/booting- blood is withdrawn from the vein and reinjected after mixing with cocaine

29. Systemic manifestations Intense rush or flash Tactile hallucinations- cocaine bugs Visual disturbances- flashing lights, snow effects. Withdrawal symptoms- Dysphoria(feeling ill at rest) Craving, anxiety, restlessness, hypersomnolence, depression, anhedonia Reverse tolerance seen. Cocaine combination preparations- 1. Speedball- cocaine + heroin 2. Liquid lady- cocaine + alcohol (coca-ethylene- psychoactive) 3. Teratogenic- ileal and genitourinary abnormalities- cocaine babies

30. Pharmacokinetics of cocaine and amphetamines Absorption- cocaine- not absorbed orally. Penetrate BBB easily Half lives- Cocaine- 50-90min Amphetamine- 5-10hrs Meth- 12hrs Metabolites- active or inactive Cocaine auto-metabolises in blood as well as in liver.

31. Cocaine metabolism The major route- hydrolysis of ester groups. Cocaine  benzoylecgonine(30-40%)ecgonine(50%) Benzoylecgonine- major urinary metabolite Found in the urine for 2 to 5 days after a binge. Detectable for 10 days Test is a valid method for verifying cocaine use.

32. Toxicity Cardiac arrhythmias, myocardial ischemia, myocarditis, aortic dissection, cerebral vasoconstriction, and seizures. Death from traumatic injuries is also associated with cocaine use. May induce premature labor and abruptio placentae. Psychiatric disorders, including anxiety, depression, and psychosis. Tolerance, dependence, and withdrawal Tolerance develops Frequent periods of withdrawal or “crash.” . Withdrawal symptoms- dysphoria, depression Sleepiness, fatigue, craving Bradycardia Reduction in symptoms over 1 to 3 weeks. Residual depression, often seen after cocaine withdrawal, should be treated with antidepressant agents.

33. Opioid narcotics Abusers can be- Medical abusers- patients with chronic pain, physicians, health staff Street abusers- other addicted people Psychological and physical dependence- severe Tolerance and cross- tolerance seen ROA – I.V. Effects- rush  euphoria  nod (sleepiness)

34. Heroin No approved medical use Metabolized in the brain into 6-monoacetylmorphine and morphine Extremely addictive Together with fentanyl a leading cause of SUD deaths Rapid neurobiological adaptations require increased doses to avoid withdrawal symptoms Causes respiratory depression Increased fatalities when combined with CNS depressants

35. Withdrawal reaction - after 8-10 hrs of last dose Immediate- lacrimation, rhinorrhea, sweating Later- restless sleep, gooseflesh(cold turkey), nausea, kicking, raised blood pressure Opioids + anti- histaminics = euphoria Cotton fever may occur- immediate pyrogenic reaction, leukocytosis subsides in 1-2 hrs

36. Tobacco/Nicotine Most widely abused Smoked as- cigarettes, cigar, snuff Chewed as- khaini/ jarda Psychological dependence- severe >60% carcinogenic compounds – lung , airway and other organs affected 2 types of tobacco smoke- Mainstream smoke- inhaled during puffing Side stream smoke- between puffs- inhaled by smokers and non-smokers Withdrawal reaction- Anger, irritability, anxiety, difficulty concentrating, drowsiness, hunger, weight gain, restlessness, decreased heart rate

37. Nicotine dependence Physical dependence Reaches brain within 10-19 secs of administration Effects- pleasure, relief of anxiety, improved performance and memory, mood modulation, skeletal muscle relaxation. Adverse effects- carcinogenic Increased risk of atherosclerosis Reproductive dysfunction Decrease sleep time, restless leg syndrome Teratogenic Might have benefits in Parkinson’s disease, schizophrenia, dementia, depression, and ADHD Leading cause of preventable death

38. REINFORCEMENT OF RECEPTORS

39. Pharmacotherapy in chronic smoking Nicotine replacement therapy-Aims Reduce withdrawal symptoms Reduce cravings Reduce reinforcing effects Provide coping strategy when craving may occur Provide alternate source to reinforce nicotine effect Available as- gums, transdermal patches, nasal spray Dose of patch- >20/day cigarette smokers- 30m 2 every 24 hrly <20/day- 20m 2 every 24 hrly

40. Varenicline a selective α4β2 - nicotinic acetylcholine receptor partial agonist

41. Bupropion- NDRI agent Decrease reinforcing effects. Dose- 150mg daily x 3 days initial dose Increased to 150mg BD -7-12 weeks Rimonabant-CB1 receptor blocker Reduce overstimulation of CB1 receptor and dependence Varenicline- partial nicotine agonist, selective nicotinic receptor modulator Eliminates reward for smoking and reduces withdrawal Anabasine - alpha 7 receptor modulator

42. Cannabinoids Source- Cannabis sativa Psychological dependence Slight tolerance Available forms- HASHISH/ charas - dried resin Bhang, sidhvi - dried leaves Ganja- small leaves and flowers ROA- smoked in cigar/ orally with sweets Early addiction stages- euphoria  laughter altered sense of time dream-like state Signs- tachycardia, conjunctival redness

43. Hallucinogens (entactogens) K/a- club drugs Psychological dependence only LSD, MDMA,MDA,DMT Sold as – thin squares of gelatin(window panes), impregnated paper(blotter acid), tablets signs of addiction a)somatic- dizziness, weakness, tremors b) perceptual- blurred vision, subjective sensation and color vision, hallucinations c) psychological- impaired memory, poor judgements d) Bad trips- severe anxiety and suicidal thoughts e) Recurrence – flashbacks or hallucinogen persisting perception disorder PCP Emotional withdrawal and catatonic posturing ROA- smoke, oral or i.v.

44. Miscellaneous Caffeine- coffee, tea, chocolate Psychological dependence Inhalants- Abused by teenagers 4. Amyl nitrite- poppers Inhaled from sealed vials or capsules Nitrous oxide- euphoria and laughter

45. Clinical categories of drugs Permissive- socially permitted ex- caffeine, nicotine, alcohol Prescriptive- therapeutic effects but can be abused ex- benzodiazipines Proscriptive- require strict control ex- marijuana, opioids, cocaine, hallucinogens Ripple effect of drug abuse Broader influence of drug abuse Initially only the user is involved then the surrounding members get influenced Leads to decreased productivity, crime, violence, legal issues etc.

46. Pharmacological approaches to treat drug dependence Aims Alleviate acute withdrawal symptoms and counter excitability a) short term use of methadone – opioid withdrawal b) benzodiazipines - alcohol withdrawal 2. Long term substitute of abused drug (stabilization/maintenance) methadone/buprenorphine- long t1/2 Nicotine patches LAAM ( levo - α-a cetylmethadol )- opioid addiction- thrice weekly 3. Block acute rewarding effects naltrexone, nalmefene , naloxone- block euphoria effects of opioids and alcohol Disulfiram- alcohol aversive therapy Flumazenil- antagonize benzodiazipines 4. Diminish craving bupropion- decrease smoking Acamprosate- decease alcohol craving Buprenorphine- heroin craving Nicotine replacement- chronic smokers

47. Anabolic steroids- Designer drugs ( legal highs) Produce similar effects as testosterone Therapeutic use- stimulate bone growth, induce male puberty, chronic muscle wasting conditions Abused by- sportsperson Adverse effects- gynacomastia , liver damage, hypercholestrolemia

48. Thank you