Drug dependence

Drug dependence

1. DRUG DEPENDENCE Dr. Ashishkumar Baheti Md Pharmacology 1

2. 2 Definitions Drug dependence: (ICD-10) A cluster of physiological, behavioural, and cognitive phenomena in which the use of a substance or a class of substances takes on a much higher priority for a given individual than other behaviours that once had greater value Dependence refers to both physical and psychological elements

3. 3 Contd… Physiological or physical dependence The physiological state of neuroadaptation produced by repeated administration of drug necessitating continued administration to prevent the appearance of withdrawal syndrome Psychological or psychic dependence A behavioural pattern of drug abuse characterized by overwhelming involvement with the use of a drug, the securing of its supply and a high tendency to relapse after its discontinuation

4. 4 Contd… Addiction Addiction is usually confused with dependence It is hard to define, with little consensus of what it means In fact it is not even defined as a condition in DSM IV When used it means psychological dependence Abuse Self administration of any drug in a culturally disapproved manner (illegal) that causes adverse consequences

5. 5 Contd… Tolerance A state of decreased responsiveness to the pharmacologic effect of a drug as a result of prior exposure to that drug Cross tolerance When exposure to drug A produces tolerance to it and also to drug B

6. 6 Contd… Withdrawal The adverse psychological or physiological reactions to abrupt cessation of a dependence producing drug usually characterized by craving, dysphoria and signs of sympathetic nervous system overactivity Reinforcement The capacity of drugs to produce effects that make the user wish to take them again

7. 7 ICD-10 Diagnostic guidelines Strong desire or sense of compulsion to take the drug Difficulties in controlling substance-taking behaviour A physiological withdrawal state Evidence of tolerance Progressive neglect of alternative pleasures or interests Persisting with substance use despite clear evidence of overtly harmful consequences A definite diagnosis of dependence should usually be made only if three or more symptoms have been present together at some time during the previous year

8. 8 Origins of substance dependence Agent (drug) Host Environment Reinforcement, availability, cost, potency, purity, mode of adm. speed of onset and termination of effects Social setting, community standards, peer influence, role models, employment & educational opportunities, environmental cues asso. with drugs Heredity, innate tolerance, psychiatric symptoms, prior experiences/ expectations, propensity of risk taking behaviour

9. 9 Genetic factors They contribute to 60% of an individuals susceptibility to most forms of drug abuse Attempts to find drug abuse genes are not yet successful Polygenic disorder Innate tolerance to a drug increases vulnerability to dependence Individuals with mutation in ALDH2 gene have low propensity for alcoholism

10. 10 Neurobiology of dependence Complex and chronic disease process occurring in brain which is modulated by genetic, developmental and environmental factors Most consistent and reproducible finding is activation of mesolimbic dopaminergic system Mesolimbic system consists of dopaminergic neurons in ventral tegmental area and their axonal projections to nucleus accumbens (NAc) and the prefrontal cortex

11. 11 Mechanism of tolerance Innate tolerance - genetically determined insensitivity Pharmacokinetic - changes in distribution or metabolism e.g. barbiturates induce their own metabolism Pharmacodynamic - adaptive changes in systems affected by drug Receptor down regulation – decrease in number, internalization

12. 12 Contd… Receptor desensitization – occupied receptors become less efficient in activating subsequent steps e.g. due to functional uncoupling of G proteins from receptor Post receptor adaptive mechanisms - e.g. opiates act by decreasing cyclic AMP. On chronic use the level of cAMP increases resulting in decrease response to opiates Conditioned tolerance – develops when environmental cues such as sights, smell or situations consistently are paired with drug administration

13. 13 Classification of drugs of abuse The drugs producing dependence can be classified Depending on their ability to produce psychological or physical dependence Depending on their characteristic effects Depending on their mechanism of action

14. 14 Classification based on dependence Type of dependence Drugs Severe Psychological + Physical Opiate or morphine type: Morphine, Codeine, Pethidine, Heroin Alcohol / barbiturate type: Ethyl alcohol, Barbiturates, BZDs Nicotine (tobacco) Psychological with mild Physical dependence Opiate antagonists: Nalorphine, Levallorphan Amphetamines Only Psychological Cocaine, LSD, Mescaline, Psilocybin, Cannabinoids, Caffeine

15. 15 Classification based on effects CNS stimulants: amphetamine, cocaine CNS depressants: alcohol, barbiturates, BZDs Narcotics: heroin, morphine, codiene Psychotomimetic: LSD, mescaline, PCP Volatile inhalants: benzene, amyl nitrite, petrol, kerosene

16. 16 RR, Relative risk of addiction; 1 = nonaddictive; 5 = highly addictive

17. 17 Contd… G, G i/o -coupled receptors; i, ionotropic receptors/ ion channels; T, monoamine transporters

18. 18 1. Opioids Derived from the juice of opium poppy, Papaver somniferum First reference to its use in 3 rd century B.C. Contains more than 20 alkaloids Morphine was isolated by Serturner in 1806 Endogenous opioid peptides were identified in early 1970’s Act on GPCR: the µ, κ and δ opioid receptors

19. 19 Opioid receptors Opioid receptors Actions µ (mu) Analgesia, respiratory depression, sedation, euphoria , miosis, reduced g.i. motility, physical dependence Κ (kappa) Analgesia, respiratory depression, dysphoria , hallucinations, miosis, sedation, physical dependence δ (delta) Analgesia, respiratory depression, reinforcing actions, reduced g.i. motility

20. 20 Contd… µ receptors are selectively expressed on GABA neurons and are inhibited inhibition of GABAergic inhibitory neurons disinhibition of dopaminergic neurons Κ receptors are expressed on and inhibit dopamine neurons

21. 21 Analgesia Anaesthesia Acute left ventricular failure Cough Diarrhoea Most commonly abused- morphine, heroin, codeine, meperidine (common among health professionals) Opioids: Therapeutic uses

22. 22 Opioid overdose Accidental, suicidal or seen in drug abusers S/S: respiratory depression, cyanosis, fall in BP and shock, miosis, flaccidity, stupor, coma, death due to respiratory failure Treatment: Respiratory support, maintenance of BP, gastric lavage Specific antidote: Naloxone 0.4-0.8 mg i.v.

23. 23 Opioid withdrawal Withdrawal is associated with marked drug seeking behaviour Physical manifestations include lacrymation, sweating, yawning, anxiety, fear, restlessness, mydriasis, tremor, insomnia, abdominal colic, diarrhoea, rise in BP, palpitation, rapid weight loss Treatment: Substitution therapy with methadone

24. 24 Contd… Clonidine : α 2 agonist acts on presynaptic receptors & inhibit release of NE Naltrexone + Clonidine : naltrexone induces withdrawal which is overcome by clonidine, then naltrexone is used for maintenance Other drugs : Levo alpha acetyl methadol (LAAM) , buprenorphine, propoxyphene, diphenoxylate, lofexidine ( α 2 agonist like clonidine )

25. 25 2. Cannabinoids Obtained from Cannabis indica (marijuana) Various forms in which it is used: Bhang derived from dried leaves, taken orally Ganja derived from dried female inflorescence, smoked Charas resinous extract from flowering tops and leaves, smoked with tobacco (hashish) Most important active principle is Δ 9 tetrahydrocannabinol ( Δ 9 THC)

26. 26 Cannabinoid receptors CB1 receptors in CNS (hippocampus, cerebellum, SN, mesolimbic pathway) and CB2 receptors in peripheral tissues Anandamide is the endocannabinoid synthesized in brain Subjective effects include feeling of relaxation & wellbeing, sharpened sensory awareness Impaired short term memory, motor incoordination, catalepsy, analgesia, antiemesis, increased appetite.

27. 27 Contd… Tolerance and physical dependence is of minor degree Withdrawal symptoms are mild and include nausea, agitation, irritability, confusion, sweating, tachycardia, etc Psychological dependence may be mild to marked No compulsive urge to take the drug Supportive treatment suffice in withdrawal state

28. 28 Cannabinoid potential uses Cancer chemotherapy induced emesis Glaucoma As a bronchodilator As an appetite stimulant As a neuronal protective in head injury Anxiety Migraine Dronabinol is the only FDA approved cannabinoid agonist currently marketed

29. 29 3. Hallucinogens Psychedelics : subjective experience due to heightened sensory awareness that ones mind is being expanded or that one is in unison with mankind or the universe Psychotomimetic : means that the experience mimics the state of psychosis Affect thought, perception and mood Include LSD, psilocybin, mescaline LSD derived from cereal fungus ergot, mescaline from a Mexican cactus and psilocybin from a fungus

30. 30 Contd… Molecular target is 5-HT 2A receptor They increase glutamate release in the cortex Produce shape and color distortion, depersonalization, hallucination, slowing of time perception, sense that colors are heard & sounds are seen Leads to rapid tolerance Their effects are not reinforcing hence they do not act via mesolimbic dopaminergic pathway

31. 31 4. Nicotine and tobacco Apart from nicotine, tobacco smoke contains carcinogenic tar and carbon monoxide and causes disease, responsible for many preventable deaths Acts on nicotinic acetylcholine receptors ( nAChR ) which are expressed on dopaminergic neurons in VTA nAChR are α 4 β 2 containing channels Shut down nicotinic receptors shortly after binding to it hence dopaminergic stimulation stops ( minirush ) Then they again switch back on so that smoker takes the next puff or smokes the next cigarette

32. 32 Contd… Produces mixture of inhibitory and excitatory effects Increased alertness and reduction of anxiety and tension Learning is facilitated Tachycardia, increased BP and reduced G.I. motility Nicotine withdrawal is mild & involves irritability and sleeplessness Highly addictive

33. 33 Harmful effects of smoking Accounts for 10% deaths worldwide & is expected to increase to 17% by 2030, mainly through Cancers (lung, esophagus, pancreas, bladder) Ischaemic heart disease Chronic bronchitis Pregnancy: low birth weight babies, retarded childhood development, increased abortion rates and perinatal mortality, preterm labour, placenta praevia Only point in favor: protects against Parkinson's disease

34. 34 Treatment of nicotine dependence “To cease smoking is the easiest thing I ever did; I've done it a thousand times” – Mark Twain Relapse is common, long term cessation in only 20% Combination of psychological and pharmacological treatment Nicotine replacement therapy: transdermal patch, chewing gum Bupropion Clonidine Nicotinic receptor antagonist: mecamylamine

35. 35 5. Alcohol (ethanol) Acts through several cellular mechanisms Ionotropic receptors: GABA A – enhances GABA mediated inhibition, NMDA (glutaminergic) - inhibition 5-HT 3 - activation Ion channel: Kir3/GIRK Transporter: (equilibrative nucleoside transporter, ENT1, related to adenosine uptake) Not known which target is responsible for DA release Enhances euphoria by acting on opiate and endocannabinoid receptors

36. 36 Alcohol metabolism 95% alcohol is metabolized by alcohol dehydrogenase (ADH), 5% excreted unchanged in urine and breath 85% occur in liver & 15% in stomach, women have 50% less stomach ADH Women are more vulnerable to acute intoxication and chronic effects

37. 37 Acute alcohol intoxication Occurs at blood levels of 150mg/dl Slurred speech, motor incoordination Increased self confidence, euphoria Highly labile mood Aggression Hypotension, gastritis, collapse, respiratory depression, coma, death Treatment is mainly supportive, dextrose infusion, insulin + fructose drip hastens alcohol metabolism

38. 38 Alcohol withdrawal Treatment Supportive, Benzodiazepines- chlordiazepoxide, Propranolol blocks effect of sympathetic overactivity chlormethiazole, carbamazepine are experimental drugs used in some countries Time (hrs) Withdrawal symptoms 6 -12 tremor, nausea, excessive sweating, agitation, anxiety 12-24 visual, auditory and tactile hallucinations 24-48 generalized seizures 48-72 delirium tremens

39. 39 Alcohol addiction: treatment Deterrent agents Disulfiram : inhibits aldehyde dehydrogenase Produces Disulfiram Ethanol reaction Use in the dose of 250-500 mg/day in first week followed by 250 mg/day maintenance dose Should be coupled with psychotherapy Ethanol Acetaldehyde ADH ALDH Acetic acid

40. 40 Contd… Anti-craving agents Naltrexone : interferes with alcohol induced reinforcement by blocking opioid receptors Acamprosate : NMDA receptor antagonist Fluoxetine : used occasionally Others: Topiramate , may provide a unique approach Ondansetron , a 5 HT 3 receptor antagonist reduced alcohol consumption in lab animals & is being tested in humans

41. 41 6. Benzodiazepines Commonly prescribed as anxiolytics & sleep medications They facilitate opening of GABA activated Cl - channels Tolerance is common Produces dependence Withdrawal symptoms are- irritability, insomnia, phono & photophopia, depression, cramps & even seizures Barbiturates were more abused, their prescription has declined after BZDs have come into market

42. 42 7. Phencyclidine and ketamine Were developed as general anesthetics Noncompetitive antagonist at NMDA receptors : decreases calcium flux into the cell and also act on σ opiate receptors which mediate dysphoria Cause intense analgesia, amnesia, delirium, stimulant as well as depressant effects, staggering gait, slurred speech, vertical nystagmus Intoxicating doses can produce catatonia, hallucinations, delusions, paranoia, disorientation & lack of judgement

43. 43 8. Cocaine Alkaloid found in leaves of Erythroxylon coca , a shrub indigenous to Andes Used as local anesthetic Blocks dopamine transporter thereby increasing dopamine concentration in NAc Also blocks NE transporter sympathetic activation increase BP, tachycardia, arrhythmias Tremors, paranoia, irritability, emotional lability Increases risk for I.C. hemorrhage, ischemic stroke, MI, seizures.

44. 44 Contd… Reverse tolerance or sensitization Repeated cocaine users may produce complex adaptation of DA neuronal system so that more and more DA is released The dose of DA which previously only induced euphoria now create an acute paranoid psychosis Mechanism is unclear Till date no specific antagonist is available and treatment of overdose remains supportive Chronic cocaine use can be treated with bromocriptine (DA agonist), amantadine

45. 45 Contd… Route of administration is nasal or intravenous It is highly addictive Withdrawal is mild characterized by craving, agitation, anxiety, fatigue, depression, exhaustion, hyper somnolence, hyperphagia Chronic signs of withdrawal are anhedonia, anergy, decreased drive, lack of ambition, increased craving Use in pregnancy impairs fetal development and produces limb malformations

46. 46 9. Amphetamines Indirectly acting sympathomimetic drugs that cause release of endogenous biogenic amines, DA & NE Exert their effects by reversing the action of biogenic amine transporters at the plasma membrane Clinical effects are very similar to cocaine but euphoria is less intense They are neurotoxic It is smoked, ingested or taken I.V.

47. 47 10. CART peptides Cocaine Amphetamine Regulated Transcript (CART) peptides is a recently identified neurotransmitter system These are released after administration of cocaine and amphetamine May play a role in drug abuse, control of stress and feeding behaviour Potential target for future drug abuse therapies

48. 48 11. Ecstasy (MDMA) Like amphetamine they act by reversing action of transporters & causing release of biogenic amines Affinity for serotonin transporter ( SERT ) Causes profound serotonin release, intracellular depletion can occur for 24 hrs after single dose ? Neurotoxic Acute toxic effects: hyperthermia, dehydration, serotonin syndrome, seizures

49. 49 12. Inhalants Recreational exposure to chemical vapors such as nitrates, ketones and aliphatic and aromatic hydrocarbons Sniffing, huffing, bagging Prevalent in children Leads to euphoria, excitement, dizziness, slurred speech, apathy, impaired judgement, coma, death is due to respiratory depression, arrhythmias or asphyxia No specific treatment, treat underlying psychiatric disorder, if any

50. 50 Principles of treatment Behaviour therapy : aversion therapies like sub threshold electric shock or emetic like apomorphine Psychotherapy Group therapy e.g. alcoholics anonymous, narcotic anonymous Detoxification : Gradual tapering of drug that has caused dependence or sudden withdrawal of drug followed by substitution therapy Specific drug therapy e.g. Disulfiram Correction of nutritional deficiencies Community treatment and rehabilitation

51. 51 Pharmacological approaches Mechanism Examples Substitution, to alleviate withdrawal symptoms Methadone-opiate, BZDs-alcohol Long term substitution Methadone, nicotine patches or chewing gum Blocking response Naltrexone-opiate, mecamylamine-nicotine Aversive therapies Disulfiram Modification of craving Bupropion, clonidine, acamprosate

52. 52 Health problems Among the injection drug users (IDU) worldwide, the prevalence of HIV varies from <5% to >80%, with annual HIV incidence between <1% & 50%. 4 out of 10 people dying with AIDS are IDU HCV prevalence is more consistent with prevalence of 50%-90% & incidence of 10%-30% per year Cardiovascular disease, Stroke, Cancer, Lung disease Hepatitis B, Obesity, Mental disorders Skin complications in IDU

53. 53 Animal models in addiction research Animal models in the field of addiction are considered to be among the best available models of neuropsychiatric disease Drugs of abuse are not only rewarding but also reinforcing , an animal will learn behaviour (e.g. pressing a lever) when paired with drug administration

54. 54 Significance of animal models Can predict abuse potential Factors involved in acquisition, maintenance, extinction, and reinstatement of drug reinforcement can carefully be extracted in laboratory-controlled situations Environmental, behavioral, and neurobiological factors that contribute to individual differences in vulnerability to drug addiction can be explored with animal models

55. 55 Reinstatement model Developed 25 yrs ago Training for 12 days Abstinence for 12 days Environmental cues Direct administration of the drug itself; Exposure to a stressor Lever pressing is reinstated

56. 56 Orange circles : pressing lever delivering cocaine Green circles : pressing lever delivering no drug Animals are first trained to self-administer an addictive drug in response to pressing a lever. The animal then undergoes a period of drug abstinence. Lever pressing can be reinstated using three modalities of stimuli

57. 57 Self administration Intracranial self stimulation Place conditioning

58. 58 Model for physical dependence Morphine i.p. injection in rats starting dose (20mg/kg), increase in dose by 20mg/kg per day till 11 day, maintenance dose till 20 days. Test drug is similarly administered with dose adjustment. On day 11 & 17, nalorphine (10mg/kg) i.p. injection Withdrawal symptoms are recorded during 30-60 min period 10 point score recorded- writhing 3, squealing 2, diarrhoea 2, teeth chattering 1, eyelid ptosis 1, wet dog type shaking 1

59. 59 Current research Active immunization (vaccine) with drug-protein conjugate vaccines has been tested for cocaine, heroin, methamphetamine, and nicotine in animal, with cocaine and nicotine vaccines in Phase II human trials Passive immunization with high affinity monoclonal antibodies has been tested for cocaine, methamphetamine, nicotine, and phencyclidine in preclinical animal models They can be used to treat overdose and to reduce relapse to drug use in addicted patients

60. 60 Contd… Dronabinol phase II clinical trial for treatment of marijuana addiction Dynorphin phase II CT for opiate related disorders and withdrawal Piracetam phase I for cocaine related disorders Modafinil phase II for methamphetamine addiction Ondansetron and topiramate phase II for alcohol abuse Baclofen , a GABA B receptor agonist have shown a significant reduction in craving

61. Thank You!