1. Chapter 4 Alcohol and Inhalants of Abuse

2. Preview We will discus the phamacokinetics and phamacodynamics of alcohol How there is tolerance and cross tolerance of alcohol Why there is a Psychological dependence for chronic users What treatment for alcohol dependance

3. Preview What are inhalants Why are they abused What are the effects of inhalants What are some treatments

4. What is Alcohol? Alcohol is a sedative It’s is primarily used for recreation not medicine 2nd Largest used psychoactive drug in the world (first is caffeine)

5. Alcohol’s chemical composition CH 3 CH 2 OH Yellow – H Black – C Red – O

6. The Phamacokinetics of Alcohol - Absorption Alcohol is both soluble in fat and water This means alcohol is absorbed though the gastrointestinal tract and through the Blood Brain barrier 20% is absorbed through the stomach the other 80% through the upper intestine

7. The Phamacokinetics of Alcohol - Distribution Alcohol easily crosses the Blood-Brain barrier because it is lipid soluble Alcohol can even cross the placental barrier where there can be an occurrence of fetal alcohol syndrome (FAS). FAS occurs in 30% to 50% of all alcoholic mothers

8. The Phamacokinetics of Alcohol – Metabolism and Excrection 95% of all alcohol is digested (metabolized) by an enzyme called alcohol dehydrogenase 85% via the liver 15% via the stomach – a full stomach can metabolize more Alcohol is exposed to first-pass metabolism 5% is excreted via the lungs

9. Metabolism of Alcohol by Men and Women Since men have naturally less fat then woman and bigger blood vesicles, men have a lower Blood Alcohol Concentration (BAC) then woman Also, woman have 50% less enzyme then men, thus the metabolism rate is slower Remember – Alcohol metabolism is zero order

10. Blood ethanol concentrations (mM) Time after ethanol administration (minutes) 10 300 Non-alcoholic Women Alcoholic Men Alcoholic Women Non-alcoholic Men Intravenous Oral

11. How the Liver Metabolizes Alcohol 1. NAD + + Ethanol  NADH + Acetaldehyde Enzyme: Alcohol Dehydrogenase 2. NAD + + Acetaldehyde  NADH + Acetic acid Enzyme: Aldehyde Dehydrogenase 3. Acetic acid  Water + CO 2 Uses ATP ATP  AMP Disulfiram inhibits Aldehyde Dehydrogenase Step 2 is the rate limiting step

12. More on Metabolism BAC is measured in grams of alcohol per liter.08 is the legal limit in New York An average person can metabolize 8 to 10 milliliters of pure alcohol per hour More than that, BAC increases Weight is a big determiner in the concentration of alcohol

13. Phamacodynamics of Alcohol Suppresses Calcium-ion Currents Alterates of cAMP and the Sodium- Pumps Also effects Glutamate systems (excitatory) and GABA Systems (inhibitory) Effects Serotonin and Dopamine Systems

14. Glutamate Receptors Inhibitor of NMDA-subtype of Glutamate Receptors Depresses responsiveness of NMDA receptors Acoamprosate an anti-craving drug to alcohol interacts with NMDA receptors Glutamate Antagonist

15. GABA Receptors Ethanol is a GABA agonist, binds to a subunit of the GABA A receptor It increases Cl- ions thus hyperpolarizing the cell Low doses of alcohol can reduce panic and anxiety

16. Other pharmacodynamic effects Chronic use of Alcohol changes mRNA of the Neuron As a result, Ach, DA, opioid and serotnin systems are effected Abuse potential maybe due to increase in dopamine

17. Pharmacological Effects Alcohol effects many different functions of the brain Alertness, motor functions, and intellectual abilities decrease Combined with other sedatives (benzodiapines), this increase the sedativeness of alcohol

18. Pharmacological Effects – Cont. Alcohol dilates blood vessels, thus releasing more body heat and decreasing blood temp. Large doses of Alcohol increases the risk of heart failure Small Doses decrease the risk of coronary disease Alcohol is a diuretic – it decrease the amount of diuretic hormone thus increasing the excretion of water

19. Psychological Effects Low amounts of Alcohol have minimal Change in behavior <.04 BAC From.04 -.10 BAC, your 4x more likely to get into an accident.12-.18 Likelihood increases to 25x.23-.29 your in a stupor.30 -.33 your in a coma.39 and greater, your dead

20. Psychological Effects – Cont. 50% of all highway crimes and accidents are alcohol related

21. Health Effects Alcohol is highly caloric but has little nutritional value Vitamin and trace element deficiencies are linked to alcohol Liver and stomach cancers

22. Tolerance Metabolic Tolerance – Increase of alcohol digesting enzyme by the liver Behavioral Tolerance – Brain adapts to amount of drug present. A tolerant person can have a BAC 2x the amount of a nontolerant and act the same Environmental – the same environment over time when drinking increases tolerance. Changing the environment decrease tolerance

23. Dependence Many be do to either increase in dopamine and/or the effect of decreased anxiety Withdrawal and alcohol seizures may occur in 10% of people who stop taking alcohol This is due to the neuron producing more glutamate to counteract the effects of increased GABA When GABA leaves, there is an overabundance of glutamate, thus causing a seizure

24. Dependence – Cont. Other effect of withdrawal include hallucinations, psychomotor, agitation, confusion This syndrome is also known as delirium tremens (DT)

25. Side effects and Toxicity Liver damage – 75% of all deaths due to alcoholism are caused by cirrhosis of the liver, the 7 th most common cause of death in the US Other effects are Panreatitis and chronic gastritis causing peptic ulcers

26. Side effects and Toxicity – Cont. The metabolizing of alcohol produces free radicals, causing cancer in the liver and some hypothesis breast cancer also Alcohol has immunosuppressive effects thus promoting tumor growth

27. Teratogenic Effects FAS – Fetal Alcohol Syndrome is accountable for 3 to 5 birth defects in 1000 Causes low intelligence, mental retardation, behavioral abnormalities There is retard body growth Facial Abnormailities

28. Teratogenic Effects – Cont. Adolescents engage in anti-social behavior These people are slow learners Congenital heart defects The point is – drinking is bad if you are pregnant, do not do it.

29. Alcoholism & It’s Pharmacological Treatment 1950s : American Medical Association recognized the syndrome of alcoholism as an “ILLNESS”  1970s : Alcoholism redefined as a “CHRONIC, PROGRESSIVE, AND POTENTIALLY FATAL DISEASE.”

30. Alcoholism & It’s Pharmacological Treatment – Cont. 1992: Alcoholism is characterized by impaired control over drinking, preoccupation w/the drug “alcohol”, use of alcohol despite adverse consequences ( impairments in such areas as physical health, psychological functioning, interpersonal functioning, and occupational functioning, as well as legal financial, and spiritual problems), and distortions in thinking, most notable DENIAL!

31. Alcoholism & It’s Pharmacological Treatment – Cont. Denial is nearly always the major obstacle (integral part) Environmental Factors seem to be less important than Genetic Factors Alcoholism is used as a “self- medication” of psychological distress.

32. Alcoholism & It’s Pharmacological Treatment – Cont. Often times alcoholism is associated with addiction to other drugs, depression, manic-depressive illness, anxiety disorder, or antisocial personality 30-50% meet criteria for major depression

33. Alcoholism & It’s Pharmacological Treatment – Cont. 33% have a coexisting anxiety disorder many have anti-social personalities some are schizophrenic 36% are addicted to other drugs 14 million Americans have serious alcohol problems. 7 million considered Alcoholics 100,000 Americans die each year of alcoholism

34. Pharmacotherapies for Alcoholic Abuse & Dependence: Eliminating the taking of alcohol is an obvious therapeutic strategy Vaillant 60 has proven POOR long-term outlook of alcoholism treatment (both pharmacologic or behavioral)

35. Goals of Pharmacotherapy for Alcohol Dependence & Abuse Reversal of the severe pharmacological effects of alcohol Treatment & prevention of withdrawal symptoms & complications Maintaining abstinence & preventing relapse by : -using agents that decrease craving for alcohol -stop the loss of control over drinking -make it unpleasant to ingest alcohol

36. Goals of Pharmacotherapy for Alcohol Dependence & Abuse – Cont. Treatment of coexisting psychiatric disorders that complicate recovery Note: No agent can reverse the acute pharmacologic effects of alcohol Pharmacotherapies are available for the treatment & prevention of withdrawal symptoms & complications in alcohol- dependent people who are decreasing or discontinuing alcohol

37. Pharmacotherapies for Alcohol Withdrawal Benzodiazepines are the drug of choice for acute alcohol withdrawal -Improve symptoms -Prevent seizures & DTs -Substituting this long-acting drug prevents or suppresses w/drawal symptoms

38. Pharmacotherapies for Alcohol Withdrawal – Cont. -The “longer-acting” benzodiazepine is either: -1. Maintained at a level low enough to allow the person to function -2. Or is withdrawn gradually

39. Drugs to Help Maintain Abstinence Alcohol-sensitizing drugs (including: disulfiram & calcium carbimide) : -Used to prevent the patient from drinking by producing an aversive reaction when consuming alcohol -The drug alters the metabolism of alcohol

40. Drugs to Help Maintain Abstinence – Cont. - Allows acetaldehyde to accumulate which in turn causes acetaldehyde syndrome (characterized by throbbing headache, nausea, vomiting, chest pain ect.)

41. Drugs to Help Maintain Abstinence – Cont. Opioid Antagonist including: Naltrexone, Nalmefene, Acamprosate are used in European Countries Naltrexone: -Used to reduce craving for alcohol -The hypothesis is that the reinforcing properties of alcohol involve the opioid system

42. Drugs to Help Maintain Abstinence – Cont. - The blockade of the system by use of naltrexone should reduce cravings by reducing the positive reinforcement associated w/ alcohol use

43. Drugs to Help Maintain Abstinence – Cont. Dopaminergic drugs: use in maintaining abstinence -Positive reinforcement associated w/ alcohol attractiveness appears to involve the dopaminergic reward system -Withdrawal may be accompanied by hypofunction of this reward system

44. Drugs to Help Maintain Abstinence – Cont. - Depression is often comorbid (<coexisting) w/ alcohol dependency & some dopaminergic drugs have antidepressant results.

45. Drugs to Help Maintain Abstinence – Cont. Serotoninergic Drugs (used to treat alcohol dependence) - Serotonin-specific reuptake inhibitors (SSRIs) (e.g. fluoxetine) : used for treating depression & anxiety. - Serotonin 5-HT1a agonist (e.g. buspirone): used for treating anxiety. Effective in treating comorbid anxiety in alcoholics but less effective at reducing alcohol consumption.

46. Drugs to Help Maintain Abstinence – Cont. -Serotonin 5-HT3 antagonist (e.g. ondansetron) : used for treating nausea.

47. INHALANTS OF ABUSE Inhalant abuse is the intentional inhalation of a volatile substance for the purpose of achieving a euphoric state Consist of chemicals that are volatile at room temperature. Inhaled substances include: Anesthetics (nitrous oxide), Household Solvents (paint thinners), Art & office supplies (markers), Household gas products (propane tanks), Household aerosol propellants (hair spray), Aliphatic nitrites & Organic Solvents (amyl nitrite capsules)

48. Why are inhalants use and who abuses them In rate studies, low concentrations of vapor increased motor activity and self-stimulation in the lateral hypothalamus Increased vapor concentrations suppressed the activation of the brain reward systems & also brought on behavioral depression Peak inhalant abuse age is 14-15 years old Some as young as 6-8 years old

49. Why are inhalants use and who abuses them – Cont. Often injuries are associated with frequent use but there are instances of “Sudden Sniffing Death Syndrome” that can occur to first time users 20% of youths have experienced inhalant abuse by the end of 8 th grade.

50. ACUTE INTOXICATION & CHRONIC EFFECTS Inhaled vapors produce rapid onset of a state of intoxication (similar to alcohol intoxication), sedation with anxiolysis, disinhibition, drowsiness, light- headedness, & euphoria. I ncreased intoxication, the user experiences ataxia (staggering), dizziness, delirium, & disorientation.

51. ACUTE INTOXICATION & CHRONIC EFFECTS – Cont. Severe intoxication,, muscle weakness, lethargy, and signs of light to moderate general anesthesia Hypoxia (lack of oxygen) hallucinations & behavior changes may occur Death usually occurs do to anoxia (lack of oxygen to the brain, cardiac arrhythmias, aspiration of vomitus, or trauma

52. ACUTE INTOXICATION & CHRONIC EFFECTS – Cont. Chronic abuse of solvents can incur serious complications such as: - PNS & CNS dysfunction, liver or kidney failure, dementia, loss of cognitive & other higher functions, gait disturbances, loss of coordination

53. Fetal Solvent Syndrome characterized by prenatal growth retardation (low birth weight, microcephaly), facial dysmorphism, & digital malformations (short phalanges, nail hypoplasia) treatment of ACUTE solvent intoxication is primarily supportive w/ supplemental Oxygen administration CHRONIC solvent abuse is much more difficult