1. Pharmacology Of Alcohol Associate Prof. Dr. Jawad Al-Musaw (2016 )
Chapter 4
Pharmacology Of Alcohol
Associate Prof. Dr. Jawad Al-Musaw (2016 )

2. 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)

3. Alcohol’s chemical composition
CH3 CH2OH
Yellow – H Black – C Red – O

4. 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

5. 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

6. 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

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

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

9. 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 + CO2
Uses ATP ATP  AMP
Disulfiram inhibits Aldehyde Dehydrogenase
Step 2 is the rate limiting step

10. 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

11. 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

12. 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

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

14. 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

15. 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

16. 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

17. Psychological Effects
Low amounts of Alcohol have minimal Change in behavior < .04 BAC
From BAC, your 4x more likely to get into an accident
Likelihood increases to 25x
your in a stupor
your in a coma
.39 and greater, your dead

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

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

20. 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

21. 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

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

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

24. 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

25. 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

26. 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.

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

28. 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!

29. 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.

30. 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

31. 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

32. 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)

33. 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

34. 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

35. 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

36. 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

37. 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

38. 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.)

39. 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

40. 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

41. 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

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

43. 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.

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