Chapter 4
Pharmacology Of AlcoholAssociate Prof. Dr. Jawad Al-Musaw (2016
)
What is Alcohol?
Alcohol is a sedativeIt’s is primarily used for recreation not medicine
2nd Largest used psychoactive drug in the world (first is caffeine)
Alcohol’s chemical composition
CH3 CH2OHYellow – H Black – C Red – O
The Phamacokinetics of Alcohol - Absorption
Alcohol is both soluble in fat and waterThis 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
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
The Phamacokinetics of Alcohol – Metabolism and Excrection
95% of all alcohol is digested (metabolized) by an enzyme called alcohol dehydrogenase85% 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
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 womanAlso, woman have 50% less enzyme then men, thus the metabolism rate is slower
Remember – Alcohol metabolism is zero order
Blood ethanol concentrations (mM)
Time after ethanol administration (minutes)10
10
10
10
300
300
300
300
Non-alcoholic Women
Alcoholic Men
Alcoholic Women
Non-alcoholic Men
Intravenous
Oral
How the Liver Metabolizes Alcohol1. 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
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
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
Glutamate Receptors
Inhibitor of NMDA-subtype of Glutamate ReceptorsDepresses responsiveness of NMDA receptors
Acoamprosate an anti-craving drug to alcohol interacts with NMDA receptors
Glutamate Antagonist
GABA Receptors
Ethanol is a GABA agonist, binds to a subunit of the GABAA receptorIt increases Cl- ions thus hyperpolarizing the cell
Low doses of alcohol can reduce panic and anxiety
Other pharmacodynamic effects
Chronic use of Alcohol changes mRNA of the NeuronAs a result, Ach, DA, opioid and serotnin systems are effected
Abuse potential maybe due to increase in dopamine
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
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
Psychological Effects
Low amounts of Alcohol have minimal Change in behavior < .04 BACFrom .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
Psychological Effects – Cont.
50% of all highway crimes and accidents are alcohol relatedHealth Effects
Alcohol is highly caloric but has little nutritional value
Vitamin and trace element deficiencies are linked to alcohol
Liver and stomach cancers
Tolerance
Metabolic Tolerance – Increase of alcohol digesting enzyme by the liverBehavioral 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
Dependence
Many be do to either increase in dopamine and/or the effect of decreased anxietyWithdrawal 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
Dependence – Cont.
Other effect of withdrawal include hallucinations, psychomotor, agitation, confusionThis syndrome is also known as delirium tremens (DT)
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 USOther effects are Panreatitis and chronic gastritis causing peptic ulcers
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
Teratogenic Effects
FAS – Fetal Alcohol Syndrome is accountable for 3 to 5 birth defects in 1000Causes low intelligence, mental retardation, behavioral abnormalities
There is retard body growth
Facial Abnormailities
Teratogenic Effects – Cont.
Adolescents engage in anti-social behaviorThese people are slow learners
Congenital heart defects
The point is – drinking is bad if you are pregnant, do not do it.
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.”
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!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.
Alcoholism & It’s Pharmacological Treatment – Cont.
Often times alcoholism is associated with addiction to other drugs, depression, manic-depressive illness, anxiety disorder, or antisocial personality30-50% meet criteria for major depression
Alcoholism & It’s Pharmacological Treatment – Cont.
33% have a coexisting anxiety disordermany 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
Pharmacotherapies for Alcoholic Abuse & Dependence:
Eliminating the taking of alcohol is an obvious therapeutic strategyVaillant 60 has proven POOR long-term outlook of alcoholism treatment (both pharmacologic or behavioral)
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
Goals of Pharmacotherapy for Alcohol Dependence & Abuse – Cont.
Treatment of coexisting psychiatric disorders that complicate recoveryNote:
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
Pharmacotherapies for Alcohol Withdrawal
Benzodiazepines are the drug of choice for acute alcohol withdrawalImprove symptoms
Prevent seizures & DTs
Substituting this long-acting drug prevents or suppresses w/drawal symptoms
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
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
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.)Drugs to Help Maintain Abstinence – Cont.
Opioid Antagonist including: Naltrexone, Nalmefene, Acamprosate are used in European CountriesNaltrexone:
Used to reduce craving for alcohol
The hypothesis is that the reinforcing properties of alcohol involve the opioid system
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 useDrugs to Help Maintain Abstinence – Cont.
Dopaminergic drugs: use in maintaining abstinencePositive reinforcement associated w/ alcohol attractiveness appears to involve the dopaminergic reward system
Withdrawal may be accompanied by hypofunction of this reward system
Drugs to Help Maintain Abstinence – Cont.
- Depression is often comorbid (<coexisting) w/ alcohol dependency & some dopaminergic drugs have antidepressant results.
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.