Chapter 4

Alcohol and Inhalants of Abuse

Preview

We will discus the phamacokinetics and phamacodynamics of alcoholHow there is tolerance and cross tolerance of alcoholWhy there is a Psychological dependence for chronic usersWhat treatment for alcohol dependance

Preview

What are inhalantsWhy are they abused What are the effects of inhalantsWhat are some treatments

What is Alcohol?

Alcohol is a sedativeIt’s is primarily used for recreation not medicine2nd 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 barrier20% 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 solubleAlcohol 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 liver15% via the stomach – a full stomach can metabolize moreAlcohol is exposed to first-pass metabolism5% is excreted via the lungs

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 womanAlso, woman have 50% less enzyme then men, thus the metabolism rate is slowerRemember – Alcohol metabolism is zero order

Blo

od e

than

ol c

once

ntra

tion

s (m

M)

Time after ethanol administration (minutes)

10

1010

10

300 300

300300

Non-alcoholic Women

Alcoholic Men

Alcoholic Women

Non-alcoholic Men

Intravenous

Oral

How the Liver Metabolizes Alcohol

1. NAD+ + Ethanol NADH + Acetaldehyde Enzyme: Alcohol Dehydrogenase

2. NAD+ + Acetaldehyde NADH + Acetic acid

Enzyme: Aldehyde Dehydrogenase3. Acetic acid Water + CO2

Uses ATP ATP AMPDisulfiram inhibits Aldehyde DehydrogenaseStep 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 YorkAn average person can metabolize 8 to 10 milliliters of pure alcohol per hourMore than that, BAC increasesWeight is a big determiner in the concentration of alcohol

Phamacodynamics of Alcohol

Suppresses Calcium-ion CurrentsAlterates of cAMP and the Sodium-PumpsAlso 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 receptorsAcoamprosate an anti-craving drug to alcohol interacts with NMDA receptorsGlutamate Antagonist

GABA Receptors

Ethanol is a GABA agonist, binds to a subunit of the GABAA receptor

It increases Cl- ions thus hyperpolarizing the cellLow 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 effectedAbuse potential maybe due to increase in dopamine

Pharmacological Effects

Alcohol effects many different functions of the brainAlertness, motor functions, and intellectual abilities decreaseCombined 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 failureSmall Doses decrease the risk of coronary diseaseAlcohol 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 related

Health Effects

Alcohol is highly caloric but has little nutritional valueVitamin and trace element deficiencies are linked to alcoholLiver 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 sameEnvironmental – the same environment over time when drinking increases tolerance. Changing the environment decrease tolerance

DependenceMany 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 GABAWhen 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 alsoAlcohol 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 abnormalitiesThere is retard body growth Facial Abnormailities

Teratogenic Effects – Cont.

Adolescents engage in anti-social behaviorThese people are slow learnersCongenital heart defectsThe 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”     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 personality 30-50% meet criteria for major depression

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

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)

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 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

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

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 use

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

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.

Drugs to Help Maintain Abstinence – Cont.

- Serotonin 5-HT3 antagonist (e.g. ondansetron) : used for treating nausea.

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)

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 oldSome as young as 6-8 years old

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 users20% of youths have experienced inhalant abuse by the end of 8th grade.

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. Increased intoxication, the user experiences ataxia (staggering), dizziness, delirium, & disorientation.

ACUTE INTOXICATION & CHRONIC EFFECTS – Cont.

Severe intoxication, , muscle weakness, lethargy, and signs of light to moderate general anesthesiaHypoxia (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

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

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