L13 Alcohol PDF - Alcohol Pharmacology

Alcohol Objectives Describe alcohol and discuss how it is made Describe the pharmacokinetics of alcohol bioavailability List the behavioral effects at different blood alcohol concentrations Describe the metabolism of alcohol Describe the pharmacodynamics and mechanism o...

Alcohol Objectives Describe alcohol and discuss how it is made Describe the pharmacokinetics of alcohol bioavailability List the behavioral effects at different blood alcohol concentrations Describe the metabolism of alcohol Describe the pharmacodynamics and mechanism of action for alcohol Describe alcohol-induced brain damage Describe tolerance development (effects of chronic alcohol use) Describe the features of fetal alcohol syndrome Discuss the causes and treatments for Alcohol Use Disorder  What is an alcohol? Methanol (Methyl Alcohol) Ethanol (Ethyl Alcohol) Isopropanol (Isopropyl Alcohol) CH3CH2OH Ethyl alcohol, or OH ethanol, is the alcohol CH3OH form in drinks; other CH3CHCH3 types of alcohol are toxic  How is it made? Yeasts break down sugar and produce carbon dioxide, ethanol, and heat Alcohol has calories but no nutritional value chronic heavy drinkers may suffer malnutrition. The pharmacokinetics of alcohol determines its bioavailability Ethanol is a small molecule that can’t be ionized (mixes readily with water) not very lipid soluble Easily absorbed from the GI tract; diffuses throughout the body, entering most tissues, including the brain Behavioral effects are described according to blood alcohol concentration (BAC) rather than amount ingested https://www.getsobars.com/pages/food-drink-101 Blood alcohol concentration (BAC) Many factors influence blood levels of ethanol, so behavioral effects are described on the basis of blood alcohol concentration (BAC) rather than the amount ingested A 12-oz can of beer, one 5- oz glass of wine, a cocktail with 1.5 oz of spirits, or a 12-oz wine cooler will each raise your BAC by the same amount Blood Alcohol Concentration Alcohol: Pharmacokinetics FIGURE 10.4 Blood levels of alcohol after oral administration FIGURE 10.5 Metabolism of About 95% of ingested alcohol is metabolized by the liver at a constant rate (1 to 1.5 ounces/hour); about 5% is excreted by alcohol (Part 1) the lungs—which can be measured with a Breathalyzer. Alcohol is oxidized by alcohol dehydrogenase and aldehyde dehydrogenase (ALDH) FIGURE 10.5 Metabolism of alcohol (Part 2) Three possible genetic variations of ALDH are responsible for large individual differences in response to alcohol. Pharmacodynamics of Alcohol Ethanol (alcohol) is a “dirty drug” – varied mechanisms Alters membrane fluidity, affects ion channels GABA GABAA agonist Glutamate CNS depressant effects Antagonist (post-synaptic) Reduces release of Glutamate (pre-synaptic) Dopamine Increased transmission of DA in limbic system Opioid Rewarding effects Increase in endogenous opioid synthesis and release  Alcohol: Pharmacodynamics: mechanisms of action Antagonist at excitatory synapses Glutamate: acute alcohol reduces its effect on NMDA receptors; reduces glutamate release in many brain areas; repeated use results in up- regulation of NMDA receptors During withdrawal, glutamate release increases, correlated with CNS hyperexcitability and seizures; excessive Ca2+ influx contributes to cell death. Frequently experienced withdrawal may be responsible for some irreversible brain damage. Alcohol - mechanisms of action Agonist at inhibitory synapses GABA: alcohol stimulates GABA release Some receptors respond to low doses of alcohol; may have a role in reinforcing effects. Repeated exposure to ethanol reduces GABA function- may contribute to tolerance and withdrawal Alcohol - mechanisms of action Ethanol increases dopamine release in the NAc by inhibiting GABA neurons in the VTA -Responsible for the reinforcing effects of alcohol  Alcohol - mechanisms of action Opioid systems: enhances release from the pituitary gland endorphins contribute to the reinforcing effects of alcohol; Blocking opioid receptors reduces alcohol self-administration. μ-opioid receptor knockout mice fail to self- administer ethanol. High levels of μ-opioid receptors correlate with scores on craving Chronic alcohol use reduces endogenous opioids available for release FIGURE 10.18 Dopamine turnover and alcohol withdrawal (Part 1) In rodents, withdrawal after chronic alcohol use reduces firing rate of mesolimbic neurons and decreases DA release in the Nacc Brain areas affected by alcohol Prefrontal cortex: judgment, decision- making, motivation (glutamate, GABA, dopamine) Amygdala: stress responses, emotional responses Hypothalamus & pituitary: Changes in sexual desire and performance Temperature regulation Stages in the development of Alcohol Use Disorder Alcohol- related cues STRESS Family history Genes Environment Sex Underlying Changes in brain vulnerability function Chronic alcohol use leads to physical dependence Physical dependence: intensity and duration of withdrawal is dependent on amount and duration of drug taking Alcohol shows cross-dependence with other drugs in the sedative- hypnotic class Hangover may be evidence of withdrawal or a sign of acute toxicity Withdrawal symptoms include tremor, anxiety, high blood pressure, rapid heart rate, sweating, rapid breathing, nausea, vomiting; some people experience delirium tremens, or DTs Tolerance to alcohol in a single exposure; effects are greater while blood level is rising and smaller while blood level is falling; may lead to driving while intoxicated  Physical dependence Alcoholism Metabolic tolerance The blue line represents blood levels before a 7-day period of drinking; the red line - after 7 days of drinking  Physical dependence Alcoholism Withdrawal symptoms: Metabolic tolerance Tremor (“the shakes”) Anxiety High blood pressure Rapid heart rate Sweating Rapid breathing Nausea and vomiting Severe withdrawal = delirium tremens (“DTs”) Convulsions, unstable blood pressure Hallucinations, disorientation The blue line represents blood levels before a Panic attacks 7-day period of drinking; the red line - after 7 days of drinking video Effects of long-term heavy alcohol use: brain damage Causes: Direct damage from the alcohol itself Elevated acetaldehyde Insufficient liver function Inadequate nutrition Especially thiamine (vitamin B1), which is critical for brain glucose metabolism Causes neuron death  Effects of long-term heavy alcohol use: Korsakoff’s syndrome Progressive permanent loss of memory function Often accompanied by confabulation Anterograde amnesia: inability to form new memories Retrograde amnesia: inability to retrieve old memories Usually worse for more recently formed memories Caused by damage to the thalamus from chronic vitamin B1 deficiency Thiamine treatment can stop the degeneration, but not reverse it Video: Dr. House Effects of long-term heavy alcohol use: liver disease Fatty liver – triglycerides accumulate in Portions of a healthy liver (left), liver cells a fatty liver (center), and a Alcohol is metabolized first, leaving fats for cirrhotic liver (right) storage Alcoholic hepatitis – liver cell damage caused by accumulation of acetaldehyde Alcoholic cirrhosis – death of liver cells stimulates scar formation Eventually blood supply is cut off Coffee has been shown to help fight liver disease, including cirrhosis Although mixing caffeine and alcohol can have other dangerous effects Caffeine can mask the depressant effects of alcohol and promote more risky behaviors Effects of long-term heavy alcohol use: Fetal alcohol syndrome Alcohol readily passes through the placental barrier and the fetus quickly reaches the same BAC as the mother. Fetal alcohol syndrome (FAS) refers to the damaging developmental effects of prenatal alcohol exposure. FAS symptoms include: (A) Distinctive craniofacial malformations in a child with FAS. (B) Fetal abnormalities in mice exposed to 1. Intellectual disability and cognitive/behavioral alcohol in utero. developmental delays 2. Low birthweight; failure to thrive and grow 3. Distinctive craniofacial malformations 4. Other physical abnormalities—cardiac defects, failure of kidney development, undescended testes, and skeletal abnormalities in fingers and toes  Treatment of Alcohol Use Disorder Detoxification: withdrawal symptoms are strong motivators and can be dangerous. BZDs such as chlordiazepoxide (Librium) or diazepam (Valium) prevent symptoms Psychosocial rehabilitation programs Individual and group therapy Residential alcohol-free treatment settings Self-help groups such as Alcoholics Anonymous (AA) Community reinforcement approach (CRA) Cognitive behavior therapy  Treatment of Alcohol Use Disorder Pharmacotherapeutic treatment of alcoholism includes two strategies: 1. Reducing withdrawal symptoms (negative reinforcement) Use alternative GABAA agonists, including benzodiazepines such as diazepam (Valium) Often used in conjunction with “detox” programs 2. Reducing positive reinforcement for longer term maintenance Generally used in conjunction with psychosocial rehabilitation programs Individual and/or group therapy Self-help groups such as Alcoholics Anonymous (AA) - video  Treatment of Alcoholism: Reducing positive reinforcement Disulfiram (Antabuse) inhibits ALDH (converts acetaldehyde to acetic acid in the normal metabolism of alcohol) Drinking even 1 oz of alcohol results in flushing, pounding heart, nausea, vomiting, etc. Naltrexone (Vivitrol) is an opioid receptor antagonist; it reduces alcohol consumption and craving and improves abstinence rates It is assumed that naltrexone reduces the positive feelings and subjective “high” by blocking the effects of alcohol-induced endorphin release Best used in conjunction with AA or other supportive therapy Best used in conjunction with AA or other supportive therapy  Multiple treatment options provide hope for rehabilitation Possible new treatments: CRF1 antagonists: repeated episodes of intoxication and withdrawal lead to increased CRF1 receptors in the amygdala, sensitization of the reactivity to stressors, and significantly elevated rates of alcohol consumption. Glucocorticoid receptor (GR) antagonist: reduced alcohol self-administration and craving Ketamine: NMDA glutamate receptor antagonist: could reverse the hyperexcitable state in withdrawal FIGURE 10.25 Glucocorticoid receptor (GR) antagonism reduced alcohol-cued craving and drinking in dependent individuals END: Next time- Exam review