Pharm 100 - Lesson B.8

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Pharm 100 - Lesson B.8
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Lesson B.8
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  1. Introduction
    Ethanol (ethyl alcohol) is one of the three most used non-medical drugs in Canada, the other twobeing caffeine and tobacco. While alcohol consumption has decreased in the past decade, the health careand social costs remain enormous as alcohol produces more health problems and deaths than all illicitdrugs combined. The major reason for the extensive use and abuse of alcohol is its ready availability andthe permissive attitudes of society, although societal attitudes to abuse of alcohol, at least to drinking anddriving, has undergone substantive changes since 1970.
  2. Historically,
    • Historically, alcohol is an old drug. It was the first sedative-hypnotic drug to be used by ancientphysicians. The use of fermented beverages can be traced back to 8000 B.C., when mead was preparedfrom honey. Traditionally, alcohol has been used for three major purposes.
    • In medicine as a sedative and hypnotic.
    • For religious and other occasions, e.g. sacramental use by Christians and Jews.C Recreational purposes.
    • The terms “alcohol” and “ethanol” are used interchangeably.
  3. Ethanol Content of Alcoholic Beverages
    • The following is a comparison of the alcohol content of different forms of alcoholic drinks.
    • 1 drink = 341 ml (12 oz.) beer (5% v/v) = 43 ml (1.5 oz.) (40% v/v)
    • = 170 ml (6 oz.) wine (10% v/v) = 17 ml absolute ethanol
    • = 13 g absolute ethanol
    • Ten to 13 ml of absolute alcohol is the amount metabolized by the liver each hour
  4. Absorption of Ethanol
    • Ethanol is absorbed rapidly from the stomach and the upper small intestine (the major site ofabsorption). The overall absorption rate for a given dose of ethanol is affected by:
    • (a) Stomach-emptying time, or the time required for the alcohol to reach the small intestine.
    • (b) Ethanol concentration in the G.I. tract.
    • The time from the last drink and the maximal blood alcohol concentration ranges from 30 to 90minutes.
  5. Distribution of Ethanol
    • Ethanol distributes throughout the total body water and readily distributes across the blood-brainbarrier
    • In pregnant women who drink alcoholic beverages, ethanol is readily transferred across the placentaand distributes throughout the total body water of the fetus.
  6. Metabolism and Excretion
    • Over 95% of ethanol in the body is eliminated by biotransformation, primarily in the liver. Theremaining 5% is excreted in the breath, urine and sweat.
    • Aldehyde dehydrogenase (ADH) converts alcohol to acetaldehyde, and in turn aldehydedehydrogenase converts acetaldehyde (ALDH) to acetic acid. Acetic acid is then further metabolized bya number of tissues. Disulfiram and calcium carbimide (drugs used to treat alcohol abuse) inhibitaldehyde dehydrogenase, and as a result, acetaldehyde accumulates and the individual will feel ill andpresumably stop abusing alcohol to stop the adverse effects of acetaldehyde.
    • The metabolism of alcohol is unusual as it occurs at a constant rate, irrespective of the blood alcoholconcentration. A constant amount of alcohol is metabolized each hour. This is because ADH becomesrate-limiting or saturated at 20 mg of alcohol per 100 ml of blood (saturation is a term used when aprocess is running at full capacity). Normally, the body rate of ethanol metabolism is about 120 mgethanol/kg body weight/hour; for a 70 kg person, the rate is 8.4 g ethanol/hour or 10.6 ml ethanol/hour. Normally, with this rate of ethanol metabolism, the blood ethanol concentration decreases at the rate of 15 mg ethanol/100 ml blood/hour.
  7. Pharmacology and Toxicology of Alcohol
    Ethanol is classified as a general central nervous system (CNS) depressant. Acute use of ethanolmore obviously affects the CNS, whereas chronic, high-dose use affects many organ systems of thebody including the CNS, cardiovascular system, gastrointestinal tract and liver. Chronic, maternal useof high-dose ethanol can adversely affect the fetus, including teratogenesis, which can manifest as thefetal alcohol syndrome
  8. Medical Uses of Ethyl Alcohol (Ethanol)
    There are very few medical uses for ethanol. Some of the current uses are: as alcohol spongesapplied topically to treat fever; as skin disinfectant; a low dose is occasionally used as an aperitif toimprove appetite and digestion; and it is an antidote in the treatment of methanol (wood alcohol)poisoning.
  9. Central Nervous System
    • Ethanol produces dose-dependent depression of CNS function:
    • disinhibition ÷ sedation ÷ hypnosis ÷ general anesthesia ÷ coma.
    • Low dose: Disinhibition (inhibition of an inhibitory pathway in the CNS). This is usually manifested by increased social interaction, e.g. talkativeness.
    • High dose: Sedation ÷ hypnosis ÷ general anesthesia ÷ coma ÷ death (respiratory depression).
    • The CNS effects are proportional to the blood ethanol concentration.
    • This is shown in the following table.
  10. graph polus tid bit
  11. Mechanism of Neuronal Action of Alcohol
    The mechanism of action of alcohol is not understood. At high concentrations of alcohol, it wasbelieved that the drug acted as a general anesthetic, that is, depressing all excitable cells in a nonselective manner. This may occur at high alcohol concentrations. At lower alcohol concentrations,alcohol binds to the GABA receptor and augments GABA-mediated neuronal transmission. The readeris reminded that GABA-mediated events are inhibitory and that the barbiturates and the benzodiazepineshave selective binding sites on the GABA receptor (see previous lessons). The interaction of alcoholwith the GABA receptor may explain the reinforcing effects of the drug
  12. Effects of Short-Term Use – Low Dose
    Alcohol is a CNS depressant, but at low dose the response observed is one of disinhibition. Drinkers feel gregarious, jovial, relaxed and more self-confident. A few individuals will feel irritable,depressed or sleepy. A number of perceptual and motor functions are impaired with low to moderatedoses of alcohol. The user thinks they can function better, i.e. drive better. They are more willing to takerisks, even though reflexes and motor skills are impaired
  13. Effects of Short-Term Use – Higher Doses
    As the dose increases, the individual may demonstrate exaggerated emotional responses, e.g. veryeffusive or aggressive. Thinking, memory, judgement, perception and motor skills are severely impaired. If the dose is sufficient, stupor, followed by coma and death can occur.
  14. Adverse Effects of Short-Term Use
    • Blackouts: This is the phenomenon where the drinker does not remember events while under theinfluence of alcohol. They are conscious, but can act in a dangerous manner. Crimes may be committed. These blackouts can be very frightening to many drinkers and may result in them seeking help.
    • Psychiatric effects: Low doses of alcohol (one to three drinks) causes relaxation, while heavydrinking (five drinks or more) often leads to depression, irritability and over-sedation. The negativemood states, in concert with impaired judgement and impulsiveness, may lead to suicide and acts ofviolence.
    • Drinking and driving: Alcohol is one of the major causes of automobile accidents. In Canada,results of a recent survey observed that 43 percent of fatally-injured drivers had consumed alcohol and 35percent were over 0.08%. The same survey found that 20% of drivers reported driving after drinking. The age group at highest risk of drinking and driving is 25 to 45 years. Impairment of driving increasesexponentially as the blood alcohol increases. To put this in perspective, a person who has a bloodalcohol level of 50 mg/100 ml is twice as likely to have an accident as a person who has not taken a drink(0 mg/100 ml blood alcohol level). If a person has a blood alcohol level of 80 mg/100 ml (0.08%), thechances of having an accident are eight times that of the non-drinker.
    • Violence: Individuals who drink heavily are more prone to violence than non-drinkers. Men whoare heavy drinkers are six times more likely to assault their wives/significant others than non-drinkers. This observation is most likely due, at least in part, to the impairment of judgement.
    • The other risks associated with excessive use of alcohol is associated with respiratory depression,coma and death. In addition, a number of comatose drinkers die each year after aspirating their vomit. Contrary to popular belief, alcohol (at all doses) does not enhance sexual performance in men; the exactopposite is true. It has been said that alcohol increases the desire, but reduces the performance.
  15. Adverse Effects of Long-Term Use
    • Central nervous system: There are a number of neurological and mental disorders associated withchronic alcohol abuse. Alcohol damages the axons of the brain, resulting in fewer connections betweenneurons. This causes alcoholic dementia. Dementia can be defined as a global decrease in cognitivefunctioning, affecting memory, judgement, and thinking.
    • Alcohol increases the metabolism of vitamin B1 (thiamine), resulting in thiamine deficiency. Thereare two conditions which result from alcohol-induced thiamine deficiency – Werniche’sencephalopathy in which the patient becomes drowsy, confused and cannot walk properly, andKorsakoff’s psychosis, a severe form of dementia.
    • The peripheral nervous system is also subject to alcohol damage. Alcohol damages the axons inthe peripheral nervous system, resulting in a peripheral neuropathy that is manifested by loss of feeling inthe feet and is often accompanied by burning pain and difficulty in walking.
  16. Ethanol Dependence
    Chronic use of ethanol, especially in high doses, can lead to a state of drug dependence, oftenreferred to as alcoholism. Ethanol drinking is a serious problem when it interferes with home life, job orscholastic performance, finances or personal mental/physical health.
  17. Tolerance to, and Dependence on, Ethanol
    • Tolerance is defined as a state in which repeated administration of the same dose of drug (ethanol)has progressively less effect, or a state in which the dose of drug needs to be increased to obtain the samequantity of effect as was produced by the original dose.
    • During chronic use of ethanol, there is a decreased intensity of ethanol action or a shortenedduration of action. A larger dose of ethanol is needed to produce the original pharmacologic effect. Recently, it has been reported that individuals can develop tolerance more rapidly to theethanol-induced impairment of performance of a task when they perform that task repeatedly under theinfluence of ethanol.
  18. Mechanism:
    • 1. Metabolic (dispositional, pharmacokinetic) tolerance due to increased ethanol metabolic rate. During chronic consumption of ethanol, the same dose produces a lower blood ethanolconcentration or maintains the blood ethanol concentration above a certain level for a shorter time.
    • 2. Cellular (functional, pharmacodynamic) tolerance. The CNS adapts to the effects of ethanol.
    • The consensus is that cellular tolerance plays a greater role in the overall development of tolerance. The extent or rate of development of tolerance depends on the individual, dose of ethanol, and frequencyof ethanol administration.
  19. Cross-tolerance:
    • 1. Occurs between ethanol and sedative-hypnotics such that a higher dose of a sedative-hypnotic drugis required for the desired therapeutic effect.
    • 2. Occurs between ethanol and general anesthetics such that a higher dose of anesthetic agent isrequired for surgical anesthesia.
  20. Physical dependence
    Physical dependence is defined as an abnormal physiologic state brought about by repeatedadministration of a drug that leads to the appearance of a characteristic and specific group of symptomswhen drug administration is stopped or decreased (withdrawal syndrome). The intensity of physicaldependence is judged by the severity of the withdrawal syndrome
  21. Withdrawal
    • The basis of physical dependence on ethanol primarily involves the CNS. Withdrawal fromethanol (CNS depressant) produces excitability of the CNS (arousal, stimulation). Hyperexcitabilityleads to tremors, irritability, restlessness, anxiety, sweating, sleeplessness, agitation, nausea, musculartension, hyperthermia, and increased heart rate. A severe ethanol withdrawal syndrome may involveconvulsions, coma and possibly death.
    • In severe cases of ethanol withdrawal, delirium tremens (DTs) may occur. Delirium tremens ischaracterized by tremulousness, auditory, visual and tactile hallucinations, confusion, psychomotoragitation, disorientation, and sleep disorders.
  22. ethanol withdrawal syndrome can be treated
    The ethanol withdrawal syndrome can be treated effectively by oral administration of diazepam,a benzodiazepine-type sedative-hypnotic drug. The pharmacological basis for this therapy involves theprinciple of cross-dependence, in which the withdrawal syndrome following cessation of use of aparticular drug is suppressed by administration of a second drug of the same or similar pharmacologicalclassification. Following successful withdrawal of the patient from ethanol, the dose of diazepam isdecreased gradually over the course of several days.
  23. Psychological dependence
    • Psychological dependence is defined as a compulsion that requires periodic or continuousadministration of a drug to produce pleasure or to avoid discomfort.
    • There is a compulsive desire to seek, obtain and drink ethanol. The drug-induced effects of relieffrom anxiety, disinhibition and euphoria are perceived as pleasurable and reinforce the use of ethanol. The development of physical dependence helps to reinforce continuous drug administration in order toavoid the withdrawal syndrome. Psychological dependence could be the most powerful factor in chronicuse of ethanol, leading to alcohol-problem-drinking. Recently, naltrexone has been demonstrated to beeffective in the treatment of the psychological dependence on ethanol. Naltrexone diminishes the cravingfor ethanol and assists in the maintenance of abstinence.
  24. Potential for Abuse
    Ethanol can produce pleasurable intoxication and is very effective in reducing tension; thus, it hassignificant reinforcing properties. The dependence liability is moderate. The ease of availability andsocial and legal acceptance contributes to ethanol’s abuse potential.
  25. Effects on the Cardiovascular System
    • Acute use: Low doses of acute use lead to vasodilation (flushing) of the vessels to the skin,resulting in a feeling of warmth. High doses of alcohol can depress the cardiovascular system and lead toalterations in the normal rhythm of the heart.
    • Chronic use: Low chronic doses of alcohol can reduce the risk of coronary heart disease andstroke. High chronic doses can lead to alcoholic cardiomyopathy (destruction of or poor heart muscle). In addition, there is an increased incidence of hypertension and stroke.
  26. Effects on the Gastrointestinal Tract
    Low doses of alcohol will stimulate gastric secretion, and hence the use of a small dose of alcoholbefore a meal to stimulate digestion and enhance appetite. Higher doses of alcohol will irritate the liningof the stomach, causing inflammation and erosion (known as gastritis). This condition causes vomitingand abdominal pain. Ulcers may be aggravated, often leading to a serious gastrointestinal bleed.
  27. Effects on the Liver
    Low doses of alcohol on occasional use does not appear to have significant adverse effects on theliver. Acute high doses of alcohol (alcohol binge) will inhibit glucose production, and in associationwith fasting, can lead to hypoglycemia (low blood sugar).
  28. Chronic high dose
    Chronic high doses of alcohol leads to alcoholic liver disease, a major cause of hospitalization anddeaths in North America. There are three stages to alcoholic liver disease. In stage 1, the liver cellsaccumulate fat, causing the liver to enlarge (fatty liver). This stage is usually asymptomatic and isreversible if the alcohol is stopped. Stage 2 is alcoholic hepatitis. The liver cells are damaged andinflamed. The stage of alcoholic hepatitis can be asymptomatic or there can be severe liver functionimpairment. With abstinence, hepatitis is usually reversible. The liver is one of the few organs whichcan regenerate. The final stage is cirrhosis. This stage is not reversible as the damaged calls have beenreplaced by scar tissue. The scar tissue in the liver can modify the blood flow from the portal vein(drains the blood from the intestine) and the blood backs up into other veins causing distention, andoccasionally these veins rupture and bleed.
  29. Effects on the Embryo/Fetus
    • Epidemiologic and laboratory animal studies have demonstrated that ethanol is a teratogen. Chronic, maternal use of high-dose ethanol throughout pregnancy can produce teratogenic effects in theembryo/fetus, which can manifest postnatally as the Fetal Alcohol Syndrome.
    • Principal features: CNS dysfunction.Pre-natal and post-natal growth deficiency.Cluster of facial abnormalities.
    • Associated features: Variable major and minor malformations of other organ systems (e.g. heart, joints).
    • The effects of chronic or occasional maternal ingestion of one drink of alcoholic beverage per dayon the embryo/fetus are not clearly understood.
    • While the above describes fetal alcohol syndrome (FAS), there is also a condition known as fetalalcohol effects (FAE), where the neonate has some but not all of the features of fetal alcohol syndrome. FAE is five times more common than FAS. The safe dose of alcohol has not been determined andabstinence is recommended
  30. Drugs Used in the Treatment of Alcoholism:Disulfiram and Calcium Carbimide (Calcium Cyanamide)
    • These drugs are used as pharmacological adjuncts to psychotherapy or group therapy, and arereferred to as alcohol-deterrent or alcohol-sensitizing drugs.
    • These drugs inhibit hepatic aldehyde dehydrogenase and result in increased acetaldehydeconcentration if the patient drinks ethanol, thereby producing cardiovascular/respiratory changes that areperceived as aversive.
  31. Alcohol and Drug Interactions
    • 1. Acute ethanol use during drug therapy (body contains ethanol).
    • (a) Ingestion of ethanol and other CNS depressants leads to an additive effect or synergism ofCNS depression.
    • (b) Ethanol inhibits biotransformation (metabolism) of certain drugs (e.g. sedative-hypnotics,phenytoin).
    • 2. Chronic ethanol use followed by drug therapy (no ethanol in body).
    • Ethanol causes proliferation (increase in growth) of the smooth endoplasmic reticulum of the livercell, leading to increased activity of the liver drug-metabolizing enzyme system. There will be increasedbiotransformation of certain drugs (e.g. sedative-hypnotics, phenytoin), if there is no co-existing ethanolinduced liver injury.

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