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University of Toronto Scarborough
Suzanne Erb

PSYC62: Drugs and the Brain Lecture 7: Sedative Hypnotics and Anxiolytics  Anxiolytics are a subset of sedative hypnotics.  Alcohol is the most common ? Sedative hypnotics and anxiolytics (General overview)  Share a similar spectrum of effects  In low doses, have a sedative, or calming effect ... tendency to induce at low doses, moderate and excitement activity o Sedative effect at low doses, hypnotic effects at higher doses. Not hypnosis as in altered state of consciousness, but hypnotic in terms of producing sleep  At higher doses, have a hypnotic, or sleep-inducing effect o Hypnotic means producing sleeping  Although anxiolytics, such as minor tranquilizers, are often included as sedative hypnotics, there are many drugs used to treat anxiety disorders that would not be considered in this classification o Many drugs that are used to treat disorders like generalized anxiety disorder, like a class of antidepressants like SSRIs, and they are very selective in that they can reduce anxiety without causing sedative hypnotic effects, and therefore are not included in this classification. Sedative Hypnotics and Anxiolytics  Three major groups (within the sedative hypnotics): 1. Benzodiazepines  Most commonly abused prescription drug medication 2. Barbiturates  Most commonly abused prescription drug medication 3. Alcohol  Alcohol is the most highly abused recreational drug. It is the drug that we will focus on in this lecture  Prototypic drug in terms of characterizing drugs as two-edged swords.  In moderate levels, has benefits, but produces dependence and has bad effects too, especially on the liver, cardiovascular system. Figure 1: Benzodiazepines and Barbiturates  Valium is the gold standard of benzodiazepines  Nembutal is an important anaesthetic Figure 2: Pharmacology of Barbiturates  Pharmacology of benzodiazepines and barbiturates  Act primarily via the GABA system, primary inhibitory NT  They facilitate GABA transmission  Barbiturates act on barb-binding sites to facilitate or enhance the activity at the GABA- A receptor  Another important barbiturates property is that they act as pharmacological antagonists at the glutamate transmitter (primary excitatory transmitter)  Barbiturates facilitates GABA and inhibits GLUT  Benzodiazepines act at the benzo-binding site on the GABA receptor to facilitate GABA ALCOHOL Alcohol  General overview of alcohol’s effects (pharmacological, physiological, and societal factors)  Animal models of alcohol dependence What makes alcohol different from other recreational drugs of abuse?  One would typically not characterize alcohol in the same way as most other recreational drugs (like cocaine, heroin, cannabis) 1. Source o Source distinguishes a lot of drugs from each other, but alcohol has a particularly unique source o The process by which alcohol is produced is quite different 2. Legal; not a regulated drug o Highly abused drug recreationally 3. May have health benefits when taken in moderation o Other drugs, you can't really say that. Although they may serve to ameliorate diseases and disorders, in a healthy state they don't do anything. Alcohol may actually improve health 4. Socially acceptable levels of consumption can lead to adverse consequences o There are socially acceptable levels, which (although they are acceptable), they can lead to adverse consequences o You can take a dose that is acceptable, but it can impair your ability to drive for example o This isn't true with other socially acceptable doses of drugs, like nicotine. o Other drugs are not socially acceptable at all. (1) Source  Alcohol is produced via a natural biological, metabolic process, as opposed to extraction from a plant on synthetic chemical processes in a lab; this makes it quite different from other drugs  Alcohol is drunk in 1 of 3 major classes of alcoholic beverages: beer, wine, hard liquor (distilled spirits).  All of these depend on the process of (A) fermentation, and hard liquor depends on the additional process of (B) distillation A. Fermentation o Fermentation begins when sugar is dissolved in water and then that sugar-water mixture is exposed to air o That exposure to air produces an environment that is ideal for supporting the life of microorganisms called yeast, which multiply rapidly by eating the sugar o They convert the sugar into ethanol and CO2 o As the yeast grows and multiplies, so does the percent ethanol concentration, up to 15% ethanol o Once the concentration reaches this upper limit, the yeast will cease to do its work o This is why fermented beverages like wine and beer are never more than 15% o The kind of beverage that is produced by fermentation depends on the type of substance o Yeast and grape = wine, yeast and grains = beer B. Distillation o Distillation was invented to increase the concentration - used to produce hard liquor o You have to heat the beverage (fermented mixture), and since ethanol has a lower boiling point than water, the steam emitted has a higher ethanol concentration than the initial mixture o Then you condense the steam, heat this mixture again, and condense again, and you get a beverage of higher and higher ethanol concentration o Heating the fermented mixture and the process is based on that alcohol boils at a very lower temperature than water - that vapor is collected and condensed into liquid form and that form has a much higher alcohol concentration - (2) Legal; not a regulated drug  Alcohol is the most widely abused drug in North America  Alcohol is not included here, it is not a controlled substance (Figure 3) o One of the only other examples is nicotine/tobacco, which is also highly abused but not controlled  Some have suggested that the omission of alcohol and tobacco from the control system is important since they are two of the most widely abused drugs  In the case of alcohol, more significantly, the exclusion of alcohol includes the exclusion of wine which is used as a sacrament in many religious rituals o This raises the issue of the religious neutrality of controlled drugs  Since any of these schedule drugs cannot be used non-medically  People believe that alcohol should become a controlled drug, but this means that it would be able to used religiously, which is a strong argument for keeping it off this table  It raises the question of whether or not alcohol should be omitted  Highly unlikely that alcohol will ever find its way onto this table, but it is an important source of debate. Figure 3 (3) May have health benefits when taken in moderation  Although alcohol is associated with many adverse effects (including dependence), like cirrhosis, decrease in reproductive capabilities, it does have benefits if taken in moderation  Other drugs can reduce symptoms of disorders and disease states, but they don't produce health benefits in an already healthy system  A number of studies have produced strong evidence that moderate drinkers are among the healthiest people in society, followed by abstainers and then far behind, heavy drinkers.  This was measured by risk of cardiovascular disease and mortality o health is based on dependent variable o Most common measure is the risk of cardiovascular disease and mortality - are individuals that are taking a moderate amount of alcohol less at risk for cardiovascular disease  This idea of alcohol in moderation may lead to benefits is best illustrated by the French paradox The French Paradox  This paradox refers to the observation by researchers studying the health of people living in France.  Although their diet is high in saturated fats (e.g. cheese), they tended to have less risk of coronary heart disease compared to other populations  If was first identified in a group of people living in Touraine, France  It was noted that they consumed relatively large amounts of wine compared to other populations  This lead to the hypothesis that it was not the saturated fats in the diet that was contributing to the reduced heart disease (obviously), but it was in fact the relatively high level of alcohol consumption.  This lead to research, and the finding that 1-2 four-ounce glasses of wine a day leads to lowered risk of heart disease  Some scientists suggest that this effect is specific to wine, whereas others say it is related to alcohol, regardless of its form  One theory states that moderate alcohol consumption leads to production of HDL (good)and takes away LDL (bad)  More research needs to be done to investigate the reasons why moderate alcohol is good.  Also, defining what is "moderate" and how the mechanism controlling why the consumption of moderate levels effects heart disease risks differs in men and women have to be elucidated (4) Socially acceptable levels of consumption can lead to adverse consequences  We know that socially acceptable levels of consumption that don't lead to over signs of intoxication can have aversive consequences, like impairing your driving, leading to injury/death  At higher levels that may indicate intoxication, but are still considered socially acceptable and don't indicate a drinking problem per say, they can lead to higher levels of assault, vandalism, unprotected sex, suicide  Potentially very adverse outcomes from socially acceptable levels  Even low amounts of alcohol can have very damaging effects on the developing fetus.  By contrast, nicotine (also a socially acceptable drug) does not lead to these adverse effects (e.g. smoking a cigarette and then driving isn't really problematic). A Two-Edge Sword  Since its introduction to society, alcohol has been considered as a two-edge sword: an important role in social occasions, but problems associated with “excess” exposure.  drinking remains part of social rituals  “Everyone enjoys a drink, but no one enjoys a drunk!”  On the one hand, alcohol clearly has a positive connotation, with respective to use by many people, in religious ceremonies, births, marriages, funerals.  On the other hand it clearly has negative social consequences, like problem drinking, which is defined differently by different cultures in different times in history (what is considered "problem drinking" has varied) o The saloon - developed to provide a social function for the frontier people and then devolved into a place for heavy drinkers  The 2 edged sword is also displayed by the ambivalence about alcohol in the public, where alcohol is still used in many situations, but many groups are trying to stop drinking, citing its bad social and health consequences. This ambivalence is modelled by the above quotation. PHARMACOLOGY OF ALCOHOL  Sites of Action: still not very clear how alcohol acts to have its effects, in part, because its effects on the CNS are so diverse o Generally, a CNS depressant  Alcohol is the prototypic depressant in the stimulant-depressant mode of classification on CNS o Exerts effects by dissolving in lipid membranes, disturbing the normal chemical actions that occur there  Alcohol acts to alter the cell membrane's anatomy by entering its internal structure, which results in a decreasing the efficiency of AP conduction along the axon, which in turn, affects NT release  Basically, it makes the neurons "sluggish" o Acts on GABA-benzodiazepine receptors  Acts on these binding sites to facilitate GABA transmission o Acts to enhance serotoninergic and dopaminergic activity  As with other drugs, it's through the DOPA system that it has its primary reinforcing effects o Overall, it is hard to pinpoint a specific effect of alcohol in the nervous system because it effects cell membranes of various systems, even (by extension) Pharmacokinetics: more is known about pharmacokinetic of alcohol  (A)Absorption: o Alcohol is classified as a food; however, it does not need to be digested before the body absorbs it  Any substance that provides calories to the body is considered "food"  Doesn't have to be digested before being absorbed into general circulation  Most alcohol that is consumed passes from stomach to intestines to be absorbed, BUT if alcohol is vaporized, can be absorbed through the lungs into the blood directly. o Factors affecting absorption include stomach contents, rate of consumption, and concentration of alcohol  Lots of factor affect absorption, if there are a lot of things in the stomach when alcohol is consumed, it slows the rate of absorption  The rate of consumption, the more rapidly it's consumed, the more rapidly its absorbed and the more rapidly its effects are felt.  The higher the concentration of alcohol, the more rapidly its absorbed into the circulation  (B) Distribution: o After absorption, the blood distributes alcohol to all of the body’s tissues  Since alcohol is very easily dissolved in water, the proportion of water in a tissue will determine the amount of alcohol that is distributed to that tissue.  Blood has a high water content, so it gets a lot of alcohol  It serves as the perfect transport mechanism to its sites of action for a substance like alcohol o Affects primarily the CNS, especially the brain  Muscle and bone have low water content, so not much alcohol distributed there  Other tissues like the tissues comprising the CNS and brain have high water content, so lots of alcohol reaches the brain  The [ ] of alcohol in the brain readily approximates the [ ] in the blood, because of the brains large blood supply and the fact that alcohol passes directly through the BBB. o Concentrations of alcohol in the body can be estimated based on Blood Alcohol Concentrations (BAC)  BAC - general unit that s considered with respect to alcohol levels in a biological system - expressed as a percentage of the weight of alcohol/100 units of blood (amount of alcohol in blood stream)  E.g. 1 drop of alcohol in a hundred drop of bloo
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