Vijay A. Ramchandani, Ph.D.

Indiana University School of Medicine

Alcohol Medical Scholars Program

1. Introduction

S1 The objective of this lecture is to review the pharmacology and neurobiology of alcohol.

S2 B. Outline

1. The first part of the lecture will review the pharmacokinetics of alcohol - aspects of absorption, distribution and metabolism - and highlight the factors contributing to the large variability in alcohol pharmacokinetics.
2. The second part of the lecture will review the pharmacodynamics of alcohol, focusing on the CNS effects, discuss aspects of alcohol tolerance, why alcohol is an addictive substance, and what neurotransmitter systems it affects.

1. Alcohol Pharmacokinetics

S3 A. Absorption

1. volume, type and alcohol concentration of the beverage - less concentrated solutions are absorbed more slowly, however very concentrated solutions can inhibited gastric emptying. Also carbonation can increase the absorption of alcohol
2. rate of drinking - the faster you drink, the faster the absorption
3. food - food has a major effect on alcohol absorption. The amount, timing and type of food all have an effect. For example, high-fat foods can significantly delay the absorption of alcohol. The effect of food on alcohol is primarily due to the delay in gastric emptying seen after meal consumption.
4. gastric metabolism, as well as hepatic first-pass metabolism can significantly decrease the bioavailability of alcohol and thus the amount of alcohol getting into the systemic circulation.

S4 B. Distribution

1. The distribution of alcohol is into total body water.
2. There are gender differences in body composition, with women having a lower proportion of total body water compared to men, even if they have the same weight. Thus, if a woman and a man, who both have the same weight, consume the same amount of alcohol, the woman would achieve higher blood alcohol levels compared to the man.

100. Metabolism

1. In the first step, alcohol is oxidized to acetaldehyde by the enzyme alcohol dehydrogenase or ADH.
2. This enzyme saturates at fairly low blood alcohol concentrations (it has a low Km and follows Michaelis-Menten kinetics). Thus at moderate blood alcohol levels seen after social drinking, it follows apparent zero-order kinetics - this means that the rate of metabolism is at the maximal capacity and has a constant rate of approximately 7-10 grams per hour (equivalent to 1-drink per hour).
3. However, the rate is extremely variable between individuals and even within individuals from day-to-day.

1. Under normal circumstances, acetaldehyde is metabolized very rapidly and usually does not accumulate or interfere with normal functioning. However, when large amounts of alcohol are consumed, accumulation of acetaldehyde may cause symptoms like headache, gastritis, nausea, dizziness, which might contribute to a hangover.
2. This is also the basis for the use of disulfiram in the treatment of alcoholism. It acts by inhibition of aldehyde dehydrogenase resulting in the accumulation of acetaldehyde and the associated symptoms make the drinking episode a very aversive one.

S7 D. Genetic variation in alcohol metabolizing enzymes: ADH

1. One of the main sources of inter-individual variability in alcohol metabolism is the genetic polymorphism in the alcohol metabolizing enzymes.
2. There are 5 functional classes of alcohol dehydrogenase arising from 7 human genes. Polymorphism occurs at the ADH2 and ADH3 loci resulting in different sub-units with different catalytic properties.
3. There are 3 sub-units arising from ADH2 and 2 sub-units arising from ADH3, each with a different prevalence in different ethnic population. For example, ADH2*1 predominates in white and black populations, while ADH2*2 predominates in Asian populations. The ADH2*3 is present in about 15% of black American populations. The isozyme corresponding to this allele has a 25% higher metabolic rate compared to the more common ADH2*1 allele. This ADH2*3 allele and the corresponding higher metabolic rate may have a protective effect against alcohol-related birth defects in pregnant black-American women who drink while pregnant.

S8 E. Genetic variation in alcohol metabolizing enzymes: ALDH

1. Polymorphism also occurs at the aldehyde dehydrogenase resulting in a variant allele - ALDH2*2. Its possessed by 50% of Asian populations (including Chinese, Japanese, Taiwanese, Korean).
2. This results in an isozyme with a decreased elimination of acetaldehyde and consequently a characteristic flushing response to alcohol, along with nausea, headache and other unpleasant experiences in this population.
3. This makes the alcohol very aversive to these individuals and may protect them from becoming alcoholic. In fact, the prevalence of alcohol dependence is almost zero in persons with the ALDH2*2 allele.

S9 F. Gender differences in alcohol pharmacokinetics

1. Differences in distribution of alcohol arise from gender differences in body composition and total body water.
2. Differences in metabolism result in women having higher alcohol elimination rates per kg body weight or lean body mass possibly related to the higher liver volumes per unit lean body mass seen in women, or due to gender differences in alcohol dehydrogenase activity.
3. The effect of the menstrual cycle on alcohol pharmacokinetics has been studied and overall there does not appear to be any effect, although the response to alcohol may be different in women during the different phases of the cycle.
4. Studies on the effect of oral contraceptives on alcohol pharmacokinetics are conflicting - with some studies showing an effect and some not.

G. Summary

1. Alcohol Pharmacodynamics

1. This slide shows the characteristic effects of alcohol at progressively increasing blood alcohol levels. Its important to note that this correlation is based on the acute use of alcohol by a socially-drinking, non-abusing individual.
2. At low BACs corresponding to 1-2 drinks (0.02-0.03%), there is mood elevation and slight muscle relaxation.
3. As BACs increase, there is increased relation, warmth, and increases in reaction time.
4. At around the legal limit of intoxication, there is impairment of balance, speech, vision, hearing and muscle coordination, accompanied by feelings of euphoria.
5. At higher BACs, there is progressive intoxication, impairment and loss of physical and mental control, until levels of 0.04-0.05 where the individual is in a deep coma and at risk of death from respiratory depression.
6. It is important to re-emphasize that this is the scenario in non-dependent individuals. Once chronic use and abuse occurs and tolerance develop, the threshold concentrations at which these effects occur are elevated.

S12 C. Tolerance (definition)

1. Tolerance can be defined as the phenomenon of decreased effect with prolonged exposure to a drug.
2. When the tolerance occurs within the time course of a single exposure to the drug it is called acute tolerance.
3. Chronic tolerance occurs over repeated uses of the drug.
4. Tolerance can be metabolic (or pharmacokinetic) - due to induction of enzymes - for example, barbiturates.
5. Tolerance can also be pharmacodynamic - due to physiological adaptation of the body to the presence of the drug - for example, most drugs of abuse.

S13 D. Tolerance (significance)

1. Tolerance is important because it is one of the primary determinants of increased alcohol drinking. When one becomes tolerant, they can no longer feel the effects of the drug, or feel a decreased effect at a given dose and this makes them increase their consumption - this can lead to the development or worsening of alcohol dependence problems.
2. Moreover, the large doses consumed can be toxic to the body and lead to organic complications like cirrhosis etc.
3. Tolerance is one of the diagnostic criteria for alcoholism per the DSM-IV (1).
4. Tolerance to alcohol also makes the individual cross-tolerant to other CNS depressant drugs like barbiturates and benzodiazepines.
5. There are genetic determinants of tolerance that might be related to the genetic risk of developing alcohol dependence.
6. Also, there are studies that show that individuals who have a low response to alcohol early in their drinking careers, which could be due to the development of tolerance, are at a greater risk for developing alcoholism later in life.

1. Alcohol Neuropharmacology and Reinforcement

1. A reinforcer in this context can be defined as a substance whose pharmacological effects are rewarding so that it drives the user to continue to use it - in other words, the effect reinforces the use of the drug.
2. In most cases the reward is positive - such as the pleasurable, euphoric effects of drugs, or the altered consciousness following the drug, or to conform to the behavior of peers.
3. If the pharmacological effect reverses an aversive state, it is called negative reinforcement - such as the relief of stress and negative emotions or the relief of withdrawal.

S15 B. Alcohol as a Reinforcer

1. There has been considerable research into understanding the neural circuits involved in reinforcement, especially regarding the dopamine (DA) system. The DA system originates in the ventral tegmental area (VTA) and connects to the nucleus accumbens, prefrontal cortex as well as hippocampus. This is the mesocorticolimbic system.
2. Activation of the VTA results in the release of DA in the nucleus accumbens and limbic system and the prefrontal cortex. This is associated with rewarding/reinforcing effects, not only for alcohol but for almost all abused drugs.

1. Animal models of alcohol preference. These are animals that have been bred for their preference to alcohol, and these animals consume large amounts of alcohol preferentially, and show innate differences in their limbic structures and neurotransmitter function compared to control animals or those that do not prefer to drink alcohol.
2. Animal models of self-administration. These are animals that have been trained to chronically self-administer alcohol. These animals show differences in neurotransmitter levels in their mesolimbic system. Also animals with cannulae directly inserted into the VTA will bar-press repeatedly for intra-cranial injections of alcohol directly into the VTA.

1. excitatory NMDA systems (red)
2. inhibitory GABA neurons (green)
3. opioid neurons and receptors (blue)

1. The effect of alcohol on the DA system is not directly with the DA receptors, but rather indirectly by increasing DA levels in the mesocorticolimbic system. This increase is associated with the reinforcing and rewarding effects of alcohol.
2. The interaction of alcohol with the opioid system is also indirect and results in activation of the opioid system. This is associated with reinforcing effects (probably via mu-receptors) and aversive effects (probably via kappa receptors). The opioid system is also involved in the craving for alcohol, and opioid antagonists, such as naloxone and naltrexone block the rewarding effects and craving for alcohol.

1. Alcohol's effect on the NMDA system has also been studied. Alcohol inhibits the NMDA receptor, not by direct interaction with the glutamate binding site, but rather by modifying the way glutamate binds to its site on the receptor complex (allosteric effect). This interaction is thought to mediate the sedative/hypnotic effects of alcohol, as well as neuroadaptation. The NMDA system is also important in withdrawal.
2. The serotonin system is also thought to play a role in the pharmacology of alcohol. The mechanism for this is unknown, but thought to modulate DA release. What is known is that increasing serotonin levels at the synapse decreases alcohol intake. These data are mostly obtained in animal studies and need further investigation.
3. Acute alcohol is also known to affect the hypothalamic-pituitary axis, possibly involving the hormone CRF (corticotrophin releasing factor). This action probably underlies the stress-reducing effects of alcohol.

S21 D. Summary

1. Conclusions

1. Disulfiram (Antabuse) is an inhibitor of aldehyde dehydrogenase, and when taken with alcohol results in the build-up of acetaldehyde levels leading to nausea, dizziness, headache and flushing, making the entire drinking experience very aversive, and thus decreasing the desire to drink.
2. Naltrexone (Revia) is approved for the treatment of alcoholism. It is an opioid antagonist originally developed for treatment of opioid addictions. It has been shown to be useful in decreasing craving for alcohol, which is associated by its ability to block opioid function, as well as in decreasing the rate of relapse compared to placebo.
3. Acamprosate is a drug, currently used in Europe, awaiting FDA approval in the US. It acts by stimulating the GABA inhibitory system and antagonizing the glutamate excitatory system, thus decreasing drinking.
4. Benzodiazepines are used primarily in the treatment of the hyperexcitability, including convulsions and hallucinations, during withdrawal.
5. SSRIs or selective serotonin re-uptake inhibitors: the animal data have shown that increased serotonin availability in the brain decreased alcohol intake. This led to several studies looking at these SSRIs in treating alcoholism, as they block serotonin re-uptake, thus increasing serotonin levels, at the synapse. However the studies have only shown modest efficacy with the best responses seen in patients who may have co-morbid depression.