Sedative drugs of abuse

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Alcohol, the barbiturates and the benzodiazepines are included in this group, all of which facilitate GABAergic activity.

Alcohol

The use of alcohol (ethanol) prepared from the fermentation of sugars, starches and other carbohydrates dates back to the beginning of recorded history. Alcohol is the most important drug of dependence in all industrialized countries, and the clinical and social problems that arise from its widespread abuse are legion. In the US, the total annual economic cost of alcoholism and its related disorders has been estimated to be approximately $80 billion, and this does not take into account the human cost, which is impossible to quantify. It has been calculated that the lifetime prevalence of alcohol abuse and alcohol dependence (alcoholism) in the United States is 5-10% for men and 3-5% for women.

The American Psychiatric Association (1994) defines ''alcohol abuse'' as a condition whereby social life is impaired for at least one month as a result of alcohol. ''Alcoholism'' is defined as the occurrence of tolerance and physical dependence that results from prolonged alcohol abuse.

It has been calculated that alcoholism now rivals heart disease and cancer as the major health problem in industrialized countries, with 9% of men and 5% of women currently at risk. In lifetime prevalence rates, alcoholism now ranks first of all psychiatric disorders. However, it is not yet possible to identify any biological, psychological, social or cultural variable which is predictive of alcohol abuse or alcoholism.

There is some epidemiological evidence to show that there is a family predisposition to alcoholism. The incidence of the illness is four times greater in the offspring of alcoholics, and the rate among identical twins is greater than among non-identical twins. There are many animal studies which also show that some inbred strains have an increased sensitivity to the effects of alcohol and have a greater alcohol intake when given a free choice. From the numerous animal and human studies it has been concluded that alcoholism is a polygenic and multifactorial problem in which genetic factors contribute to the risk of developing the illness.

Recent epidemiological evidence shows that very moderate alcohol consumption, amounting to under three units per day for men and two units for women (one unit being equivalent to about 0.25 litres of beer, one glass of wine or spirits), may protect against myocardial infarction. However, regular consumption of alcohol above 21 units per week for men and 14 units for women predisposes to brain, liver, heart and gastrointestinal tract malfunction. Additional health problems arise as a consequence of the multiple drug abuse which many alcoholics exhibit, particularly of tobacco, minor tranquillizers, sedatives and caffeine.

Criteria for the diagnosis of drug or alcohol dependence are shown in Table 15.2.

Pharmacokinetics

Alcohol is readily absorbed from an empty gastrointestinal tract; the rate of absorption is impeded by food. It is widely distributed throughout the body according to the water content of the tissue, easily penetrating both the blood-brain and placental barriers. More than 90% of the drug is oxidized in the liver to carbon dioxide and water by dehydrogenases, while the remainder is excreted unchanged through the lungs, skin and kidneys. The rate of oxidation is dependent on the degree of tolerance of the individual, the non-tolerant person oxidizing approximately 10-15 ml of absolute

Table 15.2. Criteria for diagnosis of drug or alcohol dependence

Any three of the following are sufficient for the diagnosis.

1. The substance is often taken in larger amounts or over a longer period than the person intended.

2. Persistent desire or one or more unsuccessful efforts to cut down or control substance use.

3. A great deal of time spent in activities necessary to get the substance, taking the substance, or recovering from its effects.

4. Frequent intoxication or withdrawal symptoms when expected to fulfil major role obligations at work, school, or home, or when substance use is physically hazardous.

5. Important social, occupational, or recreational activities given up or reduced because of substance use.

6. Continued substance use despite knowledge of having a persistent or recurrent social, psychological, or physical problem that is caused or exacerbated by the use of the substance.

7. Marked tolerance, i.e. the need for markedly increased amounts of the substance to achieve intoxication or a desired effect, or markedly diminished effect with continued use of the same amount of substance.

8. Characteristic withdrawal symptoms, depending on the individual drug, upon stopping its use.

9. Substance often taken to relieve or avoid withdrawal symptoms.

alcohol per hour. The alcohol metabolizing system is thus easily saturated, and its elimination is governed by "zero-order" kinetics (see Chapter 2).

The daily intake of one or two units of alcohol rapidly leads to tissue tolerance, which is not as extensive as that observed after the administration of any of the opiates and is readily lost after a few days of abstinence.

Psychological tolerance to alcohol develops at a faster rate than metabolic tolerance. Thus death from alcohol overdose can occur in a psychologically tolerant person following only a moderate increase in alcohol intake above that normally consumed.

A "reverse tolerance'' has also been described, whereby an alcoholic taking a small quantity of alcohol may become intoxicated, aggressive, and antisocial. This occurs in those who have brain or liver damage and therefore show an enhanced sensitivity to the disinhibiting actions of the drug or a decreased metabolism.

Cross-tolerance also readily occurs between alcohol and other central depressants, for example the benzodiazepines and the barbiturates.

Mode of action

Meyer, in 1901, was the first to suggest that alcohol acted like general anaesthetics by dissolving into cell membranes and thereby disrupting the lipid network that comprises the cell wall. It is now known that, at pharmacologically relevant concentrations (in the range 25-100 mmol/L), alcohol increases the fluidity of cell membranes following its acute administration, these changes correlating with the sedative effects of the drug. This suggests that alcohol produces its effects in a relatively nonspecific manner, but it is now known that the nerve membrane is structurally and functionally heterogeneous and that specific regions of the membrane are more sensitive to the disordering effects of the drug than other regions. Thus alcohol may affect the calcium flux across the nerve membrane or, by disrupting the phosphatidyl inositol system intracellu-larly, affect the intraneuronal availability of calcium. This could have a profound effect upon neurotransmitter release.

While there is little evidence to suggest that alcohol produces its pharmacological effect via a specific ''alcohol receptor'', some lipids do show a particular vulnerability to the disorganizing effects of the drug. For example, alcohol selectively inhibits monoamine oxidase-B, and not the A form, in human platelets and brain; similarly, it inhibits sodium/ potassium-dependent adenosine triphosphatase in the neuronal membrane but not in the glial membrane.

With regard to its effect on neurotransmitter function, alcohol increases adenylate cyclase activity, possibly via the membrane-bound G protein complex. The effect of alcohol on the secondary messenger system appears to depend on its location; the noradrenaline-linked cyclase in the cortex seems to be directly affected by the drug, whereas the dopamine-linked enzyme in the basal ganglia appears to be altered by a combination of changes in the membrane fluidity, together with those in the G protein-cyclase complex.

As alcohol has pronounced sedative properties, it is not surprising to find that it facilitates central inhibitory transmission. It has been shown that alcohol has a direct effect on a portion of the GABA-benzodiazepine complex that controls the chloride ion channel. In clinical studies it has been shown that such inhibitory effects may be reversed by some partial inverse benzodiazepine receptor agonists, but their development as therapeutic agents has been discontinued because they do not reverse other detrimental effects of alcohol on brain function (see Figure 15.1).

Alcohol tolerance has been explained in terms of the adaptational changes in lipids in the nerve membranes. Thus acute alcohol administration is associated with enhanced membrane fluidity due to the disordering effects of the drug, whereas after chronic administration the membranes become more rigid owing to an increased replacement of the unsaturated by saturated fatty acids. Nevertheless, it seems unlikely that such changes are due to a single type of lipid and more likely that different populations of lipids within the nerve membrane show adaptational changes at different rates.

Another approach that has been used to elucidate the biochemical mechanisms associated with tolerance in animals has been to use specific

NMDA r«eptor inhibition of/ excitatory glutamate neurotransmission disruption of Caï-flow through voltage operation channels

NMDA r«eptor inhibition of/ excitatory glutamate neurotransmission disruption of Caï-flow through voltage operation channels

GAB Ai recap Lur nerve te I budy reduced electrical activity

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