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Drug Interactions and Alcohol

DRUG INTERACTIONS AND ALCOHOL

The term alcohol-drug interaction refers to the possibility that alcohol may alter the intensity of the pharmacological effect of a drug, so that the overall actions of the combination of alcohol plus drug are additive, potentiated, or antagonistic. Such interactions can be divided into two broad categoriesPharmacokinetic and Pharmacodynamic. Pharmacokinetics are concerned with the extent and rate of absorption of the drugs, their distribution within the body, binding to tissues, biotransformation (metabolism), and excretion. Pharmacokinetic interactions refer to the ability of alcohol to alter the plasma and tissue concentration of the drug and/or the drug metabolites, such that the effective concentration of the drug at its target site of action is significantly decreased or increased. Pharmacodynamics are concerned with the biochemical and physiological effects of drugs and their mechanisms of action. Pharmacodynamic interactions refer to the combined actions of alcohol and the drug at the target site of action, for example, binding to enzyme, receptor, carrier, or macromolecules. Pharmacodynamic interactions may occur with or without a pharmacokinetic component. For many drugs acting on the central nervous system that exhibit cross-tolerance (a similar tolerance level) with alcohol, pharmacodynamic interactions with alcohol are especially important.

Most drugs are metabolized in the liver by an enzyme system usually designated as the cytochrome P450 mixed-function oxidase system, and the liver is the principal site of many alcohol-drug pharmacokinetic interactions. Two major factorsblood flow to the liver and the activity of drug-metabolizing enzymesstrongly influence the overall metabolism of drugs. Biotransformation of drugs that are actively metabolized by liver enzymes mainly depends on the rate of delivery of the drug to the liver. These may be flow-limited drugs, where the liver can transform as much drug as it receives, or capacity-limited drugs, which have a low liver-extraction ratiotheir clearance (removal from the blood) primarily depends on the rate of their metabolism by the liver.

There are a number of factors other than the drugs themselves that influence the speed and intensity of alcohol/drug interactions in the human body. These include the patient's sex, weight, age, and race; the presence or absence of food in the stomach; and history of alcohol intake. For example, the levels of alcohol dehydrogenase (ADH), a stomach enzyme that oxidizes alcohol to acetaldehyde, are lower in women than in men; lower in Asians than in Western Caucasians; and lower in alcoholics than in nonalcoholics. Elderly persons are at greater risk of alcohol/drug interactions than younger adults, because they usually take more prescription medications, are more likely to have a serious illness, and show age-related changes in the absorption and clearance of certain medications. With regard to stomach contents, food generally slows the rate of alcohol absorption. Consequently, medications that increase the rate of gastric emptying, such as erythromycin (Eryc, Ilotycin) or cisapride (Propulsid), enhance the rate of alcohol metabolism.

ALCOHOL-DRUG INTERACTIONS

Alcohol-drug interactions are complex. The consequences of using alcohol and drugs together vary with the dosage of the drug; the amount of alcohol consumed; the mode of administering the drug (oral, intravenous, intramuscular, etc.); and the nature of the drug (anticonvulsant, vasodilator, analgesic, etc.). The alcohol may alter the effects of the drug; the drug may change the effects of alcohol; or both may occur.

Alcohol-drug interactions are most important with drugs that have a steep Dose-Response Curve and a small therapeutic ratioso that small quantitative changes at the target site of action lead to significant changes in drug action. In alcoholics, changes in susceptibility to drugs are due to changes in their rates of metabolism (pharmacokinetics) and the adaptive and synergistic effects on their organs, such as the central nervous system (pharmacodynamics). The clinical interactions of alcohol and drugs often appear paradoxical: Sensitivity to many drugs, especially sedatives and tranquilizers, is strikingly increased when alcohol is present at the same time; however, alcoholics, when abstinent, are tolerant to many drugs. These acute and chronic actions of alcohol have been attributed, respectively, to additive and adaptive responses in the central nervous system (pharmacodynamic interactions).

It is now recognized that alcohol can also interact with the cytochrome P450 drug-metabolizing system, binding to P450, being oxidized to acetaldehyde by P450, increasing the content of P450, and inducing (causing an increase in the activity of) a unique isozyme of P450. Inhibition of drug oxidation when alcohol is present at the active site of P450 is due to displacement of the drug by alcohol and competition for metabolism; this increases the half-life and circulating concentration of drugs. Induction of P450 by chronic-alcohol treatment can result in the increased metabolism of drugs, as long as alcohol is not present to compete for oxidation. These pharmacokinetic interactions may contribute to either increased sensitivity or the tolerance observed with alcohol-drug interactions.

Alcohol can affect drug pharmacokinetics by altering drug absorption from the alimentary tract. For example, diazepam (Valium) absorption is enhanced by the effects of alcohol on gastric emptying. Alcohol placed in the stomach at concentrations of 1 percent to 10 percent increases the absorption of pentobarbital, Phenobarbital, and theophylline, whereas drugs such as Disulfiram and Caffeine decrease alcohol absorption by decreasing gastric emptying. Cimetidine (Tagamet)a drug used to treat stomach ulcersincreases blood alcohol concentrations by inhibiting ADH in the stomach and first-pass metabolism of alcohol. Binding of a drug to plasma proteins will change the effective therapeutic level of the drug, because when the drug is linked to the proteins, it is not available to act on the tissue. Alcohol itself and alcohol-induced liver disease cause a decreased synthesis and release of such plasma proteins as albumin. The resulting hypoproteinemia can result in decreased plasma-protein binding of such drugs as quinidine (Quinidex), dapsone (DDS), triamterene (Dyrenium), and fluorescein (Fluorescite). Alcohol may also directly displace drugs from plasma proteins.

The effects of alcohol on blood flow in the liver are controversial, although most recent reports suggest an increase; this could be significant with respect to metabolism of flow-limited drugs. At higher concentrations, alcohol can act as an organic solvent and "fluidize" cellular membranes, which may increase the uptake or diffusion of drugs into the cell.

METABOLISM

Many alcohol-drug interactions occur at the level of actual metabolism. Ethanol (ethyl alcoholcommon in wines and liquors) will compete with such other alcohols as Methanol (methyl alcoholcalled wood alcohol) or ethylene glycol (antifreeze), for oxidation via alcohol dehydrogenase. In fact, treatment against poisoning by methanol or ethylene glycol involves the administration of ethanolas the competitive inhibitoror the addition of inhibitors of alcohol dehydrogenase such as pyrazole or 4-methylpyrazole.

As discussed above, the presence of alcohol will inhibit the oxidation of drugs by cytochrome P450. Alcohol has been shown to inhibit oxidation of such representative drugs as aniline, pentobarbital (Nembutal), benzphetamine (Didrex), benzpyrene, aminopyrine, ethylmorphine, Methadone, meprobamate (Equanil, Miltown), phenytoin (Dilantin), propranolol (Inderal), caffeine, tolbutamide (Orinase), warfarin (Coumadin), phenothiazine, Benzodiazepine, Chlordiazepoxide, amitriptyline (Elavil), chlormethiazole, chlorpromazine (Thorazine), isoniazid (INH), imipramine (Tofranil), dextropropoxyphene, triazolam (Halcion), industrial solvents, and acetaminophen (Tylenol). As this partial list indicates, oxidation of many classes of drugs can be inhibited in the presence of alcohol; these include Hypnotics, Opioids, psychotropic drugs, anticonvulsants, vasodilators, antidiabetics, anticoagulants, Analgesics, and antibacterials. Chronic consumption of alcohol induces the P450 drug-metabolizing system, which could increase oxidation of drugs in sober or abstinent alcoholics. Among the drugs that may be more rapidly metabolized in abstinent alcoholics are ethoxycoumarin, ethylmorphine, aminopyrine, anti-pyrine, pentobarbital, meprobamate, methadone, theophylline (Bronkodyl, Theo-Dur), tolbutamide, propranolol, rifamycin, warfarin, acetaminophen, phenytoin, deoxycline, and ethanol itself. An important consequence of this ability of chronic ethanol intake to increase drug-clearance rates is that the effective therapeutic level of a drug will be different in an abstaining alcoholic than it is in a nondrinker. This metabolic drug tolerance can persist for several days to weeks after alcohol Withdrawal.

PHARMACODYNAMIC IMPLICATIONS

These alcohol-drug pharmacokinetic interactions can have major pharmacodynamic implications. Some examples include the following: The concurrent administration of alcohol plus amitriptyline (Elavil) to healthy volunteers resulted in an increase in the plasma-free concentration of amitriptyline, since the alcohol inhibited drug clearance. Other pharmacodynamic interactions between alcohol and amitriptyline include decreased driving skills (and other psychomotor skills), greater than additive loss of righting reflex, unexpected blackouts, and even death. Laisi et al. (1979) showed that plasma levels of the tranquilizer Diazepam (Valiuman antianxiety drug) were increased in the presence of beer and wine, so the combination of alcohol plus diazepam produced impaired tracking skills, increased nystagmus (nodding off), and impaired oculomotor (eye) coordination, as compared to diazepam alone. Therapeutic doses of the tranquilizers diazepam or chlordiazepoxide (Librium) plus alcohol have been consistently shown to produce impairment of many mental and psychomotor skills; EEG (electroencephalogram) abnormalities could still be detected sixteen hours after administration of fluorazepam in the presence of alcohol to volunteers. Alcohol also decreases the rates of elimination of several benzodiazepines in humans. Phenothiazines and alcohol compete for metabolism by P450, resulting in the decreased clearance of chlorpromazine (Thorazine), for example, and enhanced sedative effects, impaired coordination, and a severe potentially fatal respiratory depression. Alcohol inhibits the metabolism of Barbiturates, prolonging the time and increasing the concentration of these drugs in the bloodstream, so that central nervous system interactions are intensified. In humans, alcohol doubles the half-life of pentobarbital; this is associated with a 10 to 50 percent lower concentration of barbiturate sufficient to cause death by respiratory depression, as compared to the lethal dose in the absence of alcohol. Striking pharmacokinetic and pharmacodynamic interactions occur between alcohol and the hypnotic drug Chloral Hydratethe so-called Mickey Finn or knockout drops. Alcohol inhibition of Morphine metabolism increases morphine accumulation, potentiates central nervous system actions, and increases the probability of death.

OTHER CONSEQUENCES

Pharmacokinetic interactions between alcohol and drugs also have important toxicological and carcinogenic consequences. The metabolism of certain drugs produces reactive metabolites; these are much more toxic than the parent compound. The induction of P450, especially the P4502E1 isozyme by alcohol, results in the increased activation of drugs and Solvents to toxic reactive intermediatessuch as carbon tetrachloride, acetaminophen, benzene, halothane, enflurane, Cocaine, and isoniazid. In a similar manner, procarcinogenssuch as aflatoxins, nitrosamines, and aniline dyesare activated to carcinogenic metabolites after alcohol induction of P4502E1. Since P4202E1 is localized largely in the perivenous zone of the liver cell, the increased activation of these toxins (and alcohol itself) after induction by alcohol may explain the preferential perivenous toxicity of several hepatotoxins, carcinogens, and alcohol itself.

(See also: Complications ; Drug Interaction and the Brain ; Drug Metabolism ; Psychomotor Effects of Alcohol and Drugs )

BIBLIOGRAPHY

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Laisi, U., et al. (1979). Pharmacokinetic and pharmacodynamic interactions of diazepam with different alcoholic beverages. European Journal of Clinical Pharmacology, 16, 263-270.

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Arthur I. Cederbaum

Revised by Rebecca J. Frey

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