DRUG INTERACTION AND THE BRAIN

When two or more drugs are taken at the same time complex interactions may occur. Drugs can interact to change biological functions within the body through Pharmacokinetic or Pharmacodynamic mechanisms or through their combined toxic effects. Changes in the pharmacokinetic properties of a drug can include changes in absorption, distribution, metabolism, and excretion of the drug, and each of these can affect blood and plasma concentrations and, ultimately, brain levels of the drug. Although a change in the speed at which a drug reaches the bloodstream is rarely clinically relevant, a change in the amount of drug absorbed can be important, because this can lead to changes in the plasma levels of the drug, which can influence the amount of drug that reaches the brain.

The distribution of a drug throughout the body can be affected by changes in the binding of the drug to proteins in the bloodstream or by displacing the drug from tissue binding sites, both of which can affect the plasma concentration of the drug and potentially affect the amount of drug that reaches the brain. Drug metabolism can be either stimulated or inhibited, resulting in decreased or increased plasma concentrations of the drug, respectively. The stimulation (induction) of drug-metabolizing enzymes in the liver can be produced by drugs such as the Barbiturates, but a week or more is often required before maximal effects on drug metabolism are observed. As drug metabolism increases, the amount of drug available to enter the brain decreases.

The inhibition of drug metabolism often occurs much more rapidly than the stimulation, usually as soon as a sufficient concentration of the metabolic inhibitor is achieved, which results in increased plasma and brain concentrations of the drug. The renal (kidney) excretion of drugs that are weak acids or weak bases can be influenced by drugs that alter urinary pH to change the reabsorption of the drug from urine into the kidney. The active secretion of the drug into the urine can also be affected. Both processes can ultimately affect the plasma and subsequent brain concentrations of the drug. Pharmacodynamic mechanisms can either enhance or reduce the response of a given drug. For example, if two drugs are agonists for the same receptor site—Diazepam (Valium) and Chlordiazepoxide (Librium) for Benzodiazepine receptor-binding sites—then an additive biological response is likely to occur unless a maximum response is already present. If, however, an Agonist competes with an Antagonist for the same binding site (e.g., see Morphine and Naloxone in Opioids, discussed below), then a decreased biological response is likely.

Enhanced or diminished biological responses can be observed even if the drugs do not interact with the same receptor-binding sites. In this case, the net effect is the sum of the pharmacological properties of the drugs. For example, if two drugs share a similar biological response (e.g., central nervous system depression) even though they produce their effects at different sites, then the concurrent ingestion of both drugs can result in an enhanced depression of the central nervous system (see the Alcohol [ethanol] and Valium discussion below). Finally, the concurrent ingestion of two or more drugs, each with toxic effects on the same organ system, can increase the chance for extensive organ damage.

DEPRESSANTS

Alcohol (Ethanol) and Valium.

Reactions that are additive (combined) or synergistic (cooperative effects greater than the sum of the independent effects of the drugs taken alone) are common side effects that result from the consumption of two or more drugs with similar pharmacological properties. For example, although alcohol (ethanol) is considered by many to be a stimulant drug because, typically, it releases an individual's latent behavioral inhibitions (i.e., it produces disinhibition), alcohol actually produces a powerful depression of the central nervous system similar to that seen with general anesthetics. The subsequent impairment of muscular coordination and judgment associated with alcohol intoxication can be enhanced by the concurrent administration of other central nervous system depressants. Often, Valium or Librium (benzodiazepines that are considered relatively safe drugs) may be purposely ingested along with ethanol in an attempt to "feel drunk" faster or more easily. Since ethanol actually increases the absorption of benzodiazepines, and also enhances the depression of the central nervous system, the potential toxic side effects of the two drugs are augmented. Ethanol is often a common contributor to benzodiazepine-induced coma as well as to benzodiazepine-related deaths, demonstrating that interactions of these drugs with alcohol can be especially serious. Furthermore, the combination of alcohol with the Sedative-Hypnotic Barbitu-Rates (e.g., pentobarbital, secobarbital) can also produce a severe depression of the central nervous system, with decreased respiration. The intentional ingestion of ethanol and secobarbital (or Valium) is a relatively common means of Suicide.

Alcohol (Ethanol) and Opioids.

Alcohol can also enhance the respiratory depression, sedation, and hypotensive effects of Morphine and related opioid drugs. Therefore, the concurrent ingestion of the legal and socially acceptable drug ethanol with other sedatives, hypnotics, anticonvulsants, Antidepressants, antianxiety drugs, or with an Analgesic agent (such as morphine) can result in serious and potentially fatal drug interactions through a potentiation of the depressant effects of these drugs on the central nervous system. Since the 1960s, a significant number of musicians, actors, and other high-profile personalities have either accidentally or intentionally overdosed from a combination of alcohol and other central nervous system depressants. A few notable examples include actress Marilyn Monroe, musicians Jimi Hendrix, Janis Joplin, Jim Morrison, Keith Moon, and John Bonham.

STIMULANTS

Stimulants and Toxic Effects.

Synergistic toxic effects are also often obscured with other classes of drugs. For example, the concurrent ingestion of central nervous system stimulants (e.g., Amphetamine, Cocaine, Caffeine) can also produce additive side effects, especially with respect to toxic reactions involving the heart and cardiovascular system. These toxic reactions are often manifested as an irregular heartbeat, stroke, heart attack, or even death. Drugs with apparently different mechanisms of action can result in dangerous and unexpected synergistic side effects with fatal consequences. For example, some amphetamine and cocaine users often attempt to self-medicate their feelings of "overamp," or the excessive Stimulant high resulting from prolonged central nervous system stimulation, through the concurrent administration of central nervous system depressants such as alcohol, barbiturates, or heroin (i.e., a "speedball"). The rationale behind this potentially dangerous practice is that a few beers, a Quaalude, or perhaps a shot of heroin will help the individual "mellow out" for a while before inducing a stimulant high again. High doses of cocaine or amphetamine can, however, result in respiratory depression from actions on the medullary respiratory center. Therefore, the concurrent ingestion of a central nervous system stimulant (e.g., cocaine) with a depressant (e.g., heroin) can result in increased toxicity or death from the enhanced respiratory depression produced by the combination of the two drugs. The most well-known casualty from this type of pharmacological practice was comedian John Belushi.

CLINICAL USES

The principles of drug interactions can be used clinically for the treatment of acute Intoxication and for Withdrawal—by transforming, reducing, or blocking the pharmacological properties and/or the toxic effects of drugs used and abused for nonmedical purposes. Although these interactions often involve a competition with the abused drug for similar central nervous system Receptor sites, other mechanisms are also clinically relevant.

Disulfiram and Alcohol (Ethanol).

One such nonreceptor-mediated interaction involves Disulfiram (Antabuse) and ethanol (alcohol). Since an ethanol-receptor site has not yet been conclusively identified, specific receptor agonists and antagonists are not yet available for the treatment of ethanol intoxication, withdrawal, and abstinence (as they are for opioids). Disulfiram is sometimes used in the treatment of chronic Alcoholism, although the drug does not cure alcoholism; rather, it interacts with ethanol in such a way that it helps to strengthen an individual's desire to stop drinking. Although disulfiram by itself is relatively nontoxic, it significantly alters the intermediate metabolism of ethanol, resulting in a five- to tenfold increase in plasma acetaldehyde concentrations. This acetaldehyde syndrome results in vasodilatation (dilation of blood vessels), headache, difficulty breathing, nausea, vomiting, sweating, faintness, weakness, and vertigo. All of these reactions are obviously unpleasant, especially at the same time, thus well worth avoiding. The acetaldehyde syndrome therefore helps to persuade alcoholics to remain abstinent, since they realize that they cannot drink ethanol for at least three or four days after taking disulfiram. The consumption of even small or moderate amounts of ethanol following disulfiram pretreatment can result in extremely unpleasant drug interactions through the acetaldehyde syndrome.

Opioids.

Drug interactions involving opioids (morphine-like drugs) and opioid receptors are classic examples of how knowledge of the molecular mechanisms of the actions of a class of drugs can assist in the treatment of acute intoxication, withdrawal, and/or abstinence. Naloxone, the opioid-receptor antagonist, can be used as a diagnostic aid in emergency rooms. In the case of a comatose patient with unknown medical history, the intravenous administration of naloxone can provide information on whether or not the coma is the result of an opioid overdose. The antagonist competes with the agonist (usually heroin or morphine) for the opioid-receptor sites, displacing the agonist from the binding sites to reverse the symptoms of an overdose effectively and rapidly. Continued naloxone therapy and supportive treatment are often still necessary.

If, however, naloxone is administered to an individual dependent on opioids but not in a coma, a severe withdrawal syndrome develops within a few minutes and peaks after about thirty minutes. Depending on the individual, such precipitated withdrawal can be more severe than that following the abrupt withdrawal of the opioid-receptor agonist (e.g., heroin). In the former instance, the binding of the agonist to opioid receptors is suddenly inhibited by the presence of the antagonist (e.g., naloxone); even relatively large doses of the agonist (e.g., heroin) cannot effectively overcome the binding of the antagonist. Quite the contrary, respiratory depression can develop if higher doses of the agonist are administered. Therefore, opioid-receptor antagonists are not recommended for the pharmacological treatment of opioid withdrawal. Rather, longer acting, less potent, opioid receptor-agonists, such as Methadone, are more commonly prescribed.

Methadone. The symptoms associated with methadone withdrawal are milder, although more protracted, than those observed with morphine or heroin. Therefore, methadone therapy can be gradually discontinued in some heroin-dependent people. If the patient refuses to withdraw from methadone, the person can be maintained on methadone relatively indefinitely. Tolerance develops to some of the pharmacological effects of methadone, including any reinforcing or rewarding effects (e.g., the euphoria or "high"). Therefore, the patient cannot attain the same magnitude of euphoria with continued methadone therapy, although the symptoms associated with opioid withdrawal will be prevented or attenuated. Cross-tolerance also develops to other opioid drugs, so the patient will not feel the same high if heroin is again used on the street.

This type of maintenance program makes those who are heroin dependent more likely to accept other psychiatric or rehabilitative therapy. It also reduces the possibility that methadone patients will continue to seek heroin or morphine outside the clinic. In this way, the principles of drug interactions involving opioid receptors in the central nervous system have helped to stabilize Treatment strategies for opioid withdrawal and abstinence.

(See also: Accidents and Injuries ; Complications ; Neurological ; Drug Abuse Warning Network )

BIBLIOGRAPHY

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Griffin, J. P. & D' Arcy, P. F. (1997). Manual of adverse drug interactions, Fifth Edition. Oxford: Elsevier Science.

Karalliedde, L.& Henry, J. (Eds.) (1998). Handbook of drug interactions. New York: Oxford University Press, Inc.

Korsten, M. A., & Lieber, C. S. (1985). Medical complications of alcoholism. In J. H. Mendelson &N. K. Mello (Eds.), The diagnosis and treatment of alcoholism, pp. 21-64. New York: McGraw-Hill.

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Redmond, D. E., Jr., & Krystal, J. H. (1984). Multiple mechanisms of withdrawal from opioid drugs. Annual Review of Neuroscience 7, 443-478.

Sands, B. F., Knapp, C.M.& Domenic, A. (1993). Medical consequences of alcohol-drug interactions. Alcohol Health & Research World, 17, 316-320.

Nick E. Goeders

Revised by Jill Lectka