Pharmacokinetic interactions between acute alcohol ingestion and single doses of benzodiazepines, and tricyclic and tetracyclic antidepressants – an update

INTRODUCTION

Ethanol affects the metabolism of many drugs. Recently, a number of poisoning cases have been associated with alcohol and benzodiazepines whose broader therapeutic index is seen as an advantage. Such cases have become more frequent and represent a serious problem in Japan ( 1). The main clinical problem is the unpredictability of the effect of alcohol on drug pharmacokinetics, given the variable nature of alcohol use in most patients ( 2–12). Some general reviews of the interactions involving the acute combined use of alcohol, benzodiazepines ( 2–5, 7–11), tricyclic and tetracyclic antidepressants ( 2, 3, 5, 6, 8, 10, 12) have been published. Further, cytochrome P450 (P450 or CYP) and isoenzymes that catalyse drug metabolism have also been identified in recent years ( 13–16).

In this report, we review recent findings on pharmacokinetic interactions associated with the acute combined use of agents such as benzodiazepines and tricyclic and tetracyclic antidepressants with alcohol.

METABOLISM OF ALCOHOL

The liver is the major site for alcohol metabolism, and hepatic alcohol dehydrogenase (ADH) is the enzyme primarily responsible for this process. Long-term intake of large amounts of ethanol induces pathways of metabolism which are independent of ADH (17–19). Other enzymes, in particular, the microsomal alcohol-oxidizing system, involving CYP2E1, are also involved at higher dose levels of alcohol, and these metabolize up to 10% of the ingested alcohol ( 18, 20, 21). Acute alcohol ingestion is likely to cause inhibition of this group of enzymes by direct competition for binding with CYP2E1 and results in a rapid decrease in the activity of CYP2E1 ( 21).

METABOLISM OF BENZODIAZEPINES

The metabolism of benzodiazepines is catalysed mainly by CYP2C19 (for example, diazepam), 5-mephenytoin hydroxylase, and CYP3 A4 (for example, diazolam and triazolam) ( Table 1) (13–16). Clearance of benzodiazepines, via Phase I metabolism, by N-demethylation and/or hydroxylation, tends to be more affected by alcohol intake than compounds such as lorazepam ( 22) and oxazepam ( 23) which simply undergo conjugation (Phase II). Phase I metabolism is inhibited or decreases with increasing age, pre-existing liver disease (including cirrhosis or hepatitis), coadministration of some drugs (for example, cimetidine) ( 24, 25) and stimulated or induced by chronic administration of substances that induce the P450 system, such as phenobarbital or alcohol ( 12). Of these drugs, extreme care is needed in handling those metabolized by CYP2C19, since it has been reported that a pharmacogenetic component is involved ( 14, 16, 26).

Table 1. . The metabolism of benzodiazepines

METABOLISM OF TRICYCLIC AND TETRACYCLIC ANTIDEPRESSANTS

The P450 isozymes that catalyse a number of tricyclic antidepressants are mainly CYP2C19 and CYP2D6, polymorphic CYP enzymes, which produce active metabolites. Active metabolites undergo further N-demethylation and/or hydroxylation or conjugation resulting in inactive compounds that are excreted in urine. Those metabolized by CYP2C19 are nortriptyline (metabolite: E-10-hydroxydidemethyl- amitriptyline) and imipramine (metabolite: desipramine) and those metabolized by CYP2D6 are amitriptyline (metabolite: l0-hydroxyamitriptyline), clomipramine (metabolite: 8-hydroxyclomipramine), desipramine (metabolite: 2-hydroxydesipramine) and imipramine (metabolite: 2-hydroxyimipramine). Since the tetracyclic antidpressants mianserin (metabolite: 8-hydroxymianserin) and maprotiline (metabolite: ?) are also metabolized by these CYPs; these drugs may produce severe effects following normal doses in poor metabolizers (PM) of debrisoquine ( 13–16).

PHARMACOKINETIC INTERACTION BETWEEN ACUTE ETHANOL INTAKE AND A SINGLE DOSE OF BENZODIAZEPINES

Oxidation of benzodiazepines is considered to be a problem in drug interactions, but this does not apply to benzodiazepine conjugation. The following mechanism for drug interactions between ethanol and benzodiazepines has been proposed. Since both alcohol dehydrogenase and the microsomal ethanol oxidizing system CYP2E1 are involved at high blood concentrations of ethanol there is direct competitive inhibition (supra-additive or synergistic effect) during the metabolism of benzodiazepines following alcohol intake. In consequence, the depressant effects of ethanol and benzodiazepines may become a supra-additive or synergistic rather than a merely additive effect, i.e. a drug–drug interaction occurs. Other factors may also be involved, several influencing the pharmacokinetics of ethanol, e.g. absorption of not only benzodiazepines but also alcohol (e.g. gastric emptying, food), elimination (e.g. first-pass effect, hepatic blood flow), and diseases (e.g. hepatic failure). Thus, the mechanisms of the interactions between ethanol and benzodiazepines are extremely difficult to characterize. Interpretation of drug–drug interactions is further complicated when multiple drugs are administered.

PHARMACOKINETIC INTERACTIONS BETWEEN ETHANOL AND SINGLE DOSES OF TRICYCLIC ANTIDEPRESSANTS

Only a few studies of interactions between alcohol and antidepressants have been published. Tricyclic antidepressants are completely absorbed by the small intestine and mainly metabolized in the liver, whereas some of tricyclic antidepressants produce several active metabolites. It has also been reported that there are large individual differences in the pharmacokinetics of tricyclic antidpressants ( 16). Pharmacokinetic interactions possibly occur during absorption, distribution, metabolism and excretion. Since many tricyclic antidepressants are metabolized by CYP2D6, it is conceivable that combined use of these drugs results in a mutual decline in metabolic clearance, thereby elevating their concentrations in blood. No reports on pharmacokinetic interactions between ethanol and tetracyclic antidepressants have been published to date.

CLINICAL STUDIES

Sellers and Busto ( 4) have reviewed the interactions between ethanol and benzodiazepines over the period 1973–80. Their findings revealed that, in most cases, benzodiazepine concentrations are elevated when single doses of ethanol and benzodiazepines are administrated in combination, due to inhibition of their metabolism. However, some reports suggest that the blood concentration of oxazepam is unchanged by alcohol ( 27). This difference is associated with the isozymes of metabolism, as is indicated by the conjugation reaction that occurs in the metabolism of oxazepam. Recent reports suggest that, as in the case of a single dose combinations, blood concentrations are elevated, half-life (t_1/2) is extended, total body clearance (CL) is decreased, area under the drug concentration time curve (AUC) is increased and the metabolism of benzodiazepines is inhibited ( Table 2). These drugs depress respiration and lead to apnoea ( 28–30). Nonetheless, there are contradictory reports. The differences in metabolic changes reported may be attributable to many factors such as differences in dosage and administration and the time taken to consume the ethanol ( 31–34). There is little on potential of pharmacokinetic interactions between ethanol and tricyclic antidepressants, but one report suggests that the metabolism of amitriptyline is inhibited by alcohol intake ( 35).

Table 2. . Pharmacokinetic interactions between acute ethanol ingestion, and single doses of benzodiazepines, and tricyclic and tetracyclic antidepressants

CONCLUSION

Changes in the phamacokinetics of benzodiazepines, tricyclic and tetracyclic antidepressants when ingested together with alcohol depends on the amount of alcohol consumed, the presence or absence of hepatic disease and differences in dosage and administration. Ethanol induces acute impairment of the disposition of benzodiazepines and tricyclic antidepressants. This results in the impairment of many motor, sensory and neurological functions (pharmacodynamic interactions) and, possibly, sudden death ( 36–38). Such events have usually followed simultaneous major overdoses or ingestion of multiple drugs. The dangers of combined use of such drugs with alcohol always need to be clearly explained to patients. Interactions involving the acute combined use of alcohol, benzodiazepines and antidepressants alone are the subject of this paper. However, since pharmacokinetic and pharmacodynamic changes are known when these drugs are used chronically, great care is needed in handling these drugs. Community-based studies to assess the pharmacological, toxicological or clinical implications of possible alcohol–drug interactions would be of value.