Effects of calcium channel inhibitors on ethanol effects and pharmacokinetics in healthy volunteers

Alcohol,Vol. 10, pp. 505-509, 1993

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Effects of Calcium Channel Inhibitors on Ethanol Effects and Pharmacokinetics in Healthy Volunteers J A M E S P . ZACNY*~f I A N D S A N T O S H Y A J N I K *

*Department o f Anesthesia & Critical Care and tDepartment o f Psychiatry, The University o f Chicago School o f Medicine, Chicago, IL 60637 Received 21 A p r i l 1993; A c c e p t e d 25 J u n e 1993 ZACNY, J. P. AND YAJNIK, S. Effectsof calcium channelinhibitorson ethanoleffects andpharmacokinetics in healthy volunteers. ALCOHOL 10(6) 505-509, 1993.-Previous studies have shown that calcium channel antagonists alter the effects of alcohol in animals and humans. We selected a phenylalkylamine, verapamil, and a dihydropyridine, nimodipine, to determine whether these drugs would affect the subjective or psychomotor effects of ethanol in humans. Subjects ingested verapamil (80 rag, PO), nimodipine (30 and 60 rag, PO), or placebo 60 rain before drinking an alcohol (0.7 g/kg) or placebo beverage. Subjects' mood, psychomotor performance, physiological status, and blood alcohol levels were assessed up to 3 h after beverage ingestion. Alcohol increased "drunk" ratings and impaired psychomotor performance (p < 0.05). Blood alcohol levels were decreased by nimodipine pretreatment, but not by verapamil pretreatment. Subjective and psychomotor effects of alcohol were not altered as a function of nimodipine or verapamil pretreatment. Nimodipine, verapamil, and alcohol, either alone or in combination, had no effect on blood pressure or heart rate. Calcium channel inhibitor Verapamil Nimodipine Ethanol Psychomotor Blood pressure Human Pharmacokinetics

CALCIUM channel inhibitors (CCIs) are known for their efficacy in the treatment of hypertension, angina, atrial fibrillation, or tachyarrhythmias (18). These drugs lower blood pressure through their vasodilatory effects by inhibiting transmembrane movement of C a + + (9). This lowering of the levels of C a + + reaching the intracellular sites leads to a subsequent relaxation of arteriolar smooth muscle and decreased peripheral vascular resistance (9,18). These drugs are also known to possess a variety o f other effects, including those which are CNS-mediated. A number o f recent studies have demonstrated that certain CCIs have antidepressant, neuroleptic, anxiolytic-like, anticonvulsant, sedative, and analgesic properties (13,18). Besides the aforementioned effects, there are also a number of studies which indicate that CCIs may have the potential to serve as pharmacotherapeutic aids in the area of inappropriate drug use. Effects include the attenuation of the discriminative stimulus (i.e., interoceptive) or physiological effects of the abused drug (1,22), the attenuation o f seif-administration of the abused drug, including such drugs as cocaine and morphine (12), alterations of other effects of abused drugs, such

Alcohol Mood Blood alcohol level

as changes in drug-induced locomotion (15,17,23,24), and dimunition of withdrawal syndromes of different drugs (10,21). Several studies have focused on the interaction of CCIs and ethanol, and although the results are somewhat mixed, there appears to be mounting evidence that CCIs may serve as pharrnacotherapeutic agents in the treatment of alcohol abuse. Ethanol consumption has been reduced when animals are pretreated with C C I s - t h i s reduction in alcohol consumption has been documented in rats (5,20) and monkeys (19). The reduction is somewhat selective in that consumption o f water is not concurrently reduced (in fact it increases), but consumption of sweetened water is also reduced by CCI pretreatment (3). In human studies, it has been shown that verapamil pretreatment (every 8 h for six days) decreases rate of ethanol elimination and concurrently increases the duration of subjective ratings of intoxication (2). Taken with the animal studies, it may be that CCIs alter the pharmacokinetics of ethanol in such a way as to prolong its effects, resulting in decreased consumption rates. We sought to follow up on this potentially interesting interaction between CCIs and ethanol by pretreating healthy vol-

' Requests for reprints should be addressed to James P. Zacny, Department of Anesthesia and Critical Care, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637. 505

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ZACNY AND YAJNIK

unteers with CCIs prior to ethanol ingestion. Because CCIs may have different pharmacological actions, depending on their chemical structure, we investigated the effects of two commonly used CCIs from different classes, verapamil and nimodipine. Verapamil is a diphenylalkyamine and nimodipine is a d i h y d r o p y r i d i n e - b o t h reportedly inhibit dopaminergic release and activate the serotonergic system (6,7,8,11). In the present study, we examined the effects of verapamil and nimodipine pretreatment on the subjective, psychomotor, and cognitive effects of a moderate dose of ethanol in healthy volunteers. METHODS Subjects Subjects were recruited from the local university community via newspaper and bulletin board advertisements. Candidates who met screening criteria (i.e., 21-35 yrs old, consuming at least seven drinks per week and a minimum of four drinks on one occasion per week and having no current medical problems) were scheduled for a screening interview. At the interview, they completed the SCL-90 (4) and a health questionnaire, and a semistructured interview was held to determine their psychiatric and medical status. Candidates with any history of significant psychiatric disorders or substance use disorder, except for tobacco dependence, were excluded. An anesthesiologist performed a medical history and physical examination. Excluded from this study were persons who had an adverse experience with alcohol or in whom contraindications became apparent after physical examination. The study was approved by our institutional review board. Informed written consent was obtained from subjects before the first session. On testing days, subjects were not allowed to eat or drink for 2 h before the tests. Subjects were instructed to refrain from drinking alcohol for 24 h before sessions. Alcohol abstinence was verified by measuring the blood alcohol level (BAL) when subjects arrived for the session. Subjects were told not to drive a car, operate heavy machinery, or cook until the day after the study and were transported home by a

university livery service. Subjects were paid for their participation upon completion of the study. Experimental Design and Drugs Tested The study was performed as a double-blind, randomized, crossover trial. Each subject was tested in eight different test sessions, usually at intervals of about one week. Subjects received nimodipine (30 and 60 mg, PO), verapamil (80 mg, PO), or placebo. One hour later the subjects consumed a beverage that either did or did not contain 0.7 g/kg of alcohol. The lemonade-and-lime-flavored beverages that contained alcohol had 15070 ethyl alcohol by volume in the 450 ml (per 70 kg) that subjects consumed in 20 rain. Beverages were served cold in cups. Attempts were made to mask the beverages by lining the rim of each styrofoam cup with alcohol. Session Procedures Before the first session of the experiment, in a practice session, subjects were exposed to the different tests in the battery to gain familiarity with them. During experimental sessions, subjective effects evaluations, psychomotor tasks, and breathalyzer readings were performed at periodic intervals (see Table 1). A snack was served approximately 2 h after consumption of the beverage. Dependent Measures Subjective, psychomotor, and physiological effects, along with BALs served as the dependent measures in this study. Subjective effects were measured using the Visual Analog Scale (VAS) and the Drug Effects/Liking Questionnaire. The VAS consists of nine 100-mm lines, each labeled with adjectives (e.g., "drunk," "dizzy," "stimulated"). Subjects are instructed to place a mark on each line indicating how they feel at the moment, ranging from not at all to extremely. The Drug Effects/Liking Questionnaire assesses the extent to which subjects currently feel a drug effect with a scale of 1 to 5 (1 = I feel no effect f r o m it at all, 5 = I feel a very strong effect) and assesses the extent to which subjects like the drug

TABLE 1 TIMEPOINTS WHEN MEASURES WERE COLLECTED Minutes -61" Subjective effects VAS Drug effects/Liking Psychomotor performance Coordination DSST Physiological measures BAL Heart rate Systolic blood pressure Diastolic blood pressure

-60t

- 1~

0§

15¶

45

60

90

120

150

180

X X

X X

X X

X X

X X

X X

X X

X X

X X

X X

X X

X X

X X X X

X X X X

X X X X

X X X

X X X X

X

X X

X X

X X X X

X X X X

*At -61 rain, initial baseline measures were collected, tAt - 6 0 rain, CCI pretreatment. ~At - 1 rain, second set of measures taken, immediately prior to beverage insestion. §Beverage ingestion over a 20-min period. ¶Numbers 15-180 refer to minutes relative to completion of the beverage.

CALCIUM C H A N N E L BLOCKERS A N D E T H A N O L effect on a 100-ram line (0 = dislike a lot, 50 = neutral, 100 = like a lot). Psychomotor effects were measured by eyehand coordination (14) and the Digit Symbol Substitution Test (DSST) (25). Eye-hand coordination was measured by having the subject track a moving circle on a computer screen with a cross controlled by a mouse. Coordination mistakes were measured by counting the number of times that the cross exceeded a certain distance from the target circle. In the DSST, subjects replace a number with a corresponding symbol; the paper-and-pencil test is timed for 1 min, and the dependent

507 measure is the number of symbols correctly matched by the subject. Physiological effects included systolic (SBP) and diastolic blood pressure (DBP) and heart rate (HR). Blood alcohol level was measured from breath air using an Alco-sensor 3 breath analyzer (Intoximetrics Instruments, St. Louis). Data

Analysis

For each test, two repeated-measures analysis of variance were used to study I) the effects of verapamil (two levels),

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FIG. 1. Effects of nimodipine (0, 30 and 60 mg, PO) pretreatment (left frames) and verapamil (0 and 80 mg, PO) pretreatment (right frames) on "drunk" ratings of the VAS (top frames) and BALs (bottom frames) after consumption of a beverage containing 0.0 or 0.7 g/kg ethanol. Time point -61 refers to measures taken immediately before CCI pretreatment and time point - 1 refers to measures taken immediately before consumption of beverage. The rest of the time points are relative to completion of the beverage. Solid symbols indicate that that particular treatment condition differed significantly from the alcohol-alone condition, as determined by paired t tests (/7 < 0.05).

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ZACNY AND YAJNIK

alcohol (two levels), and time (six to nine levels), and 2) the effects of nimodipine (three levels), alcohol (two levels), and time (six to nine levels). F values were considered significant for p _< 0.05 with adjustments of within-factors degrees of freedom (Huynh-Feldt) to protect against violations of symmetry. When significant Verapamil or Nimodipine x Alcohol (x Time) interactions were obtained (indicating attenuation or potentiation of alcohol effects by a calcium channel antagonist), paired t tests were done comparing the combination of nimodipine or verapamil with alcohol to alcohol alone at a given time point. RESULTS Six males participated in the study. Their mean age was 25.5 _+ 4 years and they drank at least seven drinks per week and a minimum of four drinks on one occasion per week.

Subjective Effects The following significant alcohol (or Alcohol x Time) effects were obtained-drunk, dizzy, drug liking, feel drug effect, and coasting (spaced o u t ) - b u t these increases were neither potentiated nor attenuated by verapamil or nimodipine (i.e., there were no significant Verapamil or Nimodipine x Alcohol [x Time] interactions). Verapamil and nimodipine by themselves had no effects on mood. Figure 1 (top frames) shows the effects of alcohol with and without the calcium channel antagonists on "drunk" ratings of the VAS. Subjective effects, such as drunk ratings in Fig. 1, appeared to peak at 15 rain following ingestion of the beverage. Ratings showed a gradual decline in perceived effects over the remainder of the session.

Psychomotor Effects Alcohol impaired performance (i.e., significant Alcohol and/or Alcohol x Time interactions) on both the DSST and the eye-hand coordination task; the impairment was present 15 min after beverage ingestion and persisted for up to 60 rain (DSST) or 2 h (eye-hand coordination) after beverage ingestion. Neither calcium channel antagonist potentiated or attenuated the effects of alcohol on psychomotor performance (i.e., there were no significant Verapamil or Nimodipine × Alcohol [x Time] interactions). For example, DSST performance was reduced 15 min after alcohol ingestion (relative to baseline levels) by 6.0 symbols in the placebo-alcohol condition, 8.2 symbols in the verapamil-alcohol condition, and 5.1 symbols in the 60 mg nimodipine-alcohol condition.

Physiological Effects Verapamil, nimodipine, and alcohol alone had no effect on heart rate. A significant Verapamil x Alcohol interaction was obtained on heart rate, F(1, 5) = 6.3, p < 0.05, but it was not clinically significant. The interaction was due to slightly higher baseline heart rates when alcohol was given alone, relative to when verapamil preceded alcohol ingestion. Verapamil, nimodipine, and alcohol alone had no effect on SBP or DBP. No significant interactions were obtained between alcohol and the calcium channel antagonists.

Blood Alcohol Level Average peak BAL increase after alcohol ingestion (with no calcium channel antagonist pretreatment) was 0.087O70, and

the peak was recorded at 60 min after beverage ingestion. Nimodipine (60 mg) attenuated BAL after alcohol ingestion, (Nimodipine x Alcohol) F(2, 10) = 5.6, p < 0.05 (see Fig. I, bottom left frame). This attenuating effect was noted in five of the six subjects in this study. Verapamil had no effect on BAL, F(I, 5) = 0.3, n.s. (see Fig. 1, bottom right frame). DISCUSSION Alcohol at the dose tested had clear effects on both subjective effects and psychomotor effects. Verapamil and nimodipine by themselves had no effects on either of these measures, and in addition, subjects during a poststudy debriefing mentioned they felt no effects from calcium channel pretreatment. The higher dose of nimodipine significantly reduced BALs, and this effect was noted in the majority (5/6) of subjects tested. Average BAL reduction (0.02o70) was equivalent to approximately one standard drink. In the present study, the decrease in BAL by 60 mg nimodipine without a simultaneous reduction in subjective ratings of alcohol effects suggests that although our measures are obviously sensitive to alcohol effects (see Fig. 1), the measures are not sensitive enough in detecting a somewhat small difference in BALs (i.e., 0.02O7o). The lack of a verapamil effect in our study stands in contrast to a recent finding obtained after chronic administration (six days, 3 x / d a y ) of verapamil in healthy volunteers (2). In that study, verapamil slowed down the rate of ethanol elimination, and simultaneously prolonged subjective ratings of intoxication. One potential mechanism for this verapamil/ethanol drug interaction involves verapamil's ability to inhibit drug metabolism by the P450 microsomal enzyme system (2). A small inhibition of the P450 pathway by verapamil could cause a large increase in blood ethanol levels. Another potential mechanism may be inhibition of alcohol dehydrogenase (2). An obvious difference between that study and our study was the acute versus chronic administration of verapamil. Results from another recent clinical study showed that acute administration of verapamil (80 mg, 160 mg, or placebo) failed to potentiate or antagonize the inebriating effects of ethanol or BALs in healthy volunteers (16). It was suggested that larger doses of verapamil may have altered alcohol effects, but concern was raised, and rightfully so, regarding the possible adverse effects of testing supraclinical doses. In the study discussed above (16), subjects were also pretreated with nifedipine, a CCI that, like nimodipine, comes from the dihydropyridine class. Nifedipine pretreatment did not alter alcohol effects. Why nimodipine (in our study) would affect BAL but a structurally similar CCI, nifedipine, would not is admittedly unclear. Further, why nimodipine (in our study) would decrease BAL while chronic verapamil acts in such a way so as to increase both peak BAL and the BAL area under the curve (AUC) (2) is also puzzling. It is clear that further experimentation is needed with different doses of CCIs, different administration regimens (acute vs. chronic), and different doses of alcohol to determine under what conditions, what direction, and to what extent CCIs alter alcohol effects. ACKNOWLEDGEMENTS The authors would like to express their appreciation to Wesley Thompson for his assistance in conducting the studies.

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