OGAREliliE SMOKING RE
THE NSE
10 DRUGS
By VICTOR H. COHN
s the response to therapeutic agents altered in those who smoke? Such an interaction could be envisaged as occurring by any of several mechanisms. Nicotine displays biphasic actions on many systems. Small doses initially stimulate autonomic ganglia within the peripheral nervous system, sensory receptors, the neuromuscular junction, and the central nervous system. The stimulation is characteristically followed, especially with larger doses, by depression at these sites. Potentially, there are multiple sites for pharmacologic interactions by other stimulating or depressant drugs . One must recognize, however, that chronic nicotine use is associated with the development of tolerance to many of its pharmacologic effects. Thus, this type of interaction in the chronic smoker may be more theoretical than real. Of more concern is the ability of nicotine and other tobacco constituents (such as 3,4-benzpyrene and 3-methylcholanthrene) to induce
I
Victor H. Cohn, PhD, is a professor in the Department of Pharmacology, The George Washington University Medical Center, 2300 I Street, NW, Washington, DC 20037. References may be obtained from the editor of American Pharmacy. 32
microsomal enzyme systems responsible for the metabolism of many drugs and chemicals. Many drugs are inactivated, and their excretion is facilitated, by these microsomal enzyme systems. Thus, one would predict an accelerated rate of disposition, decreased intensity, decreased duration of effect, and, consequently, decreased therapeutic efficacy for such drugs in smokers. On the other hand, microsomal metabolism may yield products with enhanced pharmacologic activity; moreover, there is increasing recognition that the organ toxicity of drugs or the carcinogenic effects of some chemicals depends on metabolic activation bv these microsomal enzyme systems-. Thus one might reasonably predict increased incidence of organ toxicity from certain drugs in smokers. Smoking-induced alterations of microsomal enzyme systems do take place in humans. Conney and his co-workers 1 and subsequent investigators 2 ,3 have studied the induction of drugmetabolizing capability in human placenta. The placentas from nonsmoking women have little or no ability to hydroxylate the carcinogen (and tobacco smoke constituent) 3,4:...benzpyrene; in contrast, placentas from smoking women had a 50- to loo-fold increased capability. This
phenomenon was duplicated in the fetus. Male neonates whose foreskin was used as an enzyme source showed 3,4-benzpyrene hydroxylase activity if their mothers were smokers. Placentas from smoking women also had a two-fold increased ability to dealkylate ethoxycoumarin, and to demethylate dimethylaminoazobenzene. On the basis of analogous laboratory animal experiments, one can reasonably assume that a similar induction of microsomal enzymatic capability took place in the liver, the principal site for drug metabolism, and other organs. This investigation set out to ascertain whether any clinically relevant alterations in the response of smokers to therapeutic agents are documented in the medical literature. A MEDLINE search was constructed which tabulated all papers that had data on smoking, tobacco or nicotine and were concerned with drug interactions. The search included papers containing' animal as well as human data, since it was felt that the former might yield clues to potential interactions in humans; excluded were papers related to carcinogenicity associated with smoking or tobacco constituents. The search revealed more than 200 papers from 1966 to the present that fell into both ca tegories. American Pharmacy Vol . NS18 , No .10 Sept. 1978/ 552
A large fraction of these papers proved not to be useful; most used nicotine as a pharmacological tool to reveal the mechanism of action of other drugs. Additional references were supplied by Donald R. Shopland of the National Clearinghouse for Smoking and Health. In addition, an extensive interview/discussion was held with one of the leading researchers in this area of investigation, Dr. Alan Conney.
.~ ~ ~ .£
~
Smoking and Drug Interactions Furosemide. Smoking has .been shown to inhibit water diuresis in human . beings. Vapaatalo et al. 4 studied the influence of smoking on the diuretic response to 40 mg of furosemide in 170 healthy student volunteers. Three-hour urine volumes were not significantly altered in subjects smoking as much as one cigarette every 30 minutes throughout the experimental period, although the maximum rate of diuresis may have occurred somewhat later in the smoking group. Further, there was no significant difference in the diuretic response between nonsmokers and smokers. It was concluded that the effect of smoking on furosemide diuresis is negligible. Propranolol. In animal studies, propranolol has been shown to exaggerate the rise in blood pressure induced by cigarette smoking or by infusions of nicotine. Coffman s studied the effect of propranolol on changes in blood pressure and cutaneous vascular resistance produced by cigarette smoking in 13 normal male smokers. Smoking two unfiltered cigarettes was associated with increases in mean blood pressure, heart rate and vascular resistance (measured in the foot), and a decrease in foot blood flow. Propranolol, as expected, blocked the smoking-induced increase in heart rate. There was no difference in the percent increase in vascular resistance or blood pressure produced by cigarette smoking after propranolol. The authors conclude that in patients being treated with propranolol no excessive increase in blood pressure or cutaneous vascular resistance will result from smoking. American Pharmacy Vol. NS18, No .10 Sept. 1978/ 553
0:
Oral Contraceptives. In contrast to the two studies cited above, there does seem to be a significant interaction between smoking and oral contraceptives. Jain 6 reanalyzed data from two studies conducted by Mann et al. 7,8 in England and Wales on the rate of nonfatal and fatal myocardial infarctions (MI) among women who use oral contraceptives. The relative risk of a nonfatal MI among these women or among women smokers is almost twice as high as the risk for women who neither smoke nor use the Pill. For women who both smoke and use the Pill, the relative risk of a nonfatal MI is estimated to be 11. 7 to 1. There appears to be a synergistic effect: smoking increases the risk of nonfatal MI in women who use the Pill, and conversely, the Pill increases the risk of nonfatal MI in smoking women. Jain 9 also analyzed data on deaths due to myocardial infarctions or thromboembolism among women using oral contraceptives. The estimated risk of death from using the Pill is strongly affected by smoking. The annual mortality rates from either MI or thromboembolism were considerably lower for nonsmoking oral contraceptive users than for those who smoke. For example, for women aged 30-39 the annual mortality rate from a MI for those who use the Pill and are smokers is 10.2 per 100,000; for those who use the Pill but are nonsmokers the rate is 1.8 per 100,000; and for those women who neither use the Pill nor smoke the rate is 1.2 per 100,000. Thus there is a considerable "excess"
mortality associated with smoking and the Pill, and again, there appears to be a synergistic effect, since the risk of MI in those who use oral contraceptives and smoke is greater than the sum of the risks attributable to the Pill alone and to smoking alone. Frederickson and Ravenhold1o analyzed published data and estimated that the risk of thromboembolism in women who use oral contraceptives and also smoke is 23 to 1; the corresponding risks for nonusers who are heavy smokers was 1.5 to 1, and for nonsmoking users 7.2 to 1. Here, too, there appears to be a synergistic effect. These conclusions are supported in general by recent reports from the long-term prospective studies undertaken by the Royal College of General Practitioners (involving 46,000 women)23 and the Oxford/Family Planning Association {involving 17,000 women).24 Too few deaths have been recorded to calculate precise risks, but enhanced mortality rates from all circulatory disorders (not just MI and thromboembolism) appear to be associated with use of oral contraceptives, especially in women who smoke. One prospective study estimates that the excess annual death rate is approximately three times greater in smoking women who have used the Pill than in nonsmoking women who have used the pill. 23 This interaction has prompted the presidents of the Royal College of General Practitioners and of the Royal College of Obstetricians and Gynecologists to recommend tha t women under 35 who use the Pill either stop smoking or change to another method of contraception.
Alterations of Drug Metabolism I. Tranquilizers Benzodiazepine. Results from the Boston Collaborative Drug Surveillance Program (BCDSP) showed that central nervous system depression complicating therapy with diazepam (Valium) or chlordiazepoxide (Librium) was less common in smokers. 11 ,26 Data obtained from nine hospitals involved more than 1,200 patients with a wide variety of medical conditions. For those receiving
33
diazepam the incidence of significant drowsiness in 644 nonsmoking patients was 7.9 percent; in 389 patients who smoked 20 or fewer cigarettes per day (mean of 16 for "light smokers") the incidence was 7.7 percent; and in 181 patients who smoked more than 20 cigarettes per day (mean of 46 for "heavy smokers") the incidence was 2.8 percent. Completely analogous results were obtained in patients receiving chlordiazepoxide. This relationship was maintained at all dose levels of the drug, in both men and women, and irrespective of diagnosis. Further, the difference persisted at all levels of alcohol intake and was not influenced by tea and coffee consumption or administration of hypnotic drugs for insomnia. A reasonable explanation for the decreased incidence of this significant CNS depression in smokers is that smoking accelerates the metabolism of the benzodiazepines by inducing hepatic microsomal enzyme systems. This conclusion is supported by experimental data in animals. The same studyll failed to detect any influence of smoking on the incidence of drowsiness from phenobarbital. The authors attribute this result to the fact that phenobarbital (unlike the benzodiazepines) is itself a potent induc'e r of hepatic drug metabolizing enzymes and smoking may not further stimulate systems that are already maximally induced. Chlorpromazine. Another report from the BCDSp 12,26 showed that among hospitalized psychiatric patients, drowsiness as a side effect of chlorpromazine was more common in nonsmoking than in smoking patients. Drowsiness was observed in 16 percent of the 130 nonsmoking pa tien ts but in only 11 percent of the 201 "light" smokers (20 or fewer cigarettes per day) and 3 percent of the "heavy" smokers (more than 20 cigarettes per day). There were statistically highly significant differences. This relationship held when patients were compared at each dose level of chlorpromazine, and the results were not influenced by age, sex, use of alcohol, coffee or tea or dura-
34
pIe logistic regression analyses. Three factors were shown to be significantly related to the frequency of the hypotensive effect: nonsmoking; an admission diastolic blood pressure of 100 mm or more; and higher doses of chlorpromazine. No influence was found from ethnic group, diagnosis, duration of hospitalization, consumption of tea, coffee or barbiturates, and renal function. II. Analgesics
tion of hospitalization. Swett et al. 2 7 also reported an inverse relationship between chlorpromazine-induced hypotension (systolic pressure decreased 15 mm or more with symptoms of faintness or dizziness) and smoking in hospitalized psychiatric patients. No incidence of hypotension was seen in the group of 18 "heavy" smokers (defined for this study as smoking 40 or more cigarettes per day). The incidence of hypotension was 10.2 percent in the group of 187 nonsmokers, 7.6 percent in the 223 "light" smokers (20 or fewer cigarettes per day) and 4.6 percent in the 87 "intermediate" smokers. None of these patients received any other hypotensive medication. As might be expected, hypotension was more common at higher doses of chlorpromazine, but the effect of smoking was evident at all doses under 500 mg per day. Similarly, even though hypotension was more common in patients with initial diastolic blood pressure of 100 mm or more and/or systolic blood pressure of 140 mm or more, hypotension was observed more frequently in nonsmokers, regardless of initial blood pressure. A higher frequency of hypotension was seen in nonsmokers over 40 than in smokers of the same age; a similar frequency was seen for both smoking and nonsmoking patients under 40. A higher frequency of hypotension was observed in nonsmokers in each category of alcohol consumption. The independent effect of each of these factors was assessed by multi-
Propoxyphene. The BCDSp13,26 assessed the efficacy of propoxyphene for relieving mild to moderate pain in more than 1,000 patients, and for headache relief in 141 patients. For all patients, histories of smoking as well as use of alcohol, coffee and tea were obtained. Propoxyphene was rated ineffective in 10.1 percent of nonsmokers, 15.0 percent of "light" smokers and 20.3 percent of "heavy" smokers. This finding represents a high level of statistical significance. Propoxyphene was prescribed at two dose levels (32 mg and 65 mg); at both dose levels the drug was less effective in smokers. Stratification of the comparisons in terms of other significant factors (age, sex, race and alcohol use) showed that for each of these factors (except heavy alcohol use, i.e ., 5 or more drinks per day), propoxyphene was rated ineffective more often among smokers. Other factors (diagnostic category, duration of hospitalization, use of coffee and tea and presence of uremia) did not influence the results. Of the seven recorded adverse reactions, six occurred in nonsmokers. Approximately 90 percent of an administered dose of propoxyphene is metabolized, and the data suggest that an enhanced metabolism rate in smokers may be responsible for the drug's decreased effectiveness, as well as the decreased number of adverse reactions recorded. Pentazocine. Keeri-Szanto and Pomeroy15 used pentazocine as a supplement to nitrous oxide general anesthesia. After a priming dose of pentazocine was administered, additional doses were injected to maintain a
American Pharmacy Vol. NS18, No .10 Sept. 1978/554
constant level of anesthesia and relaxation; a set concentration of nitrous oxide was maintained for all patients. The amount of pentazocine required to maintain a constant pharmacologic response varied among the 41 patients studied. Smokers required a larger priming dose and a 50 percent greater maintenance dose than nonsmokers (3.8 vs. 2.5 j1g/kg/ min). Differences in age, sex, operative risk or site of surgery were not correlated with the difference in required dose. Since urinary excretion of pentazocine is considered to be negligible during the surgery, the authors consider their results suggestive of an increased rate of metabolism of pentazocine in smokers. Even with this quite small sample, statistically highly significant differences were found between smokers and nonsmokers. The study implies that smokers require larger and/or more frequent doses of pentazocine to maintain a desired level of analgesia. (The study also reported that patients from air-polluted urban areas required more drug than patients from pollution-free rural areas. Smoking, was however, shown to have more effect than the patient's domicile.) In a kinetic analysis of pen tazocine disposition in eight smokers (undefined) and nine nonsmokers, Vaughan and Beckett 28 found no differences in the cumulative 24-hour urinary recoveries of pentazocine. They concluded, among other things, that smoking did not affect the oxidative metabolism of pentazocine . Further work will be required to resolve this conflict. No effect of cigarette smoking was found in the disposition kinetics of meperidine in anesthetized surgical patients or healthy nonanesthetized controls. 28
Phenacetin. Pan tuck and coworkers 16,30 studied the plasma disappearance of phenacetin in 18 normal volunteers. Half the individuals smoked 15-40 cigarettes per day; half were nonsmokers. The two groups were comparable with respect to age, weight, sex, race and coffee and alcohol consumption.
American Pharmacy Vol. NS18, No.10 Sept. 1978/555
Plasma levels of phenacetin were markedly lower in the smokers (onefourth to one-sixth) than in the nonsmokers throughout the five-hour experimental period . In those subjects where it could be measured, the plasma half-life was comparable in smokers and in nonsmokers (in five smokers the half-life could not be calculated, since there was no measurable plasma concentration of the drug). The total urinary excretion of phenacetin's metabolite, N-acetyl-paminophenol (NAPAP), was comparable in smokers and nonsmokers. The plasma ratio of NAPAP to unmetabolized phenacetin was higher in the smoking group. These data are interpreted as being consistent with enhanced metabolism of phenacetin by intestinal mucosa during its absorption, or during its first pass through the liver. Concurrent studies in rats exposed to cigarette smoke are consistent with this interpretation.
Antipyrine. A number of factors in addition to smoking may alter hepatic drug metabolism, including age, alcohol consumption, caffeine consumption and use of therapeutic agents. In an important study, Vestal et al. 20 applied multiple-regression analysis to assess the contribution of these factors to observed differences in the metabolism of antipyrine, selected as a "marker" for hepatic drug metabolizing enzyme systems. Data from 307 healthy male subjects were analyzed. Cigarette smoking was found to contribute 12 percen t to the observed variance in the
anhpyrine disposition rate; it was the primary variable. Thus the study supports the evidence that cigarette smoking stimulates drug metabolism in human beings. In a more recent study, Hart et al. 31 attempted to limit some of the variables by studying antipyrine metabolism in a group of 25 smokers (11 or more cigarettes per day) before and after they had stopped smoking and in a group of 17 no-n smokers (no smoking for at least 6 weeks). All were healthy volunteers who were not using any drugs known to affect hepatic microsomal metabolism, and who used comparable amounts of tea, coffee and alcohol (less than 50g per day). Antipyrine half-lives were determined after both oral and intravenous administration. The mean half-life was approximately 15 percent lower in the smokers than in the nonsmokers. Route of administration, age and sex had no effect. Determinations repeated on eight "heavy smokers" (undefined) after two months of abstinence showed a mean increase in the half-life of 23 percent (range 3.8-41.7 percent). In contrast, repeated control determinations of half-lives in some subjects over three months showed negligible (less than 10 percent) change . Thus cigarette smoking apparently enhances antipyrine disappearance (metabolism) and, by inference, the hepatic metabolism of other drugs; this enhancement of metabolism is reversed on cessation of smoking. A 15-20 percent shorter antipyrine half-life in healthy male smokers (undefined) compared to healthy male nonsmokers was also found by Kdrishaswamy and Naidu. 32 III. Tricyclic An tidepressan ts
Imipramine. In a brief preliminary progress report, Perel et al. 14 discussed the variability in steady-state plasma levels of imipramine and desmethylimipramine in 22 hospitalized, depressed patients, all of whom received the same oral dose (3.5 mg/kg/day) of imipramine chronically. Smokers (at least 15 cigarettes or 6 cigars per day) had an average steady-state plasma level equal to 55 percent that of nonsmoking patients.
35
The plasma half-life of phenylbutazone was determined for these patients. The shortest half-life was found in patients who had the lowest steadystate plasma levels of imipramine and desmethylimipramine, and the longest half-life in those who had the highest levels. Since the plasma halflives of phenylbutazone, imipramine and desmethylimipramine are all metabolized by hydroxylation, Perel et a1. concluded that the variation in steady-state plasma levels of imipramine and desmethylimipramine may be attributed to differences in hepatic metabolism of the drugs. The metabolism is stimulated in the patients who smoke and is the major factor responsible for the lower steady-state plasma levels of the drug. The preliminary data also show a relationship between clinical effectiveness of this antidepressant drug in unipolar nondelusional patients, and its steady-state plasma level. Patients with levels below 180 ng/ml have a low probability of recovery. Thus for patients who smoke, decreased clinical effectiveness is likely unless the drug dose is increased (and monitored by determination of plasma levels).
Nortriptyline. Fifty-three patients with primary depressive illness received 150 mg of nortriptyline per day in three divided doses; no other medications were allowed . Steadystate plasma levels of nortriptyline were compared in the 22 smokers (10 or more cigarettes per day) and the 31 nonsmokers (no tobacco use for at least 4 months prior to the study) after 2 weeks of treatment. Analysis of variance of the data showed that sex, smoking status and number of cigarettes smoked had no effect on the steady-state plasma level of nortriptyline. These results of Norman et a1. 33 confirm the earlier ones of Alexanderson et a1. 34 They are in contrast to those found by Perel et a1. for the other tricyclics, imipramine and desmethylimipramine, cited above. 14 Theophylline. Jenne et a1. 17 studied the plasma half-lives of in travenous-
36
ly administered theophylline. For 14 normal, nonsmoking males the halflife was 7.2±1.8 hours; for 10 normal, smoking males the half-life was 4.1± 1 hour. This statistic represents a highly significant difference. A group of older (average age 58 vs. 33) male smoking patients had a half-life of 3·.6±1.5 hours. While these results suggest an acceleration of theophylline metabolism (renal clearance is minor for theophylline disposition) in the smoking groups, it is not possible to determine whether it is due to their smoking or to some other inducer. Six members of the patient group were taking sedatives (unspecified), some of which are very active inducers of hepatic metabolism; five patients had stopped smoking two to seven years prior to the experiment. Drug and smoking histories were not presented for the other two groups. Therapeutically, theophylline is used most commonly as aminophylline, a bronchodilator important in treating bronchial asthma. If substantiated, these data would suggest that patients who require aminophylline may derive less benefit (in terms of intensity of effect as well as duration of effect) from a standard dose of the drug, if they are also smokers. These patients would require a larger dose and/or more frequent administration of the drug to maintain the desired therapeutic benefit. In another study, Powell et a1. 18 administered a single oral dose of theophylline or aminophylline to healthy young adults . Smoking (but not sex) was found to have a highly significant effect on theophylline clearance and elimination rate constant . The half-life of theophylline in the 7 smokers (fewer than 15 cigarettes per day) was 5.4 hours, while that in the 15 nonsmokers was 8.2 hours. Although no significan t difference was found between nonsmokers and six ex-smokers (had not smoked in at least two years), with respect to halflife of theophylline, there was a trend for ex-smokers to have an elimination rate constant greater than nonsmokers but less than smokers. Essentially comparable results were also obtained by Hunt et al. 1 Q
Conclusions Each author attributed the decreased drug effect, the decreased side effects of the decreased half-life to a smoking-induced acceleration of the drug's metabolism. For most of the studies that conclusion is inferred rather than demonstrated directly. It is not unreasonable based on analogous animal experiments, but it may not be the only explanation. Indeed, Vesell, in his studies designed to assess the relative contributions of genetics and environmental factors to the wide variation in rates of drug metabolism in human beings, concluded that individual differences were amost exclusively controlled by genetic rather than environmental (which included smoking as one parameter) factors.21 Only in the in teraction of smoking with oral contraceptives did drug use by smokers result in increased toxicity. In the other papers cited, interactions and metabolic alterations were not harmful in themselves. This result .is in concordance with conclusions of the Boston Collaborative Drug Surveillance Program 22 : "In our experience with over 22,000 medical in-patients, a well defined interaction involving drug-metabolizing enzyme systems has been implicated by the attending physician in an adverse even t in less than a dozen instances." What is apparent, however is that smokers may have de creased therapeutic benefit from some drugs unless the dose of the drug is increased and/or it is administered more frequently. 0
American Pharmacy Vol. NS18, No .10 Sept. 1978/ 556
THE NSE
10 DRUGS
By VICTOR H. COHN
s the response to therapeutic agents altered in those who smoke? Such an interaction could be envisaged as occurring by any of several mechanisms. Nicotine displays biphasic actions on many systems. Small doses initially stimulate autonomic ganglia within the peripheral nervous system, sensory receptors, the neuromuscular junction, and the central nervous system. The stimulation is characteristically followed, especially with larger doses, by depression at these sites. Potentially, there are multiple sites for pharmacologic interactions by other stimulating or depressant drugs . One must recognize, however, that chronic nicotine use is associated with the development of tolerance to many of its pharmacologic effects. Thus, this type of interaction in the chronic smoker may be more theoretical than real. Of more concern is the ability of nicotine and other tobacco constituents (such as 3,4-benzpyrene and 3-methylcholanthrene) to induce
I
Victor H. Cohn, PhD, is a professor in the Department of Pharmacology, The George Washington University Medical Center, 2300 I Street, NW, Washington, DC 20037. References may be obtained from the editor of American Pharmacy. 32
microsomal enzyme systems responsible for the metabolism of many drugs and chemicals. Many drugs are inactivated, and their excretion is facilitated, by these microsomal enzyme systems. Thus, one would predict an accelerated rate of disposition, decreased intensity, decreased duration of effect, and, consequently, decreased therapeutic efficacy for such drugs in smokers. On the other hand, microsomal metabolism may yield products with enhanced pharmacologic activity; moreover, there is increasing recognition that the organ toxicity of drugs or the carcinogenic effects of some chemicals depends on metabolic activation bv these microsomal enzyme systems-. Thus one might reasonably predict increased incidence of organ toxicity from certain drugs in smokers. Smoking-induced alterations of microsomal enzyme systems do take place in humans. Conney and his co-workers 1 and subsequent investigators 2 ,3 have studied the induction of drugmetabolizing capability in human placenta. The placentas from nonsmoking women have little or no ability to hydroxylate the carcinogen (and tobacco smoke constituent) 3,4:...benzpyrene; in contrast, placentas from smoking women had a 50- to loo-fold increased capability. This
phenomenon was duplicated in the fetus. Male neonates whose foreskin was used as an enzyme source showed 3,4-benzpyrene hydroxylase activity if their mothers were smokers. Placentas from smoking women also had a two-fold increased ability to dealkylate ethoxycoumarin, and to demethylate dimethylaminoazobenzene. On the basis of analogous laboratory animal experiments, one can reasonably assume that a similar induction of microsomal enzymatic capability took place in the liver, the principal site for drug metabolism, and other organs. This investigation set out to ascertain whether any clinically relevant alterations in the response of smokers to therapeutic agents are documented in the medical literature. A MEDLINE search was constructed which tabulated all papers that had data on smoking, tobacco or nicotine and were concerned with drug interactions. The search included papers containing' animal as well as human data, since it was felt that the former might yield clues to potential interactions in humans; excluded were papers related to carcinogenicity associated with smoking or tobacco constituents. The search revealed more than 200 papers from 1966 to the present that fell into both ca tegories. American Pharmacy Vol . NS18 , No .10 Sept. 1978/ 552
A large fraction of these papers proved not to be useful; most used nicotine as a pharmacological tool to reveal the mechanism of action of other drugs. Additional references were supplied by Donald R. Shopland of the National Clearinghouse for Smoking and Health. In addition, an extensive interview/discussion was held with one of the leading researchers in this area of investigation, Dr. Alan Conney.
.~ ~ ~ .£
~
Smoking and Drug Interactions Furosemide. Smoking has .been shown to inhibit water diuresis in human . beings. Vapaatalo et al. 4 studied the influence of smoking on the diuretic response to 40 mg of furosemide in 170 healthy student volunteers. Three-hour urine volumes were not significantly altered in subjects smoking as much as one cigarette every 30 minutes throughout the experimental period, although the maximum rate of diuresis may have occurred somewhat later in the smoking group. Further, there was no significant difference in the diuretic response between nonsmokers and smokers. It was concluded that the effect of smoking on furosemide diuresis is negligible. Propranolol. In animal studies, propranolol has been shown to exaggerate the rise in blood pressure induced by cigarette smoking or by infusions of nicotine. Coffman s studied the effect of propranolol on changes in blood pressure and cutaneous vascular resistance produced by cigarette smoking in 13 normal male smokers. Smoking two unfiltered cigarettes was associated with increases in mean blood pressure, heart rate and vascular resistance (measured in the foot), and a decrease in foot blood flow. Propranolol, as expected, blocked the smoking-induced increase in heart rate. There was no difference in the percent increase in vascular resistance or blood pressure produced by cigarette smoking after propranolol. The authors conclude that in patients being treated with propranolol no excessive increase in blood pressure or cutaneous vascular resistance will result from smoking. American Pharmacy Vol. NS18, No .10 Sept. 1978/ 553
0:
Oral Contraceptives. In contrast to the two studies cited above, there does seem to be a significant interaction between smoking and oral contraceptives. Jain 6 reanalyzed data from two studies conducted by Mann et al. 7,8 in England and Wales on the rate of nonfatal and fatal myocardial infarctions (MI) among women who use oral contraceptives. The relative risk of a nonfatal MI among these women or among women smokers is almost twice as high as the risk for women who neither smoke nor use the Pill. For women who both smoke and use the Pill, the relative risk of a nonfatal MI is estimated to be 11. 7 to 1. There appears to be a synergistic effect: smoking increases the risk of nonfatal MI in women who use the Pill, and conversely, the Pill increases the risk of nonfatal MI in smoking women. Jain 9 also analyzed data on deaths due to myocardial infarctions or thromboembolism among women using oral contraceptives. The estimated risk of death from using the Pill is strongly affected by smoking. The annual mortality rates from either MI or thromboembolism were considerably lower for nonsmoking oral contraceptive users than for those who smoke. For example, for women aged 30-39 the annual mortality rate from a MI for those who use the Pill and are smokers is 10.2 per 100,000; for those who use the Pill but are nonsmokers the rate is 1.8 per 100,000; and for those women who neither use the Pill nor smoke the rate is 1.2 per 100,000. Thus there is a considerable "excess"
mortality associated with smoking and the Pill, and again, there appears to be a synergistic effect, since the risk of MI in those who use oral contraceptives and smoke is greater than the sum of the risks attributable to the Pill alone and to smoking alone. Frederickson and Ravenhold1o analyzed published data and estimated that the risk of thromboembolism in women who use oral contraceptives and also smoke is 23 to 1; the corresponding risks for nonusers who are heavy smokers was 1.5 to 1, and for nonsmoking users 7.2 to 1. Here, too, there appears to be a synergistic effect. These conclusions are supported in general by recent reports from the long-term prospective studies undertaken by the Royal College of General Practitioners (involving 46,000 women)23 and the Oxford/Family Planning Association {involving 17,000 women).24 Too few deaths have been recorded to calculate precise risks, but enhanced mortality rates from all circulatory disorders (not just MI and thromboembolism) appear to be associated with use of oral contraceptives, especially in women who smoke. One prospective study estimates that the excess annual death rate is approximately three times greater in smoking women who have used the Pill than in nonsmoking women who have used the pill. 23 This interaction has prompted the presidents of the Royal College of General Practitioners and of the Royal College of Obstetricians and Gynecologists to recommend tha t women under 35 who use the Pill either stop smoking or change to another method of contraception.
Alterations of Drug Metabolism I. Tranquilizers Benzodiazepine. Results from the Boston Collaborative Drug Surveillance Program (BCDSP) showed that central nervous system depression complicating therapy with diazepam (Valium) or chlordiazepoxide (Librium) was less common in smokers. 11 ,26 Data obtained from nine hospitals involved more than 1,200 patients with a wide variety of medical conditions. For those receiving
33
diazepam the incidence of significant drowsiness in 644 nonsmoking patients was 7.9 percent; in 389 patients who smoked 20 or fewer cigarettes per day (mean of 16 for "light smokers") the incidence was 7.7 percent; and in 181 patients who smoked more than 20 cigarettes per day (mean of 46 for "heavy smokers") the incidence was 2.8 percent. Completely analogous results were obtained in patients receiving chlordiazepoxide. This relationship was maintained at all dose levels of the drug, in both men and women, and irrespective of diagnosis. Further, the difference persisted at all levels of alcohol intake and was not influenced by tea and coffee consumption or administration of hypnotic drugs for insomnia. A reasonable explanation for the decreased incidence of this significant CNS depression in smokers is that smoking accelerates the metabolism of the benzodiazepines by inducing hepatic microsomal enzyme systems. This conclusion is supported by experimental data in animals. The same studyll failed to detect any influence of smoking on the incidence of drowsiness from phenobarbital. The authors attribute this result to the fact that phenobarbital (unlike the benzodiazepines) is itself a potent induc'e r of hepatic drug metabolizing enzymes and smoking may not further stimulate systems that are already maximally induced. Chlorpromazine. Another report from the BCDSp 12,26 showed that among hospitalized psychiatric patients, drowsiness as a side effect of chlorpromazine was more common in nonsmoking than in smoking patients. Drowsiness was observed in 16 percent of the 130 nonsmoking pa tien ts but in only 11 percent of the 201 "light" smokers (20 or fewer cigarettes per day) and 3 percent of the "heavy" smokers (more than 20 cigarettes per day). There were statistically highly significant differences. This relationship held when patients were compared at each dose level of chlorpromazine, and the results were not influenced by age, sex, use of alcohol, coffee or tea or dura-
34
pIe logistic regression analyses. Three factors were shown to be significantly related to the frequency of the hypotensive effect: nonsmoking; an admission diastolic blood pressure of 100 mm or more; and higher doses of chlorpromazine. No influence was found from ethnic group, diagnosis, duration of hospitalization, consumption of tea, coffee or barbiturates, and renal function. II. Analgesics
tion of hospitalization. Swett et al. 2 7 also reported an inverse relationship between chlorpromazine-induced hypotension (systolic pressure decreased 15 mm or more with symptoms of faintness or dizziness) and smoking in hospitalized psychiatric patients. No incidence of hypotension was seen in the group of 18 "heavy" smokers (defined for this study as smoking 40 or more cigarettes per day). The incidence of hypotension was 10.2 percent in the group of 187 nonsmokers, 7.6 percent in the 223 "light" smokers (20 or fewer cigarettes per day) and 4.6 percent in the 87 "intermediate" smokers. None of these patients received any other hypotensive medication. As might be expected, hypotension was more common at higher doses of chlorpromazine, but the effect of smoking was evident at all doses under 500 mg per day. Similarly, even though hypotension was more common in patients with initial diastolic blood pressure of 100 mm or more and/or systolic blood pressure of 140 mm or more, hypotension was observed more frequently in nonsmokers, regardless of initial blood pressure. A higher frequency of hypotension was seen in nonsmokers over 40 than in smokers of the same age; a similar frequency was seen for both smoking and nonsmoking patients under 40. A higher frequency of hypotension was observed in nonsmokers in each category of alcohol consumption. The independent effect of each of these factors was assessed by multi-
Propoxyphene. The BCDSp13,26 assessed the efficacy of propoxyphene for relieving mild to moderate pain in more than 1,000 patients, and for headache relief in 141 patients. For all patients, histories of smoking as well as use of alcohol, coffee and tea were obtained. Propoxyphene was rated ineffective in 10.1 percent of nonsmokers, 15.0 percent of "light" smokers and 20.3 percent of "heavy" smokers. This finding represents a high level of statistical significance. Propoxyphene was prescribed at two dose levels (32 mg and 65 mg); at both dose levels the drug was less effective in smokers. Stratification of the comparisons in terms of other significant factors (age, sex, race and alcohol use) showed that for each of these factors (except heavy alcohol use, i.e ., 5 or more drinks per day), propoxyphene was rated ineffective more often among smokers. Other factors (diagnostic category, duration of hospitalization, use of coffee and tea and presence of uremia) did not influence the results. Of the seven recorded adverse reactions, six occurred in nonsmokers. Approximately 90 percent of an administered dose of propoxyphene is metabolized, and the data suggest that an enhanced metabolism rate in smokers may be responsible for the drug's decreased effectiveness, as well as the decreased number of adverse reactions recorded. Pentazocine. Keeri-Szanto and Pomeroy15 used pentazocine as a supplement to nitrous oxide general anesthesia. After a priming dose of pentazocine was administered, additional doses were injected to maintain a
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constant level of anesthesia and relaxation; a set concentration of nitrous oxide was maintained for all patients. The amount of pentazocine required to maintain a constant pharmacologic response varied among the 41 patients studied. Smokers required a larger priming dose and a 50 percent greater maintenance dose than nonsmokers (3.8 vs. 2.5 j1g/kg/ min). Differences in age, sex, operative risk or site of surgery were not correlated with the difference in required dose. Since urinary excretion of pentazocine is considered to be negligible during the surgery, the authors consider their results suggestive of an increased rate of metabolism of pentazocine in smokers. Even with this quite small sample, statistically highly significant differences were found between smokers and nonsmokers. The study implies that smokers require larger and/or more frequent doses of pentazocine to maintain a desired level of analgesia. (The study also reported that patients from air-polluted urban areas required more drug than patients from pollution-free rural areas. Smoking, was however, shown to have more effect than the patient's domicile.) In a kinetic analysis of pen tazocine disposition in eight smokers (undefined) and nine nonsmokers, Vaughan and Beckett 28 found no differences in the cumulative 24-hour urinary recoveries of pentazocine. They concluded, among other things, that smoking did not affect the oxidative metabolism of pentazocine . Further work will be required to resolve this conflict. No effect of cigarette smoking was found in the disposition kinetics of meperidine in anesthetized surgical patients or healthy nonanesthetized controls. 28
Phenacetin. Pan tuck and coworkers 16,30 studied the plasma disappearance of phenacetin in 18 normal volunteers. Half the individuals smoked 15-40 cigarettes per day; half were nonsmokers. The two groups were comparable with respect to age, weight, sex, race and coffee and alcohol consumption.
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Plasma levels of phenacetin were markedly lower in the smokers (onefourth to one-sixth) than in the nonsmokers throughout the five-hour experimental period . In those subjects where it could be measured, the plasma half-life was comparable in smokers and in nonsmokers (in five smokers the half-life could not be calculated, since there was no measurable plasma concentration of the drug). The total urinary excretion of phenacetin's metabolite, N-acetyl-paminophenol (NAPAP), was comparable in smokers and nonsmokers. The plasma ratio of NAPAP to unmetabolized phenacetin was higher in the smoking group. These data are interpreted as being consistent with enhanced metabolism of phenacetin by intestinal mucosa during its absorption, or during its first pass through the liver. Concurrent studies in rats exposed to cigarette smoke are consistent with this interpretation.
Antipyrine. A number of factors in addition to smoking may alter hepatic drug metabolism, including age, alcohol consumption, caffeine consumption and use of therapeutic agents. In an important study, Vestal et al. 20 applied multiple-regression analysis to assess the contribution of these factors to observed differences in the metabolism of antipyrine, selected as a "marker" for hepatic drug metabolizing enzyme systems. Data from 307 healthy male subjects were analyzed. Cigarette smoking was found to contribute 12 percen t to the observed variance in the
anhpyrine disposition rate; it was the primary variable. Thus the study supports the evidence that cigarette smoking stimulates drug metabolism in human beings. In a more recent study, Hart et al. 31 attempted to limit some of the variables by studying antipyrine metabolism in a group of 25 smokers (11 or more cigarettes per day) before and after they had stopped smoking and in a group of 17 no-n smokers (no smoking for at least 6 weeks). All were healthy volunteers who were not using any drugs known to affect hepatic microsomal metabolism, and who used comparable amounts of tea, coffee and alcohol (less than 50g per day). Antipyrine half-lives were determined after both oral and intravenous administration. The mean half-life was approximately 15 percent lower in the smokers than in the nonsmokers. Route of administration, age and sex had no effect. Determinations repeated on eight "heavy smokers" (undefined) after two months of abstinence showed a mean increase in the half-life of 23 percent (range 3.8-41.7 percent). In contrast, repeated control determinations of half-lives in some subjects over three months showed negligible (less than 10 percent) change . Thus cigarette smoking apparently enhances antipyrine disappearance (metabolism) and, by inference, the hepatic metabolism of other drugs; this enhancement of metabolism is reversed on cessation of smoking. A 15-20 percent shorter antipyrine half-life in healthy male smokers (undefined) compared to healthy male nonsmokers was also found by Kdrishaswamy and Naidu. 32 III. Tricyclic An tidepressan ts
Imipramine. In a brief preliminary progress report, Perel et al. 14 discussed the variability in steady-state plasma levels of imipramine and desmethylimipramine in 22 hospitalized, depressed patients, all of whom received the same oral dose (3.5 mg/kg/day) of imipramine chronically. Smokers (at least 15 cigarettes or 6 cigars per day) had an average steady-state plasma level equal to 55 percent that of nonsmoking patients.
35
The plasma half-life of phenylbutazone was determined for these patients. The shortest half-life was found in patients who had the lowest steadystate plasma levels of imipramine and desmethylimipramine, and the longest half-life in those who had the highest levels. Since the plasma halflives of phenylbutazone, imipramine and desmethylimipramine are all metabolized by hydroxylation, Perel et a1. concluded that the variation in steady-state plasma levels of imipramine and desmethylimipramine may be attributed to differences in hepatic metabolism of the drugs. The metabolism is stimulated in the patients who smoke and is the major factor responsible for the lower steady-state plasma levels of the drug. The preliminary data also show a relationship between clinical effectiveness of this antidepressant drug in unipolar nondelusional patients, and its steady-state plasma level. Patients with levels below 180 ng/ml have a low probability of recovery. Thus for patients who smoke, decreased clinical effectiveness is likely unless the drug dose is increased (and monitored by determination of plasma levels).
Nortriptyline. Fifty-three patients with primary depressive illness received 150 mg of nortriptyline per day in three divided doses; no other medications were allowed . Steadystate plasma levels of nortriptyline were compared in the 22 smokers (10 or more cigarettes per day) and the 31 nonsmokers (no tobacco use for at least 4 months prior to the study) after 2 weeks of treatment. Analysis of variance of the data showed that sex, smoking status and number of cigarettes smoked had no effect on the steady-state plasma level of nortriptyline. These results of Norman et a1. 33 confirm the earlier ones of Alexanderson et a1. 34 They are in contrast to those found by Perel et a1. for the other tricyclics, imipramine and desmethylimipramine, cited above. 14 Theophylline. Jenne et a1. 17 studied the plasma half-lives of in travenous-
36
ly administered theophylline. For 14 normal, nonsmoking males the halflife was 7.2±1.8 hours; for 10 normal, smoking males the half-life was 4.1± 1 hour. This statistic represents a highly significant difference. A group of older (average age 58 vs. 33) male smoking patients had a half-life of 3·.6±1.5 hours. While these results suggest an acceleration of theophylline metabolism (renal clearance is minor for theophylline disposition) in the smoking groups, it is not possible to determine whether it is due to their smoking or to some other inducer. Six members of the patient group were taking sedatives (unspecified), some of which are very active inducers of hepatic metabolism; five patients had stopped smoking two to seven years prior to the experiment. Drug and smoking histories were not presented for the other two groups. Therapeutically, theophylline is used most commonly as aminophylline, a bronchodilator important in treating bronchial asthma. If substantiated, these data would suggest that patients who require aminophylline may derive less benefit (in terms of intensity of effect as well as duration of effect) from a standard dose of the drug, if they are also smokers. These patients would require a larger dose and/or more frequent administration of the drug to maintain the desired therapeutic benefit. In another study, Powell et a1. 18 administered a single oral dose of theophylline or aminophylline to healthy young adults . Smoking (but not sex) was found to have a highly significant effect on theophylline clearance and elimination rate constant . The half-life of theophylline in the 7 smokers (fewer than 15 cigarettes per day) was 5.4 hours, while that in the 15 nonsmokers was 8.2 hours. Although no significan t difference was found between nonsmokers and six ex-smokers (had not smoked in at least two years), with respect to halflife of theophylline, there was a trend for ex-smokers to have an elimination rate constant greater than nonsmokers but less than smokers. Essentially comparable results were also obtained by Hunt et al. 1 Q
Conclusions Each author attributed the decreased drug effect, the decreased side effects of the decreased half-life to a smoking-induced acceleration of the drug's metabolism. For most of the studies that conclusion is inferred rather than demonstrated directly. It is not unreasonable based on analogous animal experiments, but it may not be the only explanation. Indeed, Vesell, in his studies designed to assess the relative contributions of genetics and environmental factors to the wide variation in rates of drug metabolism in human beings, concluded that individual differences were amost exclusively controlled by genetic rather than environmental (which included smoking as one parameter) factors.21 Only in the in teraction of smoking with oral contraceptives did drug use by smokers result in increased toxicity. In the other papers cited, interactions and metabolic alterations were not harmful in themselves. This result .is in concordance with conclusions of the Boston Collaborative Drug Surveillance Program 22 : "In our experience with over 22,000 medical in-patients, a well defined interaction involving drug-metabolizing enzyme systems has been implicated by the attending physician in an adverse even t in less than a dozen instances." What is apparent, however is that smokers may have de creased therapeutic benefit from some drugs unless the dose of the drug is increased and/or it is administered more frequently. 0
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