Calcium binding to phosphoprotein in estrogenized rooster plasma studied by density-gradient centrifugation.
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Animals↗
Biomedical subjects
N L Benowitz
Publications and source records attributed to N L Benowitz.
Methadone-disulfiram interaction during methadone maintenance.
In an attempt to characterize a possible drug interaction between methadone and disulfiram, 500 mg/day insulfiram was administered orally for seven days to seven subjects on methadone maintenance. Plasma methadone concentrations and urinary excretion of methadone and its pyrrolidine and pyrrolidone metabolites were measured and subjective symptoms of opiate intoxication and abstinence were noted before, during, and after disulfiram administration. Mean trough plasma methadone concentrations and terminal half-lives were lowest and shortest during disulfiram treatment, although this finding was not statistically significant. The ratio of urinary methadone to its pyrrolidine metabolite decreased during disulfiram treatment in all subjects. There is no evidence to support our original hypothesis that disulfiram might inhibit methadone metabolism. In contrast, urinary excretion of the major pyrrolidine metabolite increased relative to excretion of methadone. This suggests enhanced N-demethylation during disulfiram treatment. Disulfiram had no effect on opiate intoxication or abstinence symptoms. Disulfiram may alter methadone disposition, but in this study it was shown that in doses used for management of alcoholism there was no significant interaction between disulfiram and methadone.
Adult↗
Clinical relevance of cannabis tolerance and dependence.
Psychoactive drugs are often widely used before tolerance and dependence is fully appreciated. Tolerance to cannabis-induced cardiovascular and autonomic changes, decreased intraocular pressure, sleep and sleep EEG, mood and behavioral changes is acquired and, to a great degree, lost rapidly with optimal conditions. Mechanisms appear more functional than metabolic. Acquisition rate depends on dose and dose schedule. Dependence, manifested by withdrawal symptoms after as little as 7 days of THC administration, is characterized by irritability, restlessness, insomnia, anorexia, nausea, sweating, salivation, increased body temperature, altered sleep and waking EEG, tremor, and weight loss. Mild and transient in the 120 subjects studied, the syndrome was similar to sedative drug withdrawal. Tolerance to drug side effects can be useful. Tolerance to therapeutic effects or target symptoms poses problems. Clinical significance of dependence is difficult to assess since drug-seeking behavior has many determinants. Cannabis-induced super sensitivity should be considered wherever chronic drug administration is anticipated in conditions like epilepsy, glaucoma or chronic pain. Cannabis pharmacology suggests ways of minimizing tolerance and dependence problems.
Cannabinoids↗
Cardiovascular and metabolic considerations in prolonged cannabinoid administration in man.
Safe therapeutic use of cannabinoids for prolonged periods of time requires an appreciation of pharmacologic actions with both acute and repetitive administration. Cardiovascular effects of acute delta 9-tetrahydrocannabinol (THC) administration included increased sympathetic and reduced parasympathetic tone, although sympathetic reflex responses were impaired. Thus, supine tachycardia and increased blood pressure with upright hypotension are observed. With repetitive dosing, there is a transition from increased to decreased sympathetic activity and from decreased to increased parasympathetic activity, and blood volume substantially increases. As a result, supine bradycardia and decreased blood pressure with tolerance to orthostatic hypotension are observed. Relevance of these observations to management of patients with THC, including considerations of potential drug interactions, is discussed. In other experiments, THC and cannabidiol were found to inhibit metabolism of other drugs (antipyrine and barbiturates) metabolized by liver mixed-function oxidase enzymes. Potential inhibition of drug metabolism must be considered in evaluating responses to chemotherapeutic agents in cancer patients receiving THC and responses to coadministered anticonvulsants in epileptic patients receiving cannabidiol.
Adult↗
The role of nicotine in smoking-related cardiovascular disease.
Nicotine activates the sympathetic nervous system and in this way could contribute to cardiovascular disease. Animal studies and mechanistic studies indicate that nicotine could play a role in accelerating atherosclerosis, but evidence among humans is too inadequate to be definitive about such an effect. Almost certainly, nicotine via its hemodynamic effects contributes to acute cardiovascular events, although current evidence suggests that the effects of nicotine are much less important than are the prothrombotic effects of cigarette smoking or the effects of carbon monoxide. Nicotine does not appear to enhance thrombosis among humans. Clinical studies of pipe smokers and people using transdermal nicotine support the idea that toxins other than nicotine are the most important causes of acute cardiovascular events. Finally, the dose response for cardiovascular events of nicotine appears to be flat, suggesting that if nicotine is involved, adverse effects might be seen with relatively low-level cigarette exposures.
Acute Disease↗
Tricyclic antidepressant poisoning. Management of arrhythmias.
Deaths from tricyclic antidepressant (TCA) overdose are usually due to arrhythmias and/or hypotension. Tricyclic antidepressant toxicity is due mainly to the quinidine-like actions of these drugs on cardiac tissues. Slowing of phase 0 depolarisation of the action potential results in slowing of conduction through the His-Purkinje system and myocardium. Slowed impulse conduction is responsible for QRS prolongation and atrioventricular block, and contributes to ventricular arrhythmias and hypotension. Therapies that improve conduction, e.g. hypertonic sodium bicarbonate, are useful in treating these toxic effects. Other mechanisms contributing to arrhythmias include abnormal repolarisation, impaired automaticity, cholinergic blockade and inhibition of neuronal catecholamine uptake. Toxicity may be worsened by acidaemia, hypotension or hyperthermia. Sinus tachycardia is due to the anticholinergic effects of the tricyclic antidepressants as well as blockade of neuronal catecholamine reuptake. Sinus tachycardia is generally well-tolerated and requires no therapy. Sinus tachycardia with QRS prolongation may be difficult to distinguish from ventricular tachycardia. Electrocardiograms obtained using oesophageal or atrial electrodes may be useful in determining the relationship of atrial and ventricular activity. Although QRS prolongation alone is not compromising, it is a marker for patients at highest risk of developing seizures, arrhythmias or hypotension. Ventricular tachycardia (monomorphic) is a consequence of impaired myocardial depolarisation and impulse conduction. Hypertonic sodium bicarbonate may partially correct impaired conduction and be of benefit in treating ventricular tachycardia. Since hypertonic sodium bicarbonate appears to act by increasing the extracellular sodium concentration as well as by increasing extracellular pH, hyperventilation may be less effective. Hypertonic sodium bicarbonate is of particular benefit in patients who are acidotic, since acidosis aggravates cardiac toxicity. However, administration of hypertonic sodium bicarbonate is beneficial even when blood pH is normal. Lignocaine (lidocaine) may be useful in treating ventricular tachycardia but should be administered cautiously to avoid precipitating seizures. Ventricular bradyarrhythmias are due to impaired automaticity or depressed atrioventricular conduction and can be treated by placement of a temporary pacemaker, or with a chronotropic agent, e.g. isoprenaline (isoproterenol), with or without concomitant vasoconstrictors.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Poisoning due to class 1B antiarrhythmic drugs. Lignocaine, mexiletine and tocainide.
Since most of the toxicity associated with class 1B antiarrhythmic drugs is dose-related, this review examines adverse effects seen in both therapeutic practice and accidental or premeditated overdose. Toxicity is very common with these agents and can be life-threatening. A high percentage of patients must discontinue therapy because of adverse effects. Mexiletine and tocainide are structural analogues of lignocaine (lidocaine) and toxicity is similar with all 3 drugs. With gradual intoxication (the most common form) central nervous system effects such as lightheadedness, dizziness, drowsiness and confusion are seen first. Seizures and respiratory arrest can occur. Cardiovascular toxicity is manifested by progressive heart block, reduced cardiac contraction, hypotension and asystole. Both mexiletine and tocainide may have proarrhythmic effects. Gastrointestinal toxicity is also common. Shock, hypotension, cardiac failure and beta-blocker therapy reduce lignocaine clearance and enhance the risk of intoxication during routine therapy. Both lignocaine and mexiletine elimination is impaired in severe liver disease while tocainide clearance is reduced in renal failure. Management of toxicity is largely supportive and symptomatic. Lignocaine infusion must be discontinued and decontamination of the gut in the case of oral preparations is recommended. Serious intoxication requires intensive care unit admission. Haemodialysis or haemoperfusion may be helpful in serious lignocaine and tocainide poisoning. In institutions where extracorporeal circulatory assistance is available, massive lignocaine poisoning has been successfully treated with this intervention. In the therapeutic setting serious toxicity can be prevented by close clinical surveillance and appropriate dose reduction in patients with reduced drug clearance. Because of the large interindividual variation in lignocaine pharmacokinetic parameters, therapeutic drug monitoring is recommended if results can be reported quickly. Mexiletine and tocainide have stereoselective metabolism and assays do not distinguish the more active isomers. Therapeutic drug monitoring is less useful in this situation.
Anti-Arrhythmia Agents↗
Clinical pharmacology of nicotine.
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Humans↗
Metabolism of nicotine by human liver microsomes: stereoselective formation of trans-nicotine N'-oxide.
Liver microsomes from humans catalyze the NADPH-dependent oxidation of (S)-nicotine. The principal product is the 5'-carbon atom oxidation product, nicotine delta 1',5'-iminium ion, which is efficiently converted to the gamma-lactam derivative cotinine in the presence of aldehyde oxidase. Another major product is nicotine N'-oxide. In contrast to previous reports describing in vitro or in vivo studies, formation of only trans-nicotine N'-oxide was observed. Demethylation of nicotine was not observed. Studies on the biochemical mechanism of nicotine 5-carbon atom oxidation strongly implicate one major cytochrome P-450 isoenzyme (i.e., P-450 2A6) as largely responsible for delta 1',5'-iminium ion formation. Stereoselective formation of trans-nicotine N'-oxide may be catalyzed in large part by the flavin-containing monooxygenase (form II). These conclusions are based on the effects of alternate substrates for the flavin-containing monooxygenase, heat inactivation studies, immunoblot studies, and selective substrates for cytochromes P-450. The results suggest that (S)-nicotine trans N'-oxygenation and delta 1',5'-iminium ion formation may be selective probes of human liver flavin-containing monooxygenase form II and cytochrome P-450 2A6 activities, respectively, useful for in vivo phenotyping of humans.
Chromatography, High Pressure Liquid↗
Stereoselective metabolism of (S)-(-)-nicotine in humans: formation of trans-(S)-(-)-nicotine N-1'-oxide.
The chemical synthesis and chromatographic separation of cis- and trans-(S)-nicotine N-1'-oxide diastereomers have allowed the development of methods for the quantification of (S)-nicotine N-1'-oxides during in vitro and in vivo metabolic studies. The metabolism of (S)-nicotine was investigated in the presence of microsomes, cDNA-expressed and highly purified flavin-containing monooxygenase (FMO) from pig liver, human liver, and rabbit lung. For comparison, the N-1'-oxidation of (S)-nicotine in the presence of the cytochrome P450 2B1 from rat liver, cytochrome P450 2B10 from mouse liver, and cytochrome P450 4A2 from rabbit lung was examined. The ratio of trans:cis (S)-nicotine N-1'-oxide formation for pig liver FMO1 (form 1) was 57:43. In contrast, cDNA-expressed adult human liver FMO3 (form 3) and rabbit lung FMO2 formed solely trans-(S)-nicotine N-1'-oxide. Of the cytochrome P450 enzymes examined, formation of (S)-nicotine N-1'-oxide occurred with a mean trans:cis ratio of 82:18. The stereoselectivity of (S)-nicotine N-1'-oxide formation was investigated by examining the urine of 13 healthy male smokers studied on a protocol which included free-smoking, intravenous infusion of (S)-nicotine-d2 and dermal patch administration of (S)-nicotine-d0. During cigarette smoking or administration of intravenous or transdermal (S)-nicotine, only the trans diastereomer of (S)-nicotine N-1'-oxide was observed in the urine. That the trans-(S)-nicotine N-1'-oxide metabolite was not appreciably reduced or oxidized further was investigated with infusion studies of (S)-nicotine-d2N-1'-oxide.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Systemic nicotine exposure in tobacco harvesters.
Several epidemics of nicotine intoxication have been described among tobacco harvesters; however, little is known about nicotine absorption under typical working conditions. To assess systemic nicotine absorption during a regular working shift, the authors performed an observational field study. Included in the study were 10 healthy, nonsmoking, female tobacco harvesters and a control group of 5 healthy, nonsmoking, female hospital workers. Nicotine and cotinine were measured in sequential samples of blood and urine during a regular workshift. Blood nicotine levels rose from a nadir value of 0.79 +/- 0.12 ng/ml to a peak value of 3.45 +/- 0.84 ng/ml (p < .05 [Tukey's modified t test]) in the exposed group. In the control group, levels were stable at 0.1 +/- 0.1 ng/ml (p < .01). Moreover, the mean blood nicotine level measured 3 mo following the end of exposure in 6 of 10 exposed subjects was 0.24 +/- 0.12 ng/ml (p < .01). Corresponding higher values of urine nicotine and urine cotinine were observed in the exposed versus control group (comparative p values were < .01 and < .05, respectively). Overall, tobacco harvesters absorbed approximately 0.8 mg of nicotine daily. Given that nicotine can induce adverse health effects, the authors believe that prevention of nicotine absorption in tobacco harvesters should be sought and that workers should be informed about occupational risks.
Adult↗
Evaluation of urinary trans-3'-hydroxycotinine as a biomarker of children's environmental tobacco smoke exposure.
The utility of urinary trans-3'-hydroxy cotinine (3HC) as a biomarker of environmental tobacco smoke (ETS) exposure was investigated in comparison with urinary cotinine (COT), the sum (3HC + COT), and ratio of the two nicotine metabolites (3HC/COT). Participants were 150 ETS exposed children (aged 1-44 months) and their parents. Child urine samples were collected during 3weekly baseline assessments and at interviews administered 3, 6, 12, and 18 months after baseline. Findings indicate that 3HC and COT can be measured reliably (rho = 0.96, 0.88) and show equivalent levels of repeated measures stability (rho = 0.71, 0.75). COT, 3HC, and 3HC + COT showed equally strong associations with air nicotine levels, reported ETS contamination, and reported ETS exposure (r=0.60-0.70). The intraclass correlations of 3HC/COT were lower than those for COT or 3HC. Older children had a higher 3HC/COT ratio than younger children (3.5 versus 2.2), and non-Hispanic White children had a higher ratio than African-American children (3.2 versus 1.9). These findings suggest that COT, 3HC, and 3HC + COT are approximately equivalent and equally strong biomarkers of ETS exposure in children. Moreover, 3HC/COT may provide a useful indicator to investigate age- and race-related differences in the metabolism of COT and 3HC.
Age Factors↗
Determination of methadone and its primary metabolite in biologic fluids using gas chromatography with nitrogen-phosphorus detection.
A method is described for the determination of methadone and its primary metabolite, 1,5-dimethyl-3,3-diphenyl-2-ethylidinepyrrolidine, in biologic fluids using gas chromatography with nitrogen-phosphorus detection. A simple extraction scheme is employed that is convenient for processing the large numbers of samples generated in pharmacokinetic studies. The method is sensitive enough for accurate determination of concentrations less than 5 ng/mL of both methadone and its primary metabolite in 1 mL of biologic specimens.
Chromatography, Gas↗
Caffeine effects on learning, performance, and anxiety in normal school-age children.
OBJECTIVE: The purpose of this investigation was to study the acute effects of caffeine on learning, performance, and anxiety in normal prepubertal children. METHOD: Twenty-one children were evaluated in a double-blind, placebo-controlled crossover design. Subjects were studied during four sessions, 1 week apart, under the following conditions: baseline, placebo, 2.5 mg/kg caffeine, and 5.0 mg/kg caffeine. Subjects were randomized to order of placebo and the two dosages of caffeine. Dependent measures included tests of attention, manual dexterity, short-term memory, and processing speed. Anxiety rating scales were also administered. Saliva samples were analyzed for caffeine levels. RESULTS: Caffeine improved performance on two of four measures of the Test of Variables of Attention and on a test of manual dexterity in the dominant hand. There was a trend toward increased current level of self-reported anxiety after caffeine on a visual analogue measure of anxiety. Children reported feeling significantly less "sluggish" after caffeine ingestion than after placebo ingestion. CONCLUSIONS: In a small sample size, there was indication that caffeine enhanced performance on a test of attention and on a motor task. Children also reported feeling less "sluggish" but somewhat more anxious. Because caffeine is so widely available and frequently consumed by children, these results are important and need replication.
Anxiety↗
Poisoning due to class IA antiarrhythmic drugs. Quinidine, procainamide and disopyramide.
Quinidine, procainamide and disopyramide are antiarrhythmic drugs in the class 1A category. These drugs have a low toxic to therapeutic ratio, and their use is associated with a number of serious adverse effects during long term therapy and life-threatening sequelae following acute overdose. Class 1A agents inhibit the fast inward sodium current and decrease the maximum rate of rise and amplitude of the cardiac action potential. Prolonged Q-T interval and, to a lesser extent, QRS duration may be observed at therapeutic concentrations of quinidine. With increasing plasma concentrations, progressive depression of automaticity and conduction velocity occur. 'Quinidine syncope' (a transient loss of consciousness due to paroxysmal ventricular tachycardia, frequently of the torsade de pointes type) occurs with therapeutic dosing, often in the first few days of therapy. Extracardiac adverse effects of quinidine include potentially intolerable gastrointestinal effects and hypersensitivity reactions such as fever, rash, blood dyscrasias and hepatitis. Procainamide produces electrophysiological changes that are similar to those of quinidine, although Q-T interval prolongation with the former is less pronounced at therapeutic concentrations. Hypersensitivity reactions including fever, rash and (more seriously) agranulocytosis are associated with procainamide, and a frequent adverse effect requiring cessation of therapy is the development of systemic lupus erythematosus. Of the 3 drugs, disopyramide has the most pronounced negative inotropic effects, which are especially significant in patients with pre-existing left ventricular dysfunction. As with quinidine, unexpected 'disopyramide syncope' at therapeutic concentrations has been described. Anticholinergic side effects are common with this drug and may require cessation of therapy. Disopyramide therapy may unpredictably induce severe hypoglycaemia. Severe intoxication with the class 1A agents may result from acute accidental or intentional overdose, or from accumulation of the drugs during long term therapy. Acute overdose can result in severe disturbances of cardiac conduction and hypotension, frequently accompanied by central nervous system toxicity. Decreased renal function can cause significant accumulation of procainamide and its active metabolite acecainide (N-acetyl-procainamide), resulting in severe intoxication. Mild to moderate renal dysfunction is less likely to lead to quinidine or disopyramide intoxication, unless renal failure is severe or concurrent hepatic dysfunction is present. Management of acute intoxication with class 1A drugs includes gut decontamination with provision of respiratory support and treatment of seizures as needed. Hypertonic sodium bicarbonate, by antagonising the inhibitory effect of quinidine on sodium conductance, may reverse many or all manifestations of cardiovascular toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Poisoning due to calcium antagonists. Experience with verapamil, diltiazem and nifedipine.
The calcium antagonists are a heterogeneous class of drugs which block the inward movement of calcium into cells through 'slow channels' from extracellular sites. By inhibiting phase 0 depolarisation in cardiac pacemaker cells and phase 2 plateau in myocardium, and by depressing calcium ion flux in smooth muscle cells of blood vessels, these agents may exert profound effects on the cardiovascular system, particularly in susceptible individuals or in overdose. Sinus node depression, impaired atrioventricular (AV) conduction, depressed myocardial contractility, and peripheral vasodilatation may result. Pharmacokinetic features of calcium antagonists include rapid and complete absorption from the gastrointestinal tract, with extensive first-pass hepatic metabolism yielding generally low bioavailability. The volume of distribution is generally large and protein binding is high. Elimination is almost entirely by the liver. Impaired renal function does not affect pharmacokinetics. Verapamil is the most potent inhibitor of cardiac conduction and contractility, with diltiazem also showing such effects. Nifedipine is the most potent vasodilator, but only occasionally impairs the sinus node or AV conduction. Significant pharmacodynamic effects are common during combination therapy with calcium antagonists, especially verapamil and beta-blockers. Verapamil may significantly elevate serum digoxin concentrations and may exert additive negative effects on chronotropism and dromotropism when this combination is used. Overdoses of calcium entry blockers are becoming more frequent and reflect an extension of the known pharmacodynamic profile of these agents. Typical features include confusion or lethargy, hypotension, sinus node depression and cardiac conduction defects. Onset of symptoms may be delayed if a sustained release preparation is ingested. Management of calcium antagonist overdose includes gut decontamination with lavage and activated charcoal. All symptomatic patients and patients with a history of ingesting a sustained release preparation should be admitted for ECG monitoring. If bradycardia and/or conduction defects contribute to hypotension, atropine or isoprenaline (isoproterenol) may accelerate the ventricular rate. Transvenous pacing may be required. Depressed myocardial contractility usually responds well to calcium chloride or calcium gluconate administration, but further inotropic support may be required. Peripheral vasodilation should be managed with intravenous fluids and a pressor agent such as dopamine or norepinephrine (noradrenaline).
Calcium Channel Blockers↗
Pharmacokinetics in patients with cardiac failure.
Cardiac failure is often associated with disturbances in cardiac output, autonomic nervous system activity, central and systemic venous pressures, and sodium and water metabolism. These disturbances influence the extent and pattern of tissue perfusion, may lead to tissue hypoxia and visceral congestion, and may alter gastrointestinal motility. By these mechanisms, cardiac failure potentially affects absorption and disposition characteristics of drugs, which may necessitate adjustment in dosage regimen for optimum therapy. Lignocaine is the drug which has been studied most extensively in cardiac failure. Volumes of distribution and clearance are decreased. As a drug whose metabolism is largely limited by liver blood flow, decreased blood flow to the liver accounts for some of the change in clearance, but impaired hepatic metabolism appears also to play a role in some patients. Accumulation of active metabolites of lignocaine and procainamide in patients with cardiac failure can influence therapeutic and toxic effects. Theophylline metabolism, which is largely independent of blood flow, appears to be reduced significantly in patients with severe cardiac failure and necessitates reduction of dosage. In the presence of severe cardiac failure, digoxin clearance may be less than anticipated on the basis of estimates of renal function. Quinidine plasma levels may be higher after single doses due to reduced volume of distribution. Quinidine metabolites are believed not to be pharmacologically active but may create confusion with nonspecific assays. Specific assays are recommended in cardiac failure, especially complicated by renal insufficiency. Data are lacking relating pharmacokinetic alterations to haemodynamic measurements in patients with cardiac failure. Whereas the direction of change in pharmacokinetic parameters may be predicted, variability in the magnitude of change is so great that determination of drug concentration in blood remains as essential adjunct to therapy.
Absorption↗
Clinical pharmacokinetics of lignocaine.
Lignocaine is widely used as a local anaesthetic and antiarrhythmic drug. It is commonly administered to patients with acute myocardial infarction as prophylaxis for ventricular fibrillation, although its efficacy in preventing primary ventricular fibrillation is still debated. Toxicity, sometimes with serious clinical consequence, is not uncommom and is usually related to overdosage. Blood lignocaine concentrations correlate roughly with antiarrhythmic and toxic effects and might be useful as an end point for monitoring prophylactic therapy. Administration of lignocaine as a local anaesthetic may result in blood lignocaine concentration in the antiarrhythmic or even toxic ranges. Expected peak levels for various routes of local anaesthesia are tabulated so that 'safe' total doses can be calculated. Intramuscular injection of high doses results in sustained therapeutic levels but is often associated with early minor toxicity. Lignocaine is eliminated primarily by hepatic metabolism, which appears to be limited by liver perfusion. Active metabolites may contribute to therapeutic and/or toxic effects. Disease states such as cardiac failure or drugs that alter hepatic blood flow may significantly affect lignocaine clearance. Pharmacokinetic studies in man show wide variability in drug disposition between patients, even when cardiac and hepatic status is considered, making specific dosing recommendations a problem. With intravenous injection, multicompartment kinetics is observed, with an initial rapid decline phase and initial decline in antiarrhythmic activity due to redistribution. With constant infusion, steady state concentrations of lignocaine are seen after 3 to 4 hours in normal subjects and after 8 to 10 hours in patients with myocardial infarction without circulatory insufficiency. In patients with cardiac failure, blood lignocaine concentration may continue to rise for 24 to 48 hours. In the presence of cardiac failure, decreased volumes of distribution and clearance require reduction in loading and maintenance doses. Lignocaine clearance is reduced in patients with liver disease and appears to be a sensitive index of liver dysfunction. A dosing algorithm for treatment of patients with myocardial infarction is presented.
Absorption↗