Steven Schenker

The effects of age and liver disease on the disposition and elimination of diazepam in adult man.

This study investigates the separate effects of age and hepatocellular liver disease on the disposition and elimination of diazepam (Valium) in man. The drug was given either by rapid intravenous injection (0.1 mg/kg) or orally (10 mg) to 33 normal volunteers rnaging in age from 15 to 82 yr as well as to 9 individuals with alcoholic cirrhosis, 8 with acute viral hepatitis, and 4 with chronic active hepatitis. In the normal individuals, the terminal plasma half-life of diazepam, (t 1/2 (B)) exhibited a striking age-dependence; at 20 yr the t 1/2 (beta) was about 20 h, but it increased linearly with age to about 90 h at 80 yr. The plasma clearance of diazepam in the majority of the normal subjects was between 20 and 32 ml/min and showed no significant age-dependence. Cigarette smoking did not affect the half-life or the clearance. Additionally, neither the plasma binding (97.4 plus or minus 1.2%, mean plus or minus SD) nor the blood/plasma concentration ratio (0.58 plus or minus 0.16) of diazepam showed any age-related changes (P greater than 0.05). By contrast, analysis of the intravenous data according to a two-compartment open model indicated that both the initial distribution space (V1) and the volume of distribution at steady state [Vd(ss)] of diazepam increased linearly with age (P less than 0.005). The increase in Vd(ss) was secondary to the change in V1. It appears then that the prolongation of t 1/2 (beta) of diazepam with age is primarily dependent on an increase in the initial distribution volume of the drug. The plasma concentration/time course of the metabolite, desmethyldiazepam, was also affected by age. In older individuals, the initial presence and the peak values of desmethyldiazepam were observed later and the metabolite was present in lower concentrations. Despite the profound prolongation of t 1/2 (theta) with age, the constancy of diazepam clearance indicates that drug plasma concentrations will not accumulate any more in the old than the young, and chronic dosage more in the old than the young, and chronic dosage modifications based on pharmacokinetic considerations are unnecessary. Data obtained in patients with liver disease were compared with those found in age-matched control groups. Patients with cirrhosis showed a more than twofold prolongation in the half-life of diazepam (105.6 plus or minus 15.2 vs. 46.6 plus or minus 14.2 h, P less than 0.001).

Effects of aging and liver disease on disposition of lorazepam

The disposition of lorazepam after intravenous administration (2 mg) was investigated in patients with alcoholic cirrhosis and acute viral hepatitis, and compared to that in normal subjects ranging in age from 15 to 73 yr. No statistically significant age‐dependent relationships in the drugs pharmacokinetic parameters were observed. Cirrhosis was associated with a doubling of the mean elimination half‐life (21.7 ± 7.6 to 41.2 ± 24.5 hr). This was due to a similar increase in the volume of distribution of lorazepam, caused by a reduction in the extent of the drugs plasma binding (88.6 ± 2.5 from 93.2 ± 1.8). No changes in systemic plasma clearance of either the unbound (about 11 ml/min/kg) or bound plus unbound (about 0.75 ml/min/kg) lorazepam, or urinary recovery of conjugated drug (about 50%) were detected. In contrast, there were no significant changes in the kinetics of lorazepam in the patients with acute viral hepatitis. Comparison of lorazepams systemic plasma clearance in the liver disease patients in whom studies with antipyrine and chlordiazepoxide had also been performed indicated impairment in their values but this was not the case for lorazepam. It is concluded that the degree of impairment, if any, in the metabolism of lorazepam in patients with liver disease is considerably less than that of certain other drugs including related benzodiazepines. Aging also does not lead to alterations either in distribution or metabolism as have been observed with other benzodiazepines. It is speculated that these observations may reflect characteristics of the drugs associated with their metabolic fate, i.e., glucuronidation or oxidative biotransformation.

Normal Disposition of Oxazepam in Acute Viral Hepatitis and Cirrhosis

Oxazepam (Serax) is a tranquilizer-sedative of the benzodiazepine group that is predominantly metabolized to a pharmacologically inactive glucuronide and subsequently excreted by way of the kidneys. We administered this drug as a single oral dose to seven patients with acute viral hepatitis, to six with cirrhosis, and to age-matched control subjects. Elimination half-life (T1/2) and the apparent oral plasma clearance for the drug in patients with hepatitis and cirrhosis were comparable to values obtained in age-matched controls (P greater than 0.05). In addition, the apparent volume of distribution of oxazepam, its plasma binding, blood/plasma ratio, and the rate of urinary excretion of oxazepam, predominantly as the glucuronide, were comparable (p greater than 0.05) in the two groups of patients with liver disease and their respective controls. Unlike many other sedatives, oxazepam is eliminated normally in patients with parenchymal liver disease an therefore, on pharmacokinetic grounds, seems to be an excellent sedative for use in such persons.

Amylase—its Clinical Significance: A Review Of The Literature

This review of the English literature on amylase was undertaken because no recent discussion of the subject could be located, no comprehensive list of disorders causing hyperamylasemia or hyperamylasuria is available, and several major advances in the area have been made, notably the amylase isoenzyme determination and Cam/Ccr ratio. Several important concepts have emerged from this review. First, hyperamylasemia and hyperamylasuria are not specific indices of the presence of pancreatic disease or damage. Second, serum and urinary amylase levels can be spuriously normal with hypertriglyceridemia and pancreatitis. Third, the current emphasis on diagnostic methods for measuring serum amylase isoenzymes promises to improve the specificity of this determination. It will also enhance our understanding of the sources, distribution, metabolism, and elmination of amylase. Fourth, the development of the Cam/Ccr ratio may provide a practical diagnostic tool for separating clinically significant hyperamylasemia due to pancreatitis from that caused by other factors. Both the the isoamylase determination and Cam/Ccr ratio clearly require future research to place their clinical application in the proper perspective.

Studies on the Intracerebral Toxicity of Ammonia

Interference with cerebral energy metabolism due to excess ammonia has been postulated as a cause of hepatic encephalopathy. Furthermore, consideration of the neurologic basis of such features of hepatic encephalopathy as asterixis, decerebrate rigidity, hyperpnea, and coma suggests a malfunction of structures in the base of the brain and their cortical connections. The three major sources of intracerebral energy, adenosine triphosphate (ATP), phosphocreatine, and glucose, as well as glycogen, were assayed in brain cortex and base of rats given ammonium acetate with resultant drowsiness at 5 minutes and subsequent coma lasting at least 30 minutes. Cortical ATP and phosphocreatine remained unaltered during induction of coma. By contrast, basilar ATP, initially 1.28 +/- 0.15 mumoles per g, was unchanged at 2.5 minutes but fell by 28.1, 27.3, and 26.6% (p < 0.001) at 5, 15, and 30 minutes after NH(4)Ac. At comparable times, basilar phosphocreatine fell more strikingly by 62.2, 96, 77.1, and 71.6% (p < 0.001) from a control level of 1.02 +/- 0.38 mumoles per g. These basilar changes could not be induced by anesthesia, psychomotor stimulation, or moderate hypoxia and were not due to increased accumulation of ammonia in the base. Glucose and glycogen concentrations in both cortex and base fell significantly but comparably during development of stupor, and prevention of the cerebral glucose decline by pretreatment with glucose did not obviate ammonia-induced coma or the basilar ATP fall. These findings represent the first direct evidence that toxic doses of ammonia in vivo acutely affect cerebral energy metabolism and that this effect is preferentially localized to the base of the brain.

Cimetidine impairs elimination of chlordiazepoxide (librium) in man

We have studied chlordiazepoxide (Librium) disposition and elimination in eight normal subjects before and after 1 week of cimetidine therapy, 300 mg orally four times a day. Cimetidine strikingly impaired the clearance of chlordiazepoxide from plasma, and this was, at least in part, due to decreased demethylation of the drug to N-desmethylchlordiazepoxide. Since the volume of distribution of chlordiazepoxide was not altered by cimetidine, the elimination half-life of chlordiazepoxide was also significantly prolonged by cimetidine therapy.

Normal Metabolism of Morphine in a Cirrhosis

Morphine disposition and elimination was studied in 6 healthy male subject s and 6 male patients with cirrhosis, to assess the role of differences, if any, on the reported intolerance of morphine in cirrhosis. In addition the elimination of indocyanine green was studied in the same subjects on a separate occasion. The elimination half-life of indocyanine green was increased and its plasma clearance was markedly reduced in patients with cirrhosis as compared with controls (p less than 0.05). In contrast the disposition and elimination of morphine were unaffected by moderate to severe cirrhosis. Furthermore, while marked sedation was observed in normal subjects, the cirrhotics demonstrated mild sedation with no clinical evidence of hepatic coma. The normal elimination of morphine in cirrhosis is in contrast to the decreased elimination of high clearance drugs metabolized by oxidation, such as lidocaine and meperidine. Morphine is also normally a high clearance drug that is detoxified by conjugation with glucuronic acid. Since intra- or extrahepatic shunting, or both, in cirrhosis do not significantly impair morphine clearance, we postulate that significant extrahepatic morphine conjugation may occur in both normal subjects and in patients with cirrhosis. Furthermore, the reported morphine intolerance to the central effects of morphine cannot be explained by impaired drug elimination and increased availability of morphine to cerebral receptors.

Fatty liver: biochemical and clinical considerations.

Fatty liver may be defined as an acctJmulation of lipid, consisting principally of triglycerides in most cases, which exceeds 5~ of the liver weight. The clinical importance of excess fat varies with its cause and quantity. In some instances (ie, obesity) it may be of little consequence, whereas in others (ie, fatty liver of pregnancy) it may lead to hepatic failure and death. The aim of this brief review is to summarize the main clinical and biochemical features of the principal conditions associated with significant fatty infiltration of the liver as the primary pathologic finding.

The effect of cirrhosis on the disposition and elimination of meperidine in man

The disposition and elimination of meperidine were compared in drug and alcohol‐free, age‐matched groups of 8 normal volunteers and 10 patients with cirrhosis of the liver, while controlling the urinary pH at 7.0 or more. After a single rapid intravenous injection, 0.8 mg/kg, plasma meperidine concentration declined biexponentially with the fast (α) and slow (ß) phases having half‐lives in the normal group of 0.19 hr and 3.2 hr (mean values), respectively. In the cirrhotics T½α was not changed but T½ß increased to 7.0 hr (p < 0.001), and this was associated with a reduction in the total plasma meperidine clearance from 1,316 ml/min to 664 ml/min (p < 0.002). Analysis of the data by a two‐compartment open model indicated that meperidine was extensively distributed; initial distribution volume (V1)2 1.54 lIkg and volume of distribution at steady‐state (Vdss), 4.17 lIkg in control subjects. Similar volumes of distribution were noted in cirrhotic patients. The overall first‐order elimination rate constant, k13, decreased from 0.672 hr‐1 in the normal subjects to 0.242 hrs in the cirrhotics (p < 0.001). The plasma binding (64.3%) and the blood/plasma concentration ratio (0.683) of meperidine in control subjects were not altered in cirrhosis. There were no Significant correlations found between T½ß or plasma clearance in the cirrhotics and the usual biochemical hepatic function tests. The metabolite, normeperidine, was not detected in the plasma of either group. It is concluded that the elimination of meperidine is prolonged in cirrhosis, probably due to impairment of drug‐metaboliZing activity in the liver. Accordingly, caution should be exercised when this drug is administered, particularly for long periods, to patients with cirrhosis.

Hepatic Encephalopathy: Current Status

The neuropsychiatric syndrome seen secondary to liver disease is called hepatic coma or encephalopathy, the latter term describing more comprehensively the wide neurological spectrum of this disorder. Many aspects of this subject have recently been discussed. 1 This review focuses on selected clinical features , discusses current concepts of pathology and pathogenesis, and assesses the present status of therapy of this disorder.