Barbara Ameer

Obesity, sex, and acetaminophen disposition.

Twenty‐one obese (14 women; 7 men) and 21 normal (11 women; 10 men) drug‐free and age‐matched subjects were given single 650‐mg IV doses of acetaminophen. Mean total body weights (TBW) for the groups were as follows: obese men, 134.9 kg; control men 70.6 kg; obese women, 87.9 kg; and control women, 55.0 kg; ideal body weight (IBW) was similar for all of the groups. Acetaminophen elimination half‐life (t½β) did not differ among groups. Absolute volume of distribution (Vd) was greater in obese than in control men (109 and 77 l, P < 0.05) and greater in control men than in control women (77 and 52 l, P < 0.05), but Vd corrected for TBW was smaller in obese than in control men (0.81 and 1.09 11 kg TBW, P < 0.05) and smaller in obese than control women (0.71 and 0.95 l/kg TBW, P < 0.05). Absolute metabolic clearance was greater in obese than in control men (484 and 323 ml / min, P < 0.05), in obese than in control women (312 and 227 ml/min, P < 0.05), and in control men than women (323 and 227 ml/min, P < 0.05). After correction for TBW, however, clearance between control and obese subjects of the same sex did not differ. Acetaminophen Vd is increased in obesity and in men relative to women, but the drugs distribution into body weight exceeding IBW is less extensive than that into IBW. For men the distribution ratio is 0.44 and for women, 0.31. Acetaminophen clearance increases with body weight and therefore is much greater in obese patients and in men.

Acetaminophen kinetics in the elderly.

Thirty‐two healthy men and women, 23 to 78 yr old, received single 650‐mg intravenous doses of acetaminophen and the drugs kinetics were determined from multiple plasma samples drawn over the next 8 to 12 hr. Acetaminophen elimination half‐life averaged 2.7 hr (range, 1.9 to 4.3 hr) and was not related to age or sex. Volume of distribution (corrected for weight) was larger in men than in women (0.99 and 0.86 l/kg) and declined with age in both sexes. This probably reflects increased fat per kilogram body weight in women and in the elderly, together with incomplete distribution of this nonlipophilic drug into body fat. Acetaminophen clearance tended to decline with age in both sexes, but differences were of borderline significance. On the basis of kinetic data alone, adjustment of acetaminophen dosage for the elderly is generally not necessary.

Lorazepam: A Review of its Clinical Pharmacological Properties and Therapeutic Uses

SummarySynopsis: Lorazepam1 is a 3- hydroxy- 1,4- benzodiazepine derivative in clinical use as a sedative, antianxiety and hypnotic agent. The 3-hydroxy configuration of lorazepam results in pharmacokinetic properties similar to those of oxazepam and temazepam. Unlike diazepam, lorazepam is not transformed into active metabolic products and has a relatively short half-life. However, because of differences in the lipophilicity and extent of tissue distribution, intravenous lorazepam has a slower onset of action and appears to have a longer duration of action than single doses of diazepam. Controlled therapeutic trials have shown lorazepam to be more effective than placebo as a hypnotic, in treatment of acute and chronic anxiety, in anxiety associated with functional or organic diseases and for surgical premedication. When lorazepam and diazepam have been compared at a dosage ratio of 1: 5, most studies have reported similar efficacy and tolerability. The most commonly reported side effects are dose-related consequences of central nervous system depression. Local complications following intravenous injection of lorazepam appear to occur less frequently than with diazepam. Pharmacokinetics: Lorazepam is a 3-hydroxy-1,4-benzodiazepine derivative in clinical use as a sedative, antianxiety, and hypnotic agent. The 3-hydroxy configuration of lorazepam renders it similar in its pharmacokinetic properties to oxazepam and temazepam. The major metabolic pathway of lorazepam in humans involves direct conjugation to glucuronic acid, yielding a water-soluble glucuronide metabolite. As such, the metabolic profile of lorazepam is straightforward, and does not involve transformation into active metabolic intermediates as is the case with benzodiazepines such as diazepam and chlordiazepoxide. Because glucuronide conjugation in humans proceeds at a faster rate than does oxidation, the half-life of lorazepam is considerably shorter than that of benzodiazepines such as diazepam. Furthermore, it appears that factors such as old age and hepatocellular disease have less effect on the disposition of lorazepam than on the pharmacokinetics of benzodiazepines such as diazepam that are transformed by oxidative mechanisms. Because the lipophilicity of lorazepam is much less than that of the prototype benzodiazepine, diazepam, the onset of clinical activity of intravenous lorazepam following a single dose is much slower than that of diazepam. This effect can be attributed to the slower rate of lorazepam’s passage across the blood brain barrier. Since the extent of tissue distribution of lorazepam also is less than that of diazepam, single doses of lorazepam will appear to have a longer duration of action than will single doses of diazepam. The pharmacodynamic profile of lorazepam in contrast to that of diazepam thus appears ‘paradoxical’ when one compares the difference in their elimination half-life. Physiological Effects: Lorazepam rapidly penetrates the central nervous system (CNS) after intravenous administration and produces dose-dependent CNS depression. Consequently, lorazepam at dosages of 1 mg or more causes sedation, impairment of psychomotor performance and visual function, and produces anterograde, but not retrograde, amnesia. Effects of usual therapeutic dosages have minimal effects on cardiovascular or on respiratory function in healthy subjects. Lorazepam may produce mild respiratory depression in patients with pulmonary disease. Therapeutic Studies: The principal uses of lorazepam in clinical practice include its administration as a sedative or sleep-inducing agent, and as an antianxiety agent for ambulatory and hospitalised individuals. Lorazepam also finds considerable use as a premedicant drug prior to surgical procedures. Lorazepam is an effective sleep-inducing or hypnotic agent in usual therapeutic doses of 2 to 4mg at bedtime. Both clinical efficacy and the occurrence of unwanted morning ‘hangover’ effects are related to dose, and clinicians must weigh the more predictable efficacy of higher doses against the greater likelihood of morning hangover. Parenteral lorazepam also has been used to maintain a state of sedation and muscle relaxation in patients undergoing assisted ventilation. Acute episodes of severe anxiety or panic also are effectively treated by lorazepam, particularly by the parenteral route. The most widespread use of lorazepam is in the treatment of ambulatory individuals with neurotic anxiety. The usual range of effective doses is 2 to 6mg per day, in divided doses. The majority of controlled clinical trials involving this disorder last 3 to 4 weeks; understanding of lorazepam’s benefits and potential hazards for periods longer than 10 weeks is lacking. Numerous controlled trials clearly demonstrate that lorazepam is more effective than placebo in the treatment of anxiety.When compared with diazepam, at a dosage ratio of 1: 5 the majority of controlled trials indicate that lorazepam and diazepam are approximately equivalent in efficacy. Furthermore, the incidence of unwanted side effects (primarily drowsiness and oversedation) with both drugs is similar, and appears to be dose-dependent. A few of the studies suggest that lorazepam has greater efficacy and possibly less unwanted toxicity than diazepam, but this is not a consistent finding. Lorazepam has been extensively evaluated in the treatment of anxiety associated with functional or organic medical diseases. Again, lorazepam is clearly superior to placebo in such disorders. However, its efficacy is largely confined to improvement of the anxiety component of the disease process. Lorazepam should not be expected to produce improvement as such in the natural course of medical disease, such as hypertension, ischaemic cardiovascular disease, or peptic ulcer disease.Lorazepam also finds considerable use as a premedicant prior to diagnostic or surgical procedures. The anterograde antirecall properties of lorazepam are particularly useful in this context. The sedative, anxiolytic and amnesic effects of lorazepam when used as a premedicant are dose-dependent, and probably are of faster onset following parenteral as opposed to oral doses. The duration of lorazepam’s action after single doses may be considerably longer than that of comparable doses of diazepam. This property of lorazepam may be advantageous in some circumstances, but may also be a disadvantage when residual effects of premedicant administration are undesirable. An advantage of lorazepam, however, is that local complications following intravenous administration appear to be considerably less frequent than those associated with diazepam.Lorazepam does have properties that render it a useful addition to the existing group of benzodiazepine derivatives. However, the availability of lorazepam should not be construed as a remarkable ‘breakthrough’ in the treatment of anxiety. Side Effects: Adverse effects of lorazepam are largely comprised of predictable consequences of dose-dependent central nervous system depression. The most commonly reported adverse effects are drowsiness, oversedation, weakness, impaired coordination, and sometimes disorientation and confusion. These effects are almost always reversible upon reduction of dose. Reported drug interactions with lorazepam are rare, but more well controlled pharmacokinetic studies are needed of drug interactions with lorazepam. Data available to date suggest that the disposition of lorazepam in humans is minimally altered by old age or by the presence of renal or hepatic disease. There are relatively few reports of lorazepam overdosage. However, the findings suggest that, as in the case of other benzodiazepines, serious poisoning due to lorazepam alone is very unusual.

Effect of food on acetaminophen absorption in young and elderly subjects

Abstract: Twenty‐four healthy volunteers aged 22 to 78 years received 650‐mg doses of acetaminophen (AAP) on five separate occasions. The modes of administration were: intravenous AAP by 5‐minute infusion; oral AAP as two 325‐mg tablets in the fasting state; oral AAP 650 mg as an elixir preparation in the fasting state; tablets with food; and elixir with food. Plasma concentrations of AAP were determined by high‐pressure liquid chromatography for up to 12 hours after the dose. In both the young and the elderly groups, the four oral modes of administration were significantly different with respect to peak plasma concentration (P < 0.001), time to peak plasma concentration (P < 0.001), and systemic availability (P < 0.01). Although food slowed the rate of absorption of both oral preparations, no significant difference in peak acetaminophen plasma concentration or time of peak concentration was observed as a function of age. Absolute systemic availability of elixir and tablets in the fasting state tended to be lower in the elderly subjects (P < 0.05). However, when either preparation was coadministered with food, there were no differences between the two age groups. Thus, age as such does not appear to be a critical determinant in the design of oral acetaminophen dosage schedules.

Age Does Not Alter Acetaminophen Absorption

Twenty‐eight healthy volunteers (age range, 22–78 years) received 650 mg of acetaminophen (AAP) on three separate occasions. The modes of administration were 1) intravenous, 5‐minute infusion; 2) oral, with two 325‐mg tablets; and 3) oral, with 650 mg as an elixir preparation. Plasma levels of AAP were determined in blood samples drawn up to 12 hours after the dose. The mean (±SD) kinetic variables for absorption of AAP from tablets in young and elderly were peak plasma concentration, 11.8 (±4.2) vs 10.9 (±4.1) μg/ml; peak time, 0.79 (±.54) vs 0.69 (±.40) hours after the dose; absorption half‐life, 12.6 (±9.8) vs 8.2 (±5.3) minutes; and absolute systemic availability, 79 (±9) vs 72 (±11) per cent. For AAP elixir, the corresponding values were 12.6 (±5.4) vs 13.7 (±6.0) μg/ml; 0.52 (±.24) vs 0.54 (±.51) hours; 8.6 (±6.2) vs 6.1 (±6.6) minutes; and 87 (±9) vs 80 (±9) per cent. Absolute bioavailability of both oral dosage forms was significantly less than 100 per cent in all groups. Elderly subjects tended to show lower availability of both oral preparations, but the difference was of borderline significance (P < .05). Age did not influence any other measures of absorption. Since the absorption rate of acetaminophen may be indicative of the gastric emptying rate, age does not appear to alter this rate‐limiting step in drug absorption.