Kinetics of acetaminophen absorption and gastric emptying in man.

Eight healthy male volunteers ingested an aqueous solution containing acetaminophen (20 mg/kg) and a nonabsorbable isotopic marker. The concentrations of unconjugated acetaminophen in samples of blood plasma taken at frequent intervals were measured by gas-liquid chromatography. The data points followed a smooth curve in most cases and were fitted to the classical two-compartment pharmacokinetic model to obtain KA, the apparent first-order rate constant for absorption from the gastrointestinal tract. Gastric emptying was measured simultaneously from serial scintiscans of the subject's abdomen. The subjects were also studied after intramuscular injection of meperidine (150 mg) and pentazocine (60 mg) with and without naloxone (1.2 mg). The acetaminophen absorption curves and gastric emptying patterns were consistent with negligible absorption from the stomach. A new model is proposed in which the conventional single compartment used to represent the gastrointestinal tract is replaced by two compartments: one represents the stomach and the other the small intestine, from which absorption occurs rapidly. Pharmacokinetic analysis using this model showed good agreement in all cases, and provided an estimate of KA, the first-order rate constant for drug transfer from the intestinal lumen into the systemic circulation. The mean half-time for transfer was 6.8 +/- 0.9 min. As expected, KA was greater than KG (the first-order rate constant for gastric emptying), showing that gastric emptying was rate-limiting in the absorption of acetaminophen. The value of KA was greater than KA and the two were not related. The value of KA was not equal to KG in most studies because gastric emptying was not a single exponential process.

Drugs, diseases and altered gastric emptying.

Drugs are usually given orally. They are not absorbed to any extent from the stomach but may be absorbed very rapidly from the small intestine. Thus factors influencing the rate of gastric emptying may alter the rate of absorption of most if not all orally administered drugs. Food, hormones, posture, peritoneal irritation, severe pain, gastric ulcer, diabetes and other metabolic diseases, as well as drugs such as alcohol, anticholinergics, narcotic analgesics, ganglion blocking drugs, antacids and metoclopramide all influence the rate of gastric emptying and they will, in turn, change the rate of absorption of another drug. In most instances, increasing the rate of gastric emptying and gastro-intestinal motility increases the rate of absorption of a drug but, for digoxin and riboflavin, increased gastrointestinal motility is associated with a decrease in the rate of absorption. Delayed drug absorption due to altered gastric emptying usually results in therapeutic failure, especially if the drug has a short biological half-life. At present it is not possible to predict accurately the magnitude and clinical relevance of all drug absorption interactions.

New intravenous anaesthetics and neuromuscular blocking drugs. A review of their properties and clinical use.

The newer neuromuscular blocking drugs include vecuronium and atracurium. Vecuronium is a competitive neuromuscular blocking drug with a steroid nucleus. A dose of 0.1 mg/kg has an onset time of 2 minutes and provides surgical paralysis for 20 minutes. Recovery to 90% twitch height occurs in 40 to 50 minutes. Vecuronium has few adverse effects and its use is associated with cardiovascular stability. Atracurium is a competitive neuromuscular blocking drug which undergoes Hofmann degradation and ester hydrolysis in plasma. A dose of 0.6 mg/kg has an onset time of around 2 minutes and provides surgical paralysis for 20 to 30 minutes. Recovery to 90% twitch height occurs in 60 to 80 minutes. Histamine release, usually only localised, has been reported in association with the use of atracurium. The organ-independent metabolism of atracurium allows its use in standard dosage in patients with renal or hepatic disease. Edrophonium, although not a new drug, has recently been re-evaluated for reversal of neuromuscular blockade. In a dose of 0.5 mg/kg it has been shown to be as effective as neostigmine at reversing neuromuscular blockade after recovery has started (greater than 25% twitch height recovery). However, if blockade is profound (less than 10% recovery), edrophonium is less effective. Among the newer intravenous anaesthetics are propofol (disoprofol) and midazolam. In a dose of 1.5 to 2.5 mg/kg, propofol produces sleep rapidly with a prompt recovery in 4 to 6 minutes. Induction of anaesthesia may be associated with a transient apnoea and a fall in systolic pressure. The rapid recovery has led to its use for maintenance of anaesthesia. Midazolam is a water-soluble benzodiazepine which has been used as an anaesthetic agent. The dose needed to induce sleep varies widely (0.15 to 0.5 mg/kg); onset is slow (1.5 to 5 minutes), and recovery may be prolonged. Midazolam is also used in lower doses as a sedative. Ketamine, an intravenous induction agent, has recently been used intrathecally and extradurally to provide analgesia.

Novel delivery systems: electrotransport.

Electrotransport involves the transport of ionized drugs across the skin under the influence of an electric current. This method of delivery has been used for many years to deliver drugs locally to the skin or the mouth, but now it is being studied as a means of delivering drugs for their systemic effects. Opioid analgesics may be administered via this route.

Bioavailability, pharmacokinetics, and analgesic activity of ketamine in humans.

The pharmacokinetics of ketamine in analgesic doses after intravenous, intramuscular, and oral administration was investigated in healthy volunteers. Plasma ketamine concentration-time curves were fitted by a two-compartment open model with a terminal half-life of 186 min. Absorption after intramuscular injection was rapid and the bioavailability was 93%. However, only 17% of an oral dose was absorbed because of extensive first-pass metabolism. Simultaneous measurements of the elevation of pain threshold in an ischemic exercise test showed a marked effect for 15-60 min after intramuscular injection, but little or no effect after the oral solution. Pain threshold elevation occurred at plasma ketamine concentrations above 160 ng/ml.

The measurement of gastric emptying during labour.

The author describes how the rate of paracetamol absorption may be used as an indirect measure of gastric emptying rate in clinical situations such as during labour or post-partum, when direct measurement would be impracticable.

Aspiration of gastric contents.

Inhalation of gastric contents remains an important cause of anaesthetic death. Recent data describe the acid aspiration syndrome (AAS) as the cause of 25% of maternal deaths associated with anaesthesia and 19% of all deaths totally attributable to anaesthesia (DHSS, 1982; Lunn and Mushin, 1982).

Do patients fasting before and after operation receive their prescribed drug treatment?

Periods of fasting perioperatively make normal drug treatment difficult to maintain. One hundred and seventy patients admitted consecutively for operations (excluding those having cardiac, neurosurgical, and orthopaedic operations) were studied to identify whether they received their prescribed drugs. Seventy two were receiving drugs unrelated to their operation or anaesthesia. One thousand seven hundred and forty six single prescriptions (that is, single doses) were recorded as to be given on the day of surgery and the next day, of which 256 (15%) were not administered. All prescriptions of analgesics and premedicants were given; when these were excluded the proportion of prescriptions that were not given rose to 29%. The prescriptions omitted included 38 out of 95 for drugs for cardiovascular disease, 34 out of 103 for drugs for respiratory disease, and 10 out of 61 for drugs for endocrine disorders. The omission of drugs was not known to the medical staff and may introduce variability in the response of patients perioperatively.

Effect of cisapride on morphine-induced delay in gastric emptying.

Forty patients were allocated randomly to receive one of four premedications i.m.: placebo only, morphine 10 mg plus placebo, morphine 10 mg plus cisapride 10 mg and morphine 10 mg plus cisapride 4 mg. Gastric emptying after each premedication was assessed using the oral paracetamol absorption model. The morphine only group and the morphine and cisapride 4 mg group showed delayed gastric emptying when compared with the placebo group. Delay in gastric emptying in the morphine and cisapride 10 mg group was not demonstrated. It is concluded that cisapride 10 mg prevents the delay in gastric emptying associated with the administration of morphine.

Measurement of FEV1 and FVC. Comparison of a pocket spirometer with the Vitalograph.

The performance of a pocket spirometer was compared with that of the Vitalograph to assess the extent of agreement between the instruments and the repeatability of measurements with each instrument. Both instruments showed a similar level of accuracy when measurements were repeated and in the estimation of forced vital capacity, but there was a mean difference of 201 ml in measurements of forced expiratory volume in one second, for which the Vitalograph gave the larger reading.

Effect of premedication on drug absorption and gastric emptying.

The rate of paracetamol absorption after oral administration was used as a model of drug absorption and as an indirect measure of the rate of gastric emptying in 37 patients awaiting elective general surgery after different premedications. After saline (control) and diazepam, paracetamol absorption was normal but after morphine or nefopam, absorption was delayed markedly, presumably as a result of delayed gastric emptying. After naloxone there was a small but insignificant delay.

Drug absorption after general anaesthesia for minor surgery.

Paracetamol absorption after oral administration was studied in eleven patients immediately after a short general anaesthetic for cystoscopy and also in eight healthy volunteers. There were no statistical differences between the rate of paracetamol absorption in the two groups. This suggests that oral medication may be given immediately following a short general anaesthetic when opioid drugs are avoided.

Adverse effects of opioid analgesic drugs.

Opioids were available in clinical practice since before the birth of modern anaesthesia--Setürner isolated morphine in 1806. They have a record of safety which is reflected in their high therapeutic ratios, especially the synthetic opioids introduced recently (table III). The most serious immediate adverse effect, respiratory depression, is a predictable effect related closely to analgesia. It is fortunate for anaesthetists who use opioids regularly, that recognition and treatment of respiratory problems are an integral part of their craft and that opioid antagonists are effective in reversing respiratory depression.

Pharmacokinetics and analgesic effect of ketamine in man.

The pharmacokinetics and analgesic effect of i.v. ketamine in doses of 125 microgram kg-1 and 250 microgram kg-1 were determined in five healthy volunteers. Analgesia was measured with the submaximal effort tourniquet test. Both doses of ketamine prolonged the period of pain-free ischaemic exercise while the plasma ketamine concentration was greater than 100 ng ml-1. Ketamine was distributed rapidly (T 1/2 alpha = 17 min). The elimination half-life was 186 min.

Pain relief after surgery.

Relief of pain after surgery remains poor for the majority of patients. The pain is unpleasant, and is associated with arterial hypoxaemia, venous thrombosis, myocardial ischaemia and a more florid hormonal response to surgery. Regional analgesia, systemic, subarachnoid or extradural opioids and antiprostaglandin drugs are all used to treat pain after surgery. Systemic opioids are used usually, because regional and axial techniques are labour intensive and antiprostaglandin drugs ineffective. Opioids given orally undergo extensive first pass metabolism and intramuscular doses are absorbed unpredictably. Intravenous administration avoids both problems and excellent results have been obtained using Patient Controlled Analgesia devices, but these machines are expensive. A simple regimen suitable for application to large numbers of surgical patients is required. Continuous infusion of fentanyl 100 micrograms h-1 IV begun two hours before surgery and supplemented by a single bolus dose of fentanyl 100 micrograms IV provided an effective background of analgesia.

Temazepam absorption in patients before surgery.

We have compared the rates of absorption and efficacies of temazepam 30 mg in elixir and capsule formulations in 100 patients before surgery. Both formulations provided anxiolysis and sedation, but there was wide variation in plasma concentrations of temazepam between individuals and between formulations. The presence or absence of anxiety did not influence the absorption of the preparations. It is suggested that plasma concentrations in excess of 200 ng ml-1 are required for sedation and anxiolysis, and that this may be achieved more reliably using the elixir formulation.

Fentanyl by constant rate i.v. infusion for postoperative analgesia.

Fentanyl by continuous i.v. infusion (1.5 microgram kg-1 min-1 or 0.5 microgram kg-1 min-1) was compared with placebo infusion as an analgesic regimen for 24 h after hysterectomy. The drugs were infused using a new disposable device which required no external power source. All patients were allowed morphine i.m. if they experienced pain. Patients in the higher dose fentanyl group demanded less i.m. morphine and had better pain relief after operation, without important respiratory depression.

Pharmaceutical registration and how to get a drug on the market.

In this article we describe how to get a drug onto the market and outline the product development stages. Drug development programmes and regulatory control processes are complex, so only a basic outline will be given.

Comparison of the effect of cisapride and metoclopramide on morphine-induced delay in gastric emptying.

1. The effects of metoclopramide or cisapride on morphine-induced delay in gastric emptying in patients before surgery were compared. 2. Forty patients were allocated randomly to receive one of four premedications i.m.: placebo only, morphine 10 mg alone, morphine 10 mg with metoclopramide 10 mg and morphine 10 mg with cisapride 10 mg. Gastric emptying after each premedication was assessed indirectly from the rate of absorption of oral paracetamol. 3. Cisapride 10 mg reversed the delay in gastric emptying due to morphine. Its effects were significantly greater than those of metoclopramide 10 mg.