Pharmacokinetics of drugs used in critically ill adults.

Critically ill patients exhibit a range of organ dysfunctions and often require treatment with a variety of drugs including sedatives, analgesics, neuromuscular blockers, antimicrobials, inotropes and gastric acid suppressants. Understanding how organ dysfunction can alter the pharmacokinetics of drugs is a vital aspect of therapy in this patient group. Many drugs will need to be given intravenously because of gastrointestinal failure. For those occasions on which the oral route is possible, bioavailability may be altered by hypomotility, changes in gastrointestinal pH and enteral feeding. Hepatic and renal dysfunction are the primary determinants of drug clearance, and hence of steady-state drug concentrations, and of efficacy and toxicity in the individual patient. Oxidative metabolism is the main clearance mechanism for many drugs and there is increasing recognition of the importance of decreased activity of the hepatic cytochrome P450 system in critically ill patients. Renal failure is equally important with both filtration and secretion clearance mechanisms being required for the removal of parent drugs and their active metabolites. Changes in the steady-state volume of distribution are often secondary to renal failure and may lower the effective drug concentrations in the body. Failure of the central nervous system, muscle, the endothelial system and endocrine system may also affect the pharmacokinetics of specific drugs. Time-dependency of alterations in pharmacokinetic parameters is well documented for some drugs. Understanding the underlying pathophysiology in the critically ill and applying pharmacokinetic principles in selection of drug and dose regimen is, therefore, crucial to optimising the pharmacodynamic response and outcome.

Role of repeated doses of oral activated charcoal in the treatment of acute intoxications.

While single dose activated charcoal is effective in preventing drug absorption, repeated doses not only prevent absorption but also can increase systemic drug clearance. The mechanism for the latter effect may involve interruption of enterohepatic recycling and/or promotion of drug exsorption from the systemic circulation into the gut lumen. A comprehensive review of reported studies in volunteer subjects and overdose patients showed that repeated dose activated charcoal markedly decreased the half-life and/or increased the clearance of a wide range of drugs. Side-effects of the treatment were infrequent, but included aspiration pneumonia, diarrhoea and constipation. The addition of laxatives to repeated dose charcoal treatment did not offer any significant increase in drug clearance and is not recommended. It is suggested that the optimal regimen for the use of repeat dose activated charcoal in acute drug intoxications is an initial dose of 75-100 g, followed by 50 g every 4 hours until the risks of systemic drug toxicity are reduced to an acceptable level.

Carcinoma of breast and scleroderma: four further cases and a literature review.

Four patients are described in whom scleroderma developed within 18 months of detection of breast carcinoma. Previously reported cases of this association and the relevant literature are reviewed. The available evidence suggests that in some women there may be a causal relationship between breast cancer and scleroderma or progressive systemic sclerosis.

High-performance liquid chromatographic method for measurement of pentamidine in plasma and its application in an immunosuppressed patient with renal dysfunction.

A rapid method for the quantitation of pentamidine in plasma by high-performance liquid chromatography is described. Pentamidine was extracted from plasma using a mixed solvent of 40% acetonitrile in chloroform. Reversed-phase chromatography was then performed on a mu Bondapak C-18 column, using a mobile phase of acetonitrile containing 0.1% H3PO4 and 0.1% NaCl (20:80) and the eluting peaks detected by their UV absorbance at 262 nm. The assay had a within-day coefficient of variation of less than 3.8%, an absolute recovery of 92%, and a limit of detection of 15 nmol/L. The method was applied during pentamidine mesylate treatment (4 mg/kg/day) for Pneumocystis carinii pneumonia in an immunosuppressed patient with impaired renal function. Plasma levels rose slowly to a plateau (range 530-880 nmol/L) after 7 days of treatment, suggesting a half-life of around 1.5-2 days.

Haemoglobin concentration and serum erythropoietin in renal dialysis and transplant patients.

In patients with chronic renal failure the use of the relatively new dialysis technique of continuous ambulatory peritoneal dialysis (CAPD), unlike other forms of dialysis, is consistently associated with an increase in Hb concentration, but the mechanism remains obscure. We measured Hb, haematocrit, S-erythropoietin and Hb-oxygen affinity in 3 groups of patients with chronic renal failure. (1) Untreated patients starting on haemodialysis. (2) Patients on intermittent peritoneal dialysis changing to CAPD. (3) Patients from the above 2 groups receiving renal transplants. In addition, red cell mass, plasma volume and red cell survival were measured in (2), before starting CAPD and at 6 months. There were distinctly different patterns of change in Hb concentration, Hb-oxygen affinity and S-erythropoietin in the 3 groups of patients. The increase in Hb concentration with CAPD is due to both a fall in plasma volume and an increase in red cell mass, with an increase in red cell survival. There was no change in Hb-oxygen affinity or serum erythropoietin concentration. The improvement in red cell mass and survival may be related to increased clearances of substances with mol. wt.s between 500 and 5000 daltons which accumulate in renal failure (uraemic middle molecules).

Anomalous action of tubocurarine in the tibialis anterior muscle of the cat.

Low dose infusion of tubocurarine (20 micrograms/kg per min) causes an increase in muscle contraction in tibialis anterior of the cat. Tibialis anterior muscle of 13 adult cats was indirectly stimulated via the sciatic nerve using a square wave pulse of 0.2 ms duration and supramaximal voltage at 0.06 Hz. The increase is from 5-133% of control with a mean of 36%. This is sustained for a mean of 97 min, if the infusion is ceased when maximum potentiation is achieved. Duration of potentiation is decreased by increasing the frequency of stimulation. The potentiation occurs in the presence of either rising or falling concentrations of tubocurarine, and continuing the infusion results in neuromuscular blockade. One explanation of these observations is that low dose tubocurarine may interfere with presynaptic negative feedback control of acetylcholine release.

Erythrocyte metabolism in patients on haemodialysis and continuous ambulatory peritoneal dialysis.

1. Erythrocyte metabolism was investigated and glycolytic intermediates were measured in nine patients with chronic renal failure who were subsequently treated with haemodialysis. The same investigations were performed in nine patients on continuous ambulatory peritoneal dialysis (CAPD) who had previously been treated with intermittent peritoneal dialysis (IPD) (eight patients) or dietary restriction (one patient). 2. The patients who received haemodialysis had a partially compensated metabolic acidosis before treatment. With haemodialysis, plasma phosphate (Pi) fell and base excess, erythrocyte 2,3-diphosphoglycerate (2,3-DPG), glucose consumption and lactate production rose significantly. In this group the most important influence on erythrocyte metabolism was base excess. The pattern of erythrocyte glycolytic intermediates showed that the rise in 2,3-DPG with haemodialysis was brought about within the Rapoport-Luebering shunt; there was no statistically significant decrease in haemoglobin-oxygen affinity. 3. The patients who received CAPD were not acidotic before starting this form of treatment. With CAPD, there was a significant increase in haemoglobin and fall in plasma phosphate, erythrocyte 2,3-DPG and glucose consumption. The major factors influencing erythrocyte metabolism in this group were plasma phosphate and haemoglobin concentration. The fall in 2,3-DPG was produced by inhibition of 6-phosphofructokinase (EC 2.7.1.11); despite this fall, haemoglobin-oxygen affinity was not affected.

Potentiation by gentamicin of non-depolarizing neuromuscular block in the cat.

Gentamicin 1-5 mg/kg was injected into 14 anaesthetised cats in the presence of a constant, partial, non-depolarizing neuromuscular block. Twitch response in tibialis anterior was significantly depressed from 83% to 71% of control by a dose of 1.0 mg/kg. In soleus the same dose reduced twitch response from 76% to 71%. After a cumulative dose of 10 mg/kg twitch response in tibialis anterior and soleus was 34% and 37% of control respectively. Calcium chloride 20 mg/kg restored twitch response to 66% in both muscles. Smaller doses of calcium chloride caused partial reversal which was maintained for five minutes in only 50% of instances.

Effective pulmonary blood flow in preterm and light-for-date infants.

Using a method employing low concentrations (3%) of nitrous oxide, we measured effective pulmonary capillary blood flow (Qpc eff) in 23 preterm infants, 26 light-for-date infants, and 15 infants who were both preterm and light-for-date. All infants studied had no clinical or laboratory evidence of idiopathic respiratory distress syndrome (IRDS) and were studied before the age of 48 hours. The mean Qpc eff of 175 ml/kg/min in preterm infants (a group at high risk of developing IRDS), although significantly less than the mean of 214 ml/kg/min found in light-for-date infants (a group with a low risk of developing IRDS), was similar to that reported in normal term infants. The mean result for preterm, light-for-date infants was 189 ml/kg/min. No evidence was found that preterm infants were predisposed to IRDS as a consequence of preexisting pulmonary hypoperfusion.