Although the use of cathartics and enemas is traditional, these measures are most unlikely to reduce absorption since this usually occurs rap­idly in the upper small intestine. They can only add to the misery and discomfort of the patient Efficacy in removal of drug has never been es­tablished. In one recent study, saline catharsis had no beneficial effect whatsoever on the ab­sorption of aspirin taken with charcoal (Sketris et al. 1982).

Whole Gut Lavage

One situation where attempts to empty the bowel may be helpful is in poisoning with ‘slow’ or ‘timed release’ formulations. The number of such preparations on the market is increasing and since they usually contain a much larger dose of drug than ordinary tablets, intoxication may be severe and prolonged.

In such circumstances, rapid emptying of the bowel might limit in absorption. The preferred technique is ‘whole gut lavage’ in which normal saline is given by nasogastric tube at a rate of 2 litres an hour (Woo et al. 1976). Although this technique is readily controlled and rapidly effective in emptying the bowel in conscious patients being prepared for abdominal surgery, its efficacy in removing un-absorbed drug has yet to be established. It may not be effective and could possibly be dangerous in poisoned patients with grossly depressed gas­trointestinal motility.

Activated Charcoal

Activated charcoal has great adsorptive ca­pacity and can reduce the absorption of many compounds if taken orally at the same time (Neuvonen 1982; Pond 1986). The charcoal must be given in great excess (at least 10 times the weight of the drug) and efficacy falls off rap­idly as the time interval between ingestion of the poison and administration of the charcoal increases. After 1 hour, there is little inhibitory effect on the absorption of most drugs, although a significant reduction has been reported with phenytoin.

The time interval during which ac­tivated charcoal can significantly reduce ab­sorption following overdosage may be increased by the presence of food in the stomach (Olkkola & Neuvonen 1984). Oral activated charcoal ap­pears to be as effective as emesis induced by syrup of ipecac in limiting absorption (Neuvo­nen et al. 1983), but its administration after gas­tric lavage is of little or no benefit (Comstock et al. 1982).

Although the delay between inges­tion of the drug and arrival in hospital is usually such that significant reduction in absorption by oral activated charcoal is unlikely, there is no contraindication to its use and repeated admin­istration greatly increases the elimination of some drugs.

Never­theless, poisoned patients are often unnecessar­ily subjected to these potentially harmful meas­ures, and the literature is full of anecdotal accounts of miraculous recovery attributed to such treatment (Winchester et al. 1977). Prop­erly controlled clinical trials are difficult to carry out, and very few have been published. With the possible exception of forced alkaline di­uresis for poisoning with salicylate and long act­ing barbiturates such as phenobarbitone, none of these methods for enhancement of drug re­moval has ever been shown to reduce morbidity or mortality in poisoned patients (Todd 1984).

Indeed, some studies suggest the opposite result. This is not to say that such measures are never necessary, or indeed sometimes life saving, but a more critical appraisal of their role is required.

In some cases, the drug presumed to have been taken has never been chemically identi­fied, while, in others, haemodialysis has been carried out in patients with less than therapeutic plasma concentrations of the drug in question. Other studies have shown removal of only a very small and insignificant fraction of the ingested dose, sometimes amounting to the equivalent of less than 1 tablet or capsule (see, for example, Comstock et al. 1983; Heath et al. 1983). A mis­leading impression of efficacy may be gained by the use of nonspecific analytical methods for drug assay (Prescott 1974).

Other Binding Agents

Other agents have been used in attempts to bind unabsorbed drug in the gastrointestinal tract. Paraquat, a lethal weedkiller for which there is no known antidote, binds very strongly to Fuller’s earth and bentonite, and these ad­sorbents are used routinely in the treatment of paraquat poisoning.

Although bentonite may re­duce the normally slow absorption of paraquat in pure aqueous solution in rats (Smith et al. 1974), ail the evidence points to extremely rapid absorption of paraquat from commercial weed­killers in man. Our experience of paraquat poi poi­soning has been disastrous, with no apparent benefit from the early use of bentonite.

Cholestyramine binds acidic drugs and can reduce the absorption of paracetamol (aceta­minophen) taken at the same time. Like acti­vated charcoal, however, it is virtually useless when the delay between ingestion and admin­istration exceeds 1 hour (Dordoni et al. 1973).

1. Specific antidotal therapy is available for very few poisons. The mainstay of treatment of severe poisoning is intensive supportive therapy and good nursing care.

2. The great majority of poisoned patients recover with intensive supportive therapy alone, and enthusiastic claims for the success of other treatment often cannot be justified.

3. With some important exceptions, the management of poisoning is not altered by knowledge of plasma drug concentrations. There are many pitfalls in the interpretation of drug concen­trations in poisoned patients, especially when nonspecific analytical methods are used.

4. Gastric lavage and induction of nemesis soon after ingestion may be effective in removing unabsorbed drug, but are unreliable. Adsorbents such as activated charcoal are usually ineffec­tive in limiting absorption when given more than 1 hour after ingestion.

5. Poisoned patients are often subjected to unnecessary and potentially harmful haemodialysis, haemoperfusion and diuresis. The efficacy of these measures has been established for relatively few substances in terms of reduction in morbidity and mortality or removal of toxicologically significant amounts of active drug or poison.

6. The efficacy of methods for extracorporeal removal can be predicted from pharmacokinetic principles. It depends primarily on the volume of drug distribution, plasma protein binding, rate of transfer from peripheral to central compartments, and dialysis clearance relative to the endogenous total body clearance.

7. Haemoperfusion with activated charcoal or exchange resins is more effective than haemo­dialysis in removing drugs from the blood. Peritoneal dialysis is less effective than haemodi­alysis. Drugs with large volumes of distribution cannot be removed rapidly by any of these techniques, and indications for their use are limited.

8. Forced diuresis can only increase the renal clearance of reabsorbed compounds, and clearance may be dramatically increased by appropriate manipulation of urine pH. However, the renal excretion of most drugs is insignificant in relation to the metabolic clearance. Forced alkaline diuresis is largely restricted to salicylate and phenobarbitone poisoning.

9. Repeated oral activated charcoal effectively increases the body clearance of a number of drugs. It probably acts by irreversibly binding drug diffusing from the circulation to the gut lumen and may also interrupt the enterohepatic circulation.

10. The toxicity of a few drugs and poisons can be reversed by specific antidotal therapy. Mechanisms include pharmacological antagonism, inhibition of conversion to toxic metabolites, inactivation of highly reactive alkylating intermediates, chelation and binding with drug-specific antibodies.

Although quinidine is rarely used for this purpose today, because of the advent of DC cardioversion, this study is still almost unique because it defined a target concentration based upon both the probability of therapeutic success and of toxicity.

A concentration of 8 rag/ L was shown to have an 80% chance of converting atrial fibrillation to sinus rhythm and a 20% chance of some serious toxicity. No atten­tion was paid to pharmacokinetics, The target concentration was chosen on the basis of pharmacodynamics, i.e. the effects, both good and bad, observed at particular concentrations.

Rational therapeutics – the aim of rational ther­apeutics is to achieve the desired effect with the cor­rect dose. The foundation of decision making is based on pharmacokinetics and pharmacodynamics which provide the rational principles to link dose and effect through drug concentration.

Rational therapeutics can be defined as the administration of the correct dose to achieve the desired effect. The target concentration concept is at the centre of rational therapeutics where it links dose to effect. Pharmacokinetics is the science that links dose and concentration by defining the processes of drug distribution (volume of distribution) and elimination (clear­ance).

Pharmacodynamics, on the other hand, is the science linking concentration to effect by defining the maximum effect of the drug (Emax) and the sensitivity of the target organ (as de­termined by the EC50; M£ the concentration producing 50% of Emax).

Therapeutic drug monitoring can now be placed at the centre of this therapeutic triangle. This incorporates information about doses, concentrations, and effects in an individ­ual and integrates these data to estimate more precisely the pharmacokinetic (volume of dis­tribution, clearance) and pharmacodynamic (Emax, EC50) parameters in that individual. These new values can then be used to predict the consequences of future dosing decisions and thus enable the selection of a suitable dose to achieve the desired effect, i.e. rational therapeutics.

This is because, unlike say sodium or glucose, the in­take of a drug is quite well known and the pro­cesses of distribution and elimination are usu­ally very simple and not under the control of a multitude of homeostatic controlling reflexes.

Given an accurate dosing history and one or more drug concentrations, it is possible to de­scribe the pharmacokinetic processes of distri­bution and elimination quite precisely in an individual patient and to make accurate predic­tions of concentrations at future points in time, whatever dosing regimen is used.

The ability to interpret drug concentrations and extract infor­mation so that future concentrations can be pre­dicted and a rational dosing scheme instituted, requires a different kind of intellectual effort from that needed to interpret, say, a serum glu­cose concentration. The latter is mostly inter­preted by reference to a so-called ‘normal range’ – usually the 95% confidence interval based upon measurements from a sample of a ‘normal’ population.

Under most circumstances, if the serum glucose concentration is within the “nor­mal range”, little further attention is paid to it If it is outside of the ‘normal range’, diagnostic efforts are made to determine what pathophys­iological process is disturbed. But the precise value will be used only in a semi quantitative fashion, eg. high, very high, or extremely high, or in reference to some previously defined diag­nostic threshold value; for example, diabetes mellitus may be diagnosed if the glucose con­centration is greater than 10 mmol/L.

On the other hand, all drug concentrations exceed the “normal” range because it would be abnormal to be able to detect any therapeutic substance in the serum of a normal, healthy individual.

The quantitative information provided by a drug concentration measurement can be use­fully applied with up to 2 significant figures in the determination of, say, drug clearance. This degree of precision is implicit in use of this in­formation because individual dosage decisions will often be made with 2 significant figures in the dose size.

The quantitative approach to therapeutic decision making is relatively new to the art of medicine. Most clinicians currently practicing medicine will not have been taught very much pharmacokinetics during their undergraduate training and may therefore have only a very hazy idea of the quantitative decisions that form the basis of rational therapeutics.

Furthermore, younger clinicians may be misled into thinking that the pharmacokinetics they were taught at medical school are irrelevant to modern medi­cine because their senior colleagues pay no at­tention to pharmacokinetic detail and make therapeutic decisions in a seemingly capricious fashion. Such a conclusion may be quite false because therapeutic decisions made by an ex­perienced clinician are founded upon a wide base of knowledge gained from treating many similar patients.

This prior knowledge of the character­istics of the population being treated provides an empirical, but nevertheless frequently satis­factory, guide to making an appropriate quan­titative and qualitative therapeutic decision. Recognition of the value of such prior infor­mation when faced with an individual patient about whom little is known is the basis of the latest techniques of rational, quantitative phar­macokinetic and pharmacodynamic forecasting.

For the person who must make a therapeutic choice on behalf of an individual patient, the application of quantitative pharmacokinetic principles can substitute for the advice of a more experienced colleague. For all clinicians, young and old, these same principles can be applied to new therapeutic entities and reduce the suf­fering of patients who would otherwise be ex­posed to the vagaries of a trial and error ap­proach.