1. Critical illnesses are often associated with circulatory, respiratory, hepatic and/or renal dys­function that may alter the pharmacokinetics and/or pharmacodynamics of drugs.
2. Decisions about routes of administration and doses of drugs used during medical emergen­cies must consider the physiological status of the patient, the pharmacokinetic and pharmacodynamic characteristics of the particular drug, and how the two interact.
3. Adverse drug reactions and interactions are more likely in critically ill patients due to the effect of the disease on drug kinetics, the decreased toxic-therapeutic ratio due to severe under­lying illness, and the large number of medications that such patients receive. Adverse reactions to drugs should be considered when unexplained deterioration or failure to respond to therapy are encountered.
4. Preservation of function of vital organs is a fundamental concept of critical care therapeutics. Preservation of cardiovascular functions requires attention to fluid and electrolyte status, prompt correction of arrhythmias and shock, and measures to preserve the myocardium against ischaemic injury.
5. Preservation of respiratory function requires protection of the airway, cautious use of fluids and oxygen, and prompt recognition and management of infection.
6. Preservation of cerebral function requires maintaining cerebral blood flow with adequate oxygen and glucose sufficient to meet the metabolic demands of the brain. This entails main­taining adequate systemic circulation, control of intracranial hypertension, and prompt control of seizures and hyperthermia.



7. Critically ill patients are particularly susceptible to infections, gastric stress erosions and ulcers, adult respiratory distress syndrome, pulmonary emboli, and haemostatic disorders. The risks of such complications may be reduced by meticulous care of catheters, pulmonary toilet, cautious use of fluids, prompt treatment of infection when it occurs, and selective prophylactic drug therapies.
8. Shock can be produced by many different processes including myocardial infarction, hypovolaemia, sepsis, drug overdose, burns, hypothermia, spinal cord transsection and anaphylaxis. Optimum treatment of shock depends on knowledge of the pathophysiology of the shock state and the pharmacology of the drugs.
9. Features of acute drug intoxication include coma, agitated delirium, seizures, hypo- and hyperthermia, shock, arrhythmias, aspiration and pulmonary oedema. Successful therapy of acute drug intoxication depends on the integration and application of knowledge of the pharmacology of both the intoxicating drug and the drugs used in therapy, as well as the principles of supportive critical care.

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).

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.