What are therapeutic, toxic and fatal concentrations?
The term ‘therapeutic’ as used in this text refers to concentrations of drugs normally expected following recommended doses of the substance. Clearly, the term ‘therapeutic’ has no application for some substances, e.g. illicit drugs and poisons such as organophosphates. A toxic concentration occurs when the dose of substance causes or has the potential to cause serious adverse reactions, while a fatal concentration relates to levels that are associated with fatal poisonings. Large collections of data are available in various texts and in databases concerning the potentially therapeutic, toxic and fatal concentrations of drugs and poisons. These can be an aid to establishing a likely response to a drug when interpreting a toxicological result. Unfortunately, the use of such data is subject to many restrictions and limitations. These are detailed below. Reliable assessments of the significance of any analytical finding can be made only by comparing the results with information on drug concentrations and associated clinical responses that have been reported in other related cases. In particular, it is essential that a distinction is made between acute and chronic use since repeated use of a drug may give rise to much higher blood concentrations than a single dose. This causes pharmacokinetic accumulation. For example, methadone has a half-life of about 24 h, resulting in significant accumulation of the drug in the blood and tissues for at least 5 days of dosing. Persons often develop a tolerance to drugs with repeated administration compared to their first use; hence some background knowledge on the use of drugs will assist in determining if this is a likely event. This is relevant in understanding the effects of many opioids: a potentially toxic concentration in a single dose may be easily tolerated with repeated use. Furthermore, it is essential that when toxicity to a drug is suspected the possible involvement of other drugs also is considered. Databases may not indicate whether a poisoning was due to that agent alone or in combination with other substances. Common examples here include the presence of ethanol in cases involving other central nervous system (CNS) depressant drugs, e.g. opioids, benzodiazepines. The use of cocaine or amfetamine in combination with diamorphine (heroin) is more toxic than one drug alone.
The route of drug administration, together with the nature of the dosage form, determines the rate and extent of absorption. Administration by inhalation, intravenous or intramuscular injection leads to a high bioavailability and quick and often intense response, while oral administration produces lower concentrations of longer duration. Thus, a fatal drug dose given intravenously is often much smaller than a fatal dose given by mouth because the injected drug is able to reach the site of action very rapidly. If proprietary preparations are given by the recommended route, it may be possible to make predictions of the dose from blood concentrations because comparable data are usually available. When illicit drugs or preparations are involved, prediction of blood concentration is much more difficult. Particular examples of variable and unpredicted doses include use of volatile substances through inhalation (abuse), and the smoking of cannabis, diamorphine or cocaine. In all of these cases the degree of inhalation together with the technique used greatly affects the amount of drug actually absorbed. An important source of variable absorption is through oral dosing, since this route is probably the most common. Most of the variability in absorption is related to any first-pass metabolism that occurs for drugs with low oral bioavailability. A number of factors can influence bioavailability. These include the motility of the stomach and bowel, pH and (for a small number of drugs) activity of gut enzymes that metabolise the drug before it is even absorbed. This issue also applies in situations when coexisting natural disease or injuries may affect the nature of the response to the drug, or when the very young or the elderly are being treated with drugs. The combined effect of all of these factors is to make the task of interpreting analytical results even more difficult. Pharmacokinetic and toxicological data must be used circumspectly when a specific case is being examined because there is always the possibility of misinterpretation if consideration is not given to the special circumstances of the case.
Several drugs, including salicylate (in over dose), alcohol, and possibly some hydrazines and other drugs which are metabolised by acetyl ation, have saturable elimination kinetics. With these drugs, capacity-limited elimination is complicated further by their low therapeutic index. A good example is phenytoin. A 50% increase in the dose of phenytoin can result in a 600% increase in the steady-state blood concen tration, and thus expose the patient to potential toxicity. When repeated doses of a drug are given, toler ance to the drug may arise if they affect its own disposition or response. Enzyme activities can be enhanced, which leads to an increased capacity for metabolism (e.g. patients on chronic therapy with barbiturates metabolise the drugs more rapidly than patients who have not previously taken the drugs). Alternatively, the receptor sensitivity may be modified so that the effect of a particular concentration of a drug is reduced after chronic use (e.g. the sedative effects of benzodiazepines). Increasing tolerance results in a progressively decreasing drug effect, and the need for an increased dose; habituation and addiction may be the final clinical outcome. Thus, addicts can tolerate doses of morphine that might be considered toxic or even fatal in non-addicts. Similarly, rapidly developing tolerance to the sedative effects of phenobarbital is a common feature of prolonged therapy with the drug. Epileptic patients treated with phenobarbital are often free from any adverse effects despite having blood drug concentrations normally associated with serious toxicity in patients not accustomed to taking the drug. Tolerance invariably extends the upper limit of the therapeutic range of drugs, and the reisa more marked overlap between concentrations associated with different clinical responses. When tolerance is suspected, some of the problems of interpreting data can best be resolved by reference to previous results from the same patient (e.g. results of a therapeutic drug monitoring programme). Unfortunately, in most forensic cases such background information is not avail able, and in these instances blood concentrations alone are of little value. A more reliable interpret ation of analytical data can only be made by comparison of blood concentrations with those measured in urine, bile or liver (where concentrations can be much higher in addicts), and/or by measuring the relative amounts of unchanged drug and its metabolite(s).
