Introduction
It has been said that if a drug has no side effects, then it is unlikely to work. Drug therapy labours under the fundamental problem that usually every single cell in the body has to be treated just to exert a beneficial effect on a small group of cells, perhaps in one tissue. Although drug-targeting technology is improving rapidly, most of us who take an oral dose are still faced with the problem that the vast majority of our cells are being unnecessarily exposed to an agent that at best will have no effect, but at worst will exert many unwanted effects. Essentially, all drug treatment is really a compromise between positive and negative effects in the patient. The process of drug development weeds out agents that have seriously negative actions and usually releases onto the market drugs that may have a profile of side effects, but these are relatively minor within a set concentration range where the drug’s pharmacological action is most effective. This range, or ‘therapeutic window’ is rather variable, but it will give some indication of the most ‘efficient’ drug concentration. This effectively means the most beneficial pharmacodynamic effects for the minimum side effects.
The therapeutic window (Figure 1.1) may or may not correspond exactly to active tissue concentrations, but it is a useful guideline as to whether drug levels are within the appropriate range. Sometimes, a drug is given once only and it is necessary for drug levels to be within the therapeutic window for a relatively brief period, perhaps when paracetamol (acetaminophen) is taken as a mild analgesic. However, the majority of drugs require repeated dosing in time periods which range from a few days for a course of antibiotics, to many years for anti-hypertensives and antithyroid drugs. During repeated intermediate and long-term dosing, drug levels may move below or above the therapeutic window due to events such as patient illness, changes in diet or co-administration of other drugs. Below the lowest concentration of the window, it is likely that the drug will fail to work, as the pharmacodynamic effect will be too slight to be beneficial. If the drug concentration climbs above the therapeutic window, an intensification of the drug’s intended and unintended (off-target) pharmacodynamic actions will occur. If drug levels continue to rise, irreversible damage may occur which is usually described by the word ‘toxicity’. To some extent, every patient has a unique therapeutic window for each drug they take, as there is such huge variation in our pharmacodynamic drug sensitivities. This topic is concerned with what systems influence how long a drug stays in our bodies.
Figure 1.1 The ‘therapeutic window’, where drug concentrations should be maintained for adequate therapeutic effect, without either accumulation (drug toxicity) or disappearance (drug failure). Such is human variation that our personal therapeutic windows are effectively unique for every drug we take.
Whether drug concentrations stay in the therapeutic window is obviously related to how quickly the agent enters the blood and tissues prior to its removal. When a drug is given intravenously, there is no barrier to entry, so drug input may be easily and quickly adjusted to correspond with the rate of removal within the therapeutic window. This is known as ‘steady state’, which is the main objective of therapeutics. The majority of drug use is by other routes such as oral or intramuscular rather than intravenous, so there will be a considerable time lag as the drug is absorbed from either the gastro-intestinal tract (GIT) or the muscle, so achieving drug levels within the therapeutic window is a slower, more ‘hit and miss ’ process. The result from repeated oral dosing is a rather crude peak/trough pulsing, or ‘sawtooth’ effect which you can see in the diagram (Figure 1.1). This should be adequate, provided that the peaks and troughs remain within the confines of the ‘therapeutic window ’ .
Therapeutic index
Drugs vary enormously in their toxicity and the concentrations at which one drug might cause potentially lethal effects might be 10 or 100 times lower than a much less toxic drug. A convenient measure for this is the ‘therapeutic index’. This has been defined as the ratio between the lethal or toxic dose and the effective dose that shows the normal range of pharmacological effect.
In practice, a drug (such as lithium) is listed as having a narrow TI if there is less than a twofold difference between the lethal and effective doses, or a twofold difference in the minimum toxic and minimum effective concentrations. Back in the 1960s, many drugs in common use had narrow TIs, such as barbiturates, that could be toxic at relatively low levels. Over the last 30 years, the drug industry has aimed to replace this type of drug with agents with much higher TIs. This is particularly noticeable in drugs used for depression. The risk of suicide is likely to be high in a condition that takes some time (often weeks) to respond to therapy. Indeed, when tricyclic antidepressants (TCAs) were the main treatment option, these relatively narrow TI drugs could be used by the patient to end their lives. Fortunately, more modern drugs such as the SSRIs (selective serotonin reuptake inhibitors) have much higher TIs, so the risk of the patient using the drugs for a suicide attempt is greatly diminished. However, there are many drugs (including the TCAs to a limited extent), which remain in use that have narrow or relatively narrow TIs (e.g. phenytoin, carbamazepine, valproate, warfarin). Therefore the consequences of accumulation of these drugs are much worse and happen more quickly than drugs with wide TIs.
Changes in dosage
If the dosage exceeds the rate of the drug’s removal, then clearly drug levels will accumulate and depart from the therapeutic window towards toxicity. If the drug dosage is too low, levels will fall below the lowest threshold of the window and the drug will fail to work. If a patient is established at the correct dose that does not change, then this is the oral version of ‘steady state’. So, theoretically, the drug should remain in its therapeutic window for as long as therapy is necessary unless other factors change this situation.
Changes in rate of removal
The patient may continue to take the drug at the correct dosage, but drug levels may drop out of, or exceed, the therapeutic window. This could be linked with redistribution of the drug between bodily areas such as plasma and a particular organ, or protein binding might fluctuate; however, the major factor in the maintenance of drug levels within the therapeutic window is the rate of removal and/or inactivation of the drug by bodily processes.
