Therapeutic index
When drugs are used in clinical practice, the prescriber is unable to construct a careful dose–response curve for each individual patient. Therefore, most drugs are licensed for use within a recommended dose range that is expected to be close to the top of the dose–response curve for most patients. This ensures that most patients will achieve a good clinical response without the need for frequent review and dose increases. However, this means that it is sometimes possible to achieve the desired therapeutic response at doses towards the lower end of the recommended range (or below).
The adverse effects of drugs are often dose-related in a similar way to the beneficial effects. It is possible to construct a dose-response curve for these adverse effects in the same way as shown for the beneficial effects, with higher doses usually required to cause the adverse effect. The ED50 points for each curve in the Figure indicate that the ratio between the doses that have similar proportionate effects on the two outcomes is 10/0.1 = 100. This ratio is known as the ‘therapeutic index’. In reality, drugs have multiple potential adverse effects but the concept of therapeutic index is usually reserved for those requiring dose reduction or discontinuation. For most drugs, the therapeutic index is greater than 100 but there are some notable exceptions with therapeutic indices less than 10, which are in common use (e.g. digoxin, warfarin, insulin, phenytoin, opioids). Drugs with low therapeutic indices are more difficult to prescribe and hazardous for patients but they are still preferred if there are no alternative drugs with similar efficacy (e.g. anti-cancer drugs). The doses of such drugs have to be titrated carefully for individual patients to maximize benefits but avoid adverse effects. This is done by monitoring drug effects, either clinically or using regular blood tests (often known as ‘therapeutic drug monitoring’).
Figure. Dose–response curves for the beneficial and adverse effects of a drug. Prescribers will aim to prescribe doses that maximize benefits and minimize harms, which is easier for drugs where the ratio between the dose causing harm and that causing benefit (the ’therapeutic index’) is high.
Therapeutic index
This is the fourth in a series of 4 simulations related to dose-response relationships. This simulation focuses on therapeutic index. In this simulation the learner can vary the therapeutic index by the use of a slider and observe the effects on the relative positions of the dose-response curves for the desired and adverse effects. This is a more kinesthetic approach to illustrating these concepts in that it allows the learner to experiment. Although targeted for early learners in pharmacology, students should have a basic understanding of the concepts before using the simulation.
Therapeutic index- Pharmacology Corner
This approximately 400-word essay describes the equation for therapeutic index together with easily understandable descriptions for how the ED50 and TD50 are determined from quantal dose-response relationships. Several examples of drugs with a narrow therapeutic index are provided at the end. This is appropriate for an early learner in pharmacology but they should have an understanding of dose-response relationships before viewing this resource.
In addition to providing definitions of terms for the learner (threshold, potency, efficacy) there is a description of how graded and quantal dose-response curves are obtained and the information which can be derived from each. A discussion of therapeutic index is included in relation to drug safety. This is appropriate for an early learner in pharmacology.