How Safe is this Drug? 

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As discussed in its own Tox Topic, and referred to in many others, a fundamental premise of toxicology is that “the dose makes the poison.” This observation dates back almost 500 years ago to the Swiss physician Paracelsus who wrote “The right dose differentiates a poison from a remedy.”  As a physician Paracelsus knew that it was important to not give too much of a drug.  But how much is too much, and how do we help ensure that we have a clear picture of the difference between the dose it takes to provide a benefit and the dose it takes to cause harm? To help do this, we use something called the Therapeutic Index (TI).

The Therapeutic Index compares the therapeutically beneficial dose to the toxic dose of a drug by using a simple ratio of the dose that produces toxicity to the dose needed to produce a therapeutic benefit.  The convention is to use the dose that causes either beneficial or toxic effects in 50% of people (see Figures below).  By using this simple ratio it is relatively straightforward to see how a large TI means a drug is relatively safe because the amount it takes to cause harm is far greater than the amount it takes to get a benefit.  In contrast, a low TI means that the potential for harm is greater if you take more than the directed amount.  Drugs with TI’s greater than 10 are considered relatively safe while those with TI’s less than 3 typically require tighter controls on manufacturing (to ensure that the dosing is accurate) and patient monitoring.

As an example, consider a commonly used drug – aspirin. Readily available without a prescription, aspirin is used to reduce fever and relieve mild to moderate pain from muscle aches, toothaches, common cold, and headaches. The recommended dose of so called extra strength aspirin is 500-1000 mg. The amount of aspirin necessary to cause mild toxicity symptoms in an average person is about 20,000 mg.  Thus in this case the TI would range from 20-40, meaning that it would be very difficult to harm yourself even if you mistakenly took much more than directed.

Here are some examples of low TI drugs:

  • Lithium (bipolar disorder)
  • Warfarin (blood thinner)
  • Theophylline (asthma)
  • Digoxin (various heart conditions)

And some examples of high TI drugs:

  • Benadryl (diphenhydramine, antihistamine, sleep aid)
  • Valium (sedative, hypnotic)
  • Neurontin (gabapentin, restless leg syndrome, multiple off-label neurological indications)

In summary, the TI provides important perspective on the margin of safety of a drug by comparing the amount it takes to deliver a benefit against the amount it takes to cause harm.