Understanding the Significance of Therapeutic Index

Understanding the Significance of Therapeutic Index

The therapeutic index of a drug is the ratio between the dosage that causes a toxic/lethal effect and the dosage that causes a therapeutic effect. This Buzzle write-up will help you understand the significance of therapeutic index.
PsycholoGenie Staff
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Also referred to as narrow therapeutic range (NTR) drugs or critical-dose drugs, the drugs with a narrow therapeutic index (NTI) must be used with caution. These are drugs with small differences between therapeutic and toxic doses. The larger the therapeutic index, the safer the drug is.

The term 'pharmacotherapy' refers to the use of drugs for treating diseases, whereas 'pharmacology' is the study of drug action on living systems. It is the interaction of the drug molecules and drug receptors that brings about a therapeutic effect. However, it is extremely essential to administer the drug in the right dose to achieve such an effect. If taken in large doses, certain drugs could cause adverse effects. Thus, in order to reap the benefits, it is essential to assess the right dose.

Therapeutic drug monitoring (TDM) becomes essential to determine the dose at which a drug will be safe and effective, especially with those with a narrow therapeutic index. Also, monitoring might be required when the patient is affected by a medical condition that has an adverse effect on the clearance of NTI drugs. There's no denying the fact that drug metabolism could vary from person to person. Thus, the key to avoid drug-related problems is to consider the drug's therapeutic index and other relevant factors for ensuring safety.

Definition of Therapeutic Index

Therapeutic index (TI) refers to any of the several indices that are used for measuring a drug's safety. The most common TI is the ratio of the median lethal dose to the median effective dose of a drug. The formula for TI is:

TI = LD50 / ED50

LD50 stands for median lethal dose, and ED50 stands for median effective dose. LD50 refers to the dose that would produce a lethal effect in 50% of the population, whereas ED50 refers to the dose that will produce the desired therapeutic effect in 50% of the population.

TI can also be expressed as the ratio of the median toxic dose and the median effective dose (therapeutic dose) of a drug. This index is commonly used to measure a drug's safety. The therapeutic index formula is:

TI = TD50 / ED50

TD50 stands for the median toxic dose, whereas ED50 stands for the median effective dose. TD50 refers to the minimum drug dose that would produce a toxic effect in 50% of the population, whereas ED50 refers to the minimum drug dose that will produce the desired therapeutic effect in 50% of the population.

Another related concept is that of therapeutic range (TR). TR is the range of doses/concentrations at which a therapeutic agent or drug produces a therapeutic response without causing any significant adverse effect in patients. It can be measured by:

TR = MEC / MTC

MEC stands for minimum effective concentration, whereas MTC stands for minimum toxic concentration. MEC is the minimum concentration of the drug that is required for achieving the therapeutic effect, whereas MTC is the minimum concentration at which toxicity occurs. Basically, if at a particular dosage, a drug is above MTC, it would cause adverse effects. Similarly, a drug below MEC will not produce the desired therapeutic response.

Significance

While prescribing drugs, healthcare providers rely on their clinical experience and the results of drug trials that determine the TI of a drug. The larger value of TI indicates that there is a wide margin between the toxic and effective dose, whereas a smaller value indicates that there is a narrow margin between the effective and toxic dose. In case of drugs that have a low TI, even a small increase in the dosage can produce toxic effects. Additional care must be taken while prescribing a drug with a narrow TI. Therefore, the pharmaceutical industry has been making efforts to replace NTI drugs (drugs that could be toxic at relatively low levels) with drugs with higher TIs.

Healthcare providers mostly prescribe drugs that have a wide margin of safety. However, they might sometimes prescribe NTI drugs when the medical condition is of a serious nature, and other safer options are not available. In such cases, monitoring the effects of the drug becomes essential.

Limitations

Initially, the ratio of the LD50 and ED50 was determined through animal studies. It must be noted that the ratio measured by animal studies might not be very accurate when it comes to humans. Also, human subjects cannot be used for determining a median lethal dose, for obvious reasons. To add to that, using animals for determining a lethal dose raises ethical issues.

While this ratio might not give an accurate estimate of toxicity in humans, even defining an effective dose might not be a simple task. Also, median values for animals or healthy individuals might not be right for individuals of different age groups or those affected by diseases.

Drugs with a Narrow Therapeutic Index

According to the Food and Drug Administration of the United States (FDA), narrow therapeutic range (NTR) drug products are those 'containing certain drug substances subject to therapeutic drug concentration or pharmacodynamic monitoring, and/or where product labeling indicates a narrow therapeutic range designation'. According to the Therapeutic Products Directorate of Health, Canada, an NTR drug is that wherein the ratio of the lowest concentration at which clinical toxicity occurs to the median concentration providing a therapeutic effect is less than or equal to two. Some drugs that have a narrow therapeutic index are:

➠ Warfarin
➠ Lithium
➠ Digoxin
➠ Phenytoin
➠ Gentamicin
➠ Amphotericin B
➠ 5-fluorouracil
➠ AZT (Zidovudine)

Care must be taken to determine the right dose for the aforementioned drugs in individual cases, as administration of large doses could cause adverse effects.

On a concluding note, the concept of therapeutic index has some limitations, but it is clinically significant, as it lays stress on the importance of the margin of safety of a drug. Drugs that have a narrow or relatively narrow TI are still used when safer alternatives are not available. Under such circumstances, therapeutic drug monitoring becomes extremely important. In such cases, the plasma levels of the drug should be monitored regularly.

Disclaimer: The information provided in this article is solely for educating the reader. It is not intended to be a substitute for the advice of a medical expert.