Therapeutic index and window & clinical significance

Therapeutic index

1. IKHIDERO JEMIMAH EMILOMO DESTINY IYARE Haruna Gideon Isobor nosayenmen Valerie Kukoyi temitope John joy osamhengbe A SEMINAR PRESENTATION, presented by;

2. Group 6 Topic: therapeutic index Medicine and surgery 400 level Edo state University, Uzairue .

3. Outline Introduction Definition of terms Graphical representation Mathematical representations Drugs with their therapeutic index Implications Summary References

4. INTRODUCTION The  therapeutic index  ( TI ; also referred to as  therapeutic ratio ) is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the  therapeutic effect  to the amount that causes toxicity.

5. Definition of terms Effective dose: an effective dose (ED) or effective concentration (EC) is a dose or concentration of a drug that produces a biological response. Median effective dose: minimum dose which produces the desired effect in 50% of the population (ED50). Median lethal dose: is the drug dose which kills 50% of the under trial animals (LD50). Lethal dose: The dose of a substance or of radiation likely to cause death (LD).

6. Graphical representation of therapeutic index

7. Mathematical representation of TI

8. Therapeutic index and Therapeutic window ?

9. Low therapeutic index drugs Digoxin Paracetamol (acetaminophen) Lithium Warfarin ( coumadin ) Gentamycin Vancomycin Phenytoin Insulin Antidepressants, tricyclic

10. High(wide) therapeutic index drugs NSAIDs Benzodiazepines Most antibiotics Furosemide SSRIs

11. Graphical representation of low and high TI

12. Implications of small or high TI The higher the TI the safer the drug while the smaller the TI the more dangerous is the drug. A safer drug has a higher therapeutic index A more dangerous drug has lower therapeutic index

13. Why is a higher therapeutic index ? A higher therapeutic index is preferable to a lower one:  a patient would have to take a much higher dose of such a drug to reach the toxic threshold than the dose taken to elicit the therapeutic effect . Clinical implications of a drug with a lower therapeutic index ? small increases in dose or in blood/serum concentrations could lead to toxic effects .

14. Therapeutic index in drug development. In a drug development setting, TI is the quantitative relationship between efficacy (pharmacology) and safety (toxicology), without considering the nature of pharmacological or toxicological endpoints themselves. However, to convert a calculated TI to something that is more than just a number, the nature and limitations of pharmacological and/or toxicological endpoints must be considered.

15. Range of therapeutic index For instance,   the opioid painkiller remifentanil is very forgiving, offering a therapeutic index of 33,000:1, while Diazepam, a benzodiazepine sedative-hypnotic and skeletal muscle relaxant, has a less forgiving therapeutic index of 100:1. Morphine is even less so with a therapeutic index of 70.  Paracetamol , also known by its common trade name Tylenol, has a therapeutic index of 10.

16. Less safe are cocaine (a stimulant and local anaesthetic) and ethanol (colloquially, the "alcohol" in alcoholic beverages, a widely available sedative consumed worldwide): the therapeutic indices for these substances are 15:1 and 10:1, respectively. Even less safe are drugs such as digoxin, a cardiac glycoside; its therapeutic index is approximately 2:1

17. The larger the therapeutic index (TI), the safer the drug is. If the TI is small (the difference between the two concentrations is very small) the drug must be dosed carefully and the person receiving the drug should be monitored closely for any signs of drug toxicity. Why study therapeutic index?

18. What are the limitations of therapeutic index? The therapeutic index has many limitations, notably the fact that  LD 50  cannot be measured in humans and, when measured in animals, is a poor guide to the likelihood of unwanted effects in humans .

19. Summary therapeutic index , margin of safety that exists between the dose of a  drug  that produces the desired effect and the dose that produces unwanted and possibly dangerous  side effects . This relationship is defined as the ratio LD 50 :ED 50 , where LD 50  is the dose at which a drug kills 50 percent of a test group of animals and ED 50  is the dose at which the desired effect is produced in 50 percent of a test group. In general, the narrower this margin, the more likely it is that the drug will produce unwanted effects.

20. References www.wikipedia.org.co www.britArnica.com Katzung and trevor‘s pharmacology https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4412688/ https://step1.medbullets.com/pharmacology/107009/therapeutic-index Essentials of medical pharmacology 7 th edition by kd tripathi