A recent email chain has led to this GEITP topic worth sharing, a lesson in “Genetic Differences in Drug Response.”
My original comment was that, “It would seem that all drugs exhibit interindividual differences in genetic response.”
The (slight) challenge offered to my generalized, sweeping statement was: “No, not ALL drugs.”
My answer was: “Name one drug, or one class of drugs, that are not.” The quick response was “Antibiotics.”
This quick retort, comment, represents a very interesting hypothesis –– which led to further thought:
“Do antibiotics show less genetic differences in drug response than other drugs?”
This led to a Small Lesson in Pharmacology today. “For those of you who have heard this before, you might enjoy hearing it again. For those of you who have NOT heard this before, you might enjoy hearing this again –– next time.” [~~Victor Borge, 1909-2000]
As those of us (having pharmacology training) know –– each drug shows a specific “Therapeutic Index.” For Drug A, the TI might be 10, i.e. the Toxic Dose is 10 times higher than the Effective (therapeutic, efficacious) Dose. For Drug B, the TI might be 2, i.e.the Toxic Dose is only twice that of the Effective Dose.
Consider that, in a population receiving either drug –– the range of responses is 4-fold (i.e. in some people, it takes 4 times more drug to show a beneficial effect. Thus, for the population using Drug A, 4-fold differences would be small potatoes, because Drug A is quite safe, having a TI of 10. On the other hand, for the population using Drug B, 4-fold difference would be manifest as serious problems in a substantial subset of the cohort, with some showing an efficacious response while others show a toxic response (or adverse drug reaction); these observations commonly reflect a drug such as Drug B having a TI of 2.
[a] All drugs (or other environmental chemicals) will show a Gradient in any population –– due to underlying differences in the genetic architecture of each person in that population. [“Genetic architecture” is defined as “The underlying genetic basis of any trait (phenotype), also termed “genotype-phenotype map”, i.e. the means by which each genotype (DNA sequence differences plus epigenetic effects) leads to, or contributes to, the phenotype.”
[b] The size of the Gradient will depend on the biology (uptake, distribution, metabolism, excretion) of the animals’ response to that drug or environmental toxicant.
[c] The larger the drug’s Therapeutic Index, the less likely will we see remarkable genetic differences in drug response.
[d] The smaller the drug’s Therapeutic Index, the more likely will we see important genetic differences in drug response.
[e] Such a Gradient will also likely vary –– among different ethnic populations, again due to interethnic variability in drug response.
I found online an excellent summary, comparing the “Therapeutic Window” with the “Therapeutic Index“. It is (slightly edited and) pasted below.
Therapeutic window is the range of doses that produces a therapeutic response in patients (efficacy) without causing any significant adverse effects.
Generally, therapeutic window is the ratio between minimum effective concentrations (MEC) to the minimum toxic concentration (MTC). The levels of a drug (ideally) should always be between MEC and MTC –– in order (usually) to provide risk-free therapeutic effects. If any drug crosses MTC –– then it will surely elicit toxic effects (excluding consideration of interindividual variability in drug response). And, if a drug is unable to surpass MEC, then this is defined as therapeutic failure. MEC is also called as minimum inhibitory concentration (MIC).
Therapeutic window is sometimes referred to as the “safety window,” and this can be quantified by the therapeutic index.
Therapeutic Index (TI):
Therapeutic index (TI) describes the relationship between dose of a drug that causes a toxic or lethal effect, and dose that causes a therapeutic effect. Therapeutic index is sometimes called “therapeutic ratio.”
Mathematically, you can calculate TI in the following way;
Therapeutic Index = LD50/ED50
Therapeutic Index = TD50/ED50
LD50 is the minimum amount of drug that causes adverse effects in 50% of the population. LD50 could also be replaced with toxic dose (TD50)
ED50 is the quantity of drug that produces desired therapeutic effects in 50% of the population. Such types of studies are usually conducted in animal models.
Ideally, any drug that requires a greater amount to produce toxic or adverse effects in 50% of population will have a wider therapeutic index, and vice versa. Drugs having wider therapeutic indices are safer, in comparison to those having lower therapeutic indices. Minor modifications in dosage of wide-TI drugs –– e.g. aspirin and acetaminophen –– will rarely produce toxic effects.
Additional examples –– non-steroidal anti-inflammatory drugs (NSAIDs) have wide therapeutic indices. In contrast, warfarin has a narrow therapeutic index of less than two (hence, the extreme challenge of treating physicians to “titrate the optimal dose in each specific patient.”
Examples of Drugs:
Here is a list of eight common potent drugs having low therapeutic indices;
1. Craig, C. Modern Pharmacology With Clinical Applications. 6th ed. LWW, 2003
2. Katzung, B. Basic and Clinical Pharmacology. 11th ed. McGraw Hill Medical, 2009
3. Golan, D. “Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy”. 2nd ed. LWW, 2008.
4. David E. Golan, Armen H. Tashjian, Ehrin J. Armstron. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. Pharmacodynamics, Chapter 02. P. 25-26
5. Coleman, Michael D. (2010). Human Drug Metabolism: An Introduction. John Wiley & Sons. p. 01
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