It seems like the effective dosage of most medications tend to be in the 5mg to 200mg range (although there are some medications with smaller or larger dosages). Is this an accurate observation? If so, why?

Submitted by Fbg2525 t3_10ek9vz in askscience

As the title mentions, based on casual observation, it seems to me that the effective dose of most medicine active ingredients is somewhere between 5 mg and 200 mg. There are of course exceptions like fentanyl which is incredibly potent at the scale of micrograms, and gabapentin, which is often dosed at over 1000 mg, but it seems like most medications are within a narrower range I mention above. This is surprising given vastly different molecular structures of the different medications.

My first question is, is my observation empirically accurate? Or, am I just noticing a non-representative subset of medications?

My second question is, if this is true, why? I know the range i mentioned is pretty large, but it seems narrow when considering total physically possible ranges? Why don’t we see more medications with effective dosages at the microgram scale?

One possibility that occurred to me- is this just a matter of practicality? Consuming multiple grams of medication, although possible, is inconvenient. Similarly, maybe its more expensive to manufacture super potent compounds because of the precision it requires. Are companies just choosing to develop products that work in a more convenient dosing range?

Another possibility that occurred to me- is there some law of chemistry or factor in our biology that makes this the ideal dosage range for many different compounds? E.g., the size of molecules limits potency, the body has some process that clears de minimis amounts of a compound, the average human weight somehow necessitates medications usually be in this range, etc.?

This question has been driving me crazy, so thanks to anyone who can provide some insight.

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MJBrune t1_j4tsnvf wrote

Average human size really is what it comes down to. Only so many mgs got in your blood. Only so many receptors for those chemicals. That said the range you have is far under what I typically see for ibuprofen or Tylenol. Which is in the 400 to 600 range. So you might have some observational bias in there too.

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sometimesgoodadvice t1_j4u81tt wrote

Your hypotheses are pretty spot on. There is some observational bias, I think you are mostly looking at small molecules, as biologics typically have dosages on the order of grams. Small molecules are actually not too different in size, the molecular weight may range 10x between some of the smaller and some of the larger compounds (excluding outliers) which in biology is not that much of a difference considering that typical biological molecules range from the size of water or CO2 (18 and 44 Da) all the way to protein complexes that are >1MDa.

Next, the biology. Most drugs are given systemically which means they pretty much dilute themselves in blood which is pretty close to the same volume for most people. And of course, those drugs are designed to interact/interfere with typical biological processes which through evolution and for kinetic/thermodynamic reasons utilize a relatively narrow range of concentrations in the enzymes/receptors of the body. So a relatively close range of concentrations combined with almost constant volume and relatively close range of molecular weights yields close total dosage.

Lastly, there is pharmacokinetics. Every drug you take has three competing "things" it does. The effect you are looking for, the effect you are not looking for, and removal. The first two parts determine what's called a "therapeutic window". This is the range of concentrations where the intended effect is useful and the side effects are minimized. If you are above this range, the number and severity of side-effects will increase (again more or less back to basic thermodynamics) and if you are below, then your therapy will not be potent enough to have a considerable positive effect. This window can vary quite a bit, but at first approximation will center around the concentration of other similar molecules in the blood, which we already discussed above.

Then there is the clearance. If you are lucky enough to have a large therapeutic window, it may still not be advantageous to give lots of the drug. Most drugs at higher dosages are at first cleared by first-order kinetics whether through liver or kidney. This means that the more drug there is, the faster it is cleared. As concentration decreases, so does the clearance. So imagine you have a wonderful drug that is in the therapeutic window over a range of ~1000x concentration. That means if you give the max amount, you will be active for about 10 half-lives before the concentration decreases enough to no longer provide benefit (2^10~1000). Now you take that same drug and double its concentration. You have increased it's longevity by one half-life, meaning a 10% increase (11 half-lives compared to 10) from previous dosage in how long it stays effective. But to get that 10% you used 2x the drug. Not a great trade-off.

At the end of the day, each drug will have a dosage based on how effective it is at certain concentrations, which dosages minimize side-effects, what concentrations the formulation allows, and also what will lead to the highest rate of patients actually taking the drug (tons of people are working on ways to minimize insulin injections for example). There is some economics goin on as well, but not as much since the production cost for most drugs is small compared to the price.

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Fbg2525 OP t1_j4uzhxa wrote

This is an excellent explanation. Thank you!

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