resorcinol
01-15-2009, 04:45 PM
...innate opioid tolerance (ie... take a few people who've never tried opioids, some of them will need more than average, some less than average).
Weight does effect ALL drugs to SOME degree, but I think it may be more important for some than for others.
I don't think adipose (fat) tissue has NEARLY as many blood vessels in it than the rest (not fatty) part of the body. It has some (I think it does at least) but I'm pretty sure significantly less that the rest of the body. Fat stored in the fat cells on the body requires a lot less TLC in the form of oxygen and nutrients than other parts of the body like the organs and the circulatory system's cells itself. Actually the fat itself doesn't really need anything, but the fat CELLS which hold the fat do need a little bit of TLC... but they're not very numerous, hence not many blood vessels. Fat cells are actually variant in size depending on how fat somebody is. More fat cells aren't made to accommodate the fat, but rather, the existing fat cells grow bigger to take in the excess fat that builds up when you exceed your food energy intake requirements continuously. In obese people, their fat cells are HUGE. The point is though, since there aren't many fat cells, and fat cells have relatively few mitochondria, there are less blood vessels in the fatty tissue, but there are some.
So weight should have a somewhat minor but notable influence on drug doses.
I think it varies drug by drug mainly by this factor: how lipophilic (soluble in fat) it is. If it's a very lipophilic drug, I tend to think weight will matter more for said drug. The reason being is that the drug will dissolve from the blood vessels that do pass through the fat cells into the fat, and will be removed from the bloodstream, lowering plasma concentrations (this happens with diazepam quite significantly, so it's a great example -- it's why diazepam actually suppresses seizures in a benzo or alcohol w/d case for a shorter period of time than lorazepam, despite having a way, WAY longer half life than lorazepam. The drug is eventually redistributed to the bloodstream and then metabolized and excreted, but usually after the drug that remained in the bloodstream is gone and excreted...
happens because of the simple little thing called diffusion. When those initial blood concentrations of the lipophilic drug are very high compared to the amount ... which is none initially ... in fatty tissue, a good chunk of the drug is distributed to the fatty tissue through diffusion until it's in equilibrium with the concentration in the blood -- equilibrium meaning the amount that leaves and goes back into the bloodstream is equal to the amount being taken up by the fat. The drug in the fatty tissue will only start to diffuse back into the bloodstream when at a greater rate than the amount coming in when blood concentrations exponentially decrease by first order kinetics. While it may seem like systems in equilibrium are static and not doing anything, it's not true, it's just that the amount going out of 1 into 2 is equal to the amount going into 1 from 2, creating the appearance of nothing happening. The end result is the same thought.
This end result is that by the time the lipophilic drug that got taken up into fatty tissue is diffused back into the bloodstream, you buzz / high, anxiety relief, pain relief, etc etc from that dose is LONG gone as the drug amount that was able to stay in the serum / blood and cause the primary effects is already exponentially falling in concentration. That's why Ativan (lorazpam) is preferred for 2 to 5 hourly injections, ranging anywhere in dose from 2 mg each time to 30 mg each time depending on the severity of the alcohol, benzodiazepine, or barbiturate habit. Delirium tremens (which was made a known term to the commoner because booze can cause it) isn't JUST caused by alcohol... it can be caused by ethanol (alcohol... meh, I HATE that name! alcohol is about as vague as you can get... there are trillions of possible alcohols. morphine is an alcohol. any fucking molecule with an -OH functional group somewhere in its structure is an alcohol. Ethanol is NOT a harder word to remember... it just isn't. I don't understand by they're just not called ethanolic beverages instead of "alcoholic" beverages. It would certainly help curb at least some cases of methanol and 2-propanol (rubbing alcohol) poisonings in emergency rooms among alkies. Methanol is absolutely unsuitable for drinking EVER, it will DESTROY your optic nerve and cause metabolic acidosis due to formic acid formation. 2-propanol isn't as big a deal. Here's the deal with 2-propanol:
2-propanol has a three carbon (propane) backbone while ethanol has a two carbon (ethane) backbone. With ethanol, there's only one possible positional isomer since it has only two carbons. Propanol however can have its -OH placed on the end carbon (like ethanol it doesn't matter which end carbon) OR, unlike ethanol, it can be placed on the middle carbon, carbon number 2, hence 2-propanol or isopropanol.... I guess it's a better antiseptic than regular terminal carbon -OH propanol for some reason... or maybe there's no rhyme / reason at all for using it vs propanol (it could be called 1-propanol, but that's assumed when you don't specify). Isopropanol isn't really TOO toxic (estimated to be about 2x more toxic than ethanol) but also 2x more potent as an agonist of GABA(A) receptors. However, it has other deterrents against abuse built in. Its primary metabolite is a ketone, since it's a secondary alcohol, which can't be metabolized further. This causes a wicked, awful hangover, and you'll reek of nail polish remover as it's slowly eliminated from your body. Still... doctors are always relieved when it's isopropanol and not methanol that was used as the substitute "booze" b/c methanol poisoning needs to be caught early to prevent blindness. Treatment is IV ethanol though a drip... they keep your BAC at 1.8 or sometimes 2.0 I think depending on the severity of the methanol poisoning. Ethanol has a stronger affinity for alcohol dehydrogenase than methanol, and acetaldehyde has a stronger affinity for aldehyde dehydrogenase than formaldehyde dose. Formic acid formation is severely limited and this treatment usually works without fail if caught before the damage is done.
I'm getting way off topic though. Back to weight.
I think lipophilic (fat solube) drugs are more effected be weight, since heavier people (I'm mainly referring to when that weight is fat... not muscle men who are very heavy but from bulk in muscle). Alcohol, diazepam, and THC are good examples. So for those, mg/kg dosing may be more important.
I think it applies to lipophobic (drugs that DON'T dissolve in water) to a degree too -- because other factors influence weight besides... fat. Examples: height, muscle mass. They're the main ones. If you're a bigger person not in the overweight or obese way, but even in the tall or muscled up way, you've got more blood in ya than a short scrawny guy. This makes the mg/kg dosing concept (and the usage of it for lethal dose figures) justifiable to a degree IMO. More blood / serum = lower concentration of the drug for any given dose.
So my opinion is that the effect is most noticeable in lipophilic drugs, especially for very overweight or obese people, but that it's noticeable for all drugs due to other differences in body size besides the spare tires, like height and muscle tone and bulk. Bigger body for any reason means you have more blood (which contains serum where your drugs reside) in you at any given time. More blood and thus more serum for the drug to dissolve in leads to lower concentrations of the drug in the blood... even in lipophobic drugs, and remember, it's the molar concentration in serum (usually measured in micromolar [uM] units since the amounts of most drugs in the blood are tiny and a whole Molar concentration of a solute is not a suitable unit for measuring drug concentrations in blood. uM is still Molar conc., just with the micro prefix attached to make the numbers easer to work with. Nobody wants to write down a concentration of drug in a patients serum as 0.000000007 M when they could just write 7 uM.
So, I vote that weight does matter moderately, and us featherweights out there are getting higher for cheaper ;)
I think it begins to matter less as a serious tolerance develops though... the different sized people tend to even out at the same insane tolerances after a period of time.
Weight does effect ALL drugs to SOME degree, but I think it may be more important for some than for others.
I don't think adipose (fat) tissue has NEARLY as many blood vessels in it than the rest (not fatty) part of the body. It has some (I think it does at least) but I'm pretty sure significantly less that the rest of the body. Fat stored in the fat cells on the body requires a lot less TLC in the form of oxygen and nutrients than other parts of the body like the organs and the circulatory system's cells itself. Actually the fat itself doesn't really need anything, but the fat CELLS which hold the fat do need a little bit of TLC... but they're not very numerous, hence not many blood vessels. Fat cells are actually variant in size depending on how fat somebody is. More fat cells aren't made to accommodate the fat, but rather, the existing fat cells grow bigger to take in the excess fat that builds up when you exceed your food energy intake requirements continuously. In obese people, their fat cells are HUGE. The point is though, since there aren't many fat cells, and fat cells have relatively few mitochondria, there are less blood vessels in the fatty tissue, but there are some.
So weight should have a somewhat minor but notable influence on drug doses.
I think it varies drug by drug mainly by this factor: how lipophilic (soluble in fat) it is. If it's a very lipophilic drug, I tend to think weight will matter more for said drug. The reason being is that the drug will dissolve from the blood vessels that do pass through the fat cells into the fat, and will be removed from the bloodstream, lowering plasma concentrations (this happens with diazepam quite significantly, so it's a great example -- it's why diazepam actually suppresses seizures in a benzo or alcohol w/d case for a shorter period of time than lorazepam, despite having a way, WAY longer half life than lorazepam. The drug is eventually redistributed to the bloodstream and then metabolized and excreted, but usually after the drug that remained in the bloodstream is gone and excreted...
happens because of the simple little thing called diffusion. When those initial blood concentrations of the lipophilic drug are very high compared to the amount ... which is none initially ... in fatty tissue, a good chunk of the drug is distributed to the fatty tissue through diffusion until it's in equilibrium with the concentration in the blood -- equilibrium meaning the amount that leaves and goes back into the bloodstream is equal to the amount being taken up by the fat. The drug in the fatty tissue will only start to diffuse back into the bloodstream when at a greater rate than the amount coming in when blood concentrations exponentially decrease by first order kinetics. While it may seem like systems in equilibrium are static and not doing anything, it's not true, it's just that the amount going out of 1 into 2 is equal to the amount going into 1 from 2, creating the appearance of nothing happening. The end result is the same thought.
This end result is that by the time the lipophilic drug that got taken up into fatty tissue is diffused back into the bloodstream, you buzz / high, anxiety relief, pain relief, etc etc from that dose is LONG gone as the drug amount that was able to stay in the serum / blood and cause the primary effects is already exponentially falling in concentration. That's why Ativan (lorazpam) is preferred for 2 to 5 hourly injections, ranging anywhere in dose from 2 mg each time to 30 mg each time depending on the severity of the alcohol, benzodiazepine, or barbiturate habit. Delirium tremens (which was made a known term to the commoner because booze can cause it) isn't JUST caused by alcohol... it can be caused by ethanol (alcohol... meh, I HATE that name! alcohol is about as vague as you can get... there are trillions of possible alcohols. morphine is an alcohol. any fucking molecule with an -OH functional group somewhere in its structure is an alcohol. Ethanol is NOT a harder word to remember... it just isn't. I don't understand by they're just not called ethanolic beverages instead of "alcoholic" beverages. It would certainly help curb at least some cases of methanol and 2-propanol (rubbing alcohol) poisonings in emergency rooms among alkies. Methanol is absolutely unsuitable for drinking EVER, it will DESTROY your optic nerve and cause metabolic acidosis due to formic acid formation. 2-propanol isn't as big a deal. Here's the deal with 2-propanol:
2-propanol has a three carbon (propane) backbone while ethanol has a two carbon (ethane) backbone. With ethanol, there's only one possible positional isomer since it has only two carbons. Propanol however can have its -OH placed on the end carbon (like ethanol it doesn't matter which end carbon) OR, unlike ethanol, it can be placed on the middle carbon, carbon number 2, hence 2-propanol or isopropanol.... I guess it's a better antiseptic than regular terminal carbon -OH propanol for some reason... or maybe there's no rhyme / reason at all for using it vs propanol (it could be called 1-propanol, but that's assumed when you don't specify). Isopropanol isn't really TOO toxic (estimated to be about 2x more toxic than ethanol) but also 2x more potent as an agonist of GABA(A) receptors. However, it has other deterrents against abuse built in. Its primary metabolite is a ketone, since it's a secondary alcohol, which can't be metabolized further. This causes a wicked, awful hangover, and you'll reek of nail polish remover as it's slowly eliminated from your body. Still... doctors are always relieved when it's isopropanol and not methanol that was used as the substitute "booze" b/c methanol poisoning needs to be caught early to prevent blindness. Treatment is IV ethanol though a drip... they keep your BAC at 1.8 or sometimes 2.0 I think depending on the severity of the methanol poisoning. Ethanol has a stronger affinity for alcohol dehydrogenase than methanol, and acetaldehyde has a stronger affinity for aldehyde dehydrogenase than formaldehyde dose. Formic acid formation is severely limited and this treatment usually works without fail if caught before the damage is done.
I'm getting way off topic though. Back to weight.
I think lipophilic (fat solube) drugs are more effected be weight, since heavier people (I'm mainly referring to when that weight is fat... not muscle men who are very heavy but from bulk in muscle). Alcohol, diazepam, and THC are good examples. So for those, mg/kg dosing may be more important.
I think it applies to lipophobic (drugs that DON'T dissolve in water) to a degree too -- because other factors influence weight besides... fat. Examples: height, muscle mass. They're the main ones. If you're a bigger person not in the overweight or obese way, but even in the tall or muscled up way, you've got more blood in ya than a short scrawny guy. This makes the mg/kg dosing concept (and the usage of it for lethal dose figures) justifiable to a degree IMO. More blood / serum = lower concentration of the drug for any given dose.
So my opinion is that the effect is most noticeable in lipophilic drugs, especially for very overweight or obese people, but that it's noticeable for all drugs due to other differences in body size besides the spare tires, like height and muscle tone and bulk. Bigger body for any reason means you have more blood (which contains serum where your drugs reside) in you at any given time. More blood and thus more serum for the drug to dissolve in leads to lower concentrations of the drug in the blood... even in lipophobic drugs, and remember, it's the molar concentration in serum (usually measured in micromolar [uM] units since the amounts of most drugs in the blood are tiny and a whole Molar concentration of a solute is not a suitable unit for measuring drug concentrations in blood. uM is still Molar conc., just with the micro prefix attached to make the numbers easer to work with. Nobody wants to write down a concentration of drug in a patients serum as 0.000000007 M when they could just write 7 uM.
So, I vote that weight does matter moderately, and us featherweights out there are getting higher for cheaper ;)
I think it begins to matter less as a serious tolerance develops though... the different sized people tend to even out at the same insane tolerances after a period of time.