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Diazepam pharmacodynamics vs. pharmacokinetics

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Phoenix2

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Jan 11, 2011
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7
Hi,

I'm a newbie on BL, so please excuse me if I'm posting in the wrong forum or for any other error I might be making. I'm learning....

I am prescribed diazepam 10mg tid. As we know, Diazepam has a very long half life compared to most other Benzo's. I can't argue with the basic pharmacokinetic research that proves it; it is a fact. My confusion lies with the observed divergence between long half life, but a limited period of drug effect. If you look at the drug PI or monograph, tid (3 times a day) dosing is recommended for anxiety disorders. I find that a dose of diazepam produces some anxiolysis for about 4-6 hours which makes no sense when the half life is 80-100 hours. So tid dosing is recomended, and I need to take this med 3 times a day to avoid huge ups and downs of anxiety, which both suggest a shorter duration of clinical effect than the. But I understand that the relationship is more complicated because of active metabolites, and the high degree of lipophilicity of the drug.

Thanks,

Phoenix
 
Thanks sekio. But if I get the desired clinical effect (just anxiolysis) for 4-6 hours, then it would be some kind of acute tolerance rather than the chronic tolerance seen most often w/ benzos, where even the usual dose does not work. Does that make sense? Also, from what I've read (sorry, no citations at the moment), people become quickly tolerant to diazepam's initial sedative/hypnotic effects, but not the anxiolytic effect.

I just don't understand the disparity between the half life, and length of clinical effects. If it's clinical effect and half life worked the same way as most other benzos, tid dosing wouldn't be needed, but it is specified in all the prescribing sections I've read. I know that I am tolerant, because the prescribed dose no longer makes me sleepy, it just reduces anxiety for 4-6 hours.

BTW, I am legally prescribed diazepam by a neuropsychiatrist, and I don't ever stray from my 10mg tid dose.
 
Every GABA receptor has a total 5 subtypes arranged in pentagons of which alpha, beta, gamma,seem to be the major casue of benzo activity, and each one of them have som underlying subtypes, reason why wo many fucking benzos are on the market. apart from theyse some other subtypes that play a minor role are ortho, eta, and omicron which play negligible to zero role, from what I've heard, in benzo activity since they bind on to very specific sites thus altering the calcium influx to a neuron.
Different benzo seem to exert slightly different binding profiles even-though the percievable effects are hard to notice to a novel. The reason why some benzos seem to have a greater affinity to some subtypes explain the wide variety of ben products all over the world.

Check this:
http://en.wikipedia.org/wiki/GABAA_receptor
 
yeah....Gabaergic medications are very paradoxical indeed. especially benzos. however it is as common with benzos as it is with other drugs that the effective dose's half life may sometimes be shorter than its perceived half life...or sometimes longer (ie valium doesnt reduce anxiety for 3 days after one dose but percocets will make you high for 12 hours with a mere 4hr half life).

youre also right that active metabolites play a role. there are at least 2 or three active metabolites to diazepam but they never exhibit as strong of a profile as when they are prescribed by themselves (ie oxazepam). also...its metabolites like oxazepam and nordiazepam are extemely weak and subtle in comparison to the ED profile of xanax, klonopin and other stronger meds. tolerance also develops extremllllyyy rapidly to any benzo...especially if you have the kind of brain chemistry and hyperactive metabolism that would facilitate that. what was said about the post synaptic GABAa pentameter is true. unlike drugs like temazepam which target only one or two alpha sub-units...diazepam is a lot broader and binds to nearly all alpha subunits (1-5). the two subunits responsible for sedation (alpha 1 and another i believe) are the most sensitive to stimulation and are the first to be down-regulated. the ones responsible for its anxiolytic effects take longer. i take clonazepam. its a broad spectrum benzo like diazepam with an even stronger affinity for the sedative/anti-convulsant subunits. the first time i took it, i couldnt even stand up. i fell down the stairs. id pass out while sitting up...or not be able to sit up at all. i wasnt even awake to feel its anxiolytic effects. after about a week...i was sprightly and energetic and making friends with everyone. thats why people prescribed klonopin with epilepsy are prescribed up to 20mg/day instead of the 4mg/day cap that anxiety patients have.

in other words...the more the subunits responsible for sedation are stimulated...the faster they are down-regulated and the more drug needs to be consumed to achieve the same effect. thats why you no longer feel sedated. as for general amounts of time the drug lasts...lipophilicity should actually make it act longer as fat soluble drugs cross the BBB much quicker (but not intranasally). valium and all its metabolites are just extremely subtle and any effects that match the 80-100 HL are barely noticeable. an equivalent dose of oxazepam is 15-30mg. if youre taking 10mg of valium...youre obviously not getting anywhere close to an equivalent dose of any of its metabolites. though technically...they are in your blood stream...albeit at very low quantities, which is why you dont feel a strong continuous effect. i promise you will notice the 80-100 HL, however if you quit cold turkey. it would take longer for a full withdrawal effect to set in than it would with shorter acting drugs like xanax or halcion.

finally, sleep plays a role. sleep is misconstrued for putting us in a hypo-metabolic state. but there are two kinds of metabolisms...catabolic and anabolic. sleep is characterized by a heightened anabolic state...which is responsible for restorative functions. diazepam, being an unnatural substance is quickly cleared during sleep to restore normal neuronal functions...essentially decreasing its effective half life.

if you want to increase the half life of diazepam without taking more of it...take a natural CYP3A4 enzyme inhibitor like grapefruit juice. make sure youre not taking any other medication that could have a dangerous reaction. look up that enzyme's ligands on wiki. GFjuice WILL increase its effectiveness. also...taking the natural supplement L-theanine will increase the body's natural amount of GABA by increasing glutamate decarboxylase enzymes. since GABA cant cross the BBB, its the best way to increase GABA in vivo. you will feel more sedated and relaxed. but dont expect to get much done. hope that helps.
 
IIRC the short perceived duration of diazepam in contrast to its long half life is due to rapid tissue distribution. (IE, it is redistributed from the plasma to peripheral tissues quite rapidly).
 
With chronic daily dosing the steady state concentration is more relevant to therapeutic efficacy (and thus therapeutic duration) than is the half-life (T1/2). If constant dosing is performed (time and amount) of a drug, eventually a steady state will be reached. At steady state input = output (with some fluctuations depending on frequency of dosing). In this way the plasma concentrations remains relatively constant. The target steady state concentration is that required for the therapeutic response.

The time required to reach steady state depends on the frequency of dosing not the dose (If taken every t1/2 it will take about 5 t1/2 to be reached).

Obviously drugs with a longer t1/2 can require less frequent dosing. However they do not have to be administered every t1/2. We can reach the same desired steady state concentration via two strategies (extremes): lower doses administered more frequently will result in less fluctuation of the steady state concentration whereas higher doses administered more sparsely will lead to greater fluctuations in steady state concentration. Again both will give the same steady state concentration.

Obviously drugs with a short t1/2 will tend to require more frequent dosing because the plasma concentration will stray from the steady state more rapidly.

Assuming first order kinetics (concentration dependent) of metabolism the steady state of any active metabolites will correlate with the steady state of its parent drug. So in the case of an active parent and active metabolite both steady state concentrations will be relevant. Whereas with a prodrug the steady state of the active metabolite is relevant.

With acute drug ingestion t1/2 is usually a good predictor of duration of action but not always. Again drugs with a longer t1/2 generally have a longer duration of action however there are pharmacokinetic properties which affect this. Many of these variables have been properly acknowledged in previous posts such as active metabolites, distribution patterns, acute tolerance etc. Drugs with short t1/2 will tend to have shorter durations of action. Again the same pharmacokinetic properties can affect this as well.

It is a good idea to remember that at the first t1/2, half of the initial drug concentration is still present. Thus depending on dose the drug may still be well with-in the therapeutic range after the first and even second t1/2. This is why dose can affect duration of action of acute drug effect.
 
Thanks to everyone who responded!.

I think from your responses, and my research I have a better understanding of what is going on. I think Roger&Me (Great documentary, BTW) hit it on the head with the tissue distribution, i.e it is stored in adipose tissue and slowly released when plasma concentrations drop. But as navarone//, Pharmokinetical, and bufoman point out, there are tons of other complicated factors involved. And when you add in second messenger effects that we may not even recognize yet, it becomes quite messy. Benzos are very complicated, but I think diazepam is one of the most complex in terms of it's pharmacology and pharmacokinetics. Thanks again for your knowleadgable, well explained responses!:D
 
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