Onset of Action vs. suitable blood concentration

[Mask0ff]

Hi All,

I am lightly studying pharmacology; and have come across this concept of 'onset of action'.

How long does plasma concentration of a drug have to be in the therapeutic range? Is the onset of action always at that point where the plasma concentration arrives at therapeutic range?

THX

 

[Mask0ff]

for example, with Fluvoxamine SSRI - steady state is achieved at 10+ days, but the effects are not achieved in a plurality of patients for 6-10 weeks.
But donepezil is linear at 14-21 days for both steady state and onset of action.

Am I understanding this correctly, that most drugs are linear and dose-dependent in their response, but others can take longer to achieve steady state or there are other mechanisms (like with SSRIs) that slow down their onset?

 

[Skorpio]

for example, with Fluvoxamine SSRI - steady state is achieved at 10+ days, but the effects are not achieved in a plurality of patients for 6-10 weeks.
But donepezil is linear at 14-21 days for both steady state and onset of action.

Am I understanding this correctly, that most drugs are linear and dose-dependent in their response, but others can take longer to achieve steady state or there are other mechanisms (like with SSRIs) that slow down their onset?

SSRIs are fairly unique, and there are a number of hand wavey explanations for why their onset of mood altering effects is delayed.

The oldest one that I remember is the claim that antidepressant effects are due to autoreceptor downregulation. Basically, autoreceptors are located on the presynaptic neuron and measure synaptic neuro transmitter levels. They induce release when levels are low and inhibit release when levels are high. This theory states that ssris are less functional early on due to serotonin 1 auto receptors responding to increased serotonin levels.

Antidepressant Treatment Reduces Serotonin-1A Autoreceptor Binding in Major Depressive Disorder

Chronic selective serotonin reuptake inhibitor (SSRI) administration to rodents desensitizes or downregulates raphe 5-HT[1A] autoreceptors. We previously found elevated 5-HT[1A] binding in antidepressant-naïve and not recently-medicated major ...

www.ncbi.nlm.nih.gov

A more recent claim is that ssris are directly interacting with trkb receptors to increase bdnf signaling. The delay of action is explained by the fact that the interaction is very low affinity and it takes weeks of steady state dosing to achieve proper concentrations in the brain compartment. Trkb receptors are activated by bdnf and promote neuron growth. Their activation is correlated with antidepressant effects of many drugs of diverse classes.

Antidepressant drugs act by directly binding to TRKB neurotrophin receptors - PubMed

It is unclear how binding of antidepressant drugs to their targets gives rise to the clinical antidepressant effect. We discovered that the transmembrane domain of tyrosine kinase receptor 2 (TRKB), the brain-derived neurotrophic factor (BDNF) receptor that promotes neuronal plasticity and...

pubmed.ncbi.nlm.nih.gov

I prefer the second theory.

 

[thegreenhand]

SSRIs are fairly unique, and there are a number of hand wavey explanations for why their onset of mood altering effects is delayed.

The oldest one that I remember is the claim that antidepressant effects are due to autoreceptor downregulation. Basically, autoreceptors are located on the presynaptic neuron and measure synaptic neuro transmitter levels. They induce release when levels are low and inhibit release when levels are high. This theory states that ssris are less functional early on due to serotonin 1 auto receptors responding to increased serotonin levels.

Antidepressant Treatment Reduces Serotonin-1A Autoreceptor Binding in Major Depressive Disorder

Chronic selective serotonin reuptake inhibitor (SSRI) administration to rodents desensitizes or downregulates raphe 5-HT[1A] autoreceptors. We previously found elevated 5-HT[1A] binding in antidepressant-naïve and not recently-medicated major ...

www.ncbi.nlm.nih.gov

A more recent claim is that ssris are directly interacting with trkb receptors to increase bdnf signaling. The delay of action is explained by the fact that the interaction is very low affinity and it takes weeks of steady state dosing to achieve proper concentrations in the brain compartment. Trkb receptors are activated by bdnf and promote neuron growth. Their activation is correlated with antidepressant effects of many drugs of diverse classes.

Antidepressant drugs act by directly binding to TRKB neurotrophin receptors - PubMed

It is unclear how binding of antidepressant drugs to their targets gives rise to the clinical antidepressant effect. We discovered that the transmembrane domain of tyrosine kinase receptor 2 (TRKB), the brain-derived neurotrophic factor (BDNF) receptor that promotes neuronal plasticity and...

pubmed.ncbi.nlm.nih.gov

I prefer the second theory.

was unfamiliar with that second hypothesis, interested to see where that goes. but the downregulation business also seems plausible to me. can i ask why you prefer the second?

 

[Skorpio]

was unfamiliar with that second hypothesis, interested to see where that goes. but the downregulation business also seems plausible to me. can i ask why you prefer the second?

Because I am a sucker for unified hypeotheses.

In the linked cell paper they correlate the anti depressive effect of quick acting antidepressants and slow acting antidepressants to the same mechanism. I think that is a lot more elegant and I prefer it to be true. Also the second paper tests their hypothesis by mutating the binding site that they identified to abolish antidepressant effects. I always put more stock into a mechanism if a team is able to break it with a specific intervention, than if something is just observed.

Definately give the cell paper a read, I am leaving out a part of their hypothesis where they find that the trkb receptor also is a cholesterol sensor, and brain cholesterol levels mediate activity. If you don't have access just get the paper on scihub (Google scihub and then put in the url of the paper and ittl give it to you).

 

[Mask0ff]

@Skorpio, just gave you a follow.

To be fair, I don't see where those hypothesis conflict. I understand Fluvoxamine agonises the sigma 1 receptor which leads to increased BDNF.

I'm new to pharmacology - is it common for drugs to have an onset occur far after plasma levels break into the therapeutic range?

 

[Skorpio]

@Skorpio, just gave you a follow.

To be fair, I don't see where those hypothesis conflict. I understand Fluvoxamine agonises the sigma 1 receptor which leads to increased BDNF.

I'm new to pharmacology - is it common for drugs to have an onset occur far after plasma levels break into the therapeutic range?

That papers answer to the second question is that the therapeutic range at the brain is not reached until after some time. Basically the plasma compartment diffuses slowly to the brain compartment so the brain requires a long time to reach the same drug level as the plasma.

With regards to the sigma 1 receptor. I totally have no concrete evidence of its role. The fact that so many drugs of abuse of diverse mechanisms of action are sigma agonists does pique my interest.

If you have any good sigma papers def link them.

 

[thegreenhand]

Because I am a sucker for unified hypeotheses.

In the linked cell paper they correlate the anti depressive effect of quick acting antidepressants and slow acting antidepressants to the same mechanism. I think that is a lot more elegant and I prefer it to be true. Also the second paper tests their hypothesis by mutating the binding site that they identified to abolish antidepressant effects. I always put more stock into a mechanism if a team is able to break it with a specific intervention, than if something is just observed.

Definately give the cell paper a read, I am leaving out a part of their hypothesis where they find that the trkb receptor also is a cholesterol sensor, and brain cholesterol levels mediate activity. If you don't have access just get the paper on scihub (Google scihub and then put in the url of the paper and ittl give it to you).

Just gave it the read through

certainly a convincing argument, pharmacological wise. But I’m always wary of behavioral studies in mice, so I won’t take it as gospel just yet.

it may have been in a textbook but I’ll try to find the paper too - I remember seeing somewhere that 5ht2a post synaptic receptors are also downregulated by common antidepressants. With “atypical” antidepressants like psilocybin this could make a lot of sense

 

[Mask0ff]

Just gave it the read through

certainly a convincing argument, pharmacological wise. But I’m always wary of behavioral studies in mice, so I won’t take it as gospel just yet.

it may have been in a textbook but I’ll try to find the paper too - I remember seeing somewhere that 5ht2a post synaptic receptors are also downregulated by common antidepressants. With “atypical” antidepressants like psilocybin this could make a lot of sense

What about the behavior studies of mice?