Posted by ed_uk2010 on February 13, 2015, at 14:46:27
In reply to Re: Effexor + Mirtazapine MORE effective than PARNATE! » linkadge, posted by Robert_Burton_1621 on February 13, 2015, at 10:39:01
>Aren't the NRI properties of Effexor pretty weak, even at very high doses?
Yes, weak - but not absent. The fact that venlafaxine acts as a weak NRI at high dosages, but lacks the alpha-1 adrenergic receptor blocking property of tricyclic ADs, is probably why it sometimes induces hypertension. (Alpha-1 receptor blockade in blood vessels produces vaso-dilation and a decrease in BP).
>Desipramine 0.83 most potent
>Amitriptyline 35
>Fluoxetine 240
>Venlafaxine 1060 weakestThese affinity figures are interesting but have to be seen in context in order to be useful. Desipramine appears to have high affinity for the NE transporter. In this case, we might assume it was a potent NRI. Indeed it is, as it happens. But we don't know that from this data. Why?
a) The data doesn't tell us what desipramine does when it binds to the NE transporter. Does it just bind? Does it block it? Does it reverse it?
b) How much desipramine even reaches the transporters in question when a dose is given to a patient?
c) What does desipramine do at other sites? If, for example, it was 100 times more potent at the dopamine D2 receptor as an antagonist (IT ISN'T!), it would probably be an antipsychotic active at low doses! But it isn't.... that's just an example. If this really was the case, severe side effects from excessive D2 blockage would occur if one attempted to take it at a dose producing NRI activity. In reality, desipramine's relative selectivity for the NE transporter over other sites, its good absorption and bioavailability and its high affinity for the site as a 'blocker' allows it to act as a powerful NRI clinically.Things get more complex when looking at fluoxetine and venlafaxine. We seen that venlafaxine has lower affinity for the NE transporter than fluoxetine, but on its own this is not meaningful. Clinically, venlafaxine produces weak NRI activity at high doses whereas fluoxetine does not appear to have any significant NRI activity. How? Well.....
Receptor affinities become meaningful when considering three main points....1. What is the drug concentration at the receptor/uptake site in question when the drug is given at the therapeutic dose? I imagine that fluoxetine achieves much lower levels than venlafaxine because it appears to lack any NE activity clinically, despite its higher binding affinity.
[As an aside... What influences the drug concentration at the receptor/uptake site?
a) The drug dosage and regimen.
b) The % of the dose which is absorbed.
c) The bioavailability (proportion of dose reaching the blood stream) - this depends on absorption and 'first pass' metabolism in the intestinal wall (lesser) and liver (major). Some drugs are well absorbed but then almost completely inactivated before they even reach the bloodstream, their bioavailability is therefore low.
d) Does the drug have active metabolites (conversion products)? If so, what do they do and what concentration do they achieve at the receptor sites? Venlafaxine is an example of a drug with an active metabolite. The distribution and clearance of active metabolites often occurs quite differently to the parent drug. Fluoxetine is a good example, its major metabolite is so slowly excreted it gives the drug a surprisingly long duration of action.
e) How is the drug distributed in the body? For example, how does the concentration in the brain compare with the conentration measured in the blood. Some drugs barely penetrate into the brain at all, others penetrate readily and achieve high levels. This is very relevant for psych meds.
f) Where and how rapidly is the drug excreted from the body? Lithium is a good example. It is excreted by the kidney and achieves toxic/high levels if the dose is not reduced in those with kidney impairment.]2. What is the affinity of the drug for other receptors/uptake sites/enzymes? How do they compare?
Take a theoretical drug with moderate affinity for the NE transporter and exceptionally high affinity for the histamine H1 receptor - both as an antagonist. Assuming good bioavailability and penetration into the central nervous system.... If this drug was given at a tiny dose, it would essentially act as a sedative antihistamine. A high dose, on the other hand, would saturate H1 receptors and act at the NE transporters too.
Looking at venlafaxine data, we see that although its affinity for 5-HT (serotonin) reuptake sites is far higher than its affinity for NE transporters, its affinity for 5-HT transporters also seems rather low in comparison with the SSRIs. Clinically, the serotonergic properties of Effexor are potent. A high concentration must be achieved in the synapses compared with SSRIs.3. What does the drug in question actually do at the receptor once it's there?
a) Bind - but do little or nothing.
b) Influence the binding and action of neurotransmitters. This is how benzos work. They facilitate the binding and hence action of the neurotransmitter GABA at certain of its receptors (GABA-A). This is called a PAM effect - positive allosteric modulator. Negative allosteric modulators of benzo receptors have been synthesised. Perhaps unsurprisingly, they induce severe anxiety states and seizures.
c) Block the effect of the neurotransmitter at the receptor (antagonist). A drug may do this by preventing the neurotransmitter from even binding. Alternatively, the neurotransmitter may still bind but its action is inhibited.
d) Stimulate the receptor fully in the same way as the neurotransmitter (agonist, full agonist).
e) Stimulate the receptor, but in a way which produces less effect than the neurotransmitter (partial agonist).
f) Produce an effect which is the opposite of that produced by the neurotransmitter (inverse agonist).
g) Block the activity of an enzyme of reuptake site.So... you can see there are many factors which affect the clinical effects of the drug as well as the receptor affinity data, and that most of these factors influence the clinical effects by affecting the concentration of the drug or metabolite achieved at the receptor site when given at therapeutic doses. What the drug actually does at the receptor is also immensely relevant.
> I am a neophyte at al this (as is no doubt obvious!)
You probably know more than your last psych. He doesn't sound especially well-informed.
Hope the the immense babble I've just written is of some use.
poster:ed_uk2010
thread:1040126
URL: http://www.dr-bob.org/babble/20150129/msgs/1076370.html