Posted by Jonathan on November 21, 2004, at 6:05:44
In reply to Re: Lofepramine: is it available where you live?, posted by SLS on November 20, 2004, at 21:39:40
> I might be wrong about this, but I think lofepramine is acting as a prodrug for desipramine. It is therapeutically inert, with desipramine being the active metabolite.
If I remember correctly, the following review paper contains a table giving the affinities of lofepramine, desipramine, maprotiline and nortriptyline for the noradrenaline and serotonin transporters, alpha-1, alpha-2 and beta noradrenoceptors, H1 histamine and M1 acetylcholine receptors (but not 5HT-2A/C or any other serotonin receptors, disappointingly):
N. Brunello et al. (Oct 2002) The role of noradrenaline and selective noradrenaline reuptake inhibition in depression. European Neuropsychopharmacology, 12(5), 461-475.
http://dx.doi.org/10.1016/S0924-977X(02)00057-3Unfortunately, I no longer have free access to this journal, and wouldn't advise anyone to pay $30 to download it in case I'm mistaken: the table could be in an entirely different paper! Perhaps your uni subscribes to the journal, Ed, or gives you free electronic access via Athens?
Uniquely for a teriary amine TCA, lofepramine has no significant effect on serotonin reuptake. As far as I can recall, its receptor affinity profile (from the above paper) is very similar to desipramine's, more similar than either profile is to nortriptyline's, for example. Lofepramine is *not* therapeutically inert - it's as ert as desipramine ;)
One pharmacological target molecule that can 'tell the difference' between desipramine and lofepramine is the fast sodium channel in heart muscle. Whilst desipramine blocks this ion channel at a concentration not far above the therapeutic range, accounting for this drug's cardiotoxicity and narrow therapeutic margin, lofepramine doesn't block it until a ten times higher concentration is reached.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7342685
You are still correct, Scott, that most of lofepramine's therapeutic effect is due to its active metabolite, desipramine. Almost every molecule of a therapeutic dose of lofepramine is converted in the liver into a molecule of desipramine; the blood plasma half-life of lofepramine is about five hours at therapeutic or lower concentrations. Desipramine is removed about five times slower than it is produced, with an elimination half-life of about 25 hours (subject to wide variation due to genetics and drug interactions). This means that, if someone took lofepramine by continuous infusion instead of in discrete 70 mg tablets, so that the concentration of it remained constant throughout the day, then the steady-state concentration of desipramine in his/her system would be five times that of lofepramine: more than 80% of lofepramine's therapeutic action is due, not to the drug itself, but to its active metabolite desipramine.
At higher-than-therapeutic concentrations of lofepramine, the enzyme which converts it to desipramine saturates; the rate of production of desipramine increases little and its concentration remains in the safe, non-cardiotoxic range.
I think desipramine was withdrawn in the UK about five years ago. Even before that, it was seldom prescribed: about 6000 out-patient prescriptions in England (pop. 50 of the UK's total 60 million) compared with 150 times that number for lofepramine, our third most popular TCA after dothiepin (another British oddity) and amitriptyline. To put those figures further into perspective, an NHS patient in the late 1990s was twice as likely during treatment to be bitten by a leech (Hirudo medicinalis - about 12000 prescriptions per year) as given desipramine!
Sources:
http://www.parliament.the-stationery-office.co.uk/pa/cm199798/cmhansrd/vo980720/text/80720w15.htm (scroll down)
http://www.telegraph.co.uk/health/main.jhtml?xml=%2Fhealth%2F2004%2F04%2F12%2Fhleech12.xml
poster:Jonathan
thread:418430
URL: http://www.dr-bob.org/babble/20041118/msgs/418532.html