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Confused about the MOA of antipsychotics

Discussion in 'Medical Students - MD' started by thecalccobra, Jul 27, 2011.

  1. thecalccobra

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    I don't understand why the typical antipsychotics block D2 receptors, which inhibit adenylyl cyclase in the first place, when the whole point of the treatment is to decrease levels of dopamine? Wouldn't it make sense to block D1 and D5 receptors, which activate adenylyl cyclase?
     
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  3. plsfoldthx

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    lol I was wondering this same very thing, but didnt care to delve into it because my exam was the next day :D
     
  4. plsfoldthx

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    actually now that i think about it doesnt it have to do with where the dopamine receptors are inactivated? because there is a dysregulation of dopamine activity between the nucleus accumbens/VTA and PFC... ie high dopamine in certain areas and low in others due to feedback loop problems
     
  5. armybound

    armybound urologist.
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    I think there are very few psych meds that people actually understand why and how they work. They just do. I would stop at knowing they block D2 and move on.
     
  6. Kaustikos

    Kaustikos Archerize It
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    Yeah,
    Understanding the underlying mechanism, though fun at times, can lead to more undue stress. The way I look at it is dopamine acts on two different receptor pathways that ultimately converges to do two different things. D1 stimulates cAMP while D2 inhibits, which means if you want regulation of dopamine levels, you'd need to have one pathway regulated. ie; decreased cAMP leads to unintended consequences (schizophrenia) whereas you want higher levels. So, inhibit the inhibitor to get higher cAMP.
     
  7. Mattchiavelli

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    I think the problem is that when you look at function of nerves in the CNS you have to take into account their configuration in regards to activation/inhibition... inhibiting a neuron that inhibits another leads to a net activation, and looking at just the intercellular effects of one receptor is kind of losing the forest for the trees.

    Anyway, the dopamine hypothesis of schizophrenia is a hypothesis and not a law- there is some interesting evidence that makes the picture ore complex, such as how if it is just dopamine blockade that makes antipsychotics work, why do they often take weeks of regular administration to produce maximum clinical benefit? Psychopharmacology is a lot less cut and dry than other pharm areas like drugs that act on the autonomic nervous system.
     
  8. Kaustikos

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    True, but the issue is that the drug selectively inhibits one receptor class instead of both. Which actually makes sense from a downstream mechanism and fits in nicely with your idea.

    Yeah, that's true. It's a hypothesis that has very little concrete evidence about the downstream signaling pathway. Isn't the issue with the delay in benefits is overcoming the hurdle of producing enough of the compound to maximally effect all the neurons into firing correctly? Kind of like cancer; you can't give enough of a therapeutic dose to kill the cancer completely because of the dose-limiting toxicity and so you have to wait in order to get the maximal therapeutic dose without the toxicity associated with the compound.
     
  9. Mattchiavelli

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    A good thought, but just talking concentrations you hit a steady state before the full effects come into play. Take haldol- half life of around 20 hours, 4 half lives to steady state is around 3-4 days, but I've had people tell patients it can take up to a couple of weeks to get the full effect. These drugs do cause not only the immediate effects (like giving someone a few mgs IM for acute agitation, or the relatively immediate extrapyramidal sxs) but also some long term changes in CNS function (which is the current proposed pathological basis of tardive dyskinesia).

    Antipsychotics as an MS2 reminds me of that Simpsons episode where Apu is taking the citizenship test and is asked about the cause of the civil war- he starts on a long intricate explanation and the examiner says "Just say slavery." In this case, it's "Just say D2 blockade" but if you end up in neurology or psychiatry you will start to learn the nuances of this class of drugs ;)
     
  10. richse

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    There are a lot of theories, but no one truly understands how antipsychotics work. Their efficacy was discovered by accident and people have been trying to work backwards from that ever since.
     
  11. 7737

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    I know nothing.
     
    #10 7737, Jul 29, 2011
    Last edited: Jul 30, 2011

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