Question about how L-Dopa causes Neuroleptic Malignant Syndrome?

[Deuce 007 MD]

How does this happen? Something was metioned in lecture about this and how anti-psychotics can cause Neurolepitc Malignant Syndrome, but don't antipsychotics block dopamine? Also how does giving dopamine antagonist cause Tardive dyskinesia, wouldn't blocking dopamine actually cause parkinsonism? Thanks in advance.

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[omarsaleh66]

How does this happen? Something was metioned in lecture about this and how anti-psychotics can cause Neurolepitc Malignant Syndrome, but don't antipsychotics block dopamine? Also how does giving dopamine antagonist cause Tardive dyskinesia, wouldn't blocking dopamine actually cause parkinsonism? Thanks in advance.

yo i can answer the tardive dyskinesia q:

dopamine antagonists like Haloperidol hit the D2 receptors so hard that they block dopamine receptors in that concentrated area to the extent that the dopamine receptors that arent blocked or when stimulated again, they upregulate their sensitivity. Long term usage of the drug, u can get tardive dyskinesia cuz due to chronic dopamine blocking, the brain will make alot more D2 receptors - hence causing tardive dyskinesia where u have to up the dose or something.

Now, Atypical antipsychotics are getting popular like Clozapine cuz they dont hit the D2 receptors that hard cuz they'll hit 5TH-2 receptors too. BUt there are blood risks with this drug (agranulocytosis).

later
Omar

 

[tkim]

How does this happen? Something was metioned in lecture about this and how anti-psychotics can cause Neurolepitc Malignant Syndrome, but don't antipsychotics block dopamine? Also how does giving dopamine antagonist cause Tardive dyskinesia, wouldn't blocking dopamine actually cause parkinsonism? Thanks in advance.

The most widely accepted mechanism by which antipsychotics cause NMS is that of dopamine D2 receptor antagonism. In this widely accepted model, central D2 receptor blockade in the hypothalamus, nigrostriatal pathways, and spinal cord leads to increased muscle rigidity and tremor via extrapyramidal pathways. Hypothalamic D2 receptor blockade results in an elevated temperature set point and impairment of heat-dissipating mechanisms. Peripherally, antipsychotics lead to increased calcium release from the sarcoplasmic reticulum, resulting in increased contractility, which can contribute to hyperthermia, rigidity, and muscle cell breakdown.

Beyond these direct effects, D2 receptor blockade might cause NMS by removing tonic inhibition from the sympathetic nervous system. The resulting sympathoadrenal hyperactivity and dysregulation leads to autonomic dysfunction. This model suggests that patients with baseline high levels of sympathoadrenal activity might be at increased risk. While this has not been proven in controlled studies, several such states have been proposed as risk factors for NMS.

Direct muscle toxicity also has been proposed as a mechanism of NMS.

 

[Deuce 007 MD]

My problem is I can understand how blockade of D2 receptors cause NMS, but what about my original question on how then does Leva Dopa cause NMS if it is not an antagonist of the D2 receptor, but is converted to Dopamine which is actually an agonist?

Oh yeah, thanks omar for the tardive answer.

 

[Kalel]

I think that what you are talking about is how the sudden withdrawl of levo-dopa therapy can cause a syndrome similar to NMS. In that setting, the mechanism is simlilar to how a dopamine antagonist cause NMS (sudden decrease in dopamine receptor activation). I don't think that a patient who is taking levodopa and does not decrease their dosage is at risk for developing NMS.

 

[Deuce 007 MD]

I think that what you are talking about is how the sudden withdrawl of levo-dopa therapy can cause a syndrome similar to NMS. In that setting, the mechanism is simlilar to how a dopamine antagonist cause NMS (sudden decrease in dopamine receptor activation). I don't think that a patient who is taking levodopa and does not decrease their dosage is at risk for developing NMS.

Thanks Kalel,
I think your right, I remember the lecturer saying something about L-dopa and NMS but I was half asleep and when I did look up all I saw was a power ptt w/NMS as a side affect of L-Dopa and other dopamine agonist. Since I have the lecture recorded on MP3 I thought I'd listen to it later, but w/my test tomorrow had no time, so I figured I'd ask all the smart people on SDN. Once again SDN saves my a$$.

 

[samsoccer7]

High Yield Neuro has a very good illustration. The difficulty is in determining that agonists will actually decrease the transmission to the next point, etc etc. Once you get it, you have to go over it every couple days to really remember it. Then again, you never have to know that much detail unless you enter one of the specialty fields.

 

[Stinger86]

Over time and constant exposure L-dopa loses its effectiveness and basically results in dopa-receptors that don't have their loving dopa stimulating them (producing an effect similar to neuroleptic meds)