jj123
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One of the side effects of anti-psychotic drugs is tardive dyskinesia, which can occur over a couple of months' therapy. Typical anti-psychotic drugs are to block dopamine. But one thing I am really confused is that anti-parkingson drugs, which is to promote dopamine in the CNS, also has dyskinesa kind of side effects. I thought anti-psychotic and anti-parkingson drugs have totally opposite MOA, why they have the same side effects? Any one can explain? Thanks a lot.
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| babydoc4usmle
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i think you are confusing 2 types of dyskinesia
in antypsychotic treatment goal is to stabilize relationtip between DA and Ach
same problem in treatment of Parkinsons, but the difference is that in first case with have excess in DA and treatment is to decrease it's level/activity
in Parkinsons - opposit: low DA amount activity and the goal is - to increase it
in both cases wie have dyskinesias
in SE of antypsychotics you'll have "pesudoparkinsonism" type of dyskinesia in acute cases(DA is too low) or tardive dyskinesia in chronic use (DA is too high)
and in SE of meds in Tx of Parkinsons - you can have psychosis (DA is too high) or peak dose dyskinesia (for the same reason)
this relationship of DA and Ach has very narrow "normal" window and any disproportion brings in a problem. that is why it is so hard to treat it.
just my 2 cents
any other opinions?
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| jj123
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thanks for the help.
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| mildus
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Here's what I think. Both drugs have dyskinesia, but dyskinesia is a common name for all types of involuntary movements disorders, and it includes horea, parkinsonism, atetosis... E.g. horea can develop due to higher DA and lower ACh (during therapy of parkinson's disease), while parkinsonism can develop due to higher ACh and lower DA (during therapy with neuroleptics). As you see, it is very hard to treat all of them, since you have to maintain certain equilibrium of the transmiters in the brain
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| epica
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To BabyDoc. You said
"In SE of antypsychotics you'll have "pesudoparkinsonism" type of dyskinesia in acute cases(DA is too low) or tardive dyskinesia in chronic use (DA is too high)"
Are u sure that this is the ans for this Q?
Please clarify, it's a very important Q even for step 2
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| babydoc4usmle
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done  
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| new_n_lost
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Just to Add to Wht Babydoc has explained.
Tardive dyskinesias (TDs) are involuntary movements of the tongue, lips, face, trunk, and extremities that occur in patients treated with long-term dopaminergic antagonist medications.
TD is hypothesized to result from compensatory supersensitivity of dopamine receptors following chronic blockade. Long-term blockade of dopamine D2 receptors in the basal ganglia by dopamine D2 antagonists (eg, neuroleptics) may produce TD.
Chronic dopamine blockade may result in up-regulation of dopamine receptor responsiveness.
TDs may be differentiated from acute movement disorders that commonly occur in the same patient groups. The acute movement disorders that occur as manifestations of effects of neuroleptics and other dopamine antagonists include akathisia, acute dystonia, and other hyperkinetic dyskinesias. Acute effects of dopamine antagonists also include Parkinsonian syndromes manifested by bradykinesia, rigidity, and pill rolling tremor. The acute movement disorders resulting from exposure to dopamine antagonists are commonly termed extrapyramidal syndromes (EPS).
___________________
FORUM RULES-- Those who believe in telekinesis, raise my hand. I get enough exercise just by pushing my luck --P4U World.." The pure and simple truth is rarely pure and never simple."
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| epica
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"Long-term blockade of dopamine D2 receptors in the basal ganglia by dopamine D2 antagonists (eg, neuroleptics) may produce TD."
Thanks, nnl for clarification about the receptors.
D2 is the old name, new name now in research is D2A
Now we can move to the next part.
Why some atypical (Olanzapine and Clozapine) have the low EPS?
Hint, also because of receptors( which?) Please tell me the difference.( Kaplan Pharma,page 165)
I think this is very good Q.
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| new_n_lost
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Atypical antipsychotics are associated with lower incidence of tardive dyskinesia . However, individual atypical antipsychotics may vary in their propensity to cause tardive dyskinesia, which may be, in part, because of differences in D2 receptor affinity.
Because of an upregulation of D2 receptors induced by a blockade by antipsychotics, dopaminergic hypersensitivity remains the most accepted hypothesis of tardive dyskinesia.
Olanzapine has a higher affinity and striatal occupancy rate for D2 receptors than clozapine, thus leading to greater upregulation and hypersensitivity of these receptors.
___________________
FORUM RULES-- Those who believe in telekinesis, raise my hand. I get enough exercise just by pushing my luck --P4U World.." The pure and simple truth is rarely pure and never simple."
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| babydoc4usmle
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i think i found it:
...no selective ligand has been described which is able to differentiate the D1 from the D5 receptor. On the other hand, the pharmacological profiles of the D3 or D4 receptors show distinct striking differences when compared to that of the D2 receptor.
Most neuroleptics were developed as D2 receptor antagonists and thus are expected to bind to the D2 receptor with higher affinity than to the D3 and D4 receptors. This is true for the majority of the neuroleptics, which implies that those neuroleptics are acting predominantly at D2 receptors in the human brain. However, a few neuroleptics have been found to show selectivity for the D3 or D4 receptors; through these, some aspects of the functions of the D3 and D4 receptors may be revealed.
Two antagonists, UH232 and AJ76, bind to the D3 receptor with a higher affinity than they do to the D2 receptor (54). These compounds are classified as selective for presynaptic receptors or for autoreceptors. In addition, it was found that dopamine binds the D3 receptor with a 20-fold higher affinity than the D2 receptor, a characteristic expected for autoreceptors. Furthermore, the presence of D3 receptor mRNA in the substantia nigra, a center of dopamine production, supports the hypothesis that the D3 receptor may be a presynaptic receptor... Therefore both the D2 and the D3 receptors are autoreceptors. Interestingly, the recent involvement of the D3 receptor in modulating cocaine self-administration has also been associated with its autoreceptor properties.
Clozapine, an "atypical" neuroleptic (i.e., a neuroleptic whose actions are not accompanied by adverse motor control side effects), shows a higher selectivity for the D4 receptor than for any other D2-like receptors. In schizophrenia therapy, clozapine is administered at a concentration 10-fold lower than its affinity constant for the D2 receptor, indicating that clozapine may not be primarily acting at the D2 receptor. The D4 receptor binds clozapine with a 10-fold higher affinity than does the D2 receptor (58). Therefore the D4 receptor may be the specific target of clozapine. A corollary of this is that antagonism of dopamine binding to the D4 receptor could be an important step in prevention of psychoses, a hypothesis reinforced by the low abundance of D4 mRNA in the striatum (58). Thus the lack of extrapyramidal side effects observed with clozapine treatment may be a reflection of D4 receptor localization in the CNS. These observations point to the D4 receptor as an important molecule in the etiology of psychoses.
hope this is what Epica was looking for....but i am note sure
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| epica
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Yep,Good search babydoc, thanks
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| jj123
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thank you so much for all the information. I think I got the idea.
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