Cocaethylene Synthesis and Pathophysiology: Difference between revisions
No edit summary |
No edit summary |
||
| Line 22: | Line 22: | ||
The primary physiological effects of cocaine ingestion are manifested by direct stimulation of the sympathetic nervous system in humans. The chief neuro-transmitters that mediate the properties of this stimulant are nor-epinephrine and dopamine. Both of these catecholamine neurotransmitters are released in some small level in a normal human being to maintain homeostatic parameters (i.e. blood pressure, temperature, and heart rate). However, these transmitters are released at neural synapses and reabsorbed constantly through special channels in the axon terminal. Cocaine acts to bind these reuptake channels and inhibits the return of these catecholamines which results in a build up at the synaptic cleft causing excessive stimulation of the postsynaptic catecholamine receptors. The cardiac postsynaptic receptors that respond to the buildup of catecholamines are the β1-adrenoceptors which become over-stimulated when cocaine is ingested. Activation of the β1-adrenoceptors causes a number of cascades which leads to an increase force of contraction and heart rate, namely:<br /><br /> | The primary physiological effects of cocaine ingestion are manifested by direct stimulation of the sympathetic nervous system in humans. The chief neuro-transmitters that mediate the properties of this stimulant are nor-epinephrine and dopamine. Both of these catecholamine neurotransmitters are released in some small level in a normal human being to maintain homeostatic parameters (i.e. blood pressure, temperature, and heart rate). However, these transmitters are released at neural synapses and reabsorbed constantly through special channels in the axon terminal. Cocaine acts to bind these reuptake channels and inhibits the return of these catecholamines which results in a build up at the synaptic cleft causing excessive stimulation of the postsynaptic catecholamine receptors. The cardiac postsynaptic receptors that respond to the buildup of catecholamines are the β1-adrenoceptors which become over-stimulated when cocaine is ingested. Activation of the β1-adrenoceptors causes a number of cascades which leads to an increase force of contraction and heart rate, namely:<br /><br /> | ||
[[Image:Cocaine-dopamine.gif|right|Dopamine re-uptake is inhibited in the presence of cocaine at the synaptic cleft.]] | [[Image:Cocaine-dopamine.gif|right|Dopamine re-uptake is inhibited in the presence of cocaine at the synaptic cleft.]] | ||
* β1-adrenoceptors increase intracellular cAMP which activates protein kinases to phosphorylate calcium channels which increases inward calcium which increases contraction by the calcium-dependent troponin contractile complex in cardiac muscle | |||
<br /> | |||
* β1-adrenoceptors also increases the internal automaticity of the heart which, among other factors, owes to the elevation of the heart rate by decreasing the slope of the cardiac action potential in the pacemaker | |||
<br /><br /> | <br /><br /> | ||
===='''Ethanol + Cocaine Pathophysiology'''==== | ===='''Ethanol + Cocaine Pathophysiology'''==== | ||
| Line 30: | Line 30: | ||
<br /><br /> | <br /><br /> | ||
[[Image:Aorta.svg.png|350 px|left|Aorta.]] | [[Image:Aorta.svg.png|350 px|left|Aorta.]] | ||
* Cocaethylene acts very similar to cocaine in inhibiting reuptake of dopamine and norepinephrine at the neural synapse—it should be noted that cocaethylene is an even more potent reuptake inhibitor of dopamine (leading to more pronounced feelings of pleasure) | |||
<br /> | <br /> | ||
* The half-life of cocaine is only 38 minutes, while the half-life of cocaethylene is 2.5 hours thus resulting in a prolonged period of euphoria before symptoms of dysphoria or “crash” present | |||
<br /> | <br /> | ||
* It has been suggested that binding of serotonin to cocaine results in the onset of dysphoria because cocaine can no longer inhibit reuptake—cocaethylene on the other hand has a 40-fold reduced affinity for serotonin and thus is less restricted from inhibiting catecholamine reuptake channels | |||
<br /> | <br /> | ||
* Ethanol molecules, which occupy a small side-door pocket in hCE1, have been implicated as an inhibitor of cocaine hydrolysis which would account for a reported 30% elevation of plasma cocaine concentrations in the presence of ethanol | |||
<br /> | <br /> | ||
* Cocaethylene, itself being a product of the trans-esterification reaction, acts as a competitive inhibitor for the substrate binding pocket on hCE1 which causes a reduction in the hydrolysis of cocaine | |||
<br /> | <br /> | ||
* Cocethylene has been shown to have a lower lethal dosage to kill 50% of lab animal subjects than cocaine and it has been experimentally associated with as much as a 25-fold increase in sudden death | |||
<br /><br /> | <br /><br /> | ||
===='''Human Carboxylesterase 1'''==== | ===='''Human Carboxylesterase 1'''==== | ||
| Line 56: | Line 56: | ||
The ability of hCE1 to catalyze the trans-esterification reaction of ethanol and the methyl ester on cocaine seems like a difficult case to make. The reason for this is that ethanol is ostensibly hindered sterically by the benzoyl ring of cocaine jutting out of the binding gorge which would arguably prevent ethanol from reaching the bottom of the active site to attack the tetrahedral intermediate. However, a mechanism has been proposed that would explain ethanol's ability to still attack the acyl-enzyme intermediate based on the presence of what is known as a <scene name='Cocaethylene_Synthesis_and_Pathophysiology/Flexible_site_green/1'>flexible site (green)</scene> of residues kitty-corner to the bottom of the active site. | The ability of hCE1 to catalyze the trans-esterification reaction of ethanol and the methyl ester on cocaine seems like a difficult case to make. The reason for this is that ethanol is ostensibly hindered sterically by the benzoyl ring of cocaine jutting out of the binding gorge which would arguably prevent ethanol from reaching the bottom of the active site to attack the tetrahedral intermediate. However, a mechanism has been proposed that would explain ethanol's ability to still attack the acyl-enzyme intermediate based on the presence of what is known as a <scene name='Cocaethylene_Synthesis_and_Pathophysiology/Flexible_site_green/1'>flexible site (green)</scene> of residues kitty-corner to the bottom of the active site. | ||
<br /><br /> | |||
===='''References'''==== | ===='''References'''==== | ||
<br /> | |||
http://www.nejm.org/doi/pdf/10.1056/NEJMp020174 | *http://www.nejm.org/doi/pdf/10.1056/NEJMp020174 | ||
http://oca.weizmann.ac.il/oca-bin/ocashort?id=1MX5 | *http://oca.weizmann.ac.il/oca-bin/ocashort?id=1MX5 | ||
http://emedicine.medscape.com/article/805084-overview | *http://emedicine.medscape.com/article/805084-overview | ||
http://emedicine.medscape.com/article/813959-overview | *http://emedicine.medscape.com/article/813959-overview | ||
http://emedicine.medscape.com/article/1174408-overview | *http://emedicine.medscape.com/article/1174408-overview | ||
http://www.cvphysiology.com/Blood%20Pressure/BP018.htm | *http://www.cvphysiology.com/Blood%20Pressure/BP018.htm | ||
http://www.nature.com/nsmb/journal/v10/n5/pdf/nsb919.pdf | *http://www.nature.com/nsmb/journal/v10/n5/pdf/nsb919.pdf | ||
http://archives.drugabuse.gov/nida_notes/nnvol13n2/brain.html | *http://archives.drugabuse.gov/nida_notes/nnvol13n2/brain.html | ||
http://www.nature.com/mp/journal/vaop/ncurrent/full/mp201056a.html | *http://www.nature.com/mp/journal/vaop/ncurrent/full/mp201056a.html | ||
http://www.whitehousedrugpolicy.gov/drugfact/cocaine/cocaine_ff.html | *http://www.whitehousedrugpolicy.gov/drugfact/cocaine/cocaine_ff.html | ||
http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6T10-4PDK2FG-1-1&_cdi=4876&_user=112642&_pii=S0002914907011976&_origin=search&_coverDate=09%2F15%2F2007&_sk=998999993&view=c&wchp=dGLbVzb-zSkWb&md5=5540e90fbdb07b5effbfbe4faa701e28&ie=/sdarticle.pdf | *http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6T10-4PDK2FG-1-1&_cdi=4876&_user=112642&_pii=S0002914907011976&_origin=search&_coverDate=09%2F15%2F2007&_sk=998999993&view=c&wchp=dGLbVzb-zSkWb&md5=5540e90fbdb07b5effbfbe4faa701e28&ie=/sdarticle.pdf | ||
http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6T6W-4007G86-4-1&_cdi=5041&_user=112642&_pii=037907389401638L&_origin=search&_coverDate=01%2F30%2F1995&_sk=999289997&view=c&wchp=dGLbVtb-zSkzV&md5=095f8e8ee2ec86a0c54a08e979a8375b&ie=/sdarticle.pdf | *http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6T6W-4007G86-4-1&_cdi=5041&_user=112642&_pii=037907389401638L&_origin=search&_coverDate=01%2F30%2F1995&_sk=999289997&view=c&wchp=dGLbVtb-zSkzV&md5=095f8e8ee2ec86a0c54a08e979a8375b&ie=/sdarticle.pdf | ||