Acute cocaine toxicity is a complex combination of pharmacological events occurring throughout several organ systems; however, its initiation is quite simple. By binding to a variety of membrane bound proteins such as transporters, receptors and voltage gated ion channels cocaine either initiates or inhibits a signal. The combination of these binding events causes the clinical and biochemical manifestations of a diseased state. While there are a wide variety of protein-binding events which lead to a diseased state we will concentrate on two of the most relevant binding activities, namely cocaine’s inhibition of monoamine transporters in the brain, and voltage-gated ion channels in the heart (O’Leary, 2010). By unpacking these binding events, and understanding the biochemistry associated with their pathophysiology, we will be able to understand the molecular cause of acute cocaine toxicity.
In 1989 the first paper was published documenting cocaine’s effect on cardiac cells, demonstrating that cocaine affects both fast Na+ channels and repolarizing K+ channels necessary for proper heart contraction (Przywara and Dambach, 1989). Due to its capacity to block sodium and potassium channels, cocaine can cause ventricular arrhythmias within hours, leading to depressed cardiovascular parameters (O’leary, 2010). As voltage-gated ion channels play a key role in the electrical excitability of the myocardium, allowing for coordinated electrical activity and thus concerted contraction of the heart, it is necessary to understand the mechanism of inhibition to properly contextualize the pathology.
Recent literature supports that voltage-gated ion channels undergo a use-dependent inhibition by cocaine. Sodium channels normally recover during a short rest interval between depolarizing pulses, which allow for rapid recover from hyperpolarized inactivation(Payandeh, 2011). During the transfer from a depolarized to an inactive state the channels open, allowing cocaine to enter the pathway, and transition the binding site to a high-affinity conformation. Thus Cocaine alters sodium channel recovery by preferentially binding to inactivated channel states causing a slow recovery of cocaine-modified channels. This theory of cocaine inhibition was supported by a recent scientific breakthrough which discovered a crystal structure of a sodium channel at 2.7 angstroms.
Fig. 1 Architecture of the NavAb pore ; pore volume is shown in grey. e, Electrostatic potential coloured demonstrating the areas of potential inhibitor presence. (Payandeh, 2011)
This structure revealed a potential binding site at S6 for pore blocker interaction during inactivated periods (Payandeh, 2011). Supporting the use-dependent inhibition model and explaining how pathology arises based on channel inhibition. The initiation of tachycardia and increased heart rate associated with the heart’s non-concerted contraction can lead to ischemia, worsening the effects of cocaine’s protein targets (O’leary, 2010).
Fig. 2 Use-dependent inhibition in sodium channels, each ion channel cycles through several key states, before being trapped in an inactivated state. (O’leary, 2012)
Influx of Norepinephrine
One of the primary causes of cocaine’s behavioral effects and downstream cardiac toxicity is its capacity to bind to monoamine transporters such as the norepinephrine transporter in the brain. During a neurological signaling a neurotransmitter such as norepinephrine is released from the presynaptic neuron to diffuse across the synaptic cleft. Once across this gap, norepinephrine binds to the adrinergic receptor on the postsynaptic cleft causing increased sympathetic output. To control the concentration of neurotransmitter present and thus the strength and length of the signal, a presynaptic norepinephrine transport (NRI) mediates reuptake of norepinephrine, allowing for the termination of the sympathetic signaling.
NRI belongs to a neurotransmitter/sodium symporter (NSS) family alongside other key reuptake proteins which act on serotonin and dopamine. This family of proteins couples the transport of Na+ down its concentration gradient to allow for the uptake of its respective neurotransmitter. Cocaine acts as a high-affinity inhibitor of NRI, causing a rapid increase of synaptic norepinephrine levels leading to prolonged sympathetic signaling. (Beuming et al. 2009) After Norepinephrine binds to its alpha1 or alpha2 adrenergic receptor vasoconstriction is initiated through an increase through an increase in PLC activity, signaling for increased intracellular calcium and cellular release of enothelin-1, leading to vascular constriction(Lange, 1989). This effect is amplified by a decrease production of nitrous oxide, a vasodilator. Vasoconstriction in turn causes an increase in blood pressure and thus increased heart rate and cardiac O2 demand. However, due to the increased vasoconstriction there is a decrease in O2 supply, leading to deoxygenating of the heart and Ischemia. Once the heart has been ischemic for a long period of time myocardial infarction can occur, leading to death as the heart no longer circulates blood supplying nutrients throughout the body.
Fig. 3 Carboxylesterase metabolism of cocaine and cocaethylene (CE) by ester cleavage. (Laizure, 2003).
Primarily metabolized in the liver, cocaine metabolism is dominated by hydrolytic ester cleavage at the two ester sites, rapidly creating its non-toxic metabolites, benzoylecgonine (BE) and ecgonine methyl ester (EME). Due to the non-toxic nature of its metabolites, most toxicity occurs within several hours of cocaine’s intake (Kolbrich, 2006). This metabolic pathway is significantly changed; however, when alcohol is consumed alongside cocaine usage. This combinatorial drug intake causes the formation of cocaethylene, an active metabolite formed by transesterification between cocaine and ethanol (Laizure 2008). Due to the creation of cocaethylene, which has an increased half-life, up to 4 times larger than cocaine, and the decreased cocaine metabolism associated with alcohol consumption, the combination of these drugs is an extremely dangerous practice (Laizure, 2003). When cocaine is combined with alcohol, toxicity of cocaine consumption increases drastically, making alcohol induced cocaine toxicity a significant part of ER visits based on cocaine(Teli, 2012).