Albert D. Arvallo and Ronald R. Watson

Alcohol, the most consumed drug in the world, is often not recognized as a drug or addictive by the public and the media, because of its legal use and acceptance. The public, on the other hand, recognizes cocaine as an addictive drug with traumatic effects on its users. Some users of cocaine begin to mix cocaine with alcohol as together they extend the euphoric sensation. Cocaine plus concomitant ethanol use results in cocaethylene, a compound synthesized in vivo and only identified in 1979 [2], It also has been named in the literature as ethylcocaine, ethylbenzoylecgonine, and benzoylecgonine ethyl ester [2], Therefore, we will review effects of combined alcohol plus cocaine use as well as cocaethylene in use by 4.5% of 18-25 year olds in the USA in 1988 model studies. In 1990, an NIAAA Survey reported that 5.3 million Americans had used cocaine concurrently (during the same period of time) with alcohol, and 4.6 million simultaneously (on the same occasion) with alcohol [10], It is interesting to note that 90% of cocaine users take ethanol concomitantly. Ethanol enhances and prolongs the euphoric effects of cocaine and lessens the dysphoria associated with cessation of cocaine use [9], This, therefore, is the rational for using ethanol simultaneously with cocaine. Despite its prevalence, very little research has been aimed at identifying the possible underlying biological consequences resulting from the addictive drugs [5], How do they affect key organ systems like the heart and liver?

Ethanol and cocaine have opposite pharmacologic effects. Ethanol is a central nervous system depressant. Low amounts of alcoholic beverages increase sociability, while higher levels impair cognitive ability and depress sensorimotor function. The acute in vivo cardiovascular response to moderate levels of ethanol intake involves sympathetic activation, probably due to peripheral vasodilatation, and usually results in an increase in heart rate and maintained or elevated cardiac output [3], Cardiac arrhythmia seems to be more prevalent. Delbridge et al. 's recent findings report identifying ethanol at 0.05%(v/v) as a modulator of cardiac contractility. Kinetic analyses indicate that the mechanism of action involves disturbance of sarcoplasmic reticulum function and this may contribute to arrhythmogenic vulnerability - especially in an in vivo context of heightened compensatory sympathetic drive [3], The study goes on to state that the stabilizing effects of ethanol on intracellular Ca2+ stores may be the cellular basis for the arrhythmogenic response to acute ethanol exposure -a response which is more evident in the normal than in the myopathic myocardium [3], Cocaine is a sympathomimetic agent with stimulant and local anesthetic properties [15], The pathophysiology of cocaine-related myocardial ischemia and infarction is probably multifactorial and is due to one or a combination of(l) increased myocardial oxygen demand in the setting oflimited or fixed supply; (2) marked coronary arterial vasoconstriction; and

(3) enhanced platelet aggregation and thrombus formation [11], In eight healthy cocaine addicts receiving intravenous cocaine (0.325 mg/kg or 0.650 mg/kg), it was noted that pulse and mean arterial pressure peaked 5 min post-cocaine injection and maximal response was sustained for a further 15 min and 35 min afterwards, respectively. Cocaine administration had no significant effect on peripheral oxygen saturation, and no clinically significant abnormalities of rhythm or conduction were seen on the electrocardiogram. These doses and method of single-dose intravenous cocaine administration, and our procedures for cardiovascular monitoring, appear relatively safe for laboratory studies of healthy cocaine addicts with no pre-existing cardiovascular disease. Cocaine-taking resulted in a small but statistically insignificant improvement in learning on the Digit Symbol Substitution Task [7],

The effects of individual and concurrent use of alcohol and cocaine have been studied extensively, yet much less is known about cocaethylene production and value in the effects of dual drug use. Although, the mechanism by which the combination of cocaine and ethanol may be particularly deleterious to the cardiovascular system is unknown, Pitt et al. propose two hypotheses: (l)It may markedly increase the determinants of myocardial oxygen demand and simultaneously diminish supply, leading to a marked supply: demand imbalance. In human volunteers, the use ofboth drugs produces a greater increase in heart rate than either substance alone; (2) The concomitant ingestion of cocaine and ethanol and may lead to the production of a metabolite which induces marked coronary arterial vasoconstriction, leading to myocardial ischemia, infarction, and/or sudden death [H], Animal studies indicate that the combination of ethanol with cocaine increases the lethality of cocaine [15], Morishima et al."s findings correspond with studies reported by other investigators in conscious and anesthetized rats and monkeys in which cocaethylene produced effects similar to those of cocaine at approximately equivalent doses [8], Whether cocaethylene induces coronary arterial vasoconstriction in humans is unknown [H], Incoming patients received into a hospital emergency department in a lower-income area were drug screened with no standard criteria for benzoylecgonine ester (BE). If positive for BE or cocaethylene, the patient was considered positive for cocaine use. Patients positive for drugs in addition to BE and ethanol, except for acetaminophen or salicylate, were excluded. The

Table 18.1 Symptoms reported by cocaine and alcohol concomitantly using patients

Cocaine and Ethanol

Cocaine Only

• Higher incidence of confusion

• Higher incidence of chest pain

• Lower Glasgow Coma Scale (GCS)

• Lower incidence of back and extremity pain

• Lower BUN and Ph

• Higher body temperature and a higher incidence of

• Non trauma patient heart rate higher


• More often intubated and admitted to Intensive Care

Myocardial Infarction conformed on 2 non-trauma patients


• Higher mean number of care days

• Cardiac arrhythmia inl5 patients

• Myocardial Infarction confirmed on 2 non-trauma

• Non trauma patients heart rate lower


• Respiratory failure

• Cardiac arrhythmia inl5 patients hospitalized

• Muscle spasms, convulsions, and coma

• Gastrointestinal complication

• Greater mean total Creatine Kinase

modified from [10]

modified from [10]

incidence of trauma was increased twofold in the cocaine and alcohol using group compared with the cocaine group (50% vs. 22%, p > 0.001). The cocaine/alcohol group had a higher incidence of violent trauma than the cocaine patients did (37% vs. 17%,p > 0.001) [15], There were no differences with regard to frequency of laboratory tests, or the results of determinations ofWBC count, hemoglobin, serum potassium, or blood glucose.

The combination of cocaine plus alcohol use increases the heart rate 1.5-5 times more than with either substance alone and produces a slight increase in blood pressure [15], In this same study, 91% of patients that tested positive for BE and ethanol were positive for cocaine in the serum or cocaethylene in the urine or serum. This indicates simultaneous use of cocaine and ethanol (unpublished data). Concurrent abuse of cocaine and ethanol is very high. A 1995 study estimated that 60-80% of cocaine users consume ethanol simultaneously [4], and concluded:

1 Combined alcohol and cocaine use is the rule;

2 The Drug Abuse Warning Network has identified cocaine plus alcohol combination as the most prominent substance abuse pattern among individuals presenting themselves to emergency rooms with abuse problems;

3 With alcohol plus cocaine use, users can ameliorate the unpleasant physical and psychological sequel of cocaine ingestion primarily paranoia and agitation;

4 Combined abuse of cocaine and alcohol results in alteration of the metabolic profile of cocaine and the formation of the pharmacologically active metabolite, cocaethylene [4],

In a more in depth report, nearly half of patients who tested positive for cocaethylene cited trauma as the primary reason for reporting to the emergency [12], Also 60% of the postmortem human tissue examined had cocaethylene. This led to the speculation that cocaethylene was, at least in part, responsible for the dramatic increase in the risk for sudden death in persons combining cocaine and ethanol [12]. Although, the mechanisms mediating the increased incidence of sudden death of the combined abuse of cocaine and alcohol are not identified, the formation of cocaethylene and the inhibition of cocaine metabolism are implicated [4], Studying the immune system and hepatotoxic effects of cocaine and cocaethylene during HIV infection among intravenous cocaine users shows that simultaneous administration of ethanol and cocaine potentiated the immunosuppressive effects of cocaine in mice [10]. Yet, this depended on the dose and the duration of administration. For example heroin addicts were given cocaine in small amounts which increased the depressed percentage ofE-rosette forming T cells more than heroin alone. The study indicates that a 0.6 mg/kg dose of cocaine produced a three-to-four-fold increase in natural killer cell activity in peripheral blood, and an increase in circulating natural killer cells. A similar effect on NK cell activity was also demonstrated in mice chronically treated with cocaine. Studies on isolated human T-Lymphocytes showed that cocaine in vitro acts as an up-regulator of CD2 antigen expression, suppressing the phytohemagglutinin (PHA)-induced proliferation ofT cells [10]. Cocaine also causes thrombocytopenia and the immune abnormalities observed included antiplatelet antibodies of the IgG and IgM type, disturbances in serum compliment levels and extensive circulating immune complexes [10]. With cocaethylene in mice there are also variable immunological effects. Just as there were opposite results depending on the doses and duration of ethanol and cocaine, the results shown with cocaethylene alone produced a significant inhibition of gamma-interferon, tumor necrosis factor, and also interleukin-2 formation by isolated splenocytes with a dose of 20 mg/kg injected twice daily. Administration of ethanol with cocaethylene simultaneously resulted in a stronger decreased immunological effect [10], Research was done on conscious dogs to check for the effects of ethanol and cocaethylene pharmacokinetics. Preliminary studies indicate that the dog does not form detectable quantities of cocaethylene after co-administration of cocaine and intravenous ethanol [9], while it was formed when cocaine and ethanol were consumed simultaneously in humans, monkeys, and mice. Formation of cocaethylene resulted from transesterification of cocaine by hepatic carboxylesterases in the liver. Lab studies ofhuman liver extracts indicate that inhibition ofhepatic carboxylesterase mediated metabolism of cocaine to benzoylecgonine in the presence of ethanol [9], It was thought that ethanol may have contributed to the decrease in cocaine metabolism; it is possible that cocaethylene inhibited cocaine's metabolism. Early lab studies showed no significant plasma concentrations of cocaethylene detected in the dogs when cocaine is given with intravenous ethanol. Interestingly enough, researchers were not able to detect cocaethylene in measurable quantities (725 ng/ml) in the plasma of Sprague-Dawley rats after a single dose administration of cocaine and alcohol in doses similar to the doses used in the current study (unpublished observation) [4], Not to find cocaethylene in the blood plasma in the dog was unexpected, as smaller doses of co-administered cocaine and cocaethylene given to human subjects have been shown to result in measurable cocaethylene plasma concentrations [14], Further studies must be done in species that resemble humans to determine the pathways and significance of the cocaine and cocaethylene combination. Studies on microsomial fractions on rats, Beagle dogs, and humans suggest that large interspecies differences in hepatic carboxylesterase activity may exist [14],

The in vivo studies of dogs and humans show that cocaethylene formation is greater in humans, which is in contrast to our in vitro incubation studies in hepatic microsomes that clearly demonstrate much greater cocaethylene in the dog than human microsomial preparations. Hepatic drug metabolism, in vitro, has successfully predicted in vivo metabolism of drugs. However, cocaine is subject to extra hepatic hydrolysis in the plasma and possibly other sites are not present in hepatic microsomal preparations. Therefore, interspecies differences in extra hepatic cocaine metabolism could affect the correlation between in vitro and in vivo metabolism [14],

The toxicity from combined cocaine plus ethanol use is not due to enhanced sensitivity to alcohol in cocaine abusers. The blunt response to alcohol in limbic regions and in cortical regions connected to limbic areas could result from a decreased sensitivity of reward circuits in cocaine abusers [16], In rats, cocaethylene exposure during the brain growth spurt period causes teratogenic effects slowing brain growth. Cocaethylene is a neuroteratogen as indicated by altered concentrations of catecholamines and indoleamines in developing brains. There was a region-specific alteration in neurotransmitter levels in response to six days of cocaethylene exposure. It also seems that cocaethylene is more similar to ethanol than cocaine in terms of neuroteratogeneis [2], Sobel and others studied the interaction of cocaethylene and cocaine and of cocaethylene and alcohol on schedule-controlled responding in rats [13], Their statement concerning blood levels was indicative that they do not know the contribution of cocaethylene to the effects of cocaine and alcohol consumed concurrently. It is their contention that blood levels of cocaine, ethanol and cocaethylene must be directly and concurrently determined when cocaine and alcohol are co-administered to begin to unravel the interaction of cocaine and alcohol. It was thought that the doses of cocaethylene and cocaine and/or of cocaethylene and alcohol may have contributed to the greater effects produced by concurrent use of cocaine and alcohol. Other research mentioned measured cocaine and cocaethylene concentration in postmortem human cerebral cortex and showed that combined use of cocaine and ethanol increased the risk of death 18-fold [14],

In the first primate study, the effects of intravenously administered cocaine on extracellular dopamine in the primate were compared to the effects to those of cocaethylene [6], Here, numerous biochemical and pharmacological differences between primates, rodents and dogs that make it important to study primates if immediate extensions to clinical research studies are to be made. The results suggest that the reported differences in potency between cocaine and cocaethylene at producing euphoria in clinical research studies may be due to decreased potency of cocaethylene at blocking 5-HT and/or norepinephrine uptake [6], Both cocaethylene and cocaine are equipotent and were found to increase extracellular dopamine in the caudate nucleus. Cocaethylene retains similar activity to cocaine, including inhibition of the dopamine transporter [14], When a pleasurable event is occurring, it is accompanied by large increase in the amounts of dopamine released in the nucleus accumbens by neurons. In the normal communication process, dopamine is released by a neuron into a synapse (the small gap between two neurons) where it binds with specialized proteins (called dopamine receptors) on the neighboring neuron, thereby sending a signal to that neuron. Drugs of abuse interfere with this normal communication process. Cocaine, for example, blocks the removal of dopamine from the synapse, resulting in an accumulation of dopamine. This buildup of dopamine cause continuous stimulation of receiving neurons probably resulting in the euphoria commonly reported by cocaine abusers [\]. In most case studies, the potentiality of cocaine and cocaethylene seem to point to equal potency in vitro experiments, by analyzing organs, or in vivo by measuring blood plasma and the drug concentrations. As yet, there are discrepancies as to when the potency of cocaine plus ethanol was stronger than cocaethylene effects compared to cocaine or ethanol alone as various researches indicates. But it seems that when cocaine is abused with alcohol, cocaine effects and toxicity can be increased further because of the formation of cocaethylene. In the organs of 60% of the addicts seeking medical attention in emergency rooms or human postmortem specimens, the compound cocaethylene has been found. We still need to investigate the factors that affect the inhibition of cocaine metabolism by ethanol or that affect the fraction of cocaine dose metabolized to cocaethylene. We also need to know how to determine how changes in the cocaine metabolic profile and the formation of cocaethylene are reflected in the pharmacological effects [4],

Defeat Drugs and Live Free

Defeat Drugs and Live Free

Being addicted to drugs is a complicated matter condition that's been specified as a disorder that evidences in the obsessional thinking about and utilization of drugs. It's a matter that might continue to get worse and become disastrous and deadly if left untreated.

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