| Summary Cocaine addiction is a considerable threat to the integrity of the cardiovascular system. Most visits to emergency services related to drug use are for cardiovascular reasons caused by cocaine. Unlike other addictive drugs, cocaine exerts its various, often severe, adverse effects through numerous pathophysiological pathways. This article analyzes the cardiovascular effects of cocaine and the therapeutic options for them. |
The use of chewed coca leaves, either as a stimulant or as an instrument of communication with the gods, has been recorded since 2500 BC. The acceptance of cocaine in European culture was much later and was reactivated towards the end of the 19th century when prestigious doctors such as Sigmund Freud recommended it against depression and indigestion (3). In 1884, dissolved cocaine powder was applied to the cornea of a frog for the first time and it could be said that this was the birth of local anesthesia (1).
The use of cocaine continued despite the fact that it was prohibited in the United States since 1914, reaching 2 million people in 2007 (5). Its many detrimental effects on the cardiovascular system were soon recognized. This article describes current knowledge about the complex relationship between cocaine and the cardiovascular system and attempts to make specific recommendations on the best ways to deal with the cardiac toxic effects of cocaine. .
PHARMACOKINETICS AND PHARMACODYNAMICS
Cocaine is a natural alkaloid extracted from the leaves of Erythroxylum coca , first isolated in 1860 (6). It is metabolized by hepatic and plasma esterases to active and inactive metabolites (7) that are finally excreted in the urine (8). The onset and duration of the effects of cocaine depend on the route of use.
In general, intravenous and inhalation routes (i.e. smoking) have a very rapid onset of action (seconds) and short duration (30 min) in relation to absorption through the mucosa (oral, nasal, rectal, vaginal) (9 ).
The excretion of cocaine and its metabolites is the same by any route of ingestion; The half-life is 60-120 min and that of its metabolites is approximately 4-7 hours (7). These half-lives can be considerably prolonged with repeated doses. (10).
The hemodynamic effect of cocaine is dose dependent.
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ARTERIAL HYPERTENSION
Cocaine potentiates acute sympathetic effects on the cardiovascular system(46), with consequent increases in inotropic and chronotropic effects and increased peripheral vasoconstriction. This vasoconstrictor response is also affected by the increase in endothelin-1 values (16), the impairment of vasorelaxation induced by acetylcholine (17), the disorder of intracellular calcium handling (19) and the blockade of nitric oxide. (ON) synthetase (18).
Furthermore, vasoconstriction of specific arterial beds was found to be induced by the sodium channel blocking effect of cocaine (44). In a clinical study, intranasal administration of 2 mg/kg of cocaine produced an acute 10% - 25% increase in blood pressure (23).
There is abundant evidence of the possible induction of chronic hypertension in cocaine addicts; This induces endothelial damage and increases vascular fibrosis (49). Furthermore, cardiac hypertrophy and renal mesangial fibrosis were demonstrated in autopsies of cocaine addicts (50).
However, only a 20% prevalence of chronic hypertension was found in a study carried out with 301 cocaine addicts (51). In the CARDIA ( Coronary Artery Risk Development in Young Adults ) study , which investigated the long-term cardiovascular effects of drug addiction in 3,848 participants, no differences were found in the rates of chronic hypertension in the 1,471 cocaine addicts over 7 years relative to the rest of the cohort (52). There is no data to explain this controversy.
AORTIC DISSECTION
In the International Registry for Aortic Dissection (IRAD), which obtained data from 17 international centers, the prevalence of cocaine addiction among cases of acute aortic dissection (AD) was only 0.5% (53), but two Single-center studies (54,55) reported 37% and 9.8% prevalence of cocaine addiction in cases of acute AD, the majority in young patients (mean age 41 ± 8.8 years and 47 
6.8 years, respectively). Cocaine induced cellular apoptosis and necrosis in vascular smooth muscle with consequent weakening of the vascular wall (20).
An echocardiographic study carried out in cocaine addicts showed reduced aortic elasticity, increased dimensions of the thoracic aorta and stiffness in relation to normal control subjects (57). It is also necessary to consider the route of cocaine consumption. Hue et al. (54) reported that 13 of 14 patients with acute AD-related AD smoked crack.
The rapid onset of action of smoked cocaine triggers an acute hemodynamic response and its short duration of action induces frequent use at short intervals (58), exposing the patient to repeated episodes of hemodynamic stress.
MYOCARDIAL ISCHEMIA AND INFARCTION AND APPROACH TO BEST PAIN
The risk of myocardial infarction (MI) increases up to 24 times in the first hour after cocaine abuse
Cocaine-induced myocardial ischemia results from increased myocardial oxygen demand as a result of increased inotropic and chronotropic effects (15), which is inappropriately accompanied by coronary vasoconstriction and a prothrombotic state.
Accelerated atherosclerosis in cocaine addicts was demonstrated in an autopsy study comparing non-addicts and cocaine addicts who died with acute coronary thrombosis (27). An increase in the number of mast cells per coronary segment was found in the addicts, suggestive of an increased local inflammatory state.
However, we did not adjust between groups for an important confounder such as smoking (27). Another large-scale autopsy study demonstrated epicardial coronary artery disease in 28% and small vessel disease in 42% of cocaine-related sudden deaths. An unusual mechanism for coronary thrombosis, plaque erosion, was also found in cocaine addicts (28).
Considering the detrimental effect that cocaine can have on the balance of oxygen supply and demand, it is not surprising that precordialgia is the reason for consultation in emergency services in addicts (59) and that the risk of myocardial infarction (IM) will increase up to 24 times in the first hour after cocaine abuse (60).
Diagnosing cocaine-related MI can be difficult. Most of these patients have a pathological electrocardiogram (ECG) (61,62) and increased creatinine kinase (62,63) (although cardiac troponin more accurately identifies cases of MI) (64). Furthermore, not all cocaine-related pain is cardiac; It may be, for example, of pleuritic or musculoskeletal origin. (66,67).
Weber et al. (61) carried out a prospective study with 344 cocaine addicts evaluated for chest pain. High-risk patients (ST elevation >1 mm, increased cardiac troponin, recurrent precordialga, and hemodynamic instability) were hospitalized. The remaining 302 patients were monitored in the emergency department with ECG and cardiac troponin for 12 hours before being discharged.
During a 30-day follow-up, there was no mortality in this group and only 1.6% suffered MI (61). Because complications tend to appear shortly after the consultation, even if the patient suffers an MI (68), these and other data (69) supported the safety of the 12-h observation approach in cocaine-related chest pain, also suggested by the 2012 recommendations of the American College of Cardiology/American Heart Association (ACC/AHA). (70). It is important to note that ST elevation is prevalent among cocaine addicts and therefore the definition of “high-risk patients” is less reliable.
The basis for treating cocaine-related chest pain with nitrates (73), phentolamine (a receptor blocker) (23), or verapamil (calcium channel blocker) (74) comes from studies showing regression of coronary vasoconstriction with any of these drugs in the controlled environment of the cardiac catheterization laboratory.
It should be noted that, although coronary vasoconstriction was demonstrated, none of the participants in these clinical studies suffered from precordialgia and that each of these drugs induced significant tachycardia (23, 73, 74), which could aggravate the demand for myocardial oxygen in patients exposed to cocaine.
TREATMENT WITH ß-BLOCKERS.
Considering the favorable hemodynamic effects of β-blockers, the general approach to treatment with β-blockers after cocaine exposure was initially positive (75,76).
A clinical case in 1985 (77) suggested that selective blockade of b-receptors could produce paradoxical hypertension due to unopposed receptor stimulation. Another suggested harmful effect of ß-blockers is coronary vasoconstriction , confirmed by animal studies (80), although in these studies it was not found that cocaine alone, without propranolol, induced coronary vasoconstriction.
In several clinical studies, propanol was not shown to have an effect on cocaine-induced coronary vasoconstriction, although no effects on BP or tachycardia were found (81, 82). It was suggested that the case report of a patient treated with metoprolol after consuming 1000 mg of cocaine and who suffered cardiovascular collapse and death (83) would be an example of the possible detrimental relationship between cocaine and β-blockers, although the patient did not He experienced increased BP after treatment with metoprolol and had also consumed a high dose of cocaine, which could have been responsible for the collapse.
As a result of this idea, an ACC/AHA scientific statement on the treatment of chest pain and MI associated with cocaine in 2008 recommended against using β-blocker treatment in these patients (84).
However, either due to lack of adherence to these recommendations or because not all patients disclose their cocaine addiction when receiving emergency treatment, reports have been published of numerous patients treated with β-blockers after exposure to cocaine. which generally showed neutral or favorable cardiovascular effects (85–87). Furthermore, prospective studies on the safety of β-blockers in patients exposed to cocaine also showed favorable results (88,89).
| The 2012 ACC/AHA recommendations state that non-selective β-blockers could be considered in patients with persistent hypertension or tachycardia after cocaine use, as long as they were treated with a vasodilator (70). |
β -Blockers are an essential treatment to mitigate hyperadrenergic states, decrease oxygen demand, and are considered a life-saving treatment in ischemic heart disease, heart failure (HF), and cardiomyopathies.
The hypertensive response as a consequence of unopposed α-stimulation after treatment with β-blockers in patients exposed to cocaine is rarely seen or may even be the opposite. Likewise, indirect evidence for the safety of non-selective β-blockers in cocaine-induced coronary vasoconstriction can be found in a retrospective study in which the increase in troponin was similar in patients treated or not treated with β-blockers ( 86).
APPROACH TO COCAINE-INDUCED PRECORDIALGIA
When a patient presents with cocaine-related chest pain, he or she should be evaluated first with the history, physical examination, and vital signs, followed by the ECG and cardiac troponin. Patients who continue to have ST elevation on the ECG should be referred directly for coronary arteriography with possible angioplasty and stent placement (70).
Cocaine addicts who received a stent had an increased risk of thrombosis (91), either due to the prothrombotic effect of continuous cocaine abuse or due to lack of adherence to antiplatelet treatment, and therefore the type of stent should be chosen. stent accordingly.
Although drug-eluting stents are occasionally used to treat cocaine addicts (92), most cocaine addicts receive metal stents (93), which are recommended by the 2008 and 2012 ACC/AHA scientific statements for cocaine addicts (70.84).
The authors of this article use simple metal stents and, if necessary, clopidogrel. They also examine platelet function before discharge to rule out resistance to clopidogrel. Fibrinolytic treatment for suspected MI should be weighed against the risk of cocaine-related AD. Patients with high-risk characteristics will be hospitalized with close monitoring.
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MYOCARDIOPATHY, MYOCARDITIS AND HEART FAILURE
Although myocardial scarring is considered the main cause of left ventricular (LV) dysfunction in cocaine addicts, experiments in animals (95) and in humans (96) showed that intracoronary cocaine administration caused acute increases in pressures. of the LV, dilation of the LV and decreased contractility.
These results are consistent with case reports of cocaine-exposed patients who experienced the acute onset of HF with normal coronary arteries on arteriography (97,98). Likewise, chronic HF and LV dysfunction have been reported in cocaine addicts without ischemic heart disease (99).
The pathophysiology behind these data includes cocaine-induced adrenergic discharge (46), a disorder similar to pheochromocytoma-induced cardiomyopathy and Takotsubo cardiomyopathy (reported in cocaine addicts) [100]).
A complex report on histological and immunohistochemical data found in cocaine-induced cardiomyopathy versus idiopathic dilated cardiomyopathy showed significant increases in myocyte volume and reactive oxygen species in cocaine-induced cardiomyopathy, although magnetic resonance imaging results were comparable between both groups (104). Cocaine induces myocarditis through high concentrations of catecholamines, creating myocardial necrosis and immune reaction or through the induction of eosinophilic myocarditis (30).
ARRHYTHMIAS
High doses of cocaine prolong the QT interval
The high frequency of normal-appearing hearts in cocaine-related mortality (108) is probably due to arrhythmias. Increased sympathetic tone induced by cocaine is related to increased risk of cardiac arrhythmias (32,109). Combined with the induction of myocardial ischemia and prolonged cardiac repolarization, this increase in sympathetic tone could induce ventricular ectopy, QT prolongation, torsade de pointes , and ventricular fibrillation (VF) (33,68).
Myocardial lesions caused by cocaine-induced myocarditis could produce ventricular arrhythmias, either in the acute phase or after recovery (110).
Cocaine is a potent myocardial blocker of ion channels of sodium, potassium and calcium currents. Inhibition of voltage-gated sodium channels causes increased slowing of conduction and even complete lack of excitability (39). In turn, cocaine-induced tachycardia could exacerbate sodium channel blockade. The sodium-blocking effect of cocaine could also increase myocardial dispersion of repolarization in susceptible individuals, producing Brugada-type ST segment elevation and predisposition to VF (36).
A dose-dependent effect of cocaine on sodium channels was observed; In a series of cases of cardiac arrests related to cocaine, cardiac asystole was found in patients exposed to high doses of the drug and Brugada-type ST elevation and VF in patients exposed to low doses (41).
The sodium channel blocking effects were intensified in circumstances often found in cocaine addiction; Increased acidity, as a result of local ischemia or the systemic effect of cocaine (111), increased the effect of cocaine on sodium channels (112).
Likewise, cocaethylene , a byproduct of co-consumption of cocaine and alcohol, aggravates the inhibition of cardiac ion channels (113). Opposite to the effect of sodium channels on depolarization, the inhibitory effect of cocaine on the repolarizing potassium channel encoded as KCNH2 produces prolongation of the QT interval, early afterdepolarizations, and ventricular tachyarrhythmias (35).
Alcohol consumption and cocaethylene production also increase potassium channel blockade and QT prolongation (114), effects that could be aggravated by the consumption of methadone, which prolongs the QT interval and is often used by cocaine addicts (115).
| In summary, high doses of cocaine prolong the QT interval through the inhibitory effect of the drug on potassium and calcium channels, and simultaneously cause bradycardia due to the blockade of sodium channels, an alteration that predisposes to torsade de pointes . |
Cocaine-induced hyperthermia, either due to a hypermetabolic state (117) or due to insufficient heat dissipation (38), is another important systemic effect of the drug . (118). Various electrocardiographic changes and cardiac arrhythmias have been demonstrated in cocaine-related (78) as well as non-cocaine-related hyperthermia (119). This mechanism could explain the higher frequency of mortality associated with cocaine in warm environments (118). Finally, the nerve blocking effect of the drug could directly affect the neurovegetative system with nerve blockade and paradoxical bradycardia (40).
APPROACH TO COCAINE-INDUCED ARRHYTHMIAS
The patient’s general condition should be evaluated first, including the degree of excitability, body temperature, hemodynamic stability, pH, and the presence of ischemia (40). Immediate ECG and continuous monitoring are recommended during the initial evaluation period. Look for QT prolongation and electrolyte imbalance.
In the case of hyperthermia , cooling must be initiated. Treatment with sodium bicarbonate counteracts the sodium-blocking effect of cocaine, while correcting increased acidity (120). Increased sympathetic tone should be treated with benzodiazepines (84).
Non-selective β -blockers are useful in this context. Because most patients respond well to this treatment, antiarrhythmic medications are usually not needed and, if used, should be done with caution. Since the mechanism of action of Class 1A/1C medications is similar to that of cocaine, they should be used. avoid (112).
Lidocaine could be a safe alternative in case of prolonged ventricular arrhythmias (121).
There are no data on the efficacy and safety of amiodarone (122).
Intravenous lipid emulsion may be useful in extreme cases of cocaine intoxication (124).
PULMONARY HYPERTENSION
A retrospective study of 340 patients with pulmonary hypertension (126) showed that those with idiopathic pulmonary hypertension were 10 times more likely to have a history of stimulant drug use than patients with pulmonary hypertension and a known risk factor. However, specific data on cocaine-induced pulmonary hypertension are less conclusive.
A study on the acute effect of intravenous cocaine on the pulmonary vasculature showed that cocaine did not cause an increase in pulmonary arterial pressure (127); However, chronic crack smokers had an increased risk of pulmonary hypertension (128).
VASCULITIS
Cocaine-induced destructive midline lesions have been rarely mentioned (132,133) and can be attributed to severe vasoconstriction, ischemia of the nasal mucosa, repeated traumatic injury caused by insufflated cocaine crystals, and recurrent local infections, but also to vasculitis with positive antineutrophil cytoplasmic antibodies (ANCA), (formerly Wegener’s disease) (133).
Another type of ANCA-positive cocaine-related vasculitis has more systemic features, with fever, purpuric skin lesions, acute kidney injury, and glomerulonephritis (134). It is important to know that the relationship between cocaine and vasculitis is confused, since both types of vasculitis are related to the adulterant levamisole , which induces the production of autoantibodies (133,134). The topic needs more research.
CARDIOVASCULAR ACCIDENT (CVA)
Single-center registries demonstrated an increased frequency of cocaine addiction in patients with both ischemic and hemorrhagic stroke (135,136), especially in those <60 years of age. A logistic regression model in > 3,000,000 hospitalized patients confirms these data (137).
The mechanisms involved in cocaine-related stroke are:
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A case-control study with more than 1000 stroke patients showed that although a similar proportion of participants in both groups were exposed to cocaine, the timing of cocaine use (<24 hours before) was related to the onset of stroke. (138).
However, only 26 of the 1,090 stroke cases were related to cocaine use, a finding similar to previous studies demonstrating a contradictory relationship between cocaine and stroke risk (139). The 2015 AHA recommendations for the treatment of spontaneous intracranial hemorrhage (141) recommend toxicological screening in all patients.
CONCLUSIONS
Cocaine addiction is a considerable threat to the integrity of the cardiovascular system. In contrast to other drugs, such as heroin or methamphetamines, which exert their harmful effects through a limited mechanism, cocaine has numerous pathophysiological pathways through which it affects the cardiovascular system.
Cocaine is also highly addictive and significantly influences behavior (145). Disappointing reports about the current prevalence of addiction in adolescents (146) could increase awareness of the possible future harmful effects of this dangerous drug.
