Cardiovascular, cerebrovascular and arterial pathology in cocaine users as imaged by magnetic resonance imaging and positron emission tomography.a Cocaine’s acute and chronic toxicity mechanisms on the vessel, heart, and the central nervous system (CNS), and their interactions. Cocaine, compared to other illicit drugs, poses a particular risk for vascular disease and is most involved in emergency room visits (40.3%), with highest rates for men aged 35–44 years, amounting to a vast social and economic burden . For example, 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) and magnetic resonance imaging (MRI), PET/MR, allow simultaneous investigation and tracking of brain, cardiac and the carotid arteries function and structure in the same individuals.
Fig. 1. Cocaine’s acute and chronic toxicity mechanisms.
- While smoking crack or sniffing cocaine, there is a vast accumulation of the drug in the heart affecting myocardial tissue directly .
- Multimodality imaging studies could promote the identification of CUD with silent pre-symptomatic atherosclerosis in the brain, heart and arteries 100–104.
- For such a short and simple-looking word, acute has a rather bewildering range of meanings.
- We present the main mechanisms of acute and chronic cocaine-induced toxicity on vessels, brain and heart (Fig. 1) and the common vascular and systemic effects of cocaine use in humans (Fig. 2).
For example, vasoconstriction, a main underlying cause of ischemic strokes, may result from the increased availability of epinephrine, norepinephrine, and serotonin (especially in large and medium-sized brain vessels) in the vasculature due to cocaine blockade of their reuptake 55–57. In addition, cocaine induces disruption of cerebral autoregulation of blood flow (maintaining relatively constant blood flow despite changes in perfusion pressure) and global reduction in cerebral glucose metabolism . In addition to ischemic heart disease , other complications include multiple foci of mid-wall and subepicardial late enhancement in the apical septum and apical lateral wall and coronary vasoconstriction 2,16,23. Cocaine creates an elevated immune system inflammatory state with decreased basal anti-inflammatory markers (e.g., interleukin-10) 42,51, and increased pro-inflammatory cytokines (e.g., tumor necrosis factor alpha, Interleukin 1β) 42,51, all contributing to vascular disease (e.g., endocarditis).
Vascular disease in cocaine addiction
Cerebral vasospasm is pharmacologically induced via cocaine’s potent sympathomimetic properties and an increase of endothelin-132,34. These mechanisms underlie inadequate myocardial oxygen equilibrium, which may lead to ischemia and manifest as angina or infarction 2,13. Cocaine induces acute cardiotoxicity through multiple pathways (Fig. 1, left box). It was recently demonstrated that cocaine elicits autophagy involving nitric oxide and glyceraldehyde-3-phosphate dehydrogenase signaling cascade .
Stimulation of dopamine cells in the ventral tagmental area increases blood pressure and this effect is antagonized by the dopamine D2 receptor blockers . In addition, cocaine blocks reuptake of catecholamines in the presynaptic neurons in the central and peripheral nervous systems, resulting in increased catecholamines, sympathetic output and stimulation 2,19. At high doses, cocaine is markedly more dangerous than other central nervous system stimulants, including amphetamines , and can cause sudden cardiac death through its effect on sodium channels and local anesthetic actions 13,14,16. Underlying this addiction is CUD’s association with abnormal brain morphology and function involving inefficiencies in circuits that coordinate reward and self-control processes . Furthermore, the phenomenology of CUD consists of repeated drug use leading to tolerance, withdrawal, and compulsive drug-seeking behavior with inability to abstain, despite adverse effects to medical, social and occupational functioning. “Crack-Cocaine” was introduced in the mid-1980s involving a new route of administration, smoking (as opposed to sniffing), which enhances vascular toxicity.
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These factors include the life-course and complexity of CUD, comprised of years (often, decades) of concomitant alcohol and/or tobacco and/or other drug use, potentiating vascular toxicity. Thus, atherosclerosis may impact cognitive and behavioral functioning even before arterial narrowing results in a stroke. Cocaine-induced chronic neurotoxicity consists of monoamine re-uptake inhibition, anti-cholinergic activity, and alpha-adrenergic stimulation . Other reports document aortic damage including dilatation , reduced strain, compliance and distensibility 74,80, and increased stiffness index and pulse wave velocity .
Fig. 2. Cocaine-induced major pathophysiological load to the cardiovasculature, cerebrovasculature, and arteries.
Heart mechanisms adapted from Ref. ; figure based on following references 2,5,6,10,13,15–19,23–44. Despite advances in characterization of addiction, knowledge about the contribution of vascular aging to brain impairments in human CUD is scarce. We review major postmortem and in vitro studies documenting cocaine-induced vascular toxicity. Although the Crack-Cocaine epidemic has declined, its vascular consequences are increasingly becoming evident among individuals with cocaine use disorder of that period, now aging. Www.merriam-webster.com/dictionary/acute. But rarer and more serious ones include acute gallstone disease, pancreatitis and serious allergic reactions.
Chest pain 8,13,76 and cerebrovascular events 5,31,63 may occur within minutes to just a few hours from cocaine use. As evident from this review, there is ample data on cocaine-induced endothelial dysfunction, vasoconstriction, and accelerated atherosclerosis. The first line of treatment for cocaine induced sodium channel blockade is alkalization with hypertonic sodium bicarbonate.
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Thus, prevention of secondary harms and halting of further disease progression in CUD mandates cessation of cocaine use and cigarette smoking, limitation of alcohol consumption, as well as enhancing healthy life routines (e.g., regular health monitoring, physical activity, sleep, diet, stress management). Finally, and perhaps most importantly, cocaine abstinence or even reduced use promotes reduction in endothelial-1 damage 45,46. Medication to reduce inflammation (e.g., recombinant IL-10, soluble receptor medication such as Etanercept) may be helpful to control cocaine induced inflammatory cascade . The issue is complicated further by the fact that contaminants such as procainamide, quinidine and antihistamines, which are often mixed with the cocaine, may contribute to the effects seen and influence the underlying pathophysiology . Studies in healthy populations reveal association between cognitive deficiencies and atherosclerosis, indicating that there is an inflammatory pathway that reduces the brain’s executive control network efficiency 82–84. Advanced atherosclerosis of intracranial vessels is noted as the cause of cocaine-induced stroke in numerous studies 4,29.
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Treatment for cocaine-induced acute vascular events may be similar to indications in patients with traditional risk-factors, with few exceptions. Additionally, genetic factors leading to variability in reaction to cocaine can enhance hemodynamic responsiveness, incidence of coronary vasoconstriction, and vascular damage . In addition to cocaine-specific effects, there are secondary harms resulting from synergetic effects between multiple environmental, psychosocial and behavioral factors comprising the addiction phenomenology that could in turn enhance potential vascular damage. Additional in vivo examinations are clearly required to solidify knowledge concerning early vascular disease detection in CUD, especially, the assessment of carotid plaque composition for determining risk profiles and predicting future clinical events in CUD.
- Atherosclerosis of the carotid arteries is of particular relevance to CUD because these arteries supply blood to the brain regions that are implicated in the cognitive impairments documented in CUD 39–41.
- It was recently demonstrated that cocaine elicits autophagy involving nitric oxide and glyceraldehyde-3-phosphate dehydrogenase signaling cascade .
- “Crack-Cocaine” was introduced in the mid-1980s involving a new route of administration, smoking (as opposed to sniffing), which enhances vascular toxicity.
- Other reports document aortic damage including dilatation , reduced strain, compliance and distensibility 74,80, and increased stiffness index and pulse wave velocity .
- Sudden increases in arterial pressure can induce aneurysms (a localized widening of an artery or vein, resulting from weakening of vessel wall), arteriovenous malformations (abnormal connection between arteries and veins, bypassing the capillary system) and hemorrhagic strokes .
When vessels are stressed, endothelin-1 (a vasoconstrictor protein produced by vascular endothelial cells) is elevated and nitric oxide (a blood vessel dilator) decreases, leading to vasoconstriction acute and chronic effects of cocaine on cardiovascular health pmc 35,36. There is also evidence that the cardiovascular actions of cocaine are mediated in part by dopamine , via central and peripheral mechanisms . However, the accelerated development of vascular disease remains mostly undetected and asymptomatic presentation of vascular pathology in CUD results in silent disease progression. Cocaine-induced damage to the cardiovascular and cerebrovascular systems is widely reported, and is linked with hypertension, tachycardia, ventricular arrhythmias ,myocardial infarction 3,4, stroke 4,5, resulting in severe functional impairments or sudden mortality 6–10.
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Acute is also frequently used to describe less troublesome matters, such as keenness of perception (“an acute observer” or “an acute sense of smell”), a type of angle (one measuring less than 90 degrees), or the demand for urgent attention (“acute danger”). It retains this meaning today, but can also refer to the severity of more general matters, such as “acute embarrassment” or “an acute shortage.” For such a short and simple-looking word, acute has a rather bewildering range of meanings.
We present the main mechanisms of acute and chronic cocaine-induced toxicity on vessels, brain and heart (Fig. 1) and the common vascular and systemic effects of cocaine use in humans (Fig. 2). Findings consist of the major mechanisms of cocaine-induced vasoconstriction, endothelial dysfunction, and accelerated atherosclerosis, emphasizing acute, chronic, and secondary effects of cocaine. Furthermore, chronic cocaine-use reduces capillary flows in brain and may be responsible for cerebrovascular small-vessel ischemic disease (e.g. cocaine-induced leukoaraiosis), possibly involving genetic factors 65,66.
Thus, cocaine induces microischemia in various types of vessels and arteriolar branches that is exacerbated with repeated use and is likely to be a contributor to its neurotoxic effects . Additional findings point to reduced arterial caliber, focal narrowing in the anterior (and middle cerebral arteries) and posterior cerebral circulation as well as communicating arteries . Carotid artery dissection might also be caused by cocaine mediated apoptosis of vascular cells leading to ischemic stroke, although the mechanism is not fully understood .
Cocaine’s chronic effects on the vessel (Fig. 1, upper box) 10,23,24 consist of repeated endothelial damage leading to premature and severe atherosclerosis in various organs 10,19. Sympathomimetic effects generate a rise of heart rate, blood pressure and myocardial contractility, which enhance myocardial oxygen demand, whereas myocardial oxygen supply is decreased by coronary vasoconstriction and enhanced thrombosis. This cascade reduces blood flow following cocaine use and can lead to acute organ damage. Additional mechanisms implicated in cocaine induced vasoconstriction include increases in calcium .
Atherosclerosis of the carotid arteries is of particular relevance to CUD because these arteries supply blood to the brain regions that are implicated in the cognitive impairments documented in CUD 39–41. Such an examination in a rat cortical brain identified a 2.9 ± 0.5 min lag time between the peak neuronal and vascular responses to cocaine . Furthermore, vasoconstriction at presynaptic nerve terminals increases the release of calcium from the sarcoplasmic reticulum in cerebral vascular smooth muscle cells 32,33.
