Cardiovascular effects of cocaine

# Overview
- Cocaine (benzoylmethylecgonine) is a naturally occurring alkaloid obtained from the leaves of Erythroxylon cocca, trees that are indigenous to Peru, Columbia and Bolivia.  The natives of the South American Andes have used cocaine for at least 5000 years, and have a word for the distance an Indian can walk while under the effects of one coca leaf.  Alfred Neiman isolated cocaine from the plant in 1860, and since that time it has been a drug of choice for many, including the Coca Cola company (~1888 - 1914).  In 1884 Sigmund Freud advocated its use for the relief of depression and chronic fatigue, describing it as a magical drug.  He even wrote the Song of Praise to cocaine.  Unfortunately, he later discovered tolerance, dependency and withdrawal depression.
- Cocaine is usually snorted as a hydrochloride salt, but it may be smoked as the free base or crack after alkalinizing the salt and extracting the base with nonpolar solvents such as ether. Crack pops when heated (hence the name), is not water-soluble, melts, but does not decompose when heated, and vaporizes at higher temperatures, thus allowing it to be smoked. The free base can be injected IV, and is often combined with heroin to form a speedball. It is often cut (mixed) with other agents that increase is bulk (mannitol and lactulose), mimic its stimulant properties (caffeine) or its local anesthetic effects (procaine, lidocaine) in order to increase its selling price.
- It is currently considered one of the most commonly abused illicit drugs, with approximately one of every three American males and one of every 5 American females trying it at least once. Approximately 5-10% of all emergency department visits are thought to be related to cocaine use.

# Pharmacology
Cocaine is well absorbed through all mucous membranes, however oral administration is not popular as cocaine is destroyed by gastric acid. It is detoxified by plasma and liver cholinesterases to benzoylecgonine and methyl ecgonine, which are water soluble and excreted in the urine. The serum half-life of cocaine is 45-90 minutes, however, depending on the route of administration and a patients intrinsic cholinesterase activity, metabolites can be detected in the urine for up to 48 hours. When given locally, it acts as an anesthetic due to blockade of fast sodium channels during membrane depolarization, thereby blocking the initiation and transmission of electrical signals. In the heart, this is manifest as prolongation of the PR, QRS and QT intervals. Systemically, it blocks the presynaptic reuptake of both norepinephrine (NE) and dopamine (DA), and stimulates the presynaptic release of NE, producing an excess of these neurotransmitters at the postsynaptic receptor. Additionally, cocaine has been shown to increase catechol release from the adrenal medulla. The stimulation of beta-receptors results in activation of adenylate cyclase, increased cyclic adenosine monophosphate (cAMP), and increased Ca++ influx into the myocardial cells. alpha-stimulation, activates phospholipase C and protein kinase C, which also increase intracellular Ca++. It has also been shown to cause DA release in the brain, which may explain some of its addictive properties. 

# Association with Cardiovascular Diseases

## Why MI?
- Although ischemia, infarction and sudden death are more common in chronic users, they have all been reported in first-time users as well. All routes of administration have also been associated with adverse cardiovascular effects. The typical patient with cocaine induced MI is a young man who smokes cigarettes but has few other risk factors for coronary artery disease (CAD). Myocardial ischemia and infarction likely results from the combination of:
Increased myocardial oxygen demand  due to increased heartrate (HR) and mean arterial pressure (MAP).
The effects of cocaine on inotropy are confusing. Some studies suggest a decrease in inotropy, mediated by the blockade of Na+ channels, whereas others report an increase in inotropy mediated by sympathetic stimulation.  Overall, it seems that the direct negative inotropic effects of cocaine outweigh the positive effects.
Coronary vasospasm  even in the setting of increased demand. This is thought to result at least in part, from alpha-adrenergic stimulation as it can be reversed with the beta-blocker phentolamine. Additionally, giving a beta-blocker (e.g. propranolol) will result in unopposed alpha stimulation, and has been shown to further worsen coronary blood flow.
The vasoconstriction seen after cocaine administration occurs in both the diseased and nondiseased segments of the coronary arteries, however atherosclerotic segments tend to have a greater degree of narrowing than healthy segments. Some authors explain this finding with the hypothesis that the normal segments have a greater ability to produce endothelium-derived relaxing factor which counteracts the alpha-adrenergic vasoconstriction. The diseased segments, have less endothelium-derived relaxing factor (EDRF), and are subject to more vasoconstriction.
Enhanced platelet aggregation and thrombus formation - cocaine enhances adenosine diphosphate (ADP) induced platelet aggregation, thromboxane production, alpha-granule release and fibrinogen binding. Additionally, serum concentrations of plasminogen-activator inhibitor are increased, and protein C and AT III are decreased. Vasospasm and stasis have also been thought to contribute to thrombus formation.
Accelerated atherosclerosis  is thought to result from damage to the endothelium possibly caused by recurrent vasospasm.  Cocaine has also been shown to potentiate cholesterol-induced atherosclerosis in rabbits.
- Increased myocardial oxygen demand  due to increased heartrate (HR) and mean arterial pressure (MAP).
The effects of cocaine on inotropy are confusing. Some studies suggest a decrease in inotropy, mediated by the blockade of Na+ channels, whereas others report an increase in inotropy mediated by sympathetic stimulation.  Overall, it seems that the direct negative inotropic effects of cocaine outweigh the positive effects.
- The effects of cocaine on inotropy are confusing. Some studies suggest a decrease in inotropy, mediated by the blockade of Na+ channels, whereas others report an increase in inotropy mediated by sympathetic stimulation.  Overall, it seems that the direct negative inotropic effects of cocaine outweigh the positive effects.
- Coronary vasospasm  even in the setting of increased demand. This is thought to result at least in part, from alpha-adrenergic stimulation as it can be reversed with the beta-blocker phentolamine. Additionally, giving a beta-blocker (e.g. propranolol) will result in unopposed alpha stimulation, and has been shown to further worsen coronary blood flow.
The vasoconstriction seen after cocaine administration occurs in both the diseased and nondiseased segments of the coronary arteries, however atherosclerotic segments tend to have a greater degree of narrowing than healthy segments. Some authors explain this finding with the hypothesis that the normal segments have a greater ability to produce endothelium-derived relaxing factor which counteracts the alpha-adrenergic vasoconstriction. The diseased segments, have less endothelium-derived relaxing factor (EDRF), and are subject to more vasoconstriction.
- The vasoconstriction seen after cocaine administration occurs in both the diseased and nondiseased segments of the coronary arteries, however atherosclerotic segments tend to have a greater degree of narrowing than healthy segments. Some authors explain this finding with the hypothesis that the normal segments have a greater ability to produce endothelium-derived relaxing factor which counteracts the alpha-adrenergic vasoconstriction. The diseased segments, have less endothelium-derived relaxing factor (EDRF), and are subject to more vasoconstriction.
- Enhanced platelet aggregation and thrombus formation - cocaine enhances adenosine diphosphate (ADP) induced platelet aggregation, thromboxane production, alpha-granule release and fibrinogen binding. Additionally, serum concentrations of plasminogen-activator inhibitor are increased, and protein C and AT III are decreased. Vasospasm and stasis have also been thought to contribute to thrombus formation.
- Accelerated atherosclerosis  is thought to result from damage to the endothelium possibly caused by recurrent vasospasm.  Cocaine has also been shown to potentiate cholesterol-induced atherosclerosis in rabbits.

## Cardiomyopathy
Animal and human studies have shown that cocaine causes an acute depression in left ventricle (LV) function as measured hemodynamically (increased left ventricular end diastolic pressure (LVEDP)), echocardiographically (LV dilation), and angiographically (decreased stroke volume (SV)). This is thought to be mediated by the effects of cocaine on the Na+ channel, and largely independent of coronary arterial blood flow. A similar finding occurs in patients with pheochromocytoma, and it is hypothesized that excess catechols may have a toxic effect on the myocardium stemming from an increase in myocardial intracellular calcium.
Cocaine induced cardiomyopathy is often reversible with cessation of drug use.

## Endocarditis
- IV cocaine is strongly associated with the development of endocarditis. Unlike heroin, IV cocaine is not heated prior to use, and therefore may contain many more infectious agents. For some unknown reason, endocarditis is more likely to be left sided as compared to other IV drugs.

## Arrhythmia
- There have been many case reports of cocaine induced ventricular tachycardia (VT), ventricular fibrillation (VF), sudden death, accelerated ventricular rhythms, and supraventricular tachycardias.  These arrythmias have been seen in patients with ischemia, as well as in those without.  It is felt that the arrhythmogenic effects of cocaine stem from its membrane stabilization effects (fast Na+ channel), with resultant QT prolongation, as well as its sympathomimetic effect, causing increased automaticity, decreased AV node refractoriness, and increased His-Purkinje system conduction velocity.

## Other
- Cocaine has also been associated with contraction bands necrosis (seen in 93% of patients with cocaine-related sudden death), myocarditis, hypertension, aortic rupture, pneumopericardium (possibly from self induced positive end-expiratory pressure (PEEP) to enhance the drugs effects) and cerebrovascular aneurysms.

# Drug Combinations
- Tobacco
The effects on myocardial oxygen demand and supply are magnified when cocaine is combined with cigarette smoking.  Pitts et.al. found an increase in rate-pressure product, and a decrease in coronary artery diameter (diseased segments with more vasoconstriction than normal segments) with both cocaine and tobacco, however the combined effects were greater than either one alone. pitts
- The effects on myocardial oxygen demand and supply are magnified when cocaine is combined with cigarette smoking.  Pitts et.al. found an increase in rate-pressure product, and a decrease in coronary artery diameter (diseased segments with more vasoconstriction than normal segments) with both cocaine and tobacco, however the combined effects were greater than either one alone. pitts
- Alcohol
Also interacts with cocaine, and it has been shown that the risk of drug-induced sudden death is 18-fold higher when alcohol and cocaine are used in combination, than with either drug independently.  Although the exact mechanisms are unknown, it is postulated that the combination of alcohol and cocaine worsens the supply: demand relationship.  Patients using both drugs together tend to have higher heart rates, however, the effects of alcohol on coronary diameter are controversial.  Some authors report vasoconstriction, and others report vasodilation.  In addition, the use of both drugs together has been associated with the formation of a unique metabolite, cocaethylene, which potentiates cocaines effects by blocking DA reuptake.
- Also interacts with cocaine, and it has been shown that the risk of drug-induced sudden death is 18-fold higher when alcohol and cocaine are used in combination, than with either drug independently.  Although the exact mechanisms are unknown, it is postulated that the combination of alcohol and cocaine worsens the supply: demand relationship.  Patients using both drugs together tend to have higher heart rates, however, the effects of alcohol on coronary diameter are controversial.  Some authors report vasoconstriction, and others report vasodilation.  In addition, the use of both drugs together has been associated with the formation of a unique metabolite, cocaethylene, which potentiates cocaines effects by blocking DA reuptake.

# Diagnosis

## History and Symptoms
- Timing
Despite the fact that peak blood levels are achieved after ~ 30 minutes of intranasal use, and the t12 is 45-90 minutes, some patients experience the onset of symptoms several hours after drug administration.  It is felt that the metabolites, benzoylecgonine and ethyl methyl ecgonine, also have vasoconstrictor effects, and recurrent vasoconstriction is seen as their levels increase, even though the blood levels of cocaine are decreasing.
- Despite the fact that peak blood levels are achieved after ~ 30 minutes of intranasal use, and the t12 is 45-90 minutes, some patients experience the onset of symptoms several hours after drug administration.  It is felt that the metabolites, benzoylecgonine and ethyl methyl ecgonine, also have vasoconstrictor effects, and recurrent vasoconstriction is seen as their levels increase, even though the blood levels of cocaine are decreasing.

## Gross Pathological Findings
Images shown below are courtesy of Professor Peter Anderson DVM PhD and published with permission.  PEIR, University of Alabama at Birmingham, Department of Pathology
- Cocaine Abuse: Gross focal scars mostly subendocardial woman in twenties. Sudden death
- Cocaine Abuse: Gross focal scars mostly subendocardial woman in twenties. Sudden death
- Cocaine Abuse: Gross focal scars mostly subendocardial woman in twenties. Sudden death
- Cocaine Abuse: Gross focal scars mostly subendocardial woman in twenties. Sudden death

## Microscopic Pathological Findings
Images shown below are courtesy of Professor Peter Anderson DVM PhD and published with permission.  PEIR, University of Alabama at Birmingham, Department of Pathology
- Cocaine Abuse: Micro low mag H&E scar in myocardium woman in twenties. Sudden death
- Cocaine Abuse: Micro high mag small artery in epicardium with vacuolated medial smooth muscle cells questionable evidence of previous vascular spasm woman in twenties. Sudden death
- Cocaine Abuse: Micro med mag small artery in myocardium with marked intimal thickening questionable evidence of previous injury due to spasm woman in twenties. Sudden death
- Cocaine Abuse: Micro high mag small artery in myocardium with marked intimal thickening and vacuolated smooth muscle cells in media questionable evidence of previous spasm woman in twenties. Sudden death
- Cocaine Abuse: Micro low mag scars in myocardium woman in twenties. Sudden death
- Cocaine Abuse: Micro high mag myocardial scar woman in twenties. Sudden death
- Cocaine Abuse: Micro med mag small myocardial artery intimal thickening possibly due to vasospasm woman in twenties. Sudden death
- Cocaine Abuse: Micro high mag H&E small artery in epicardium with vacuolated medial smooth muscle cells possible evidence of previous spasm woman in twenties. Sudden death

# Risk Stratification and Prognosis
- The outcome in these patients, from a cardiovascular standpoint, is relatively good.  Approximately 6% of patients with cocaine-associated CP will have an infarction.  Additionally, one-year survival is ~ 98%.

# Treatment

## Management
- There have been no large randomized prospective trials to compare treatment strategies in patients with cocaine induced ischemia.
- Avoid beta-blockers.
- Labetalol (an alpha and beta blocker) has been advocated as the drug of choice for heart rate and blood pressure control in a patient with cocaine induced ischemia.  In a study by Lange et.al., labetalol was shown to reduce MAP, but did not relieve cocaine induced coronary vasospasm.  They attribute this to a predominance of beta-blockade over alpha-blockade at standard pharmacologic doses.
- Nitroglycerin and verapamil have both been shown to reduce both MAP and coronary vasospasm (in diseased and normal areas), and therefore are touted as first line agents in these patients.
- Thrombolytics have been shown to be successful in the treatment of patients with cocaine induced myocardial infarction (MI). There is no data on heparin and aspirin (ASA), however, it makes sense that they would be of value.
- Benzodiazepines are helpful in controlling symptoms of agitation and increased catechol output, and have been shown to reduce heartrate and blood pressure in patients with cocaine intoxication.
- Phentolamine (1mg) can be given to try and reduce vasoconstriction in patients with continued CP despite the above measures.  The major side effect is hypotension.