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Heavy alcohol use (defined as at least 5 drinks per day on >5 days of the week) has been documented in 7% of the US population and is even more common in patients presenting for surgery. Alcohol abuse is a major risk factor for perioperative morbidity and mortality,41 yet many clinicians often fail to recognize it. Achieving preoperative abstinence before elective surgery substantially reduces postoperative complications.42 Blood alcohol concentrations as low as 0.05 mg/dL produce acute hemodynamic effects that may have important consequences for patients with heart disease. Mildly intoxicating doses of alcohol reduce myocardial contractility in vitro and cause left ventricular dysfunction in vivo. Such actions cause further reductions in global cardiac performance in patients with preexisting cardiomyopathy. The mechanism responsible for alcohol-induced myocardial depression is unclear. The ingestion of alcohol increases cardiac output in healthy individuals because systemic vascular resistance declines. Conversely, alcohol and its metabolites also indirectly enhance sympathetic nervous system activity, thereby producing tachycardia, arterial vasoconstriction, and attenuation of baroreceptor reflex control of the circulation.43 These actions combine to increase myocardial oxygen consumption and may contribute to the development of myocardial ischemia or infarction in heavy drinkers with coronary artery disease. Myocardial ischemia or infarction may also occur during alcohol withdrawal in patients with coronary artery disease as a result of elevated sympathetic nervous system tone or coronary vasospasm.
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A strong causal relationship between alcohol abuse and hypertension has been established.44 The combination of chronic alcohol use and withdrawal enhances centrally mediated sympathetic nervous system activity and produces hypertension by overwhelming the direct, but transient, vasodilatory effects of the drug and its metabolites.43 Heavy alcohol use is linked to the development of coronary atherosclerosis and is associated with increased morbidity and mortality resulting from coronary artery disease.45 Conversely, consumption of modest amounts of alcohol produces cardioprotection against ischemic injury.46 Several large-scale epidemiologic studies provided compelling evidence that chronic consumption of small amounts of alcohol reduces cardiovascular mortality, decreases the incidence of coronary artery disease, and improves survival during acute myocardial infarction. Despite these convincing data, substantial individual variability exists, and "rebound" phenomena that theoretically increase the risk of cardiovascular complications are also known to occur with abrupt cessation of alcohol intake. This latter caveat may be of particular importance because temporary abstinence from alcohol consumption is required during the perioperative period.
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Chronic alcohol abuse produces a dilated cardiomyopathy characterized by myocardial hypertrophy, chamber dilatation, interstitial fibrosis, disruption of myocyte organelle structure, and severe contractile dysfunction (ie, alcoholic cardiomyopathy). These alterations cause irreversible congestive heart failure.47 Advanced cirrhosis produces changes in systemic hemodynamics that may obscure the presence of alcoholic cardiomyopathy. Increases in cardiac output occur in response to declines in systemic vascular resistance in patients with decompensated cirrhosis.48 There is correlation between the extent of hepatic dysfunction and the magnitude of reduction in systemic vascular resistance.48 Abnormal arterial-venous shunting that accompanies chronic hepatic dysfunction does not appear to be responsible for the decrease in afterload. Instead, enhanced production of nitric oxide is a major cause of cirrhosis-induced declines in peripheral resistance.49 Notably, the presence of ascites (and the consequent reduction in left ventricular preload) may stimulate compensatory sympathetic nervous system–mediated vasoconstriction that attenuates this vasodilation.
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Atrial or ventricular arrhythmias are frequently observed in alcohol abusers, most often after a binge-drinking episode. This "holiday heart" effect usually develops in otherwise healthy subjects without heart disease or abnormal serum electrolytes. An increased risk of sudden cardiac death was also reported in alcohol abusers with or without coronary artery disease, presumably because of malignant ventricular arrhythmias.50
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Alcohol abuse produces many pulmonary complications that are related to the acute and chronic effects of the drug.51 Alcohol is a potent depressant of respiratory drive, and intoxication may produce hypoxemia, hypercarbia, acidosis, atelectasis, and respiratory failure. These complications may be more pronounced in patients with preexisting pulmonary or airway pathology (eg, chronic obstructive or restrictive lung disease, obstructive sleep apnea, upper airway neoplasm). An altered level of consciousness and compromise of airway protective reflexes during acute intoxication predisposes to aspiration pneumonitis and adult respiratory distress syndrome. Alcohol ingestion exacerbates bronchospastic lung disease, especially in the presence of histamine-sensitive asthma. Acetaldehyde-induced mast cell degranulation with the release of histamine, leukotrienes, and other inflammatory mediators appears to be a major mechanism for alcohol-induced bronchospasm. Conversely, other patients with asthma report symptomatic improvement with alcohol ingestion. Thus the acute effects of alcohol on airway reactivity may be unpredictable and patient specific. Chronic alcohol abuse also causes several important pulmonary complications in patients with cirrhosis. Large quantities of ascitic fluid reduce vital and functional residual capacities, thereby producing atelectasis, tachypnea, dyspnea, and rapid arterial oxygen desaturation during anesthetic induction. Movement of ascitic fluid across the diaphragm to the pleural space may worsen this clinical picture. Abnormal pulmonary arterial-venous shunts produce hypoxemia in patients with alcoholic cirrhosis. This "hepatopulmonary syndrome" is observed in as many as 15% of patients with cirrhosis and occurs as a result of reduced pulmonary vascular resistance.52 Enhanced nitric oxide production and altered hepatic metabolism of estrogen and progesterone are possible etiologies of hepatopulmonary syndrome. Conversely, a small minority of patients with alcoholic cirrhosis develops pulmonary hypertension, most likely because the liver fails to metabolize circulating vasoactive substances. The diagnosis of this "portal" pulmonary hypertension may be overlooked because many of the signs and symptoms of right ventricular failure mimic those of chronic hepatic dysfunction. Depression of immunologic function, concomitant tobacco abuse, and malnutrition probably contribute to this increased incidence of pneumonia.
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Seizures and cerebrovascular accidents are common in alcohol abusers. Anticonvulsant medications are usually unnecessary for the treatment of alcohol withdrawal seizures because these events are usually self-limited. Seizures occur less frequently during active alcohol consumption. Similar to previously reported reductions in cardiovascular risk associated with moderate alcohol consumption, several epidemiologic studies have suggested that daily ingestion of small quantities of alcohol may reduce the risk of cerebrovascular accidents (Fig. 24-3).53 In contrast, chronic alcohol abuse is strongly associated with stroke.
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Sustained impairment of cognitive function or frank dementia frequently occurs in chronic alcohol abuse. Severe alterations in cognitive function may jeopardize the ability to obtain informed consent and may also undermine compliance with perioperative treatment. Thiamine deficiency accompanies alcohol-induced malnutrition and produces Wernicke encephalopathy. Confusion, memory and attention deficits, nystagmus, and ataxia characterize Wernicke encephalopathy, which is initially fully reversible with appropriate thiamine replacement. Irreversible memory deficits, amnesia, inability to recall new information, and confabulation are major features of Korsakoff syndrome. Peripheral compression nerve palsies ("Saturday night palsy"), rhabdomyolysis, and compartment syndromes commonly occur because alcohol abusers may lose consciousness and remain immobile for prolonged periods. Alcohol-induced myelopathy and polyneuropathy probably occur as a direct result of drug toxicity, but malnutrition most likely also plays an important contributing role.
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Alcoholic liver disease is the most well-recognized complication of alcohol abuse. Hepatic failure resulting from alcohol abuse is responsible for over 25 000 deaths annually in the United States.54 Until it was recently surpassed by chronic HCV infection, alcohol-induced hepatic cirrhosis was the most common indication for liver transplantation in this country. Fatty liver may be observed in chronic alcohol abusers, but this change may also occur after several days of binge drinking in otherwise healthy subjects. Clinical signs and symptoms of alcohol-induced fatty liver include nausea, vomiting, anorexia, and right upper quadrant pain, whereas liver function tests remained preserved or only modestly elevated. The relative perioperative risk associated with alcoholic fatty liver has not been formally studied, but it may be prudent to delay elective surgery until abstinence is achieved and clinical symptoms resolve. Fever, jaundice, abnormal liver function tests, and right upper quadrant pain characterize the presentation of alcoholic hepatitis. Severe alcoholic hepatitis is associated with high mortality, is often accompanied by ascites, encephalopathy, and coagulopathy, and is a contraindication to elective surgery.55 Portal hypertension, ascites, esophageal varices, hepatic encephalopathy, spontaneous bacterial peritonitis, and coagulopathy resulting from decreased synthesis of coagulation factors and thrombocytopenia typify end-stage liver disease resulting from cirrhosis. A history of sustained alcohol abuse and characteristic abnormalities in liver function tests establishes the diagnosis of alcoholic liver disease, in addition to clinical signs and symptoms. Markedly increased blood γ-glutamyl transferase concentrations are accompanied by elevations in aspartate aminotransferase (AST) that usually exceed those of alanine aminotransferase (ALT), hyperbilirubinemia, hypoalbuminemia, and prolonged prothrombin time. The severity of alcoholic cirrhosis determines surgical risk; mortality rates for alcohol abusers with Child's classification A, B, and C hepatic disease undergoing abdominal surgery were identified as 10%, 31%, and 76%, respectively.56
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Alcohol abuse is associated with gastrointestinal complications that are significant for anesthesia care. For example, alcohol abusers are predisposed to acid aspiration. Gastroesophageal reflux occurs frequently during alcohol ingestion because of reductions in lower esophageal sphincter tone. Chronic alcohol use also reduces maximal lower esophageal sphincter pressure. Upper gastrointestinal hemorrhage also increases aspiration risk during anesthetic induction and may occur as a result of esophageal, gastric, or duodenal mucosal injury, esophageal varices, or vomiting-induced tears of the gastroesophageal junction (Mallory-Weiss syndrome). Severe upper gastrointestinal bleeding may cause profound hypovolemia requiring aggressive volume replacement and often compels urgent endoscopic or surgical intervention. Active upper gastrointestinal hemorrhage with or without esophageal varices is a relative contraindication to transesophageal echocardiography. Alcohol abuse is also a major risk factor for acute and chronic pancreatitis.
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Hepatorenal syndrome is the most devastating renal complication of chronic alcohol abuse: It is almost always fatal without liver transplantation. Profound hepatic dysfunction, splanchnic vasodilation, and intense renal arterial vasoconstriction are characteristic features of hepatorenal syndrome.57 Progressive oliguric renal failure and reduced glomerular filtration rate that are unresponsive to volume administration, a gradual increase in serum creatinine concentration, and a markedly reduced urine sodium concentration established the diagnosis of hepatorenal syndrome in the absence of other causes of nephrotoxicity. Hepatorenal syndrome may occur in conjunction with a major complication of alcohol-induced end-stage liver disease (eg, sepsis, upper gastrointestinal hemorrhage) but may also develop insidiously without any apparent underlying cause.
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Alcohol abuse produces several acid–base and electrolyte abnormalities because of gastrointestinal losses and malnutrition. Perhaps the most frequent severe metabolic complication is alcoholic ketoacidosis, an anion gap acidosis that usually occurs in alcohol abusers after binge drinking. Hypokalemia is common in alcohol abusers; it occurs as a result of gastrointestinal tract losses combined with secondary hyperaldosteronism and may worsen preexisting hepatic encephalopathy or precipitate rhabdomyolysis. Other common electrolyte abnormalities are hypomagnesemia and hypophosphatemia. Gastrointestinal loss, malnutrition, and alcohol-induced renal tubular dysfunction combine to produce these deficiencies.
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Alcohol causes direct bone marrow toxicity and pancytopenia. Iron and folate deficiency with or without acute or chronic blood loss and hemolysis resulting from red blood cell fragility contribute to anemia. Leukopenia and neutrophil dysfunction increase the risk for infection. Thrombocytopenia may be especially profound, and, when combined with reduced coagulation factor synthesis, it substantially increases the risk of bleeding from gastrointestinal causes, trauma, or surgery.
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The clinical pharmacology of barbiturates and benzodiazepines is discussed in Chapter 42. Briefly, barbiturates, benzodiazepines (including the ultra–short-acting agent flunitrazepam, known as the "date rape" drug), and the gamma-aminobutyric acid (GABA) derivative γ-hydroxybutyrate (GHB, termed "liquid ecstasy") act through GABA receptors to exert anxiolytic, anticonvulsant, amnestic, and sedative effects.58 The major complications of barbiturate or benzodiazepine abuse are respiratory depression and overdose, especially in the presence of alcohol or opioids. Barbiturate or benzodiazepine abuse produces sedation, obtundation, or coma with eventual loss of airway protective reflexes. Progressive alveolar hypoventilation, hypoxemia, respiratory acidosis, and death subsequently occur. Mortality from barbiturate-induced respiratory depression was previously not uncommon, but the clinical use of these drugs for the treatment of anxiety disorders has been largely supplanted by benzodiazepines or specific serotonin reuptake inhibitors, which have a greater margin of safety. Nevertheless, death resulting from benzodiazepine overdose has been reported, most often in conjunction with the abuse of other drugs.
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Heroin is the most commonly abused opioid in the United States. The Office of National Drug Control Policy estimates that more than 900,000 individuals in this country suffer from heroin addiction.59 Heroin and other opioid abusers are at substantially increased risk for a wide variety of devastating medical complications. The clinical pharmacology of opioids is reviewed in detail in Chapter 42. This section focuses on the relevant pathology specifically associated with opioid abuse. Cardiovascular stability is a hallmark of administration of opioids, and even large quantities of opioids (such as those previously used during cardiac anesthesia) usually produce relatively small changes in systemic hemodynamics. Most naturally occurring and synthetic opioids dilate venous capacitance and splanchnic arteriolar vessels. These actions cause modest reductions in arterial pressure independent of histamine release (eg, heroin, morphine). Opioids also modestly reduce heart rate but do not affect left ventricular function or cardiac output under most conditions. Opioids exert cardioprotective effects against infarction60 and may also produce antiarrhythmic actions in ischemic myocardium. As a result, opioid abuse usually produces few, if any, direct cardiovascular consequences, in sharp contrast to stimulants such as cocaine or amphetamines. As mentioned previously, endocarditis is the most important cardiovascular complication of opioid abuse.
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Pulmonary complications are more common; they are responsible for as many as 20% of hospital admissions for opioid abuse. Substances that contaminate the drug or those related to the route of administration cause acute or chronic respiratory consequences. For example, magnesium silicate (talc) is frequently used in oral pharmaceutical preparations or those mixed with an illicit opioid to dilute the drug. Injection or inhalation of magnesium silicate or other contaminants may cause pulmonary granulomatosis, a form of diffuse micronodular interstitial fibrosis characterized by cough, dyspnea on exertion, and diminished diffusion capacity. This "talc granulomatosis" is similar to the presentation of sarcoidosis and may be complicated by direct occlusion of pulmonary arterial branches by granulomas. In addition to this vascular occlusion, chronic hypoxemia and reactive pulmonary arterial vasoconstriction resulting from interstitial fibrosis also contribute to the development of pulmonary hypertension and right ventricular failure. Bullous emphysema is another complication of talc granulomatosis. Septic pulmonary embolization is a frequent complication of injection opioid abuse, as a result of thrombophlebitis or endocarditis. Mycotic aneurysms also occur because of pulmonary vascular seeding with septic emboli. Rupture of a pulmonary mycotic aneurysm may cause life-threatening hemoptysis. Attempted opioid injection into the internal jugular or subclavian vein ("pocket shooting") may cause pneumothorax, hemothorax, chylothorax, and empyema. Smoking or nasal inhalation of opioids produces particulate substances that are distributed throughout the bronchial tree and contribute to mucosal irritation, inflammation, fibrosis, or granulomatosis. Chemical compounds produced by ignition of drugs or solvents also produce mucosal damage. Thus patients who use inhaled opioids are susceptible to the development of bronchospasm, bronchitis, airway injury, or hemoptysis. Barotrauma may occur during inhaled opioid abuse as a result of intense inhalation and breath holding performed to maximize drug uptake. Smoke forcefully exhaled from one user into the lungs of another ("shotgunning") may also cause barotrauma. Finally, chronic abuse of inhaled opioids is associated with the development of emphysema.
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The direct actions of opioids on control of respiration, airway reactivity, pulmonary arterial vascular tone, and immunologic response to infectious agents produce several other pulmonary consequences. Opioids bind to mu2 receptors in the pons and medulla, thereby attenuating respiratory automaticity, inhibiting airway protective reflexes, and reducing the influence of carbon dioxide on respiratory drive in a dose and route of administration-dependent manner. These actions produce respiratory depression, a major cause of mortality associated with opioid overdose.61 Loss of airway reflexes combined with a diminished level of consciousness further predisposes the opioid abuser to aspiration pneumonitis and its associated complications. Heroin-induced histamine release from mast cells may cause bronchospasm in drug abusers with asthma. This histamine release may occur because of direct activation of mu opioid receptors or through an IgE-mediated mechanism. Noncardiogenic pulmonary edema occurs in as many as half of patients presenting with intravenous or inhalational opioid overdose and is associated with substantial mortality. Opioids may directly increase pulmonary capillary permeability, thereby facilitating accumulation of protein and fluid in the alveoli by hydrostatic forces. A neurogenic mechanism may also cause pulmonary venoconstriction, thereby increasing pulmonary capillary permeability.62 Histamine release by some opioids also contributes to constriction of pulmonary veins and enhances permeability of pulmonary capillary membranes. Aspiration pneumonitis and pneumonia often complicate the management of patients with opioid-induced pulmonary edema. A hypersensitivity pneumonitis, characterized by cough, dyspnea, and bilateral pulmonary infiltrates, may present several days after nasal heroin inhalation. Opioid abuse attenuates neutrophil and macrophage phagocytosis, reduces T- cell and killer cell activity, decreases CD4 cell count, promotes leukocyte apoptosis (programmed cell death), depresses white blood cell chemotaxis, and inhibits delayed hypersensitivity reactions.63 These immunologic effects markedly increase the risk and severity of pulmonary infection in the chronic opioid abuser.
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Opioid abuse is associated with neurologic consequences. Seizures are a rare side effect of heroin or morphine abuse or withdrawal, and the occurrence of seizures in patients who have abused these opioids should prompt investigation of other potential etiologies. In contrast to the findings with heroin or morphine, seizures may occur with meperidine abuse because of the epileptogenic properties of normeperidine, a major meperidine metabolite.64 Seizures have also been reported after intravenous abuse of the combination of the mixed opioid agonist-antagonist pentazocine and the antihistamine tripelennamine ("T's and Blues") may also cause seizures. Infectious disease-related complications or renal failure account for most of the hemorrhagic strokes in opioid abusers. A myelopathy distinguished by sensory deficits, paraparesis, and urinary retention has been described in heroin abusers that may be related to spinal cord infarction or vasculitis. Immunologically mediated Guillain-Barré syndrome and brachial or lumbar plexopathies have been reported in heroin abusers. Last, inhalation of heroin vapors produced by heating the drug on metal foil ("chasing the dragon") rarely causes a crippling, often fatal leukoencephalopathy.
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Heroin use is associated with the development of focal and segmental glomerulosclerosis. This so-called heroin nephropathy is probably a manifestation of coincident HIV or HCV infection and is not an independent disease process.
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More than 3.6 million Americans are chronic cocaine users.66 Most of the medical consequences of cocaine abuse are related to the pharmacologic properties of the drug67 or infectious disease implications of its use. In addition to its well-known local anesthetic effects, cocaine produces intense vasoconstriction in nearly all vascular beds. Cocaine inhibits presynaptic reuptake of norepinephrine, enhances actions of circulating endogenous catecholamines, and augments centrally mediated sympathetic nervous system activity. These actions produce tachycardia and hypertension, thereby increasing myocardial oxygen consumption. Cocaine also causes direct epicardial coronary artery vasoconstriction, coronary vasospasm, and prothrombotic effects (eg, increased platelet adhesion and aggregation). These combined actions may produce myocardial ischemia and infarction.68 Indeed, Mittelman et al reported that the risk of myocardial infarction was increased by greater than 20-fold during the first hour after cocaine use compared with other times.69 Cocaine use may be responsible for as many as 25% of acute myocardial infarctions in subjects between 18 and 45 years of age70 independent of route or frequency of administration, drug quantity, or plasma concentration. With the exception of smoking, risk factors for coronary artery disease are most often absent. Angiographically documented coronary stenoses are present in only 50% of these patients.68 Cocaine inhibits sarcolemmal Na+, voltage-dependent Ca2+, and K+ channel conductance attenuates Ca2+-induced Ca2+ release from the sarcoplasmic reticulum and reduces myofilament Ca2+ sensitivity.71 When combined with the sympathomimetic and vagolytic actions of the drug, these electrophysiological effects may produce ventricular arrhythmias and sudden cardiac death independent of ischemia or preexisting heart disease. Accelerated coronary atherosclerosis occurs in chronic cocaine abusers and contributes to the risk of myocardial ischemia and infarction.72 Release of inflammatory cytokines, repeated exposure to elevated circulating catecholamines, enhanced vascular endothelial permeability permitting intimal diffusion of atherogenic lipoproteins, and chronic vasospasm are postulated mechanisms for this accelerated atherosclerosis. Cocaine abuse causes focal myocarditis and necrosis. These pathologic findings are very similar to those observed in disease states in which serum catecholamine concentrations are chronically increased (eg, pheochromocytoma). Cocaine-induced hypertension contributes to the development of left ventricular hypertrophy, dilated cardiomyopathy, and congestive heart failure, especially in patients with preexisting essential or alcohol-induced hypertension. Cocaine abuse is a major risk factor for acute aortic or coronary dissection, peripheral vascular insufficiency, and limb ischemia. A greater risk of aortic or mitral valve endocarditis may occur in intravenous cocaine compared with heroin or amphetamine abusers.68
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The pulmonary complications of cocaine abuse occur as a result of drug inhalation and are exacerbated by habitual tobacco or marijuana smoking. Like other inhaled drugs of abuse, inhalation of cocaine may cause bronchospasm, chronic bronchitis, barotrauma, hemoptysis, or pulmonary fibrosis.73 Inhaled cocaine produces intense pulmonary vasoconstriction and increases vascular permeability because of its sympathomimetic properties. These actions contribute to limited diffusion capacity similar to that observed in chronic tobacco smokers. More ominously, inhaled cocaine may cause diffuse alveolar hemorrhage or noncardiogenic pulmonary edema resulting from increased pulmonary capillary permeability.73 Cocaine-induced pulmonary edema may also occur because of high negative intrathoracic pressures during inhalation or increases in sympathetic nervous system activity in the pulmonary circulation.73 Despite the acute pulmonary vascular effects of cocaine use, pulmonary infarction has been rare. Irreversible pulmonary hypertension may occur in cocaine abusers resulting from pulmonary arterial medial hypertrophy and the frequent development of interstitial fibrosis mediated by the deposition of talc, silica, or other substances used to "cut" the drug.73 Inhaled cocaine suppresses B- and T-lymphocyte function and impairs the activity of alveolar macrophages, thereby predisposing the abuser to pulmonary infection. A delayed eosinophilic hypersensitivity pneumonitis that bears many similarities to Loeffler disease has also been described after cocaine inhalation. Pleuritic chest pain, hemoptysis, diffuse infiltrates, hypoxemia, fever, and eosinophilia are characteristic features of this "crack lung" syndrome that usually occurs within hours after binge abuse.74 Upper airway complications, including mucosal irritation and burns, are common among cocaine abusers. Vasoconstriction produced by nasal cocaine inhalation may cause septal perforation, acute or chronic sinusitis, epiglottis, airway obstruction, or an upper airway vasculitis that resembles Wegener granulomatosis.73 Severe upper airway burns may also occur as result of freebasing, a potentially explosive chemical process in which a flammable solvent is used to transform cocaine from a salt to a base, thereby increasing the drug's potency. Drugs users who smoke crack cocaine also have a higher incidence of tuberculosis compared with those who inhale other drugs of abuse.
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Cerebrovascular accident and seizure are 2 primary acute neurologic complications associated with cocaine abuse. Ischemic strokes, including transient ischemic attacks and cerebral infarction, constitute approximately half of all cocaine-induced cerebrovascular accidents and may be attributed to the combination of cerebral vasoconstriction and a prothrombotic state. Indeed, direct cerebral vasoconstriction was observed using magnetic resonance angiography during administration of cocaine to healthy volunteers.75 Cocaine-induced hypertension is responsible for most hemorrhagic strokes. Chronic cocaine abusers may suffer from cognitive dysfunction as a result of multi-infarct dementia. Cocaine-induced seizures are usually single grand mal events that most often resolve without the need for therapeutic intervention. Notably, such seizure activity may be observed without signs or symptoms of systemic drug toxicity. Seizures occur more frequently with an inhalational or intravenous compared with an intranasal route of administration. Interestingly, seizures may also develop several hours after cocaine abuse, presumably because benzoylecgonine (a cocaine metabolite) has epileptogenic effects.
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Cocaine abuse has several gastrointestinal and hepatic consequences. Mesenteric vasoconstriction and the direct toxic effects of cocaine on intestinal mucosa cause large or small intestinal ischemia, infarction, or perforation. Bowel obstruction or acute drug toxicity has been reported with the intentional ingestion of wrapped packages of cocaine ("stuffing" or "packing") that is performed to smuggle the drug or avoid imminent arrest when in its possession.76 These complications often require immediate surgical intervention. Cocaine hepatitis is a relatively rare disorder caused by hepatic vasoconstriction combined with toxic oxidative metabolites generated through cytochrome P450 3A1, a secondary route of cocaine metabolism. Cocaine hepatitis develops shortly after drug use and is most often associated with evidence of systemic toxicity. Simultaneous alcohol abuse induces P450 enzymatic activity and facilitates the development of cocaine hepatitis. Cocaine hepatotoxicity also occurs in patients with reduced plasma pseudocholinesterase activity (the major route of cocaine metabolism) because the P450 3A1 pathway assumes a greater role for drug metabolism. Centri- or panlobular hepatic necrosis and marked elevations in serum aminotransferase concentrations are characteristic findings in patients with cocaine hepatitis.
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Other acute and chronic renal diseases are quite common in patients who abuse cocaine and are often related to infectious diseases, especially in intravenous users. A nephrotic syndrome characterizes HIV or hepatitis nephropathy, whereas glomerulonephritis results from bacterial endocarditis or sepsis. A mixed nephritic-nephrotic syndrome is most often observed with chronic HCV infection. Renal infarction, accelerated hypertension, rhabdomyolysis, or thrombotic microangiopathy contributes to cocaine-induced renal insufficiency.77 The pronounced sympathomimetic actions of cocaine and its prothrombotic effects cause direct renal arterial vasoconstriction and thrombosis. These actions produce acute renal ischemia and infarction. Cocaine-induced hypertension clearly worsens preexisting renal insufficiency. Cocaine abuse also causes rhabdomyolysis and acute tubular necrosis. A final cause of acute renal insufficiency in cocaine abusers is thrombotic microangiopathy, a syndrome that may occur and accompany hemolytic uremic syndrome or renal infarction.78
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Amphetamines, including d,l-amphetamine, methylphenidate, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"), cause a wide variety of acute and chronic medical consequences. In recent years, abuse of MDMA and methamphetamine has increased dramatically, attracting the attention of federal regulatory agencies and the national media. Similar to the actions of cocaine, amphetamines produce sympathetic nervous system activation, inhibit the presynaptic reuptake of biogenic amines, and exert direct agonist actions on peripheral α- and β-adrenoreceptors to varying degrees depending on minor structural variations in their β-phenylethylamine chemistry. Amphetamines cause dose-related hypertension that may be sustained for several hours depending on each drug's pharmacokinetics. Tachycardia is also observed with methylphenidate and MDMA ingestion because these drugs produce relatively greater β1-adrenoceptor stimulation than other amphetamines. These hemodynamic effects increase myocardial oxygen consumption and may produce acute myocardial ischemia and infarction, malignant ventricular arrhythmias, and sudden cardiac death. Notably, the cardiovascular effects of amphetamines are potentiated by strenuous physical activity, and deaths attributed to MDMA at nightclubs or dance parties ("raves") may be related to this additive effect.79 Pathological examination of hearts from amphetamine abusers often demonstrates focal necrosis and myocarditis consistent with chronic catecholamine exposure. Amphetamines produce arterial vasospasm and promote thrombosis as a result of their sympathomimetic effects, and these actions further contribute to myocardial injury. Methamphetamine abuse also causes necrotizing angiitis, a vascular disease of the intima and media that is very similar to polyarteritis nodosa.
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Similar to the findings with inhaled opioids and cocaine, inhalation of amphetamines may cause barotrauma, mucosal irritation and hemoptysis, and cardiogenic or noncardiogenic pulmonary edema.73 Amphetamine overdose may produce central nervous system depression or seizures. Aspiration is quite common under these conditions. In contrast to cocaine, amphetamines are sequestered within pulmonary parenchyma. When combined with pulmonary arterial vasoconstriction, this pulmonary sequestration contributes to the well-known relationship between chronic methamphetamine or methylphenidate abuse and pulmonary hypertension. Epidemiology studies indicated a strong link between the amphetamine derivative fenfluramine and pulmonary hypertension in many patients who had been prescribed the drug as an appetite suppressant.80 Amphetamines also reduce immune function and increase the risk of bacterial, viral, or fungal pneumonia. For example, inhaled amphetamine increases immunosuppressive cytokine expression and reduces CD4 cell number. These actions may predispose the HIV patient to pulmonary infection.
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Cerebrovascular accidents in amphetamine abusers may be ischemic or hemorrhagic in origin. Similar to cocaine, amphetamine-induced ischemic strokes may occur because of cerebral vasoconstriction.81 Hypertension is the most common cause of amphetamine-induced hemorrhagic stroke. In contrast to seizures produced by cocaine, clinical signs and symptoms of drug toxicity often accompany seizures occurring as a result of amphetamine abuse. Psychological effects are also prevalent with amphetamine abuse. Exaggerated paranoia is a characteristic feature of active drug use, whereas withdrawal may cause prolonged clinical depression as a result of the absence of a stimulant effect.
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Fulminant hepatic failure requiring urgent liver transplantation was reported in MDMA abusers.82 Such hepatic failure may occur acutely independent of drug dose or may develop days or even weeks after abuse. Delayed drug metabolism by cytochrome P450 2D6 in susceptible patients with reduced enzymatic activity or an immunologically mediated cause are proposed mechanisms by which this delayed hepatoxicity occurs. Jaundice, pruritus, severe hyperbilirubinemia, elevated transaminases (AST more than ALT), hypovolemia, hyperthermia, and rhabdomyolysis concomitant with drug abuse are prominent features of MDMA-induced hepatic failure. Methamphetamine use is also associated with the development of HAV. Amphetamine abuse alters kidney perfusion, and accelerated hypertension and acute renal failure are well-known complications of methamphetamine and MDMA abuse. Necrotizing vasculitis with microaneurysm formation and thrombosis may also occur, leading to renal ischemia and chronic renal insufficiency. Rhabdomyolysis and acute tubular necrosis often accompany MDMA abuse, especially during exercise-induced hyperthermia and hypovolemia. Interestingly, many MDMA abusers recognize the risk of developing acute hypernatremia under these conditions and attempt to prevent this complication by ingesting large quantities of water, thereby inadvertently causing neurologically significant hyponatremia.
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Marijuana or hashish abuse increases heart rate and cardiac output and reduces systemic vascular resistance. As a result, arterial blood pressure is maintained. These hemodynamic effects mirror serum Δ-9-tetrahydrocannabinol (the psychoactive drug in marijuana and hashish) concentration, are more pronounced following inhalation compared with other routes of administration, and are often accompanied by ventricular ectopy. The cardiovascular actions of marijuana are usually well tolerated by healthy subjects but may have important consequences for patients with heart disease. Marijuana-induced tachycardia increases myocardial oxygen consumption. Elevated carboxyhemoglobin levels resulting from smoking the drug reduce myocardial oxygen supply. Thus patients with coronary artery disease who abuse marijuana are at risk of developing myocardial ischemia or infarction.83 The pulmonary complications of marijuana smoking are similar to those produced by tobacco smoking. Chronic bronchitis and emphysema occur in marijuana smokers, and the additional use of tobacco clearly exacerbates these diseases. Marijuana smoking causes more tar deposition and higher carboxyhemoglobin concentrations than tobacco smoking.84 These effects are related, at least in part, to sustained inhalation and breath holding, which are performed to maximize drug uptake. Like tobacco smoking, marijuana smoking weakens pulmonary defenses, including alveolar macrophage function, cytokine formation, and ability to combat oxidative stress against pathologic organisms. Chronic, heavy marijuana smoking may also contribute to the development of lung or oropharyngeal cancer. Marijuana is often contaminated with fungi or actinomycetes, inhalation of which may cause an infection or a hypersensitivity reaction. Immunosuppressed marijuana users, including those with HIV, are particularly vulnerable to pulmonary aspergillosis.
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Similar to cocaine and amphetamines, phencyclidine and lysergic acid diethylamide (LSD) are potent sympathomimetics. Phencyclidine or LSD ingestion causes tachycardia and hypertension, increases myocardial oxygen consumption, produces coronary artery vasoconstriction or vasospasm, and creates a prothrombotic effect. These actions may combine to cause acute myocardial ischemia or infarction. Severe hypertension, left ventricular hypertrophy, and malignant ventricular arrhythmias also occur in chronic phencyclidine and LSD abusers. Notably, the mechanisms by which phencyclidine and LSD stimulate the sympathetic nervous system are somewhat different than cocaine or amphetamines. As a result, cardiovascular cross-tolerance between phencyclidine or LSD and other stimulants may not occur. In addition to cardiovascular consequences, phencyclidine and LSD abuse produce neurologic effects. Like ketamine, phencyclidine causes an acute dissociative state that bears a striking resemblance to schizophrenia. The phencyclidine abuser may be highly agitated and experience delusions, hallucination, and paranoia. Paradoxically, frank catatonia may be present. LSD also produces hallucinations that limit compliance with treatment. LSD users often report "flashbacks" (hallucination recurrence that is temporally remote from drug abuse itself). Abuse of large quantities of phencyclidine, LSD, or other hallucinogens (such as mescaline) may produce seizures, myoclonus, and coma. Phencyclidine or LSD abuse may cause ischemic or hemorrhagic stroke through direct cerebral vasoconstriction or hypertension, respectively. Hyperthermia and acute liver necrosis resembling malignant hyperthermia has been reported in phencyclidine abusers.85 Rhabdomyolysis and acute tubular necrosis may also occur with the abuse of hallucinogens.
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Inhalants include volatile hydrocarbons (eg, hexane, xylene, toluene) contained in paints, solvents, and adhesives. Teenagers frequently abuse inhalants because they are inexpensive and readily available. These drugs may be directly sniffed or forcefully inhaled using an airtight container ("huffing") to produce rapid intoxication. Inhalant abuse causes many respiratory complications, including asphyxiation resulting from respiratory depression, bronchospasm in the presence or absence of preexisting asthma, airway mucosal irritation, hemoptysis, hypersensitivity pneumonitis, aspiration, and barotrauma.86 Methemoglobinemia and resultant cyanosis may occur with abuse of amyl nitrate or related compounds ("poppers"). Suffocation by a plastic bag used as an inhalant container has also been reported. Toluene inhalation may cause a white matter dementia in which extrapyramidal signs and symptoms, cerebellar ataxia, and oculomotor effects are present. Inhaled toluene also causes a nonanion gap metabolic acidosis and hypokalemia resulting from formation of the metabolite hippuric acid. Lead encephalopathy has been described in individuals who inhale gasoline. Inhalation of hexane-containing adhesives produces a progressive sensory-motor polyneuropathy ("glue sniffer's neuropathy").