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cocaine Cocaine is well absorbed following contact with the oral, nasal, gastrointestinal, rectal, and vaginal mucosa; by the pulmonary alveoli following inhalation; and by intravenous injection. Oral administration reaches peak concentrations in approximately 60 minutes. Effects from nasal insufflation begin almost immediately, and peak concentrations occur within 30–60 minutes. Intravenous and inhalational use of cocaine produces very rapid distribution of cocaine to both the central nervous system and the systemic circulation. Cocaine is rapidly hydrolyzed to its major metabolite, ecgonine methyl ester (EME). EME, formed by hydrolysis by liver and plasma esterases, accounts for 30–50 per cent of the parent product. Nonenzymatic hydrolysis results in the formation of the other major metabolite, benzoylecgonine, which accounts for approximately 40 per cent of the parent product. Other minor metabolites (norcocaine, ecgonine, and cocethylene) constitute the remainder of cocaine’s degradation products. The activity of plasma cholinesterase determines the relative concentrations of the various metabolites and quite possibly affects the degree of toxicity that develops. The biologic half-life of cocaine is 0.5–1.5 hours. A relatively minor amount is excreted unchanged in the urine. Benzoylecgonine and EME are also excreted in the urine , because of a long elimination half-life, assays typically detect benzoylecgonine for as long as 48–72 hours following cocaine use. Pathophysiology The effects of cocaine are related to its sympathetic nervous system effects, central nervous system stimulation, and local anesthetic effects. The initial effect of cocaine on the cardiovascular system is vagotonic, producing a transient bradycardia; however, the increased sympathetic stimulation rapidly produces tachycardia and hypertension. In the peripheral nervous system, cocaine inhibits the reuptake of both epinephrine and norepinephrine and stimulates the presynaptic release of norepinephrine. The resulting increased concentration of norepinephrine at the postsynaptic α and β receptors accounts for the stimulatory effects of cocaine. In the central nervous system, the mechanism of increased stimulation has not been as well defined. Enhanced release of norepinephrine and excitatory amino acids and/or blockade of neuronal reuptake of dopamine, serotonin, and excitatory amino acids might account for the observed effects. The vascular effects of cocaine include arterial vasoconstriction, in situ thrombus formation, platelet aggregation, and accelerated atherosclerosis are the principal factors responsible for cocaine-induced ischemia in many vascular beds. These effects have been best described in the heart. Cocaine-induced hypertension, tachycardia, and left ventricular hypertrophy increase myocardial oxygen demand at the same time that blood flow is diminished by coronary artery vasoconstriction, enhanced platelet aggregation, in situ thrombus formation, and premature atherosclerosis. This combination makes cocaine a potent precipitant of myocardial ischemia. Coronary vasoconstriction is further exacerbated by β-adrenergic blockade. Most cocaine-using patients are also cigarette smokers and the combination of cocaine and nicotine has a synergistic effect on coronary vasoconstriction. Clinical presentation Cardiovascular Effects Acutely, cocaine causes arterial vasoconstriction and enhanced thrombus formation. Chronic cocaine use can result in accelerated atherosclerosis, and left ventricular hypertrophy. These effects provoke myocardial ischemia or infarction. Aortic dissection and rupture occur less commonly after use of cocaine. Supraventricular and ventricular dysrhythmias may occur. The negative inotropic effects of cocaine may cause acute depression of left ventricular function and congestive heart failure. Chronic cocaine use can result in dilated cardiomyopathy. Neurologic Effects Most cocaine-intoxicated patients are anxious or agitated. Bland cerebral infarcts, hemorrhagic infarcts, and subarachnoid hemorrhages occur. Seizures may occur secondary to infarction or hemorrhage or in their absence. Patients who remain extremely lethargic and are difficult to arouse for up to 24 hours after cocaine use may have the “cocaine washed-out syndrome.”[ Patients with the cocaine washed-out syndrome assume normal sleep postures and can occasionally be aroused to full orientation, in contrast to lethargic patients with subarachnoid hemorrhage or other intracranial catastrophes. Vascular Ischemia In addition to cardiovascular and cerebrovascular ischemia, ischemia of the mesenteric, renal, pulmonary, and ophthalmic arteries can occur. Rhabdomyolysis Skeletal muscle injury may result in rhabdomyolysis. Most patients present without signs and symptoms of muscle injury, and the diagnosis of rhabdomyolysis is made by demonstration of myoglobinuria and/or measurement of serum creatine kinase. Patients with severe rhabdomyolysis may have lactic acidosis and life-threatening hyperkalemia. Body Packers Patients with continued toxicity despite treatment may be body packers. Most body packers will be asymptomatic unless leakage occurs. Recent travel or transportation of the patient from an airport should raise suspicion of body packing. Symptomatic patients should be considered a major medical emergency and must be evaluated for surgical removal of the packets. Obstetric and Neonatal Effects Obstetric complications secondary to cocaine use include premature labor as a result of increased uterine contractility as well as abruption placenta. Symptoms of neonatal cocaine withdrawal usually begin within 24–48 hours of birth. Withdrawal results in infants with jitteriness, irritability, poor eye contact, and vigorous sucking. In utero cocaine exposure may also result in infants with a small head circumference and low birth weight. Rapid diagnosis and treatment of neonatal withdrawal are imperative because of the risk of seizures and cardiovascular collapse. The physician should be thorough and exclude alternative diagnoses such as sepsis, hypoglycemia, and electrolyte abnormalities. The use of drug screens is unreliable for assessing neonatal withdrawal because the drug may have been metabolized and excreted prior to birth. Benzodiazepines and phenobarbital are effective agents for the treatment of stimulant withdrawal. Treatment If the patient is agitated, sedation with benzodiazepines is needed. Hyperthermic patients should be cooled with restricted activity; iced water baths or tepid water with fans may be used, depending on the severity of the hyperthermia and clinical status of the patient. Cooling blankets are not adequate for severe hyperthermia, and antipyretics are not effective. Hypotensive patients should receive intravenous fluids. If pressor support is necessary, norepinephrine should be used. Hypertension and sinus tachycardia are generally transient and do not require specific treatment in most cases. When treatment is necessary for mild to moderate hypertension, benzodiazepines can be used. For malignant or refractory hypertension, IV nitroglycerin, nitroprusside, or phentolamine can be used. Beta-adrenergic blockade has not been demonstrated to be useful, and may exacerbate hypertension and myocardial ischemia by facilitating unopposed α-adrenergic stimulation. Supraventricular tachycardia, in hemodynamically stable patients, can be treated with benzodiazepines followed by either calciumchannel antagonists or adenosine. Hemodynamically unstable patients should be cardioverted. Ventricular dysrhythmias may be managed with benzodiazepines to decrease central sympathetic stimulation and with sodium bicarbonate or lidocaine as antidysrhythmic agents.[ Ischemic chest pain should be treated with benzodiazepines, aspirin, and sublingual nitroglycerin. Refractory pain can be treated with either morphine sulfate or intravenous nitroglycerin, Patients who do not respond to this regimen can be treated with phentolamine or verapamil. Patients with unstable angina should receive heparin according to standard protocols. Beta-adrenergic antagonists and mixed alpha-beta antagonists should not be used in patients with cocaine-induced myocardial ischemia because they increase coronary artery vasoconstriction and decrease myocardial blood flow. Pulmonary edema should be treated with diuretics, morphine, and nitroglycerin according to standard protocols. Seizures are usually brief and transient. If necessary, seizures can be managed with benzodiazepines. If high doses do not control the seizures, phenobarbital should be used. Seizures are usually brief and transient. If necessary, seizures can be managed with benzodiazepines. If high doses do not control the seizures, phenobarbital should be used. Asymptomatic body packers should receive activated charcoal to limit cocaine absorption and whole bowel irrigation to decrease gastrointestinal transit time.