Hypoxia and Medicine

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Neurologic complications of cocaine, amphetamine, and their derivatives By: Douglas J Lanska MD MS MSPH FAAN Veterans Affairs Medical Center Great Lakes VA Healthcare System, Tomah, WI Department of Neurology University of Wisconsin, Madison, WI Abuse of certain illicit drugs can be complicated by ischemic stroke, intracerebral or subarachnoid hemorrhage, and other neurologic complications (Mathew and Wilson 1991; Baquero and Alfaro 1994; Auer et al 2002). Such agents include the sympathomimetic drugs cocaine and amphetamine, and their derivatives, including "crack," methamphetamine ("meth" or "crystal" or "speed"), "ecstasy," and "eve." Cocaine and amphetamine are strong risk factors for stroke in adolescents and young adults in most (Kaku and Lowenstein 1990; Petitti et al 1998), but not all (Qureshi et al 1997; 2001) epidemiological studies. There are multiple pathophysiological mechanisms for the cerebrovascular diseases related to use of these drugs, including vasospasm, altered platelet function, excitotoxicity, hyperthermia, and acute severe hypertension, which can cause endothelial disruption, loss of cerebral autoregulation, and hemorrhage. In many cases with abuse of such drugs, intracerebral hemorrhage is associated with an underlying vascular malformation (Klonoff et al 1989; Levine et al 1991; Daras et al 1994; Konzen et al 1995; Fessler et al 1997; McEvoy et al 2000; Auer et al 2002). In addition, individuals who abuse such drugs are also potentially susceptible to particulate embolization (from contaminants injected with intravenous drug abuse), cardiac arrhythmias, mycotic aneurysms, and endocarditis. Synergistic vasoconstrictive effects may occur with combined use of sympathomimetic agents in both human reports (Lambrecht et al 1993; Vallee et al 1993) and animal models (Wang et al 1990). Interestingly, basilar artery vasospasm has been produced in animal models by combined administration of cocaine and amphetamine (Wang et al 1990) and basilar artery thrombosis has been reported with combined abuse of cocaine and "ecstasy," an amphetamine derivative (Vallee et al 1993). Cocaine. Cocaine (benzoylmethylecgonine) is a potent sympathomimetic and CNS stimulant derived from the leaves of the shrub Erythroxylon coca, which grows primarily on the slopes of the Andes mountains in South America (Klein et al 2000; Lange and Hillis 2001). Cocaine is administered by inhalation (of smoked "crack," ie, the freebase or alkaloidal form which can be smoked), intranasally ("snorting"), and intravenously ("mainlining"), or less commonly orally ("chewing"; it is poorly absorbed by the gastrointestinal tract), intramuscularly, intravaginally, sublingually, or rectally. Cocaine hydrochloride is a water-soluble powder or granule that is readily absorbed through all mucous membranes, but that decomposes when heated, whereas alkaloidal or freebase cocaine is heat-stable and can be smoked. Alkaloidal or freebase cocaine is known as "crack" because of the popping sound that it produces when heated. Crack cocaine is the most potent and most addictive form of the drug, and smoking it can deliver cocaine to the circulation within seconds to minutes producing a short-lasting euphoria or "high." Although cocaine itself is metabolized by plasma and liver cholinesterases and is detectable in blood or urine only for several hours after use, cocaine metabolites can be detected in blood or urine for 24 to 36 hours after use, and in hair for weeks or months. Cocaine is frequently abused by adolescents and young adults in the United States (Brown et al 1992; Moliterno et al 1994; Hollander 1995; Lange and Hilllis 2001). Particularly since 1983, with the introduction of "crack" (alkaloidal or freebase form of cocaine), use of cocaine in the United States has increased dramatically (Daras et al 1994). Twenty three to 30 million Americans have used cocaine at least once (including reportedly over 30% of men and 20% of women between ages 26 and 34 years), and 2 to 5 million use it regularly (Moliterno et al 1994; Hollander 1995; Lange and Hillis 2001). Cocaine is responsible for approximately 30% of all drug-related visits to emergency rooms (Hollander 1995; Lange and Hillis 2001). When given systemically, cocaine's effects are mediated through modulation of synaptic transmission (Lange and Hillis 2001). Cocaine causes powerful sympathomimetic effects by blocking presynaptic reuptake of norepinephrine, epinephrine, and dopamine, while also stimulating the presynaptic release of norepinephrine, causing excess amounts of these neurotransmitters to stimulate the corresponding postsynaptic receptors, particularly alpha receptors peripherally (Hollander 1995; Lange and Hillis 2001). The pathogenesis of cocaine-related neurologic complications is heterogeneous, and depends in part on the dose administered and the form of cocaine used (Levine et al 1991). Abuse of alkaloidal ("crack") cocaine results in approximately equal frequencies of ischemic and hemorrhagic strokes, while cocaine hydrochloride is much more likely to be associated with hemorrhagic stroke (approximately 80% of the time) (Levine et al 1991). Cardiovascular, neurologic, and psychiatric complications are common with cocaine abuse (Moliterno et al 1994; Hollander 1995; Lange et al 2001; Kloner and Rezkalla 2003). Acute toxicity is dose-related and characterized by sympathomimetic effects, including acute and possibly profound hypertension, headache, tachycardia, hyperthermia, cardiac arrhythmias, and possibly seizures (Klein et al 2000). In some cases, profound acute toxicity occurs from rupture of packets of cocaine that have been ingested or inserted into the vagina or rectum by drug smugglers ("body packers" or "mules") (Levine et al 1990; Klein et al 2000). Cocaine, especially recent use of cocaine, is the illicit drug used most frequently in drug-related strokes (Kaku and Lowenstein 1990); the relative risk for stroke among drug abusers is 6.5 compared with nondrug abusers, and this increased to 49.4 for patients whose symptoms began within 6 hours of drug administration (Kaku and Lowenstein 1990). The higher potency of crack compared with cocaine hydrochloride has been associated with a marked increase in the frequency of cocaine-related strokes (Klonoff et al 1989; Daras et al 1994). Stroke may follow the use of cocaine by any route of administration (Klonoff et al 1989). Cocaine can produce severe cerebral vasospasm, multifocal or diffuse cerebral ischemia, ischemic and hemorrhagic stroke, intracerebral hemorrhage (particularly in the basal ganglia, but also in the deep cerebral hemispheres and the brainstem), subarachnoid hemorrhage, seizures, movement disorders, dizziness, anxiety, paranoia, hallucinations, insomnia, confusional states, stupor and coma, and possibly vasculitis (Klonoff et al 1989; Meza et al 1989; Nalls et al 1989; Sloan et al 1991; Brown et al 1992; Sloan and Mattioni 1992; Daras et al 1994; Reeves et al 1995; Nolte et al 1996; Johnson 1998a; Klein et al 2000; Broderick et al 2003; Buttner et al 2003; Vallee et al 2003; Bolouri and Small 2004). Cocaine is a major risk factor for aneurismal subarachnoid hemorrhage in young people (Levine et al 1987; 1990; 1991; Devore and Tucker 1988; Klonoff et al 1989; Rowley et al 1989; Strickland et al 1993; Daras et al 1994; Nolte et al 1996; Herning et al 1999; Broderick et al 2003). It is thought that cocaine induces a sudden rise in systemic arterial pressure, which precipitates vasospasm, endothelial disruption, disruption of cerebral autoregulation, with resultant intracranial hemorrhage, often in association with underlying aneurysms or arteriovenous malformations (Klonoff et al 1989; Levine et al 1991; Daras et al 1994; Konzen et al 1995; Fessler et al 1997). Indeed, chronic cocaine use appears to induce earlier clinical presentations in patients with incidental neurovascular abnormalities compared to similar non-cocaine users (Fessler et al 1997). Evidence for a true vasculitides is not compelling and most studies have failed to find any indication of vasculities, suggesting that the pathologic findings are a consequence of pharmacodynamic effects of cocaine and not a cocaine-induced vasculopathy (Nolte and Gelmann 1989; Nolte et al 1996). There is also a significantly increased risk of ischemic changes in the cerebral white matter and insular subcortex white matter (Bartzokis et al 1999a; 1999b). In some cases, vascular imaging and histopathologic studies suggest vasospasm of large arteries produced secondary intravascular thrombosis (Konzen et al 1995). Cocaine administration is associated with dose-dependent global and regional reductions in brain blood flow (Wallace et al 1996; Johnson et al 1998a), likely due to an immediate and brief period of vasoconstriction or vasospasm (Strickland et al 1993; Konzen et al 1995; Herning et al 1999). Cocaine-induced vasospasm can be partially blocked with calcium channel antagonists (Johnson et al 1998b; 2001). Chronic cocaine use can produce sustained brain perfusion deficit and persistent neuropsychological changes with deficits in attention, concentration, new learning, visual and verbal memory, word production, and visual-motor integration (Strickland et al 1993). Other manifestations of cerebral ischemia can result from direct embolization of foreign material injected with the drug diluents; mycotic aneurysms; as well as primary cardiac problems, including cardiac arrest (even in young patients), cardiac arrhythmias, cardiomyopathy with associated atrial or ventricular thrombus, aortic dissection, and endocarditis resulting from intravenous drug abuse (Kaku and Lowenstein 1990; Petty et al 1990; Sauer 1991; Sloan and Mattioni 1992; Moliterno et al 1994; Hollander 1995; Neiman et al 2000; Lange and Hillis 2001; Lange et al 2001; Kloner and Rezkalla 2003; Bolouri and Small 2004). Cocaine use during pregnancy can produce fetal hypoxia, intracerebral hemorrhage, and congenital malformations (Heier et al 1991; Brown et al 1992; King et al 1995). In a retrospective case-control study, maternal cocaine use was significantly associated with increased risks of neonatal stroke and congenital malformations (particularly neural tube defects), attributed to cocaine-induced vasospasm in the third and first trimesters, respectively (Heier et al 1991). Transcranial Doppler ultrasound studies of newborns who were exposed to cocaine in utero demonstrate increased flow velocities in intracranial arteries consistent with the vasoconstrictive effects of cocaine (King et al 1995). The mechanisms of cocaine-related cerebrovascular disease remain somewhat controversial, with several explanations proposed with varying degrees of support from human studies and animal models (Muir and Eliis 1993; Daras et al 1994; Kosten 1998; Buttner et al 2003; Fandino et al 2003). Proposed pathophysiologic contributors (not necessarily mutually exclusive) include pharmacologically-induced vasospasm, rapid transient increases in systemic blood pressure, disruption of cerebrovascular autoregulation (particularly with increasing levels of acute or hyperacute hypertension), impaired endothelium-dependent vasorelaxation, apoptosis of cerebral vascular muscle cells, arteritis, myocardial infarction with cardiac arrhythmias, impaired hemostatis, increased platelet aggregation, decreased global and regional cerebral blood flow, and cocaine-induced cerebral excitotoxicity (Kelley et al 1993; Muir and Ellis 1993; Daras et al 1994; Havranek et al 1996; Heesch et al 2000; Buttner et al 2003; Fandino et al 2003; Su et al 2003; Bolouri and Small 2004). Cocaine-induced vasospasm is thought to be mediated by endothelin-1, an extremely potent, 21-amino acid vasoconstrictor peptide produced by vascular endothelial cells; endothelin receptor antagonists can block cocaine-induced vasospasm in animal models (Fandino et al 2003). Cerebral vascular smooth muscle cells can undergo rapid apoptosis in response to cocaine, which may contribute to cerebral microvascular damage and strokes (Su et al 2003). In addition, work in animal models suggests that some of the adverse neurologic complications of cocaine use are medicated by changes in calcium or magnesium concentrations in vascular smooth muscle cells or brain, including precipitation of cerebral vasospasm by rapid elevation of intracellular free calcium and depletion of magnesium in vascular smooth muscle cells (Altura and Gupta 1992; Altura et al 1993; 1997; Zhang et al 1996). Amphetamine and derivatives, including methamphetamine and "ecstasy." Amphetamine is another potent sympathomimetic drug that can cause a wide variety of vascular complications, including stroke, aneurismal rupture, and myocardial infarction, similar to the case with cocaine (Chen et al 2003). Methamphetamine (aka: meth, crystal, speed) is a derivative of amphetamine that also acts as a CNS stimulant. Amphetamine and methamphetamine are administered in several ways (eg, orally, or by injection, smoking, or snorting). Prolonged use at high levels can produce dependence. Methamphetamine was widely used clinically in the 1950s and 1960s for treatment of depression and obesity (Anglin et al 2000). Until the late 1980s, methamphetamine use was endemic in California and relatively restricted to that state, but use has subsequently broadened with increased use, particularly in the Midwest (Anglin et al 2000). Approximately 2% of the US population have tried methamphetamine at some point in their lives. "Ecstasy" and "eve" are newer drugs of abuse, being ring-substituted amphetamines (3,4-methylenedioxymethyl-amphetamine, or MDMA, and 3,4-methylenedioxyethylamphetamine, or MDEA, respectively) that have greatly increased in popularity in the United States in the last decade. Neurologic and psychiatric complications of amphetamine, methamphetamine, and other amphetamine derivatives are similar to those seen with cocaine, and include ischemic and hemorrhagic strokes, anxiety, paranoia, hallucinations, and insomnia (Lambrecht et al 1993; Perez et al 1999). In some cases, intracranial hemorrhage occurs in the setting of underlying vascular malformations (Auer et al 2002). Pathological studies have suggested multiple pathophysiological mechanisms of brain and other organ damage, including perivascular hemorrhagic and hypoxic changes similar to those of heat stroke and other forms of hyperthermia (Milroy et al 1996). References: Altura BM, Gebrewold A, Altura BT, Gupta ARK. 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