ChemistryCocaine (benzoylmethyl ecgonine) is the psychoactive alkaloid of the coca plant (Erythroxylon coca). Cocaine is the only naturally occurring local anaesthetic. Unlike amphetamines, which structurally resemble dopamine and noradrenaline, cocaine has a similar structure to other synthetic local anaesthetics. Like amphetamines, cocaine is a weakly basic substance and can exist in a free base form or as the salts of various acids (Budavari, 1996). The salt forms of cocaine are water-soluble; the free base form ('crack cocaine') is sufficiently volatile for it to be inhaled via smoking. Salts of cocaine (e.g. cocaine hydrochloride) are both water and fat soluble (Budavari, 1996). Like amphetamines, cocaine also exists in two enantiomeric forms (Gatley, 1991).
PharmacokineticsCocaine is well absorbed when administered via mucous membranes (e.g. intranasally), the gastrointestinal tract and intravenously. Peak concentrations occur within five to ten minutes after intravenous injection or smoking and within 60 minutes after intranasal administration (Cone, 1995). Cocaine is shorter acting than amphetamines and effects or blood levels may diminish after as little as one hour (Inaba, 1989).
Some cocaine is excreted unchanged in the urine, but the majority is metabolised to benzoylecgonine, ecgonine methyl ester, norcocaine and other metabolites (Jufer, Wstadik, Walsh, Levine & Cone, 2000; Klingmann, Skopp & Aderjan, 2001). Although cocaine has a short half-life, elimination half-lives of cocaine metabolites are substantially longer (Jufer et al., 2000). The half-life of cocaine may increase after chronic dosing (Jufer et al., 2000; Moolchan, Cone, Wstadik, Huestis & Preston, 2000).
PharmacodynamicsCocaine also enhances the activity of dopamine. It does this by blocking its reuptake into the nerve terminal via the transporter and thus increasing the amount of dopamine available to act at receptors in the synapse (Silvia et al., 1997; Volkow, Wang, Fischman, Foltin et al., 2000). Cocaine may also block reuptake of noradrenaline and serotonin (Rasmussen, Carroll, Maresch, Jensen et al., 2001; Ritz, Cone & Kuhar, 1990), with some authors suggesting that it may enhance noradrenaline release (Tuncel, Wang, Arbique, Fadel et al., 2002).
In addition to these effects cocaine is also a local anaesthetic agent. Like other local anaesthetics, it produces direct effects on cell membranes — cocaine blocks sodium channel activity and thus prevents the generation and conduction of nerve impulses in electrically active cells, such as myocardial and nerve cells (Knuepfer, 2003).
Effects on the user
Sought-after effectsLike amphetamines, cocaine produces euphoria and sustained mood elevation (Epstein, Silverman, Henningfield & Preston, 1999; Mendelson, Mello, Sholar, Siegel et al., 2002). It also increases energy and self-confidence, promotes talkativeness, alleviates fatigue and enhances mental alertness (Brownlow & Pappachan, 2002).Top of page
Other behavioural effectsAspects of psychomotor performance may be enhanced (Stillman, Jones, Moore, Walker & Welm, 1993). At higher doses or during chronic use adverse effects increase. Euphoria may be replaced with restlessness, excitability, sleeplessness, loss of libido, nervousness, aggression, suspicion and paranoia, hallucinations and delusional thoughts (Estroff, Schwartz & Hoffmann, 1989).
Physiological effectsCocaine use produces a wide spectrum of physiological effects. One of the most studied involves the effects of cocaine on the cardiovascular system. The cardiac effects of cocaine are complex and whilst they act as sympathomimetic agents, the actual effects observed vary with dose and route of administration.
In animal studies, results have been conflicting. Cocaine has been reported to produce increases in arterial systolic and diastolic blood pressures, left ventricular pressure, cardiac output and heart rate (Schwartz, Janzen, Jones & Boyle, 1989), whereas others demonstrated a decreased cardiac performance, reporting a dosedependent decrease in blood pressure, coronary blood flow and cardiac output (Beckman, Parker, Hariman, Gallastegui et al., 1991).
Cocaine may produce a transient slowing of heart rate after use (Tuncel et al., 2002). It appears that at more moderate doses, the sympathomimetic effects of cocaine predominate, leading to an increase in blood pressure and heart rate. However, at higher doses or more rapid infusion rates, blood pressure and cardiac output are negatively influenced. With increasing doses of cocaine, the peripheral sympathomimetic effects may be limited by either the direct negative inotropic effects of cocaine (slowing heart rate) or by myocardial ischaemia (Baumann, Perrone, Hornig, Shofer & Hollander, 2000).
In human studies, cocaine administration leads to increased heart rate, systolic blood pressure and pupil diameter and reduced skin temperature (Stillman et al., 1993). Increases in myocardial (heart) oxygen consumption may be related to cardiovascular adverse events (Summers, Bradley, Piel & Galli, 2001). Cocaine also inhibits endogenous fibrinolysis, increases thrombogenicity and enhances platelet aggregation via increased production of thromboxane (Auer, Berent & Eber, 2001; Baumann et al., 2000).
Cocaine has a range of effects on the body's heat regulatory (thermoregulatory) system. It may lead to increased core body temperature, decreased heat perception and impairment of sweating and skin blood flow (Crandall, Vongpatanasin & Victor, 2002). This combination of increased heat production, impaired heat dissipation and altered behavioural responses to increased body temperature may lead to dangerous or fatal hyperthermia (Crandall et al., 2002). These effects may be amplified by the context of cocaine use, such as dancing in crowded nightclubs. Cocaine use may also produce headaches (Satel & Gawin, 1989).Top of page
ToxicitySymptoms of intoxication include bizarre, erratic and violent behaviour. Users experience tremors, vertigo, muscle twitches, paranoia and other symptoms of psychosis. Physical symptoms include chest pain, nausea, intense thirst, blurred vision, fever, muscle spasms, convulsions and coma (Brownlow & Pappachan, 2002).
Chronic cocaine use can lead to a range of cardiac complications. Acute myocardial infarction and myocardial ischaemia are the most common cardiac complications associated with cocaine use (Hollander, Hoffman, Burstein, Shih & Thode, 1995; Qureshi, Suri, Guterman & Hopkins, 2001). A range of cocaine-related effects are thought to contribute to myocardial ischaemia and infarction risk. These include increased oxygen demand, vasoconstriction of coronary arteries, increased platelet aggregation and thrombus formation (Lange & Hillis, 2001). Potentially fatal arrhythmias and dysrhythmias may also occur (Benchimol, Bartall & Desser, 1978; Nanji & Filipenko, 1984).
Longer-term complications include accelerated atherosclerosis, cardiomyocyte apoptosis, sympathoadrenal-induced myocyte damage, chronic arrhythmias, cardiac hypertrophy and dilated cardiomyopathy (Brownlow & Pappachan, 2002; Knuepfer, 2003).
Regular cocaine use has also been associated with a number of abnormalities in the cerebral vasculature. The most common complications are haemorrhagic or thromboembolic strokes, but cerebral haemorrhage may also occur.The pathogenesis of cocaine-related cerebrovascular events is complex. It has been suggested that contributing factors may include cocaine-related rapid increases in blood pressure, smooth muscle effects producing vasospasm and ischaemia, vascular malformations and enhanced platelet aggregation (Auer et al., 2001). Other neurological complications include seizures (Dhuna, Pascual-Leone, Langendorf & Anderson, 1991; Lason, 2001; Lathers, Tyau, Spino & Agarwal, 1988; Satel & Gawin, 1989); sensitivity to seizures may be increased by chronic exposure.
Some individuals are vulnerable to cocaine-induced excited delirium. This is characterised by hyperthermia, extreme behavioural agitation and, in some cases, violent behaviour. This may also result in cardiac collapse and sudden cardiac death. Rhabdomyolysis may also occur (Merigian & Roberts, 1987). This may be part of the same syndrome as delirium, induced by changes in dopamine processing associated with chronic use of the drug rather than acute toxic effects (Ruttenber, McAnally & Wetli, 1999).
Regular intranasal use of cocaine may lead to damaging effects on the nasal mucosa. This ranges in severity from chronic rhinitis, reduced sense of smell, nosebleeds and septal perforation (Schwartz et al., 1989) to more serious damage such as necrosis of the sinonasal tract and oronasal fistula (Braverman, Raviv & Frenkiel, 1999; Gertner & Hamlar, 2002; Mari, Arranz, Gimeno, Lluch et al., 2002). This is thought to be mediated by ischaemia secondary to vasoconstriction, although adulterants may also play a role (Mari et al., 2002). Smoking of crack cocaine can lead to a variety of acute pulmonary complications, including severe exacerbations of asthma and an acute lung injury syndrome associated with a broad spectrum of histopathologic changes ('crack lung') (Tashkin, 2001). Habitual cocaine smoking may also produce more subtle long-term pulmonary consequences due to chronic alveolar epithelial and microvascular lung injury (Brownlow & Pappachan, 2002; Tashkin, 2001) including pulmonary oedema and pulmonary haemorrhage.
It is unclear whether cocaine use produces neurotoxicity. Since cocaine does not induce dopamine release, it may pose a lower risk for neurotoxic effects than other agents such as methamphetamine (Cappon, Morford & Vorhees, 1998). Cocaine use has been associated with certain neurological abnormalities (Fein, Sclafani & Meyerhoff, 2002; Franklin, Acton, Maldjian, Gray et al., 2002; Li et al., 2001). However, whether this represents neurotoxicity, neuroadaptation or other aetiology has not been established.