Pathophysiology of cocaine abuse : European Journal of Anaesthesiology | EJA

Secondary Logo

Journal Logo


Pathophysiology of cocaine abuse

Brownlow, H. A.*; Pappachan, J.

Author Information
European Journal of Anaesthesiology 19(6):p 395-414, June 2002.
  • Free


History of cocaine ingestion

Cocaine is a central nervous stimulant and an anaesthetic (Fig. 1). It is extracted from the leaves of the Erthroxylon coca plant. The original method of ingestion was chewing the leaves, often mixed with ash or lime. Line drawings on pottery found in South America show coca chewing as part of the culture some 4000 years ago and remnants of coca leaves have been found in tombs in both Peru and Bolivia dating to this period. It was through the Spanish invading South America that coca leaves eventually reached Europe during the Sixteenth Century. They were brought from South America by the explorers, but unlike the tea, coffee and tobacco, coca leaves did not become popular until the Nineteenth Century (deterioration of the leaves en route caused a loss in their potency).

Figure 1:
Chemical structure of cocaine.

Cocaine, as it is known today, was first synthesized and extracted by the German chemist Albert Niemann in 1855, although it was not until the 1880s that its medicinal effects were observed. Sigmund Freud noticed its effects and published his report On Coca in which he recommended cocaine to treat a variety of conditions including morphine addiction. This was unsuccessful and often left his patients addicted to cocaine instead. Freud personally used the drug many times and reported: 'cocaine wards off hunger, sleep and fatigue'. The first physician to use cocaine and recognize its local anaesthetic properties was William Halsted in 1884, a surgeon working at the Johns Hopkins Hospital in Baltimore, MD, USA. He became addicted to cocaine leading to a temporary period away from practice. In that same year, Carl Koller, an ophthalmologist, noticed the local anaesthetic properties of cocaine. When trickled into the eye of a frog, the absence of a twitch response to a sharp instrument was noticed.

Until recently, cocaine was found in many domestic products. Coca-Cola, introduced by John Pemberton in 1886, was made with cocaine-laced syrup and caffeine. The cocaine content was dropped in 1903. Vin Mariani (coca wine) was a mixture of coca and wine (6 mg cocaine per ounce of wine). Cocaine and coca appeared in cigarettes, cigars, inhalants, coca liquors, cocaine crystals and cocaine solutions for hypodermic injection. Even in 1902, 92% of all the cocaine sold in major cities in the USA was in the form of an ingredient in tonics or potions available from local pharmacies. Production of pharmaceutical cocaine was increasing rapidly to meet demand. In 1883, Merck produced 0.75 lb (0.34 kg) of cocaine, but by 1884 had produced 158 352 lb (71 978 kg) of the drug. Cocaine was also employed by the military, being given to troops to combat fatigue. Eventually, scepticism surrounded cocaine use when reports of fatal poisoning, alarming mental disturbances and addiction began circulating. In 1914, non-clinical use of cocaine was banned in the USA and it became illegal in Europe after the First World War. The popularity of cocaine began in the late 1960s, which coincided with a decrease in the use of amphetamines. In the late 1970s and early 1980s, a cocaine epidemic began, stimulated by the widespread availability of inexpensive 'crack' cocaine in the USA - this cocaine epidemic continues today. Approximately 19% of Americans between 18 and 25 yr of age confess to having used cocaine and 1% to using cocaine more than once a week [1]. Cocaine use in the UK is increasing, and although numbers are relatively small, the Office for National Statistics (ONS) figures for drug-related deaths in England and Wales between 1993 and 1997 show a 58% increase in the number of cocaine-related deaths (Table 1)[2]. These deaths (accidental and suicide) occurred within a similar age group to opiate-related deaths (which also showed a marked increase) but were among a much younger age group than benzodiazepine, barbiturate or acetaminophen (paracetamol)-related deaths, which only showed an 18% increase (Fig. 2)[2]. With more of the drug being produced illegally in South America, the wholesale value is falling (US$55 000 per kg in 1981 to US$25 000 per kg in 1984), further increasing its popularity. Young single people are the most frequent users, with males outnumbering females by two to one. No association between cocaine use, education, occupation and/or socio-economic status has been noted.

Table 1:
Number of deaths where selected substances were mentioned on the death certificate, including with other drugs and with alcohol in England and Wales, 1993-1997.
Figure 2:
Mean age at death for selected substances, 1993-1997. ▪: Males; □: females.

Preparations of cocaine

Cocaine or benzoylmethylecgonine is an ester of benzoic acid and methylecognine. Plant sources differ in the amount they contain [3]. Peruvian and Colombian leaves contain 0.5-1% alkaloids, while Indonesian leaves have 1.5-2.5%. In the former, the major alkaloid is cocaine; in the latter, there is very little cocaine, the alkaloids consisting chiefly of ecgonine derivatives such as benzoylecgonine and methylecognine. The Java leaves contain small quantities of the alkaloid tropocaine, which is absent in the South American leaves. Cocaine has a molecular weight of 303.36 and when treated with hydrochloric acid becomes cocaine hydrochloride salt. This salt is freely soluble in water, which allows it to be injected, but its lipid solubility also enables it to be absorbed through the nasal mucosa [4]. In contrast, cocaine alkaloid, also known as freebase or crack cocaine, is a colourless, odourless, crystalline substance, insoluble in water but soluble in ether, acetone or alcohol [5]. Its melting point is 98°C. On heating, this freebase converts into a stable vapour that can be inhaled.

Although crack and freebase are the same chemical forms of cocaine, they are produced by different techniques. To manufacture freebase cocaine, cocaine hydrochloride is first dissolved in water, ammonia is then added, followed by ether as a solvent. The cocaine base dissolves in the ether layer and can be extracted by evaporation of the ether at relatively low temperatures [4]. This process, called 'freebasing', results in a purer form of cocaine than crack. It is usually smoked from pipes or mixed with tobacco and smoked, which can be dangerous since residual ether may ignite, resulting in serious burns to the trachea or to the face [6,7]. Use of freebase cocaine has recently declined, being replaced by the easier to manufacture, cheaper and more available crack cocaine. Crack is manufactured by dissolving cocaine hydrochloride in water, mixing it with baking soda and heating. The cocaine-base precipitates into a soft mass that hardens on drying - hence the name 'rocks' of cocaine. Crack cocaine can be smoked by inhaling the vapour from heated crystals or by mixing with tobacco and gives a characteristic 'cracking' sound when heated.

Cocaine is generally sold on the street as a fine white powder contained within a fold of paper (a 'wrap'). Slang terms for the drug are Charlie, snowflake, blow, gold dust, baseball, Bernice, White lines, coke and 'C'. Street dealers dilute it with inert but similar-looking substances such as cornstarch, talcum powder and sugar, or with drugs such as procaine and benzocaine, or central nervous system (CNS) stimulants such as amphetamines and ketamine. This is known as 'cutting the drug' and results in a better financial yield. By adding local anaesthetic drugs to the powder, the analgesia produced by the pure drug is mimicked, convincing the prospective buyer they are buying powder rich in cocaine.

Pharmacokinetics of cocaine

Any mucous membrane can act as a port of entry for cocaine and, as with any local anaesthetic, the systemic effect is greatly influenced by the route and speed of administration. It is usually 'snorted', but may be absorbed through the mucous lining of the mouth, rectum or vagina. It can be injected (producing a more intense feeling), but smoking is most common. It is rapidly absorbed from the lungs and reaches the cerebral circulation in approximately 6-8 s. When injected, the drug takes approximately twice as long to reach the brain [7]. Snorting cocaine produces euphoria in about 3-5 min [8]. Its vasoconstrictive properties slow its own absorption and achievement of peak plasma concentrations can be delayed for up to 60 min [9]. Cocaine has a relatively short half-life in plasma ranging from 0.5 to 1.5 h, with highest concentrations being found in the brain, spleen, kidney and lung [5]. It is rapidly cleared from the plasma by esterases, of which the most important is plasma cholinesterase. Eighty to 90% of cocaine is metabolized to form ecgonine methyl ester and benzoylecgonine. The methyl esters are formed by rapid enzymatic hydrolysis by plasma and liver esterases and have a half-life of 4 h. Benzoylecgonine is formed mainly by spontaneous non-enzymatic hydrolysis and to a lesser extent enzymatic hydrolysis. It has a half-life of about 6-7.5 h. Ten to 20% of cocaine undergoes N-demethylation in the liver to norcocaine, a cocaine metabolite with considerable pharmacological activity [3,4,10]. Approximately 1-5% of cocaine is not metabolized and undergoes urinary clearance [3,10]. Screening individuals for cocaine abuse employs mass spectrometry and can be used to confirm the presence of either cocaine or its metabolites for up to 6-14 days from a urine sample. In the presence of alcohol, metabolism is altered with cocaine becoming transesterified by a liver esterase to ethylcocaine (cocaethylene). This metabolite has significant pharmacological activity with a median half-life of about 2.5 h [11].

Concentrations of plasma cholinesterase and hence the half-life of the drug vary [4]. Brock and Brock [12] showed significant effect on individual plasma cholinesterase activity by body weight, height, gender and cholinesterase-1 phenotype (but not by age) among healthy volunteers. Varying body weight explained one-quarter of this observed biological variance. As well as interindividual variations, intra-individual variations in plasma concentration of the enzyme were observed over the 8 month study. Gender differences with cocaine pharmacology exist. Males achieve higher peak plasma cocaine concentrations and experience a greater number of intense good and bad effects from the drug compared with females. Despite these differences in blood concentrations and subjective effects, peak heart rates did not differ between the sexes, suggesting that females may be more sensitive than males to the cardiovascular effects of the drug [13]. This may vary even within the menstrual cycle, with higher peak levels being found during the follicular phase compared with the luteal phase.

Cultural differences exist, with black subjects more likely to suffer rhabdomyolysis, excited delirium or electrocardiographic (ECG) changes (see below). Plasma cholinesterase concentrations cannot explain these differences. Cocaine toxicity does seem to be linked to, but not fully explained by, levels of plasma cholinesterase activity. Life-threatening complications occur in patients with lower plasma cholinesterase activity than less toxic controls, but relatively healthy cocaine users have lower plasma cholinesterase activity than controls not using cocaine. This could partly be explained by the influence of diet on plasma cholinesterase concentrations. Drug addicts suffer calorie and protein malnutrition, the extent related to the intensity of drug addiction, female gender, and the disturbance of social and familial links [14]. Studies in mouse have shown that protein and calorie malnutrition is associated with a reduction in plasma cholinesterase activity and enhanced cocaine toxicity [15]. In rats, the intravenous (i.v.) administration of butyrylcholinesterase (BChE) successfully prevents the hypertensive and dysrhythmogenic effects of cocaine, as well as increasing the lethal dose 3-4-fold [16]. Such dietary factors may be partially responsible for variations in plasma cholinesterase activity and cocaine susceptibility in human beings. Benefits in human beings from the exogenous administration of esterases are awaited.

General pharmacology of cocaine

Cocaine blocks reuptake 1, the reuptake of catecholamines into the presynaptic nerve terminals (reuptake 2 is a similar transport process existing in the tissues, but less selective and less easily saturated). This occurs in both central and peripheral nervous systems and causes the accumulation of catecholamines in synaptic clefts. The result is increased receptor stimulation (α-adrenoreceptor, β-adrenoreceptor and dopamine) via an indirect sympathomimetic action. Inotropes must be used with care in patients abusing cocaine, as cardiovascular responses (arterial and left ventricular pressure, contractility and heart rate) will all be potentiated by the concurrent administration of α-adrenoreceptor, β-adrenoreceptor or dopamine agonists. Cocaine shifts the dose-response curve of norepinephrine to the left and enhances its maximal effects. Results from anaesthetized cats suggest this potentiation of cardiac responses to adrenergic stimuli may involve presynaptic mechanisms to block the reuptake of norepinephrine, and postsynaptic mechanisms to raise the maximal responses [17]. The latter may result from the inhibition of the central sympathetic outflow or from activation of cardiac calcium channels leading to an increased sensitivity to norepinephrine.

Cocaine is also a local anaesthetic and competitively blocks the fast voltage-sensitive sodium channels of nerve cells, and by preventing the fast inward Na+ current, it prevents the depolarization of the cell membrane. Cocaine decreases both the rate of depolarization and amplitude of the action potential and causes a slowing of conduction. It can block myocyte potassium channels [18,19]. Cocaine blocks anticholinergic receptors (occurring at 20-fold higher concentrations than producing euphoria) [10] and blocks both serotonin binding sites as well as preventing its reuptake [20].

Cocaine and the CNS

The effects of cocaine on the CNS depend on several factors: the amount of drug taken and the user's past drug experience, and route of administration. A small dose would be 100 mg with several hundred milligrams constituting a large dose. Cocaine produces a sense of euphoria, energy, increased self-confidence, talkativeness and mental alertness (especially to the sensations of sight, sound and touch) or paradoxically generates feelings of anxiety or panic. It suppresses the need for both food and sleep, an effect popularizing its use among 'supermodels'. With larger doses, the 'high' may lead to bizarre, erratic and violent behaviour. Users experience tremors, vertigo, muscle twitches, paranoia or something closely resembling amphetamine psychosis. Physical symptoms include chest pain, nausea, intense thirst, blurred vision, fever, muscle spasms, convulsions and coma. With repeated use, euphoria is replaced by restlessness, extreme excitability, insomnia, loss of libido, paranoia, and eventually hallucinations and delusional thoughts. With protracted use drug tolerance develops. Larger doses are needed to achieve the same effect. Amounts as high as 10 g have been reportedly taken. Development of tolerance can occur after as little as 1 week and it depends on the dose, duration and frequency of cocaine use [21]. The mechanism probably involves an absolute or relative attenuation of dopamine receptor stimulation in the nucleus accumbens. Animal model experiments suggest that glutamate transmission (an inhibitory neurotransmitter) in the nucleus accumbens may also play a major role in this development of tolerance [22]. Among heavy cocaine users, an intense psychological dependence can occur; addicts suffer severe depression and physical symptoms (sweating, agitation, tachycardia, tachypnoea, labile blood pressure) on drug withdrawal. This experience, the 'crash', is extremely unpleasant, often compelling the user to restart drug abuse. In the intensive care setting, sedation, particularly with benzodiazepines and/or clonidine, is particularly useful, combined with maintenance of cardiovascular stability (β-adrenoreceptor blockade and antihypertensive drugs) and a quiet, dimly lit environment.

Neuropharmacology of cocaine

Central nervous system effects are caused by enhanced and more sustained stimulation of dopamine, nor-epinephrine and serotonin receptors. The euphoria is due to stimulation of dopamine receptors in the mesolimbic and mesocortical areas of the brain [3,10]. Cocaine also suppresses activity in the pontine nucleus and the locus coeruleus, alleviating feelings of fear and providing anxiolysis. Continued use gradually depletes dopamine stores in the presynaptic neurons of the brain. To compensate, the numbers of dopamine receptors in the brain increase [5]. This depletion of dopamine, particularly in the striatal area of the brain, may explain some of the neurological and psychiatric complications of the drug.

Chronic cocaine use is associated with modestly reduced levels of striatal dopamine and dopamine transporter systems, but the significance of this is not fully understood [23]. With continued use, increased doses of the drug are needed to produce the same euphoria. Only partial tolerance develops to the cardiovascular effects [4,11]. This difference can cause extreme myocardial stimulation, sometimes resulting in death.

CNS complications

Migraine-like headaches

Migraine-like headaches can occur in the absence of previous headaches or a family history of migraine [20,24]. It is thought they relate to the sympathomimetic or vasoconstrictive effects of cocaine, whilst headaches following cocaine withdrawal, or those exacerbated during a cocaine 'binge', may relate to cocaine-induced alteration of the serotoninergic system [20].

Cerebrovascular disease

Cocaine can cause ischaemic or haemorrhagic strokes. They occur with equal frequency after smoking crack cocaine, with haemorrhagic strokes more common with cocaine hydrochloride use. Crack-cocaine-induced strokes are 45% ischaemic and 55% haemorrhagic. Cocaine hydrochloride-induced strokes are 80% haemorrhagic (41% have associated cerebral vascular aneurysms). Patients with known intracerebral aneurysm on cocaine, present at an earlier age than non-cocaine users. In a controlled study of patients with subarachnoid haemorrhage and cocaine addiction versus those with haemorrhage and no addiction, the average age of presentation was 32.8 compared with 52.2 yr [25]. The cocaine-induced hypertension predisposes these patients to aneurysmal rupture.

Cerebrovascular accidents can occur by any route of abuse (inhaled, snorted or injected) with the mean age of presentation being 34 ± 2 yr [26-28]. The time frame for the onset of symptoms can be anything from immediate to 3 h [26-29] and in some patients up to 24 h [27]. Not surprisingly, with these strokes occurring in a relatively young population, most patients (73%) have no prior risk factors for cerebral vascular events [26].

Cerebral ischaemia and infarction

Patients with ischaemic strokes commonly present with confusion, aphasia, dysarthria, hemiplegia, cerebellar infarcts, paraesthesiae, incontinence or an unsteady gait [29]. The mortality rate associated with such strokes is about 11% [30]. Mechanisms responsible include vasospasm, sudden onset of hypertension, myocardial infarction with cardiac dysrhythmias and the production of emboli [31], increased platelet aggregation and increased thromboxane production [32,33] and vasculitis [34].

The commonest cause of ischaemia is cerebral artery vasospasm. This is due either to the sympathomimetic properties of cocaine or its direct effect on calcium channels [35], releasing intracellular calcium from the sarcoplasmic reticulum in cerebral vascular smooth muscle cells. Cocaine also depletes levels of intracellular magnesium [36-38] and, as magnesium is normally involved in the modulation of both calcium entry and intracellular calcium release [41], may produce vasospasm by both direct and indirect mechanisms.

Cocaine-induced cerebral ischaemia, if due to a process of vasculitis [34,39,40], may be accompanied by abnormal or normal cerebral angiography. Abnormal findings consist of arterial irregularity, narrowing or occlusion. In patients with normal angiographic findings, the diagnosis can be made from brain tissue obtained during haematoma evacuation and shows a leukocytoclastic angiitis of the small vessels [34,39,41]. No other evidence of systemic vasculitis may exist from either clinical or laboratory investigations. The vasculitis predominantly affects small cerebral arterioles and is probably a hypersensitivity angiitis [39].

Haemorrhagic strokes

These may be intracerebral or subarachnoid haemorrhages. The usual clinical presentation is of headaches, altered mental status, neurological deficits or seizures. Often there is a rapid deterioration in neurological status followed by death. Of patients presenting with subarachnoid haemorrhage, 78% have an underlying vascular abnormality (berry aneurysm of the circle of Willis or an arteriovenous malformation) compared with 48% of patients with intracerebral haemorrhage [42]. Acute hypertension from cocaine can cause rupture of the aneurysm or malformation, producing either subarachnoid [26,42-44] or intracerebral haemorrhage.

This hypertension damages the elastic tissues of cerebral arteries, causing ancurysmal bulging of their walls [45-47]. This may affect cerebral autoregulation, leading to an increased blood flow to certain areas [48] with consequent vascular rupture and haemorrhage. Following the initial vasospastic episode, it is possible that reperfusion, with an acute increase in blood flow, may lead to rupture of an already damaged vessel [28,42,45].

At a cellular level, cocaine-associated vasculopathy is accompanied by leukocyte infiltration of cerebral vessels and increased expression of endothelial adhesion molecules, intercellular adhesion molecules and endothelial leukocyte adhesion molecules [49].


Cocaine causes primary seizures (focal or general) and secondary seizures [50]. Seizures can occur with any route of abuse and occur in about 10% of patients with acute cocaine intoxication (mean age 28 yr) [20,51]. These seizures are mostly single, generalized convulsions and occur more commonly with chronic use. The fit usually takes place within minutes of taking cocaine and almost always within 90 min. This correlates well with achievement of peak plasma concentrations [20,51]. In addicts with pre-existing epilepsy, cocaine makes fits more likely (especially in females) [51]. Small doses of cocaine can cause subthreshold stimulation of the limbic system (the 'kindling effect' of cocaine) and makes a fit more likely to occur [52].

Cocaine-induced seizures can be fatal, with death from hypoxia, hyperthermia or acidosis. Hyperthermia is generated by the intense muscular activity of the fit and is exacerbated by an inability to dissipate because of vasoconstriction. Hypothalamic thermal regulatory dysfunction is thought to be a contributing factor, with the resultant hyperthermia causing a lowering of the CNS's threshold for seizure [50]. Seizures may also be a secondary phenomenon, related to intracerebral haemorrhage, ischaemia or vasculitis. The mechanism for the development of seizures seems to involve three receptor types: serotonin, sigma opioid and muscarinic M1 receptors. Cocaine, by blocking presynaptic serotonin binding sites in the brain and inhibiting the reuptake of serotonin, causes serotonin to accumulate. This results in intense stimulation and seizure development [20]. The role of the sigma and muscarinic receptors in causing seizures is less clear [53], but it does seem that norepinephric mechanisms have no role in cocaine-induced seizures [54]. Late fits following cocaine abuse are probably due to the cocaine metabolite benzoylecgonine. These are often repetitive and focal, but rarely lethal [55].

Drug therapy for cocaine seizures is problematic. Most conventional antiepileptic drugs are either ineffective or only effective at doses producing significant sedative and ataxic effects. Clobazam, flunarazine, lamotrigine, topiramate and zonizamide are ineffective against seizures up to doses that produce significant motor impairment. In contrast, felbamate, gabapentin, loreclezole, losigamone, progabide, remacemide, stiripentol, tiagabine and vigabatrin produce dose-dependent protection against cocaine-induced convulsions [56,57]. Drugs that enhance γ-aminobutyric acid-mediated neuronal inhibition in a manner distinct from barbiturates, and benzodiazepines offer the best protective/behavioural side-effect profiles with the functional antagonists of Na+ and Ca2+ channels generally ineffective [56].

Disorders of movement

Cocaine causes dopamine to accumulate in the synaptic clefts of the basal ganglia where intense stimulation can lead to the production of movement disorders. These can present as Tourette's syndrome, dystonias, tardive dyskinesias, choreoathetosis, akathisia or acute dystonic reactions. These choreiform movements are described by lay persons as 'crack dancing', or among Hispanic communities as boca torcida or twisted mouth [58]. In patients already suffering movement disorders, cocaine makes the condition worse [59].

Cardiac complications

Cocaine causes cardiac complications after both acute and chronic use and by all routes. Underlying cardiac disease is not a prerequisite for cocaine-related cardiac complications, neither are they limited to massive doses of the drug.

Acute myocardial infarction and ischaemia

Cocaine blocks the myocardial presynaptic reuptake of norepinephrine, leading to an excess at post-synaptic receptor sites. The resultant adrenergic stimulation increases both heart rate and blood pressure. It also increases the calcium concentration in cardiac myocytes via β- and α-adrenergic receptor stimulation and facilitates calcium uptake by the troponin-actin-myosin contractile protein complexes. Myocardial and left ventricular contractility are therefore increased. This results in an increased myocardial oxygen demand [60] but because of the coronary arterial vasoconstriction produced by cocaine [61-63], there is a concomitant decrease in myocardial oxygen supply. This supply and demand imbalance is supported by cardiac catheterization data where cocaine-induced decreases in myocardial oxygen supply were alleviated by α-adrenergic receptor-blocking drugs, such as phentolamine [62]. Compensatory mechanisms in normal coronary arteries maintain myocardial oxygen supply. Cocaine overwhelms these local autoregulatory mechanisms. In individuals with coronary atherosclerosis, the vasodilatory reserve is already reduced. Vascular atherosclerosis impairs both the release of nitric oxide and prostacyclin from arterial endothelial cells, leaving coronary endothelial-mediated vasodilatation significantly impaired, making infarction from cocaine use more likely.

Cocaine can also induce arterial thrombosis and several pathological and arteriographic studies have demonstrated occlusive arterial thrombi in patients with myocardial infarction [64-68]. This is probably triggered by a combination of arterial vasoconstriction, platelet aggregation [69] and fibrin deposition. Cocaine acutely alters plasma concentrations of endogenous substances that regulate thrombus formation, such as tissue-plasminogen activator [70,71], plasminogen activator inhibitor [72,73] and lipoprotein (A) [74,75]. It may also possibly stimulate the release of substances from vascular endothelium or circulating platelets to promote thrombosis or inhibit thrombolysis. This thrombogenic potential may differ from person to person. Molitterno and colleagues [76] found plasminogen activator inhibitor activity increased by as much as 59% in some individuals, whereas there was little change in others. Cocaine in concentrations similar to those found clinically induces activation of individual platelets and the platelet response to physiological agonists in vitro or in animal models. Recent studies by Heesch and colleagues have shown the same to be true in humans [77]. Cocaine exposure caused platelet activation, α-granule release and platelet-containing microaggregate formation at doses commonly used by abusers. Platelet inhibitors should therefore be considered early in patients suspected of cocaine-related ischaemia or thrombosis. The mechanism of platelet activation is not yet clear. Catecholamines such as norepinephrine might activate platelets directly or by the induction of haemodynamic stress.

Acute myocardial infarction with cocaine can be manifested as Q-wave or non-Q-wave infarcts [78-84]. Ages of presentation range from 19 to 44 yr, with an average of 32 yr. Most were chronic users, although a small number did suffer infarcts with the first use. In young patients with normal coronary arteries, infarction may be caused by diffuse spasm of epicardial and intramural coronary arteries. This α-adrenergic-mediated spasm leads to an increase in coronary vascular resistance and a decrease in myocardial blood flow [62]. Cocaine causes vasoconstriction by promoting an influx of calcium into myocardial cells through calcium channels or via Na+/Ca2+ exchange [85,86]. Studies show that the reduction in coronary blood flow is out of proportion to the degree of coronary vasoconstriction and probably also implicates an effect of cocaine on intramural blood vessels [87]. Cocaine accelerates pre-existing coronary atherosclerosis [88-90]. Post mortems on chronic cocaine abusers (mean age 32 yr) dying from acute myocardial infarction revealed severe atherosclerotic plaques in 30-40% of cases [87].

The diagnosis of myocardial ischaemia or infarction can be difficult in cocaine addicts. Chest pain can occur with or without positive ECG findings, abnormal ECG being found in 56-84% of patients with cocaine-associated chest pain [91]. Abnormalities consist of increased QRS voltage, prolonged PR, QRS or QTc intervals, ST elevation and right-axis deviation (increased QRS voltage and ST elevation is more common among blacks) [92]. There is often no evidence of elevations in serum creatine phosphokinase (CK-MB) [93] or cardiac troponin I and T concentrations [94]. Cocaine-induced thoracic skeletal muscle injury, myocarditis or coronary vasospasm is offered as a diagnosis in such patients. Crack-induced thermal airway injury may also be a cause of chest pain. Conversely, if an ECG is normal in a patient with chest pain, reversible ischaemia is unlikely (demonstrated by myocardial perfusion scans) [95].

The use of thrombolytics with cocaine-associated ECG changes and elevated enzymes can be difficult. Case reports exist of intraventricular bleeding after their use [96]. The Cocaine Associated Myocardial Infarction (CAMI 1995) Study Group considered the safety of thrombolytic use and drew conclusions that 'it remains unclear whether thrombolytic therapy is an important therapy for patients with cocaine-associated myocardial infarction' [97]. However, it would seem prudent to administer aspirin in cases of cocaine-induced chest pain.

Cardiac dysrhythmias and sudden death

Reports of bradydysrhythmia [97], ventricular tachycardia, [99] accelerated idioventricular rhythm [100], ventricular fibrillation [18,101] and sudden death [102] are described after use of cocaine. Cocaine increases the plasma concentrations of norepinephrine as well as increasing cardiac intracellular calcium concentrations. In this way, it can provoke delayed or late after-depolarization, ventricular extrasystoles and ventricular tachycardia [18]. It also prolongs the action potential duration and induces early after-depolarization by the blockade of potassium-efflux channels, increasing calcium concentrations in myocytes.

Large doses of cocaine cause cardiac myofilaments to 'slide' past each other, producing an amorphous mass of myofilaments incapable of contraction [103-105]. This mass (a myocardial contraction band) acts as a focus for cardiac dysrhythmias [105]. Cocaine may also precipitate dysrhythmias by its blockade of fast sodium channels. In this regard, it closely mimics flecainide, a drug well known to cause dysrhythmias [106]. By blocking the sodium channels, a localized area of conduction block occurs and ventricular depolarization is heterogeneous, resulting in ventricular re-entrant dysrhythmias. Blockade of myocyte potassium channels [18,19] further enhances the likelihood of re-entrant cardiac dysrhythmias occurring. If myocardial infarction has occurred, the differing rates of depolarization and repolarization of infarcted and healthy muscle act as a focus for the development of dysrhythmias. Acidaemia, if present, enhances myocardial irritability. Patients with prolonged QRS complexes and QTc duration can have these conduction disorders reversed if hyperventilation, sedation, cooling and sodium bicarbonate infusions are used to normalize pH [107]. Parker and colleagues [108] demonstrated a reversal of prolonged PR, QTc and QRS duration by the administration of sodium bicarbonate (sodium chloride was given as a control to demonstrate that the effect was due to pH manipulation and not sodium loading).

Dilated cardiomyopathy

Dilated cardiomyopathy secondary to cocaine use has been reported [109,110] and is reversible in some patients [111-114]. Many had cardiomyopathy in the absence of coronary artery disease. Left ventricular hypertrophy and segmental wall motion abnormalities are common and occur in 54 and 21% respectively of asymptomatic abusers [115]. These abnormalities of systolic and diastolic function can be visualized by ultrasound before the onset of clinical symptoms [116].

Explanations for the cardiomyopathy are multifactorial. Catecholamine-induced hypertension will certainly cause an increase in myocardial afterload and ventricular dilatation and it is feasible that if cocaine use is infrequent, the pathology could be reversible. Persistent use could explain the irreversible damage seen at post mortem, consisting of scattered foci of myocyte necrosis, the existence of contraction-band necrosis, myocarditis and foci of myocyte fibrosis [117,118]. Atherosclerosis or coronary artery vasospasm may contribute to the muscle damage.


Myocarditis is a common finding in addicts at post mortem. Of patients between the ages of 28 and 33 yr, 20% have evidence of acute myocarditis (small areas of myocyte necrosis and extensive loss of myofibrils) [119]. This may explain chest pain among individuals with abnormal electrocardiographs, later found to have normal cardiac enzyme concentrations. The myocarditis is thought to be either a direct toxic effect of cocaine on myocardium or a hypersensitivity myocarditis.

Aortic rupture/dissection, coronary artery occlusion

Cocaine causes both acute and chronic dissection of the aorta [120-122]. Transient severe elevations in arterial pressure cause a shearing effect on the thoracic aorta and may trigger the dissection in conjunction with other pathological processes, such as direct toxic damage to the vascular endothelium, thrombosis or vasculitic changes. Coronary artery occlusion may result either from involvement of the coronary arteries in an aortic dissection or as a result of α-adrenergic activity on coronary receptors [121,123].

Pulmonary complications

Acute respiratory symptoms

The freebase form of cocaine is most frequently, but not exclusively, associated with pulmonary complications. These usually develop several hours after use, although occasionally within minutes [124]. Symptoms consist of productive cough, chest pain with or without shortness of breath, haemoptysis, and exacerbations of asthma. The frequency of such symptoms varies within studies (Table 2). Differences probably reflect the other substances with which the cocaine is smoked (tobacco, heroin, marijuana). Black sputum production is characteristic of smoking crack cocaine and is attributed to inhalation of carbonaceous residue from butane- or alcohol-soaked cotton torches or cigarette lighters used to ignite it [129].

Table 2:
Frequency of symptoms among cocaine smokers.

Chest pain, if reported, usually occurs within 1 h of smoking and is pleuritic in nature. It is caused by high concentrations of cocaine or toxic irritation by combustion products. However, other potential causes of chest pain should not be overlooked, e.g. myocardial ischaemia or infarction, aortic dissection, pneumothorax and pneumomediastinum. Haemoptysis reported in 6-26% of crack users [127,128] results from rupture of bronchial submucosal vessels or bleeding from the alveolar capillary membranes.

Airway injury

Thermal airway injury occurs either from damage by the products of combustion or from the ignition of highly volatile ethers used in the extraction process of the drug. This may be severe enough to cause tracheal stenosis [7].


Rebhun reported three cases where cocaine caused asthma [130]. Only one patient had a previous history of asthma or hay fever and developed rhinitis, nasal itching, cough and shortness of breath (without audible wheeze), the symptoms of which were relieved by bronchodilators. The other patients suffered bronchospasm, one at the time of smoking the crack and the other 2 months after stopping the drug. Rubin and Neugarten described six asthmatic patients needing hospitalization after smoking cocaine [131]. Three were severe enough to warrant mechanical ventilation of the lungs. All were smokers whose symptoms occurred at the time of, or soon after, taking the cocaine. All six responded to bronchodilators and corticosteroids. The role of adulterants in cocaine eliciting a hypersensitivity response is not known and cannot be excluded as being partly or entirely responsible in the above cases.

Eosinophilic lung disease/interstitial pneumonitis

There have been several reports of eosinophilia after cocaine exposure [132-135]. Patients suffered fever, cough, wheezing and hypoxaemia, and demonstrated peripheral lung infiltrates on chest radiography. They had both elevated blood eosinophil counts and immunoglobin E (IgE) concentrations. Bronchoalveolar lavage demonstrated elevated eosinophil counts and transbronchial biopsies showed both inflammation and eosinophilia. All responded favourably to steroids. Isolated reports of interstitial pneumonitis with crack cocaine can be found. In one such case, a 33-yr-old female suffered severe respiratory failure and death [136]. No response was shown to either high-dose corticosteroids or cyclophosphamide.

Bronchiolitis obliterans and organizing pneumonia (BOOP)

BOOP documented by open-lung biopsy was reported in a 32-yr-old male crack user presenting with a 10-day history of non-productive cough, fever and dyspnoea unresponsive to antibiotics [136]. Symptoms improved dramatically after corticosteroid therapy with the diminished diffusing capacity improving. The patient was left with an obstructive ventilatory defect. A similar patient reported by Dani and colleagues was a 30-yr-old female presenting with agitation and dyspnoea [137]. She was 33 weeks' pregnant but otherwise fit having developed a nonproductive cough and dyspnoea 1 week before admission. She suffered severe hypoxia with a PaO2 of only 5.5 kPa. Her chest radiograph showed diffuse alveolar infiltrates. Bronchoalveolar lavage found no pathogens and an open-lung biopsy revealed areas of fibroblastic plugs occupying the terminal bronchioles and alveolar spaces and thickened interstitium infiltrated with mononuclear cells (histopathological findings consistent with a diagnosis of BOOP). She was unresponsive to high dose corticosteroids and died from adult respiratory distress syndrome 48 days after admission.


Pneumothorax, pneumomediastinum and pneumopericardium can all occur after smoking crack cocaine [138-145]. The presenting complaint is usually chest pain or dyspnoea. The mechanism behind the barotrauma is either an increase in intra-alveolar pressure caused by deep inhalation followed by a Valsalva manoeuvre (which causes more of a 'hit'/intense feeling) or a result of severe coughing. Shesser and colleagues reported a case of pneumomediastinum and bilateral pneumothoraces in a 26-yr-old freebase user after 'mouth-to-mouth breathing' with a partner [144]. This manoeuvrc, often referred to as 'a blow-back', led to alveolar rupture. Most pneumothoraces need only conservative management, but occasionally chest drain insertion is required. No deaths from cocaine-induced barotrauma have yet been described.

Pulmonary oedema

The first reported case of pulmonary oedema from cocaine occurred in a 36-yr-old male who had immediate onset dyspnoea after injecting freebase cocaine [146]. He died of refractory hypotension and respiratory failure 3 h after the injection. It also occurs after smoking the drug [147]. The pathogenesis of the oedema is not clear. A variety of mechanisms have been postulated. One suggests that changes in the central adrenergic outflow may result in an increase in pulmonary microvascular pressure that, in turn, may affect pulmonary vascular permeability [147]. This is similar to the mechanism underlying neurogenic pulmonary oedema. An alternative hypothesis is that cocaine induces an increase in the systemic vascular resistance, resulting in transient left ventricular dysfunction and the development of alveolar flooding. This hypothesis is supported by canine studies where sustained hypertension developed after cocaine administration. During this hypertensive phase, the dogs developed elevated left ventricular end-diastolic, left atrial, pulmonary artery and central venous pressures. Increased amounts of lung water could be detected [148]. A third possibility is that cocaine could have a direct effect on vascular permeability. This is supported by studies showing an elevation in protein concentrations seen in bronchoalveolar lavage specimens.

Pulmonary haemorrhage/infarction

Diffuse alveolar haemorrhage, associated with dyspnoea and haemoptysis, is a common manifestation of cocaine abuse. Massive haemoptysis can occur, but occult haemorrhage is far more common, being found in 30% of post mortems [149,150]. Occasionally, cocaine-induced rhabdomyolysis is associated with chest pain and haemoptysis, thereby mimicking a pulmonary embolus [151]. Measurement of serum creatine phosphokinase concentration, as well as the presence of urinary myoglobin, establishes the diagnosis [152,153]. Possible mechanisms for pulmonary bleeding consist of vasoconstriction of the vascular bed (resulting in anoxic cell damage), a direct toxic effect of the inhaled substances on the alveolar epithelium or cocaine-induced thrombocytopenia [154]. Rarely, pulmonary infarction occurs from crack cocaine abuse and may be due to a cocaine-induced hypercoagulable state, due to enhanced platelet aggregation or an effect on protein kinases [155].

Abnormalities of pulmonary function

Several studies have examined the effects of cocaine on lung function with differing results (Table 2). Wess and colleagues described substantial reductions in diffusing capacity (DLCO) in two freebase smokers [156]. Itkonen and colleagues found no abnormalities in either spirometry or lung function tests in 19 freebase users but 10 of the 19 had a DLCO <70% of the predicted normal values [126]. Tashkin and colleagues considered two groups of patients: one group using tobacco with marijuana and freebase, and one taking drugs without tobacco [127]. The authors concluded the differences in DLCO could be solely attributable to tobacco smoking. Other studies on habitual cocaine smokers failed to show a decrease in diffusing capacity [157]. The intensity of cocaine use and the type of adulterants present probably account for these discrepancies. Suggested mechanisms for cocaine-related decrease in diffusing capacity include direct damage to the alveolar capillary membrane, damage to the vascular bed and interstitial disease due to concurrent i.v. abuse. Other confounding variables exist. Firstly, cocaine abuse may result in anaemia causing a decrease in diffusing capacity, or alveolar haemorrhage, causing an increase in diffusing capacity. More definitive conclusions will require the study of larger numbers of patients.

Pulmonary granulomas/hilar adenopathy

Pulmonary granulomatosis is well described in i.v. drug users. Talc filler is the most commonly implicated agent. Cooper and colleagues described a case of pulmonary granulomatosis in a 26-yr-old addict who vehemently denied injecting, admitting only to snorting cocaine [158]. Chest radiography showed bilateral miliary opacities and fibreoptic transbronchial lung biopsy showed foreign body granulomas, containing numerous birefringent needle-shaped particles. The authors believed that the particles reached the lungs via the airways rather than the bloodstream.

Dicpinigatis and colleagues recently reported a case of crack cocaine use mimicking sarcoidosis [159]. A 39-yr-old male addicted to crack cocaine for several years presented with progressive dyspnoea and chest radiography showed bilateral interstitial pulmonary infiltrates and hilar lymphadenopathy. He had markedly raised angiotensin-converting enzyme activity and an open-lung biopsy showed interstitial and perivascular collections of histiocytes. Paratracheal nodes were enlarged and found to contain similar material but no granulomas characteristic of sarcoid. This association of crack cocaine with features typical of sarcoidosis had not previously been described.

Histopathology of the lung

Exposure to cocaine in vivo enhances the ability of polymorphoneutrophils (PMNs) to kill certain bacteria such as Staphylococcus aureus. It also increases their antitumour activity as measured by an antibody-dependent cell-mediated cytotoxicity assay [160]. Short-term exposure to cocaine is known to enhance both the production of interleukin (IL) 8, a potent PMN chemoattractant and neutrophil-activating factor [160]. Alveolar macrophages obtained from cocaine smokers are severely limited in their ability to kill both bacteria and tumour cells [161]. These effects on lung white cells by cocaine could be implicated in either lung injury, susceptibility to infectious disease or cancer. Barskey and colleagues studied the histopathological and molecular alterations in bronchial biopsy specimens and brushings in smokers of marijuana, cocaine and/or tobacco smokers compared with non-smokers [162]. They found that smoking cocaine and/or marijuana was associated with alterations in histopathological parameters linked to an increased risk of cancer.

Gastrointestinal complications


The use of addictive drugs such as cocaine affects food and liquid intake, taste preference, and body weight. Changes in specific nutrient status can develop and nutrition-related conditions could affect the sensitivity to, and the dependence on, drugs. Cocaine addiction is often associated with protein deprivation and produces preferential fat and glycogen store utilization. This protein deprivation may well explain reduced concentrations of plasma cholinesterase found in cocaine addicts [15]. Cocaine also acts as an appetite suppressant. These factors can lead to a severely malnourished individual, which may have marked effects on patients' ability to recover from major surgery/debilitating illnesses, wound healing and ventilator dependence in intensive care.

Gastroduodenal ulceration and perforation

Gastrointestinal complications are less commonly reported than those in the cardiovascular or CNS. Acute gastrointestinal ischaemia is the commonest and should be considered as a diagnosis in young patients presenting with intestinal ischaemia (especially if urine screening is positive). The ischaemia is due to intense α-adrenoreceptor stimulation by norepinephrine and a decrease in blood supply to the mucosa. This may be exacerbated by the anti-cholinergic action of cocaine [10] and its effects on medullary centres, slowing gastric emptying and prolonging exposure to gastric acid. The mean age of presentation is 30 (range 22-48) yr and 75% of patients have no previous history of peptic ulceration [163,164]. Abramson and colleagues operated on 24 patients with perforated peptic ulcers, of whom five were regular crack users [165]. At presentation, they had no fever or raised white cell count. Five agematched controls all showed elevated white cell counts and a much longer duration of symptoms. Four of the five controls had perforations in the duodenum, whereas all five crack users had gastric perforation.

Acute bowel ischaemia and perforation

Ischaemic colitis is a rare complication of cocaine use but can result in perforation of the large bowel. Again, these patients often have no risk factors but their presentation bears a good temporal relationship to the use of cocaine [166-168]. They are usually between 25 and 40 yr of age and have either been using large doses [169] or had a single large dose (up to 4 g) the day before the symptoms developed [170]. The pathological process is probably α-adrenergic-mediated but may also be secondary to thrombus formation [171,172]. Whichever mechanism is responsible, it can be severe enough to progress to gangrene of the bowel and subsequent perforation [173].

Bodypackers, bodystuffers, mules

The gastrointestinal tract is the commonest place to hide packages of cocaine from customs or police officers, either swallowed or inserted rectally. These drug traffickers known as 'bodypackers', 'bodystuffers or 'mules' can have as much as 3-8 g of concealed cocaine. It is often placed in condoms, which may become damaged, disrupted or cause bowel obstruction. Disastrous consequences result if rupture occurs, exposing the individual to very high doses of cocaine. June and colleagues described 46 cases of bodystuffers presenting to a regional emergency centre [174]. Seventy-four per cent remained asymptomatic, 18% had mild symptoms (hypertension and tachycardia), 4% had moderate symptoms (agitation and fever) and two patients (4%) had severe symptoms (seizures and cardiac dysrhythmias resulting in death). Radiographic searches for these packages are often negative. McCarron and Wood found 12 of 47 patients had no evidence of the packages revealed by abdominal radiography [175]. A negative finding is even more likely if the packages are wrapped in cellophane. Most body-packers can be treated conservatively with purgation, but close observation of patients is needed in case packages break or leak. If bowel obstruction develops, surgical intervention is necessary.


Cocaine is hepatotoxic but the mechanism is not yet fully understood. The oxidative metabolism of cocaine to norcocaine nitroxide has been postulated to be essential, probably via a multistep cytochrome P450-dependent N-oxidative pathway. The toxicity of norcocaine has been shown to be dose-related in mouse [176] and is potentiated by alcohol [177]. In human beings, the site of liver damage in pathology specimens is not consistent. Reports of fulminant hepatic failure showing midzonal necrosis and periportal microvesicular fatty change throughout all the lobules [174] are in contrast to the areas of well-demarcated necrosis demonstrated by Wanless and colleagues [178]. Patients typically show marked increases in serum aminotransferase concentration, mild-to-moderate increases in prothrombin time, myoglobinuria and moderate uraemia.

Pancreatic disease

The role of cocaine in pancreatic disease is unclear. Whether it causes pancreatitis is under debate, but a role in diabetes mellitus seems more likely. Diabetic cocaine users have more admissions for ketoacidosis and are less likely than controls to have an intercurrent illness identified as the precipitating factor. This is partly due to poor insulin compliance, but may also be an effect of cocaine on counter-regulatory hormones involved in glucose metabolism. Chronic use of cocaine may predispose individuals to the development of pancreatic adenocarcinoma [179]. Larger studies are necessary to substantiate this view.

Endocrine disease

Many of the acute effects of cocaine on the endocrine system are consistent with its actions as a monoamine reuptake inhibitor, blocking the uptake of serotonin. Acute cocaine administration stimulates the release of gonadotrophins, ACTH and cortisol or corticosterone, and suppresses prolactin production. Interpretation of clinical data is difficult though because of concomitant use of other drugs. However, animal studies do show an interference of the drug with both oestrual cycles in rats and menstrual cycles in rhesus monkeys and the disorders of the menstrual cycle parallel those reported by females. Further work is needed to clarify the role of cocaine role in endocrine disorders.

Renal complications

Accelerated hypertension and renal failure

There is no doubt that cocaine causes acute elevation of arterial pressure but whether it is sustained is less clear. Brecklin and colleagues considered 301 black males admitted for treatment of addiction and compared both their systolic and diastolic blood pressures to age- and race-matched controls [180]. No significant difference in blood pressure was found in the cocaine group. Of those studied, 20% had acutely elevated blood pressure, but values returned to normal within 1 day. In contrast, Thakur and colleagues reported two cocaine abusers who developed features of biopsy proven accelerated/malignant hypertension, persistent hypertension and renal failure with rapid progression to end-stage renal disease [181]. This did not reverse following control of the blood pressure.

Rhabdomyolysis and myoglobinuria producing acute renal failure

Of patients presenting with cocaine-related problems to emergency departments, 24% had acute rhabdomyolysis, one-third of whom develop renal failure [152,182]. Patients usually present with muscle pains and tenderness and have biochemical evidence of hyperkalaemia, hyperphosphataemia, hyperuricaemia, raised concentrations of creatine kinase, lactate dehydrogenase, aspartate aminotransferase and creatinine. Myoglobin and granular casts are found in the urine [183,184] and creatine kinase concentrations can be as high as 85 000 U L−1 (MM isoenzyme was found in skeletal muscle) [185]. Different mechanisms may be responsible for the development of rhabdomyolysis. Prolonged vasoconstriction in the arteries within muscle could result in death of muscular tissue. Cocaine could have a direct toxic effect on muscles or cause muscular damage secondary to prolonged immobility following cocaine coma. The mechanism of the renal failure is probably multifactorial. Myoglobin released from damaged muscle causes renal tubular obstruction and tubular damage leading to a decreased glomerular filtration rate [152]. Alterations in blood flow may also be important [152,184]. Cocaine decreases renal artery flow and may also cause intrarenal vasoconstriction, leading to medullary hypoxia and tubular dysfunction [186].

Excited delirium

Patients with cocaine-associated rhabdomyolysis may suffer a condition known as excited delirium. The two conditions share many of the same features and are even thought to be different stages of the same syndrome. Both sets of patients are more likely to be male, young, black and have experienced features of excitement, delirium and hyperthermia. They are also less likely to have suffered seizures [187]. It is thought that chronic cocaine use disrupts dopaminergic function and, when coupled with recent cocaine use, precipitates agitation, delirium, aberrant thermoregulation, rhabdomyolysis and sudden death. Restraint (for violent agitation and hyperactivity) of such individuals is dangerous. A recent retrospective study from Ontario, Canada, found 21 unexpected deaths from excited delirium, all of which were restrained and 38% of which were due to cocaine use [188]. Death was not due to exceptionally high cocaine concentration, blood levels being similar to other recreational cocaine users. It is possible that susceptible individuals release high levels of endogenous catecholamines in response to restraint and that this, coupled with already high levels from cocaine use, proves to be fatal.

Thrombotic microangiopathy and acute renal failure

Two variants of thrombotic microangiopathy can lead to the development of renal failure, thrombotic thrombocytopenia purpura (TTP) [189] and haemolytic uraemic syndrome (HUS) [9,190]. Clinically, TTP patients present with haemolytic anaemia, neurological changes, altered mental state, renal dysfunction, thrombocytopenia and fever. The less common HUS presents with haemolytic anaemia. Mechanisms involved in cocaine-induced thrombotic microangiopathy include endothelial injury, vasoconstriction and/or impairment of vasodilatation, procoagulant activity and antiplatelet activity. Good responses to fresh frozen plasma, plasma exchange and haemodialysis give a favourable outcome in both TTP [191] and HUS, although patients may be left with a degree of renal insufficiency.

Renal infarction

This may occur from i.v. injection or snorting of cocaine [192,193]. Patients present with a sudden onset of flank pain, fever, nausea, vomiting, and either microscopic or gross haematuria and proteinuria. Increased adrenergic stimulation associated with underlying renal artery atherosclerosis is thought to lead to end-organ infarction [194]. Imbalance between thromboxane production (from vasospasm-damaged endothelium) and prostacyclin production may play a role, with thromboxane increasing platelet aggregation and causing vasoconstriction and prostacyclin decreasing platelet aggregation and causing vasodilatation [195,196].

Focal segmental glomerulosclerosis

Cocaine increases the release of IL-6 by macrophages. IL-6 augments mesangial cell proliferation and may in turn lead to the development of focal segmental glomerulosclerosis [197].

Cocaine-induced scleroderma

Case reports exist suggesting that cocaine may be capable of initiating scleroderma in an already susceptible individual or may unmask the disease at an earlier stage in a subclinical setting [198,199].

Reproductive system

Maternal/placental pharmacology of cocaine

Cocaine crosses the placenta by simple diffusion and causes fetal hypoxia by vasoconstriction of uterine and placental vessels. The decreased blood and oxygen flow to the fetus results in depressed somatic and nervous system development [200]. The cocaine metabolite norcocaine also causes somatic and neurobehavioral disturbances in cocaine-exposed neonates [201]. Mother and fetus also possess lower than normal amounts of plasma cholinesterase, resulting in greater hepatic N-demethylation of cocaine to norcocaine [202,203].

Effects on pregnancy

Increased circulating norepinephrine constricts uterine vessels and increases uterine contractility [204]. Spontaneous abortion, abruptio placentae, placenta praevia and still births may all result. Acute maternal hypertension can also precipitate abruptio placentae [204].

Prematurity, low birth weight and intrauterine growth retardation

Preterm delivery occurs in 17-29% of pregnant cocaine users. Cocaine stimulates both α- and β-adrenergic receptors in the myometrium leading to premature rupture of membranes, infection of the uterus and preterm labour [205]. Low birth weight (<2.5 kg) occurs in about 25% of infants exposed to cocaine. The cause is multifactorial: (a) cocaine causes intermittent reductions in placental blood flow secondary to vasoconstriction, (b) cocaine suppresses maternal appetite leading to poor maternal and fetal nutrition and (c) cocaine stimulates the fetal sympathetic nervous system increasing metabolism of both fat and glycogen stores.

Congenital malformations

Cocaine causes marked teratogenicity (Table 3). It affects about 10-15% of exposed fetuses, most frequently involving the CNS. Adverse effects show a dose-response relationship and are almost certainly due to hypoperfusion during the development of the embryo [206]. The severity of the malformations reflects the timing and location of the vasoconstriction during fetal development [207]. Some of this morbidity does not persist. Hypertonia, for example, is transient, the majority of children outgrowing it by the age of 24 months [208]. The results of long-term follow up of cocaine-exposed infants are contradictory. Some studies show higher perinatal morbidity, significant developmental and cognitive delay [209], but no overall increase in mortality rates (higher rates are only seen if the infant is of low birth weight) [210]. Others suggest few if any consistent differences in developmental functioning compared with demographically similar, non-exposed, age-matched controls [211]. Confounding factors in the study designs probably mask this paucity of cocaine-related findings.

Table 3:
Effects of maternal cocaine use in neonates.


The properties of cocaine as a local anaesthetic and vasoconstrictor have benefits for medicinal use in ear, nose and throat surgery, but when abused have the potential to be extremely dangerous. It causes acute and chronic disease affecting the central nervous, cardiovascular, respiratory, gastrointestinal and renal systems, as well as interfering with both haemostasis and endocrine function. Devastating pathology in the fetus, both short- and long-term, can result from its abuse in early or late pregnancy. Placental function is markedly altered, placing the life of the mother and her fetus at risk and resulting in the malformation of the developing fetal systems. The effects of the drug are varied, showing inter- and intraindividual variation dependent on the amount of the drug taken, the route of abuse, nutritional status, gender, whether used alone or in combination with other drugs, and whether previous exposure has occurred. Cocaine is capable of causing this morbidity or mortality on single or repeated use. It remains a very dangerous recreational drug, particularly in the light of its increasing availability and decreasing street price.


1. National Institute on Drug Abuse. National Household Survey on Drug Abuse Population Estimates. HHS 91-1732. Washington, DC, USA: US Department, 1990.
2. Office for National Statistics Report: ONS drug-related deaths database: first results for England and Wales 1993-97. Health Statistics Quarterly 2000.
3. Benowitz NL. Clinical pharmacology and toxicology of cocaine. Pharmacol Toxicol 1993; 72: 3-12.
4. Warner EA. Cocaine abuse. Ann Intern Med 1993; 119: 226-235.
5. Prakash A, Das G. Cocaine and the nervous system. Int J Clin Pharmacol Ther Toxicol 1993; 31: 575-581.
6. Khalsa ME, Tashkin DR, Perrochet B. Smoked cocaine, patterns of use and pulmonary consequences. J Psychoactive Drugs 1992; 24: 265-272.
7. Taylor RF, Bernard GR. Airway complications from free-basing cocaine. Chest 1989; 95: 476-477.
8. Scott DB. Maximum recommended doses of local anaesthetic drugs. Br J Anaesth 1989; 63: 373-374.
9. Keung K, Morgan D, Cobos E. Cocaine-induced microangiopathic hemolytic anemia and thrombocytopenia simulating thrombotic thrombocytopenic purpura. Ann Hematol 1996; 72: 155-156.
10. Fleming JA, Byck R, Barash PG. Pharmacology and therapeutic applications of cocaine. Anesthesiology 1990; 73: 518-531.
11. Wilson LD, Henning R, Suttheimer C, et al. Cocaethylene causes dose-dependent reductions in cardiac function in anaesthetised dogs. J Cardiovasc Pharmacol 1995; 26: 965-973.
12. Brock A, Brock V. Plasma cholinesterase activity in a healthy population group with no occupational exposure to known cholinesterase inhibitors; relative influence of some factors to normal inter- and intra-individual variations. Scand J Clin Lab Invest 1990; 50: 401-408.
13. Lukas SE, Sholar M, Lundahl LH, et al. Sex differences in plasma cocaine levels and subjective effects after acute cocaine administration in human volunteers. Psychopharmacology 1996; 125: 346-354.
14. Santolaria-Fernandez FJ, Gomez-Sirvent JL, Gonzalez-Reimers CE, et al. Nutritional assessment of drug addicts. Drug Alcohol Depend 1995; 38: 11-18.
15. Cahill-Morasco D, Hoffman RS, Goldfrank LR. The effect of nutrition on plasma cholinesterase activity and cocaine toxicity in mice. J Toxicol Clin Toxicol 1998; 36: 667-672.
16. Lynch TJ, Mattes CE, Singh A, et al. Cocaine detoxification by human plasma butyrylcholinesterase. Toxicol Appl Pharmacol 1997; 145: 363-371.
17. Sabra R, Khoury HA, Bechara G, Sharaf LH, El Bizri NM. Post-junctional mechanisms involved in the potentiation of cardiac adrenergic responses by cocaine. Eur J Pharmacol 2000; 397: 139-150.
18. Billman GE, Hoskins RS. Cocaine-induced ventricular fibrillation: protection afforded by calcium antagonists verapamil. FASEB J 1988; 2: 2990-2995.
19. Przywara DA, Dambach GE. Direct action of cocaine on cardiac cellular activity. Circ Res 1989; 65: 185-192.
20. Dhuna A, Pascual-Leone A, Langendorf F, Anderson DC. Epileptogenic properties of cocaine in humans. Neurotoxicology 1991; 12: 621-626.
21. Hammer RP, Egilmez Y, Emmett-Oglesby MW. Neural mechanisms of tolerance to the effects of cocaine. Behav Brain Res 1997; 84: 225-239.
22. Cornish JL, Kalivas PW. Glutamate transmission in the nucleus accumbens mediates relapse in cocaine addiction. J Neurosci 2000; 20: RC89.
23. Wilson JM, Levey AI, Berbergeron C, et al. Striatal dopamine, dopamine transporter and vesicular monoamine transporter in chronic cocaine users. Ann Neurol 1996; 40: 428-439.
24. Satel SL, Gawin FH. Migrainelike headache and cocaine use. J Am Med Assoc 1989; 261: 2995-2996.
25. Fessler RD, Esshaki CM, Stankewitz RC, Johnson RR, Diaz FG. The neurovascular complications of cocaine. Surg Neurol 1997; 47: 339-345.
26. Daras M, Tuchman AJ, Koppel BS, et al. Neurovascular complications of cocaine. Acta Neurol Scand 1994; 90: 124-129.
27. Klonoff DC, Andrews BT, Obana WG. Stroke associated with cocaine use. Arch Neurol 1989; 46: 989-993.
28. Levine SR, Brust IC, Futrell N, et al. Cerebrovascular complications of the use of the crack form of alkaloidal cocaine. N Engl J Med 1990; 323: 699-704.
29. Jacobs IG, Roszler MH, Kelly IK, Klein MA, Kling GA. Cocaine abuse; neurovascular complications. Radiology 1989; 170: 223-227.
30. Daras AJ, Marks S. Central nervous system infarction related to cocaine abuse. Stroke 1991; 22: 1320-1325.
31. Petty GW, Brust JC, Tatemichi TK, Barr MJ. Embolic stroke after smoking 'crack' cocaine. Stroke 1990; 21: 957-962.
32. Rezkalla SH, Mazza JJ, Kloner RA. Effects of cocaine on human platelet in healthy subjects. Am J Cardiol 1993; 72: 243-246.
33. Togna G, Tempesta E, Togna AR, et al. Platelet responsiveness and biosynthesis of thromboxane and prostacyclin in response to in vitro cocaine treatment. Haemostasis 1985; 15: 100-107.
34. Krendel DA, Ditter SM, Frankel MR, Ross WK. Biopsy-proven cerebral vasculitis associated with cocaine abuse. Neurology 1990; 40: 1092-1094.
35. Konzen JP, Levine SR, Gracia JH. Vasospasm and thrombus formation as possible mechanism of stroke related to alkaloidal cocaine. Stroke 1995; 26: 114-118.
36. Altura BM, Gupta R. Cocaine induces intracellular free Mg deficits, ischaemia and stroke as observed by in-vivo31P-NMR of the brain. Biochem Biophys Acta 1992; 1111: 271-274.
37. Altura BM, Zhang A, Cheng TP, Altura BT. Cocaine induces rapid loss of intracellular free Mg2+ in cerebral vascular smooth muscle cells. Eur J Pharmacol 1993; 246: 299-301.
38. He GO, Zhang A, Altura BT, Altura BM. Cocaine-induced cerebrovasospasm and its possible mechanism of action. J Pharmacol Exp Ther 1994; 268: 1532-1539.
39. Fredericks RK, Lefkowitz DS, Challa VR, Troost BT. Cerebral vasculitis associated with cocaine abuse. Stroke 1991; 22: 1437-1439.
40. Kaye BR, Fainstar M. Cerebral vasculitis associated with cocaine abuse. J Am Med Assoc 1987; 258: 2104-2106.
41. Merkel PA, Koroshetz WJ, Irizarry MC, Cudkowitz ME. Cocaine-associated cerebral vasculitis. Semin Arthritis Rheum 1995; 25: 172-183.
42. Green RM, Kelly KM, Gabrielsen T, Levine SR, Vanderzant C. Multiple intracerebral hemorrhages after smoking crack cocaine. Stroke 1990; 21: 957-962.
43. Lichtenfeld P, Rubin DB, Feldman RS. Subarachnoid hemorrhage precipitated by cocaine snorting. Arch Neurol 1984; 41: 223-224.
44. Schwartz KA, Cohen JA. Subarachnoid hemorrhage precipitated by cocaine snorting. Arch Neurol 1984; 41: 705.
45. Caplan L. Intracerebral hemorrhage revisited. Neurology 1988; 38: 624-627.
46. Kibayashi K, Mastri AR, Hirsch CS. Cocaine induced intracerebral hemorrhage; analysis of the predisposing factors and mechanisms causing hemorrhagic strokes. Hum Pathol 1995; 26: 659-663.
47. Nolte KB, Gelman B. Intracerebral hemorrhage associated with cocaine abuse. Arch Pathol Lab Med 1989; 113: 812-813.
48. Kelly PA, Sharkey J, Philip R, Ritchie JM. Acute cocaine alters cerebrovascular autoregulation in the rat neocortex. Brain Res Bull 1993; 31: 581-585.
49. Gan X, Zhang L, Berger O, et al. Cocaine enhances brain endothelial adhesion molecules and leukocyte migration. Clin Immunol 1999; 91: 68-76.
50. Holland RW, Marx IA, Earnest MP, Ranninger S. Grandmal seizures temporally related to cocaine use: clinical and diagnostic features. Ann Emerg Med 1992; 21: 772-776.
51. Pascual-Leone A, Dhuna A, Altafullah I, Anderson DC. Cocaine-induced seizures. Neurology 1990; 40: 404-407.
52. Pascual-Leone A, Dhuna A, Langendorf F. Suggestion of kindling with habitual cocaine abuse. Epilepsia 1990; 31: 662.
53. Ritz MC, George FR. Cocaine-induced seizures and lethality appear to be associated with distinct central nervous system binding sites. J Pharmacol Exp Ther 1993; 264: 1333-1343.
54. Jackson HC, Ball DM, Nutt DJ. Noradrenergic mechanisms appear not to be involved in cocaine induced seizures and lethality. Life Sci 1990; 47: 353-359.
55. Konkol RJ, Erickson BA, Doerr J, Hoffman RG, Madden IA. Seizures induced by the cocaine metabolite benzoylecgonine in rats. Epilepsia 1992; 33: 420-427.
56. Gasior M, Ungard JT, Witkin JM. Preclinical evaluation of newly approved and potential antiepileptic drugs against cocaine-induced seizures. J Pharmacol Exp Ther 1999; 290: 1148-1156.
57. Magnus L. Non-epileptic uses of gabapentin. Epilepsia 1999; 40: 66-72.
58. Daras M, Koppel BS, Atos-Radzion E. Cocaine-induced choreoathetoid movements ('crack dancing'). Neurology 1994; 44: 751-752.
59. Cardoso FE, Jankovic J. Cocaine-related movement disorders. Mov Disord 1993; 8: 175-178.
60. Boehrer JD, Molitero DJ, Willard JE, et al. Hemodynamic effects of intranasal cocaine in humans. J Am Coll Cardiol 1992; 20: 90-93.
61. Flores ED, Lange RA, Cigarro RG, Hills LD. Effect of cocaine on coronary artery dimensions in atherosclerotic coronary artery disease: enhanced vasoconstriction at sites of significance. J Am Coll Cardiol 1990; 16: 74-79.
62. Lange RA, Cigarro RG, Yancy CW, et al. Cocaine-induced coronary artery vasoconstriction. N Eng J Med 1989; 321: 1557-1562.
63. Rongiane AJ, Steg PG, Gal D, Isner JM. Cocaine causes endothelium independent vasoconstriction of the vascular smooth muscle. Circulation 1988; 78: 436-438.
64. Isner JM, Estes N III, Thompson PD, et al. Acute cardiac events temporally related to cocaine abuse. N Engl J Med 1986; 315: 1438-1443.
65. Minor RL Jr, Scott BD, Brown DD, Winniford MD. Cocaine-induced myocardial infarction in patients with normal coronary arteries. Ann Intern Med 1991; 115: 797-806.
66. Rezkella SH, Hale S, Kloner RA. Cocaine induced heart disease. Am Heart J 1990; 120: 1403-1407.
67. Smith HWB, Liberman HA, Brody SL, et al. Acute myocardial infarction temporally related to cocaine use. Ann Intern Med 1987; 107: 13-18.
68. Stenberg RG, Winniford MD, Hillis LD, et al. Simultaneous acute thrombosis of two major coronary arteries following intravenous cocaine use. Arch Pathol Lab Med 1989; 113: 521-524.
69. Heesch CM, Steiner M, Hernandez JA, Ashcraft J, Eichhorn EJ. Effects of cocaine on human platelet aggregation in vitro. J Toxicol 1996; 34: 673-684.
70. Hans M, Collen D. Secretion of tissue-type plasminogen activator and plasminogen activator inhibitor by cultured human endothelial cells: modulation by thrombin, endotoxin, and histamine. J Lab Clin Med 1987; 109: 97-104.
71. Markwardt F, Klocking HP. Studies on the release of plasminogen activator. Thromb Res 1976; 8: 217-223.
72. Kriuthof EKO, Tran-Thang C, Bachman F. Studies on the release of plasminogen activator inhibitor by human platelets. Thromb Haemost 1985; 55: 201-205.
73. Sprengers ED, Kluft C. Plasminogen activator inhibitors. Blood 1987; 69: 381-387.
74. Maeda S, Abe A, Seishma M, et al. Transient changes of serum lipoprotein (A) as an acute phase protein. Atherosclerosis 1989; 78: 145-150.
75. Sgoutas DS, Lattouf OM, Finlayson DC, Clark RV. Paradoxical response of plasma lipoprotein (A) in patients undergoing cardiopulmonary bypass. Atherosclerosis 1992; 97: 29-36.
76. Molitterno DJ, Lange RA, Gerard RD, et al. Influence of intranasal cocaine on plasma constituents associated with endogenous thrombosis and thrombolysis. Am J Med 1994; 96: 492-496.
77. Heesch CM, Wilhelm CR, Ristich J, et al. Cocaine activates platelets and increases the formation of circulating platelet containing microaggregates in humans. Heart 2000; 83: 688-695.
78. Ascher E, Stauffer JC, Gaasch WH. Coronary artery spasm, cardiac arrest, transient electrocardiographic Q-waves and stunned myocardium in cocaine-associated acute myocardial infarction. Am J Cardiol 1988; 61: 939-941.
79. Cregler LL, Mark H. Relation of myocardial infarction to cocaine abuse. Am J Cardiol 1985; 56: 794-795.
80. Kossowsky WA, Lyon AF, Chou SY. Acute non-Q wave myocardial infarction. Chest 1989; 96: 617-621.
81. Mathias DW. Cocaine associated myocardial ischemia: review of clinical and angiographic findings. Am J Med 1986; 81: 675-678.
82. Patel R, Haider B, Ahmed S, Regan TI. Cocaine related myocardial infarction high prevalence of occlusive coronary thrombi without significant obstructive atherosclerosis. Circulation 1988; 78: 436-439.
83. Schachne JS, Roberts BH, Thompson PD. Coronary-artery spasm and myocardial infarction associated with cocaine. N Eng J Med 1984; 310: 1665-1666.
84. Simpson RW, Edwards WD. Pathogenesis of cocaine-induced ischemic heart disease: autopsy findings in a 21-year old man. Arch Pathol Med 1986; 110: 479-484.
85. Isner JM, Chokshi SK. Cardiovascular complications of cocaine. Curr Probl Cardiol 1991; 16: 89-123.
86. Welder AA, Grammas P, Melchert RB. Cellular mechanisms of cocaine cardiotoxicity. Toxicol Lett 1993; 69: 227-235.
87. Nunez BD, Miao L, Kuntz RE, et al. Cardiogenic shock induced by cocaine in swine with normal coronary arteries. Cardiovasc Res 1994; 28: 105-111.
88. Dressler FA, Malekzadeh S, Roberts WC. Quantitative analysis of amounts of coronary arterial narrowing in cocaine addicts. Am J Cardiol 1990; 65: 303-308.
89. Kolodgie FD, Virmani R, Cornhill F, Herderick EE, Smialek I. Increase in atherosclerosis and adventitial mast cells in cocaine abusers an alternative mechanism of cocaine-associated coronary vasospasm and thrombosis. J Am Coll Cardiol 1991; 17: 1553-1560.
90. Wilson LD. Rapid progression of coronary artery disease in the setting of chronic cocaine. J Emerg Med 1998; 16: 631-634.
91. Hollander JE, Lozano M, Fairweather P, et al. Abnormal electrocardiograms in patients with cocaine-associated chest pain are due to normal variants. J Emerg Med 1994; 12: 199-205.
92. Chakko S, Sepulveda S, Kessler KM, et al. Frequency and type of electrocardiographic abnormalities in cocaine abusers (electrocardiogram in cocaine abuse). Am J Cardiol 1994; 74: 710-713.
93. Merigian KS, Park LJ, Leeper KV, Browning RG, Giometi R. Adrenergic crisis from crack cocaine ingestion; report of five cases. J Emerg Med 1994; 12: 485-490.
94. McLaurin M, Apple FS, Henry TD, Sharkey SW. Cardiac troponin I and T concentrations in patients with cocaine-associated chest pain. Ann Clin Biochem 1996; 33: 183-186.
95. Feldman JA, Bui LD, Mitchell PM, et al. The evaluation of cocaine-induced chest pain with acute myocardial perfusion imaging. Acad Emerg Med 1999; 6: 103-109.
96. LoVecchio F, Nelson L. Intraventricular bleeding after the use of thrombolytics in a cocaine user. Am J Emerg Med 1996; 14: 663-664.
97. Hollander JE, Burstein JL, Hoffman RS, Shih RD, Wilson LD. Cocaine-associated myocardial infarction. Clinical safety of thrombolytic therapy. Cocaine associated myocardial infarction; CAMI Study Group. Chest 1995; 107: 1237-1241.
98. Castro VJ, Nacht R. Cocaine-induced bradyarrhythmia: an unsuspected cause of syncope. Chest 2000; 117: 275-277.
    99. Inoue H, Zipes DP. Cocaine-induced supersensitivity and arrhythmogenesis. J Am Coll Cardiol 1988; 11: 867-874.
    100. Benchimol A, Bartall H, Desser KB. Accelerated ventricular rhythm and cocaine abuse. Ann Intern Med 1978; 88: 519-520.
    101. Nanji AA, Filipenko JD. Asytole and ventricular fibrillation associated with cocaine intoxication. Chest 1984; 85: 132-133.
    102. Mittelman RE, Wetli CV. Cocaine and sudden 'natural death'. J Forensic Sci 1987; 32: 11-19.
    103. Karch SB, Billigham ME. Myocardial contraction bands revisited. Hum Pathol 1986; 17: 9-13.
    104. Karch SB, Billigham ME. The pathology and the etiology of cocaine-induced heart disease. Arch Pathol Lab Med 1988; 112: 225-230.
    105. Tazelaar HD, Karch SB, Stephens BG, Billigham ME. Cocaine and the heart. Hum Pathol 1986; 18: 195-199.
    106. Bauman J, Grawe JJ, Winecoff AP, Hariman RJ. Cocaine-related sudden death: a hypothesis correlating basic science and clinical observations. J Clin Pharmacol 1994; 34: 902-911.
    107. Wang RY. pH-dependent cocaine-induced cardiotoxicity. Am J Med 1999; 17: 364-369.
    108. Parker RB, Perry GY, Horan LG, Flowers NC. Comparative effects of sodium bicarbonate and sodium chloride on reversing cocaine-induced changes in the electrocardiogram. J Cardiovasc Pharmacol 1999; 34: 864-869.
    109. Duell PB. Chronic cocaine abuse and dilated cardiomyopathy. Am J Med 1987; 83: 601.
    110. Weiner RS, Lockhart JT, Schwartz RG. Dilated cardiomyopathy and cocaine abuse; report of two cases. Am J Med 1986; 81: 699-701.
    111. Chokshi SK, Moore R, Pandian NG, Isner M. Reversible cardiomyopathy associated with cocaine intoxication. Ann Intern Med 1989; 111: 1039-1040.
    112. Henzlova MI, Smith SH, Prachal VM, Helmcke FR. Apparent reversibility of cocaine-induced congestive cardiomyopathy. Am Heart J 1991; 122: 577-579.
    113. Lam JB, Shub C, Sheps SG. Reversible dilation of hypertrophied left ventricle on phaeochromocytoma: serial two-dimensional echocardiographic observations. Am Heart J 1985; 109: 613-615.
    114. Om A, Ellham S, Ornato JP. Reversibility of cocaine-induced cardiomyopathy. Am Heart J 1992; 124: 1639-1641.
    115. Chakko S, Fernandez A, Mellman TA, et al. Cardiac manifestations of cocaine abuse: a cross-sectional study of asymptomatic men with a history of long-term abuse of crack cocaine. J Am Coll Cardiol 1992; 29: 1168-1174.
    116. Mondillo S, Agricola E, D'Aprile N, Nicoletti A, Palazzuoli V. Evaluation of diastolic function in patients addicted to recreational cocaine. Minerva Cardioangiol 1997; 45: 489-493.
    117. Kloner RA, Hale SA, Rezkalla S. The effects of acute and chronic cocaine use on the heart. Circulation 1992; 85: 407-419.
    118. Peng SK, French WJ, Pelikan PC. Direct cocaine cardiotoxicity demonstrated by endomyocardial biopsy. Arch Pathol Lab Med 1989; 113: 842-845.
    119. Virmani R, Robinowitz M, Smialek JE, Smyth DF. Cardiovascular effects of cocaine; an autopsy study of 40 patients. Am Heart J 1988; 115: 1068-1076.
    120. Barth CW III, Bray M, Roberts WC. Rupture of the ascending aorta during cocaine intoxication. Am J Cardiol 1986; 57: 496.
    121. Cohle SD, Lie JT. Dissection of the aorta and coronary arteries associated with acute cocaine intoxication. Arch Pathol Lab Med 1992; 116: 1239-1241.
    122. Edwards I, Rubin RN. Aortic dissection and cocaine abuse. Ann Intern Med 1987; 107: 779-780.
    123. Pavon-Jimenez R, Garcia-Rubira JC, Calderon-Leal J. Total occlusion of the left main coronary in a young cocaine user. Int J Cardiol 1999; 70: 87-90.
    124. Brody SL, Slovis CM, Wrenn KD. Cocaine related medical problems: consecutive series of 233 patients. Am J Med 1990; 88: 325-331.
    125. Delbono EA, O'Brien K, Murphy RLH. Lung sound abnormalities in cocaine freebasers. Substance Abuse 1989; 10: 201-208.
      126. Itkonen J, Scholl S, Glassroth J. Pulmonary dysfunction in freebase cocaine users. Arch Intern Med 1984; 144: 2195-2197.
      127. Tashkin DP, Simmons MS, Coulson AH, Clark VA, Gong H. Respiratory effects of cocaine 'freebasing' among habitual users of marijuana with or without tobacco. Chest 1987; 92: 638-644.
      128. Suhl J, Gorelick DA. Pulmonary function in male freebase cocaine smokers. Am Rev Respir Dis 1988; 137: 488-492.
      129. Klinger JR, Bensadoun E, Corrao WM. Pulmonary complications from alveolar accumulation of carbonaceous material in a cocaine smoker. Chest 1992; 101: 1171-1173.
      130. Rebhun J. Association of asthma and freebase cocaine. Ann Allergy 1988; 60: 339-342.
      131. Rubin RB, Neugarten J. Cocaine associated asthma. Am J Med 1990; 88: 438-439.
      132. Clinicopathologic Conference. Respiratory failure and eosinophilia in a young man. Am J Med 1993; 94: 533.
      133. Forrester JM, Steele AW, Waldron JA, et al. Crack lung: an acute pulmonary syndrome with a spectrum of clinical and histopathological findings. Am Rev Respir Dis 1990; 142: 462-467.
      134. Kissner DG, Lawrence WD, Selis JE, et al. Crack lung; pulmonary disease caused by cocaine abuse. Am Rev Respir Dis 1987; 136: 1250-1252.
      135. Oh PI, Blater MS. Cocaine induced eosinophilic lung diseases. Thorax 1992; 42: 478-479.
      136. O'Donnell AE, Mappin G, Sebo TJ, et al. Interstitial pneumonitis associated with crack cocaine abuse. Chest 1991; 100: 1155-1157.
      137. Dani YH, Lippmann ML, Goldberg SK, Walkenstein MD. The pulmonary complications of cocaine. Chest 1995; 107: 233-240.
      138. Aroesty DJ, Stanley RB, Crockett DM. Pneumomediastinum and cervical emphysema from the inhalation of freebase cocaine: report of three cases. Otolaryngol Head Neck Surg 1986; 94: 372-374.
      139. Birrer R, Calderon J. Pneumothorax, pneumomediastinum, and pneumopericardium following Valsalva manoeuvre during marijuana smoking. NY State J Med 1984; 84: 619-620.
      140. Bush MN, Rubenstein R, Hoffman I, et al. Spontaneous pneumomediastinum as a consequence of cocaine use. NY State J Med 1984; 84: 618-620.
      141. Miller WE, Spiekerman RE, Hepper NC. Pneumomediastinum resulting from performing Valsalva manoeuvre during marijuana smoking. Chest 1972; 62: 233-234.
      142. Morris JB, Sluck J. Pneumomediastinum in a young male cocaine user. Ann Emerg Surg 1985; 14: 194-196.
      143. Seaman ME. Barotrauma related to inhalational drug abuse. J Emerg Med 1990; 8: 141-149.
      144. Shesser R, Davis C, Edelstein S. Pneumomediastinum and pneumothorax after inhaling alkaloidal cocaine. Ann Emerg Med 1981; 10: 213-215.
      145. Weiner MD, Putman CE. Pain in the chest in a cocaine user. J Am Med Assoc 1987; 258: 2087-2088.
      146. Allred RJ, Ever S. Fatal pulmonary oedema following intravenous freebase cocaine use. Ann Emerg Med 1981; 10: 441-442.
      147. Cucco RA, Yoo OH, Creglar L, Chang JC. Non-fatal pulmonary edema after freebase cocaine smoking. Am Rev Respir Dis 1987; 136: 179-181.
      148. Lang SA, Maron MB. Hemodynamic basis for cocaine induced pulmonary edema in dogs. J Appl Physiol 1991; 71: 1166-1170.
      149. Murray RJ, Albin RJ, Mergner W, Criver GJ. Diffuse alveolar hemorrhage temporally related to cocaine smoking. Chest 1988; 93: 427-429.
      150. Murray RJ, Smialek JE, Golle M. Pulmonary artery medial hypertrophy in cocaine users without foreign particle microembolization. Chest 1989; 96: 1050-1053.
      151. Justiniani FR, Cabeza C, Miller B. Cocaine associated rhabdomyolysis and hemoptysis mimicking pulmonary embolism. Am J Med 1990; 88: 316-317.
      152. Roth D, Alacron FJ, Fernadez FA, et al. Acute rhabdomyolysis associated with cocaine intoxication. N Engl J Med 1988; 319: 673-677.
      153. Rubin RB, Neugarten J. Cocaine induced rhabdomyolysis masquerading as myocardial ischemia. Am J Med 1989; 86: 551-554.
      154. Leissinger CA. Severe thrombocytopenia associated with cocaine use. Ann Intern Med 1990; 112: 708-710.
      155. Delaney K, Hoffman RS. Pulmonary infarction associated with crack cocaine use in a previously healthy 23-year-old woman. Am J Med 1991; 261: 607-608.
      156. Wess RD, Goldenheim PD, Mirin SM, Hales CA, Mendelson JH. Pulmonary dysfunction in cocaine smokers. Am J Psychiatry 1981; 138: 1110-1112.
      157. Dean NC, Clark HW, Doherty JJ, et al. Pulmonary function in heavy users of freebase cocaine. Am Rev Respir Dis 1988; 137: 489-494.
      158. Cooper CB, Bai TR, Heyderman E. Cellulose granulomas in the lung of a cocaine sniffer. BMJ 1983; 286: 2021-2022.
      159. Dicpinigatis PV, Jones JG, Frymus MM, Folkert VW. Crack cocaine-induced syndrome mimicking sarcoidosis. Am J Med Sci 1999; 317: 416-418.
      160. Baldwin GC, Buckley DM, Roth MD, Kleerup EC, Tashkin DP. Acute activation of circulating polymorphonuclear neutrophils following in vivo administration of cocaine. A potential etiology for pulmonary injury. Chest 1997; 111: 698-705.
      161. Baldwin GC, Tashkin DP, Buckley DM, et al. Marijuana and cocaine impair alveolar macrophage function and cytokine production. Am J Respir Crit Care Med 1997; 156: 1606-1613.
      162. Barskey SH, Roth MD, Kleerup EC, Simmons M, Tashkin DP. Histopathologic and molecular alterations in bronchial epithelium in habitual smokers of marijuana, cocaine, and/or tobacco. J Nat Cancer Inst 1998; 90: 1198-1205.
      163. Kram HB, Hardin E, Clark SR, Shoemaker WC. Perforated ulcers related to smocking crack cocaine. Ann Surg 1992; 58: 293-294.
      164. Lee HS, LaMaute HR, Pizzi WF, Picard DL, Luks F. Acute gastroduodenal perforations associated with use of crack. Ann Surg 1990; 211: 15-17.
      165. Abramson DL, Gertler JP, Lewis T, Kral G. Crack-related perforated gastropyloric ulcer. J Clin Gastroenterol 1991; 13: 17-19.
      166. Niazi M, Kondru A, Levy J, Bloom AA. Spectrum of ischemic colitis in cocaine users. Dig Dis Sci 1997; 42: 1537-1541.
      167. Papi C, Candia S, Masci P, et al. Acute ischaemic colitis following intravenous cocaine use. Ital J Gastroenterol Hepatol 1999; 31: 305-307.
      168. Sudhakar CB, Al Hakeen M, MacArthur JD, Sumpio BE. Mesenteric ischemia secondary to cocaine abuse; case reports and literature review. Am J Gastroenterol 1997; 92: 1053-1054.
      169. Endress C, Gray DG, Wollshlaeger A. Bowel ischemia and perforation after cocaine use. Am J Roentgenology 1992; 159: 73-75.
      170. Freudenberger RS, Cappell MS, Hutt DA. Intestinal infarction after intravenous cocaine administration. Ann Intern Med 1990; 113: 715-716.
      171. Boutros HH, Pautler S, Chakrabarti S. Cocaine-induced ischemic colitis with small-vessel thrombosis of colon and gallbladder. J Clin Gastroenterol 1997; 24: 49-53.
      172. Hoang MP, Lee EL, Anand A. Histologic spectrum of arterial and arteriolar lesions in acute and chronic cocaine-induced mesenteric ischemia; report of three cases and literature review. Am J Surg Pathol 1998; 22: 1404-1410.
      173. Jawahar D, Leo PJ, Anandarao N, Pachter B. Cocaine-associated intestinal gangrene in a pregnant woman. Am J Emerg Med 1997; 15: 510-512.
      174. June R, Aks SE, Keys N, Wahl M. Medical outcome of cocaine bodystuffers. J Emerg Med 2000; 18: 221-224.
      175. McCarron MM, Wood JD. The cocaine body packer syndrome. Diagnosis and treatment. J Am Med Assoc 1983; 250: 1417-1420.
      176. Ndikum-Moffor FM, Schoeb TR, Roberts SM. Liver toxicity from norcocaine nitroxide, an N-oxidative metabolite of cocaine. J Pharmacol Exp Ther 1998; 284: 413-419.
      177. Oztecan S, Dogru-Abbasoglu S, Mutlu-Turkoglu U, Calay Z, Aykac-Toker G, Uysal M. The role of stimulated lipid peroxidation and impaired calcium sequestration in the enhancement of cocaine induced hepatotoxicity by ethanol. Drug Alcohol Depend 2000; 58: 77-83.
      178. Wanless IR, Dore S, Gopinath N, et al. Histopathology of cocaine hepatotoxicity; Report of four patients. Gastroenterology 1990; 98: 497-501.
      179. Duarte JG, do Nascimento AF, Pantoja JG, Chaves CP. Chronic inhaled cocaine abuse may predispose the development of pancreatic adenocarcinoma. Am J Surg 1999; 178: 426-427.
      180. Brecklin CS, Gopaniuk-Folga A, Kravetz T, et al. Prevalence of hypertension in chronic cocaine user. Am J Hypertens 1998; 11: 1279-1283.
      181. Thakur V, Godley C, Weed S, Cook ME, Hoffman E. Case reports. Cocaine-associated accelerated hypertension and renal failure. Am J Med Sci 1996; 312: 295-298.
      182. Welch RD, Todd K, Krause GS. Incidence of cocaine-associated rhabdomyolysis. Ann Emerg Med 1991; 20: 154-157.
      183. Parks JM, Reed G, Knochel JP. Case report; cocaine-associated rhabdomyolysis. Am J Med Sci 1989; 297: 334-336.
      184. Singhal P, Horowitz B, Quinones MC, et al. Acute renal failure following cocaine abuse. Nephrology 1989; 52: 76-78.
      185. Campbell BG. Cocaine abuse with hyperthermia, seizures and fatal complications. Med J Aust 1988; 149: 387-389.
      186. Leblanc M, Herbert MI, Mongeau IG. Cocaine-induced acute renal failure without rhabdomyolysis. Ann Intern Med 1994; 121: 721-722.
      187. Ruttenber AJ, McAnally HB, Wetli CV. Cocaine-associated rhabdomyolsis and excited delirium; different stages of the same syndrome. Am J Forensic Med Pathol 1999; 20: 120-127.
      188. Pollanen MS, Chiasson DA, Cairns JT, Young JG. Unexpected death related to restraint for excited delirium; a retrospective study of deaths in police custody and in the community. CMAJ 1998; 158: 1603-1607.
      189. Volcy J, Nzerue CM, Oderinde A, Hewan-Iowe K. Cocaine-induced acute renal failure, hemolysis, and thrombocytopenia mimicking thrombotic thrombocytopenic purpura. Am J Kidney Dis 2000; 35: E3.
      190. Tumlin JA, Sands JM, Somerea A. Hemolytic uremic syndrome following 'crack' cocaine inhalation. Am J Med Sci 1990; 299: 366-371.
      191. Byrnes JJ, Khurana M. Treatment of thrombotic thrombocytopenic purpura with plasma. N Engl J Med 1977; 297: 1389-1390.
      192. Goodman PE, Rennie WP. Renal infarction secondary to nasal insufflation of cocaine. Am J Emerg Med 1995; 13: 421-423.
      193. Sharff JA. Renal infarction associated with intravenous cocaine use. Ann Emerg Med 1984; 13: 1145-1147.
      194. Fogo A, Superdock R, Atkinson JB. Severe arteriosclerosis in the kidney of cocaine addict. Am J Kidney Dis 1992; 20: 513-515.
      195. Heng MC, Haberteld G. Thrombotic phenomena associated with intravenous cocaine. J Am Acad Dermatol 1987; 16: 462-468.
      196. Kramer RK, Turner RC. Renal infarction associated with cocaine use and latent protein C deficiency. South Med J 1993; 86: 1436-1438.
      197. Mattana J, Gibbons N, Singhal PC. Cocaine interacts with macrophages to modulate mesangial cell proliferation. J Pharmacol Exp Ther 1994; 271: 311-318.
      198. Attoussi S, Faulkner ML, Oso A, Umoru B. Cocaine-induced scleroderma and scleroderma renal crisis. South Med J 1998; 91: 961-963.
      199. Lam M, Ballou SP. Reversible scleroderma renal crisis after cocaine use. N Engl J Med 1992; 326: 1435.
      200. Gingras JL, Weese-Mayer DE, Hume R, O'Donnell K. Cocaine and development mechanisms of fetal toxicity and neonatal consequences of prenatal cocaine exposure. Early Human Dev 1992; 31: 1-24.
      201. Hawks RL, Kopin I, Colburn RW, Thoa NB. Norcocaine: a pharmacologically active metabolite of cocaine found in brain. Life Sci 1974; 15: 2189-2195.
      202. Chasnoff U, Lewis DE. Cocaine metabolism during pregnancy. Pediatr Res 1988; 23: 257-259.
      203. Chasnoff U, Lewis DE, Griffith DR, Willey S. Cocaine and pregnancy: clinical and toxicological implications for the neonate. Clin Chem 1989; 35: 1276-1278.
      204. Chasnoff U, Burns W, Scholl SH, Burns KA. Cocaine use in pregnancy. N Engl J Med 1985; 31: 666-669.
      205. Hurd WW, Robertson PA, Riemer K, Goldfien A, Roberts JM. Cocaine directly augments the alpha-adrenergic contractile response of the pregnant rabbit uterus. Am J Obstet Gynecol 1991; 164: 182-187.
      206. Chiriboga CA, Brust JC, Bateman D, Hauser WA. Dose-response effect of fetal cocaine exposure on newborn neurological function. Pediatrics 1999; 103: 79-85.
      207. Hoyme HE, Iones KL, Dixon SD, et al. Prenatal cocaine exposure and fetal vascular disruption. Pediatrics 1990; 85: 743-747.
      208. Chiriboga CA, Vibbert M, Malouf R, Suarez MS, Abrams EJ, Heagarty MC. Neurological correlates of fetal cocaine exposure; transient hypertonias of infancy and early childhood. Pediatrics 1995; 96: 1070-1077.
      209. Singer LT, Yamashita TS, Hawkins S, Cairns D, Baley J, Kliegman R. Increased incidence of intraventricular hemorrhage and developmental delay in cocaine-exposed, very low birth weight infants. J Pediatr 1994; 124: 765-771.
      210. Ostrea EM Jr, Ostrea AR, Simpson PM. Mortality within the first 2 years in infants exposed to cocaine, opiate, or cannabinoid during gestation. Pediatrics 1997; 100: 79-83.
      211. Tronick EZ, Beeghly M. Prenatal cocaine exposure, child development, and the compromising effects of cumulative risk. Clin Perinatol 1999; 26: 151-171.

      PHARMACOLOGY; SUBSTANCE-RELATED DISORDERS; cocaine-related disorders; TROPANES; cocaine; crack cocaine

      © 2002 European Academy of Anaesthesiology