History of Cocaine Use - Medical and Recreational Uses
Disclaimer: This dissertation has been submitted by a student. This is not an example of the work written by our professional dissertation writers. You can view samples of our professional work here.
Any opinions, findings, conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of UK Essays.
Cocaine through the ages: from elixir to poison.
Cocaine, a plant alkaloid derived from coca leaves is a potent stimulant of CNS and has local anesthetic action as well. Historically, it was ingested in the form of chewing coca leaves, to suppress hunger and fatigue. With discovery of its local anesthetic properties, cocaine was introduced into world of medicine and a local anesthetic, but over last few decades, gained popularity as drug of abuse. Cocaine carries with it great potential for addiction and abuse. It is administered through various routes, smoking free-base crack and intranasal inhalation being most popular. It's primarily metabolized in liver and distributed to all body tissues. Due to lipid nature it tends to concentrate in brain and adipose tissues with chronic administration. It's mainly eliminated through kidneys, but saliva and stools are also routes of excretion. A number of health hazards have been shown to be associated with cocaine use including, cardiac abnormalities, psychological disturbances, addiction potential and renal failure with or without rhabdomyolysis. Acute and chronic cocaine toxicities with sufficient collected data are included. Techniques for detecting cocaine in blood including enzyme linked immunoassay and POCT (Point of care screening tests) have also been discussed. An analysis of recent trends in cocaine uses have been studied and presented along with graphical illustrations of epidemiological evidence to support the data.
Introduction and objective:
Objective: to display how cocaine has evolved through time in its uses and available forms, from simple coca leaf chewing custom of South Americans in 2500 BC to modern forms of freebase-coke among others as one of the most commonly abused toxic drug.
Data was mainly collected from electronic resources, but text on immunology and pharmacology was also consulted. From electronic sources, I mainly used search engines using a number of keywords including ; history of cocaine, crack, pharmacokinetics of cocaine, mode of action , coca leaf, acute cocaine poisoning, chronic cocaine toxicity, Karl Koller, Sigmund Freud, Immunoassay, etc. I also went through a number of journals available online, and a number of researches conducted which related to cocaine. My aim was to find changes in cocaine use from its discovery to date, and show, with help of collected data, that it has moved in a negative direction.
- Brief history:
Cocaine, use of which, according to some sources, date back to at least 1200 years, has now, rightfully, earned itself a place in drugs of abuse list among others like Caffeine, Nicotine, Amphetamine, etc. To date, cocaine's uses have evolved from gaining popularity as topical anesthetic agent, and as component of energizing drinks to becoming one of the most abused drugs in the world. It is a powerfully addictive stimulant drug, which acts by interfering with cerebral and peripheral synaptic transmission among neurons. Mode of action has been described in greater detail later in pharmacodynamics section, but for brief introduction, it interferes with reuptake of, and thereby enhance duration of action of, monoamines, dopamine, serotonin and nor epinephrine Brain PF et.al (1989). It also produces membrane stabilizing effect, more commonly referred to as local anesthetic effect. Latter is achieved through modulation of voltage gated sodium channels and consequent blockade of sensory impulses conduction from that part of the neuron to central nervous system. Brain PF et.al (1989)
Earliest records of cocaine use reveal it to be a part of South American custom of chewing coca leaves. This use is believed to date back to 2500BC. Steven Cohen (1981) Practice of chewing mixture of tobacco and coca leaves was defined by Nicolás Monardes, in 1569, to induce “great contentment”. Cocaine is the active component of coca leaves, which also contains nicotine. Karch SB (1998).
In 1859, Italian doctor, Paulo Montegazza, after witnessing coca use by natives of Peru, and getting mesmerized by it, decided to study the effects of cocaine on himself. After his studies he concluded his findings into a paper in which he declared cocaine to be medically useful in treating furred tongue in the morning, flatulence and whitening the teeth. Steven R. King (1992).
In 1863, French chemist, Angelo Mariani, introduced popular cocavine, Vin Mariani. Vin Mariani wasproduced from mixture of 6 mg coca leaves per fluid ounce of Bordeaux wine. Courtwright DT (2001) Angelo Mariani, creator of Vin Mariani, which later became the hallmark of cocavines was honored with Vatican gold medal by Pope Leo XIII for this achievement. Ethanol, a component of vin mariani, is believed to extract cocaine from coca leaves. In 1884, the concept of cocavine was adopted by John S. Pemberton, with introduction of Pemberton's French Wine Coca. After prohibitions imposed on cocaine use and manufacture of cocaine-containing products including cocavine in 1885, Pemberton introduced carbonated, non-alcoholic form of Vin Mariani and called it Coca-cola. Richard Ashley (1975). From 1906 onwards, however, after Pure Food and Drug act was passed, decocainised forms of coca were used for manufacture of coca-cola.
In 1884, Austrian physician Sigmund Freud, recommended cocaine for treatment of morphine and alcohol addiction. A strategy that was later employed in 1879 when cocaine was used to treat morphine addiction. Steven Cohen (1981). In his published word, Über Coca, Sigmund defined effects of cocaine in following words:
“...exhilaration and lasting euphoria, which in no way differs from the normal euphoria of the healthy person...You perceive an increase of self-control and possess more vitality and capacity for work....In other words, you are simply normal, and it is soon hard to believe you are under the influence of any drug....Long intensive physical work is performed without any fatigue...This result is enjoyed without any of the unpleasant after-effects that follow exhilaration brought about by alcohol....Absolutely no craving for the further use of cocaine appears after the first, or even after repeated taking of the drug...”
In 1985, use of cocaine for induction of spinal anesthesia was accidentally discovered by American neurologist Leonard Corning while he studying the effects of cocaine on spinal nerves in a dog and accidentally pierced the dura matter. Corning JL (1885) Cocaine was, however, not used as anesthetic in spinal surgery until 1989 when first planned cocaine induced spinal anesthesia was administered in a surgery, by August Bier. A. Bier, (1899)
Coca leaves have traditionally been used as suppressants for fatigue, thirst, and hunger. Its use has now been limited to Andean countries, where coca leaf chewing and coca tea consumption are still practiced. Industrially, coca leaves serve as source of drug cocaine, and in some cosmetic and food industries, including coca cola. Richard Ashley (1975) From 1980s to date, cocaine has gained popularity as drug of abuse, and has widely replaced heroin and other narcotics as drug of abuse, being used in different forms and administered via various routes. Richard Ashley (1975)
Discovery of cocaine, as local anesthetic, is claim to fame for Austrian ophthalmologist, Karl Koller. Koller's name is credited with demonstration of anesthetic effect of cocaine, in 1884. Karl Koller was a close associate of Sigmund Freud who in same year recommended cocaine to be employed in treatment for morphine and alcohol addiction. Hruby K (1986). Koller studied effects of cocaine on eye by applying the drug to his own eye and later pricking it with pins. He presented his findings to the Heidelberg Ophthalmological Society in same year. Hruby K (1986)
After successfully experimenting on himself, Koller used cocaine as local anesthetic in eye surgeries, a use that continues to this day. Cocaine was later employed in other fields including dentistry for induction of local anesthesia, Today, however, cocaine has largely been replaced by other local anesthetic agents like lidocaine, xylocaine, bupivacaine, etc, which produce local anesthetic effect as efficiently and do not carry potential for abuse.Hruby K (1986)
Friedrich Gaedcke, aGerman chemist, was first person to successfully isolate cocaine from coca leaves, in 1855. An improved isolation process was, however, developed by Albert Niemann, who was enrolled as a Ph.D. student at a German university, University of Gottingen , in 1859. Niemann wrote a dissertation describing steps of isolation which was published in 1860 and was entitled, “ Über eine neue organische Base in den Cocablättern” (On a New Organic Base in the Coca Leaves). F. Gaedcke (1855)
Formal Chemical Name (IUPAC) for cocaine:
Chemical structure of cocaine: Structure of cocaine molecule was first defined by Richard Willstätter in 1898.
Medicalisation and popularization:
Ever since its discovery, cocaine's medical uses were quickly exploited through research and experimentation. Spanish physicians described first medical uses of cocaine as early as 1596, but the use of cocaine did not become more widespread until 1859, when Albert Niemann isolated the drug from coca leaves. Soon after it was isolated, cocaine was used to try to cure almost all the illnesses and maladies that were known to man. (Albert Niemann 1860)
1859's Montagezzi's discovery about cocaine being useful in treating furred tongue in the morning, flatulence and whitening the teeth, was one of the earliest recorded studies that signified possible medical importance of cocaine.
In 1879, Vassili von Anrep, of the University of Würzburg, demonstrated analgesic properties of cocaine in an experiment that he conducted on a frog. He prepared two separate jars, one containing cocaine-salt solution, other containing salt water serving as control. One of frog's legs was submerged in cocaine solution and other in control followed by stimulation of leg in different ways. Reactions in two legs varied considerably. In the same year, cocaine began to be used in treatment of morphine addiction.
The commercial production of purified cocaine gained momentum only in the mid-1880s. Its greatest medical value was in ophthalmology. Eye-surgery stood in desperate need of a good local anesthetic. This was because in eye operations it is often essential for a conscious patient to move his eye as directed by the surgeon - without flinching. Karl Koller's demonstration of anesthetic properties of cocaine in 1884 was an important breakthrough establishing cocaine's importance, medically when it was introduced in Germany as local anesthetic for eye surgery. (Altman Aj et.al 1985)
Koller's discovery was later followed in 1985 by Leonard Corning's accidental demonstration of cocaine's use in induction of spinal anesthesia, which became formally employed in spinal surgery in 1989 when first planned cocaine induced spinal anesthesia was administered by August Bier.
Medical use of cocaine has largely been restricted to induction of local anesthesia. Even as local anesthetic agent, discovery of hazardous effects of cocaine use led to early development of safer alternative drugs like lidocaine, etc.
One of its first non medical uses of cocaine was in military. In 1883 Theodor Aschenbrandt administered cocaine to members of the Bavarian army. It was found that the drug enhanced their endurance on maneuver. His positive findings were published in a German medical journal, which brought the effects of this wonder drug to a wider medical audience, including Sigmund Freud.
Following is taken from “On cocaine” by Sigmund Freud.
“A few minutes after taking cocaine, one experiences a certain exhilaration and feeling of lightness. One feels a certain furriness on the lips and palate, followed by a feeling of warmth in the same areas; if one now drinks cold water, it feels warm on the lips and cold in the throat. One other occasions the predominant feeling is a rather pleasant coolness in the mouth and throat.
During this first trial I experienced a short period of toxic effects, which did not recur in subsequent experiments. Breathing became slower and deeper and I felt tired and sleepy; I yawned frequently and felt somewhat dull. After a few minutes the actual cocaine euphoria began, introduced by repeated cooling eructation. Immediately after taking the cocaine I noticed a slight slackening of the pulse and later a moderate increase.
I have observed the same physical signs of the effect of cocaine in others, mostly people my own age. The most constant symptom proved to be the repeated cooling eructation. This is often accompanied by a rumbling which must originate from high up in the intestine; two of the people I observed, who said they were able to recognize movements in their stomachs, declared emphatically that they had repeatedly detected such movements.
Often, at the outset of the cocaine effect, the subjects alleged that they experienced an intense feeling of heat in the head. I noticed this in myself as well in the course of some later experiments, but on other occasions it was absent. In only two cases did coca give rise to dizziness. On the whole the toxic effects of coca are of short duration, and much less intense than those produced by effective doses of quinine or salicylate of soda; they seem to become even weaker after repeated use of cocaine.”
Cocaine was sold as over the counter drug until 1916. It was widely used in tonics, toothache cures, patent medicines, and chocolate cocaine tablets. Prospective buyers were advised (in the words of pharmaceutical firm Parke-Davis) that cocaine "could make the coward brave, the silent eloquent, and render the sufferer insensitive to pain".
Cocaine was a popular ingredient in wines, notably Vin Mariani. Coca wine received endorsement from prime-ministers, royalty and even the Pope. The Vatican gold medal that Angelo Mariani received for it will forever signify the popularity of cocaine through that period of time.
By the late Victorian, era use of cocaine had appeared as a vice in literature, for instance, Arthur Conan Doyle's fictional Sherlock Holmes.
Number of admissions to drug treated programme in each year is plotted against time for both cocaine and heroin. Graph clearly displays the shift in trend from use of heroin towards cocaine. A combination gaining popularity is speedball, which is formulated by mixing heroin with cocaine.
From 1980s to date, cocaine has gained popularity as drug of abuse, being used in different forms and administered via various routes, as evident by figure above which displays the escalation in crack / cocaine usage with concomitant reduction in heroin use.
In first part of the twentieth century, with addictive properties of cocaine becoming more apparent with studies, cocaine found itself legally prohibited. Harrison Narcotics Tax Act (1914) outlawed unauthorized sales and distribution of cocaine incorrectly classifying it as a narcotic.
In United Nations' 1961 Single Convention on Narcotic Drugs, cocaine was listed as Schedule I drug, thereby making its manufacture, distribution, import, export, trade, use and possession illegal unless sanctioned by the state.
In 1970's controlled substances act, cocaine was listed as a Schedule II drug in United States. It carries high abuse potential but also serves medicinal purpose. It is a class A drug in the United Kingdom, and a List 1 drug of Opium law in the Netherlands.
In late 90s and early 2000s, crack became very popular among Americans and in past few years has also taken its toll on UK. According to an estimate, U.S cocaine market exceeded $ 70 billion in year 2005, demonstrating the popularity of this menace. News reports are flooded with celebrity arrests on charge of cocaine posession or use. A section on recent facts and figures related to cocaine discusses the modern trends in greater detail later.
Along with amphetamine, cocaine is one of the most widely abused drugs in the world. Powerful stimulant properties of cocaine are beyond doubt. By inhibiting neuronal reuptake of excitatory neurotransmitters, dopamine, serotonin and norepinephrine, cocaine enhances synaptic concentrations of these neurotransmitters in specific brain areas; nucleus accumbens and amygdala which are referred to as the reward center of brain. During 1980s, cocaine widely replaced heroin as drug of abuse, due to its euphoric properties, wide availability and low cost.
Different forms and Routes of administration of cocaine:
Crack, freebase or smokable form of cocaine, was produced and became popular drug of abuse in 1980s. Earliest reports of crack use indicate an epidemic in Bahamas from 1980. By 1985, crack gained popular ranking among drug users across America.Crack is produced by mixing 2 parts cocaine hydrochloride with one part baking soda (sodium bicarbonate). It differs from cocaine hydrochloride in being more volatile, a property that makes it better suited for inhalation administration (smoking) than cocaine hydrochloride. Smoking freebase cocaine releases methylecgonidine, an effect not achieved with insufflation or injection (described later), thereby making it a specific test marker for freebase cocaine smokers. Studies suggest that methylecgonidine is more harmful to heart, liver and lungs than other byproducts of cocaine. Inhalation leads to rapid absorption of cocaine into bloodstream via lungs, reaching brain within five seconds of ingestion. Following rush exceeds snorting in intensity but does not last long.
Ancient tradition of South Americans to chew coca leaves in same manner is tobacco, is another method of cocaine consumption. Alternatively, coca leaves may be consumed like tea by mixing with liquid. Coca leaf consumers have raised a controversy over whether it should be abandoned or not. Rationale behind this controversy is that strong acid in our stomach hydrolyzes cocaine, attenuating its effects on brain; therefore, unless it is taken with an alkaline substance, such as lime, which neutralizes stomach's acid, cocaine intake should not be criminalized. Cocaine is also used as oral anesthetic, both medically and unofficially. Cocaine powder is applied to gums to numb the gingiva and teeth. Colloquial terms for this route of administration are; "numbies", "gummies" and "cocoa puffs".
Another method for oral administration, commonly known as snow bomb, is to pack cocaine in rolled up paper and swallowing it.
Colloquial terms for which are; "snorting," "sniffing," or "blowing" is believed to be most commonly employed method of cocaine ingestion in west. Cocaine is poured on a flat, hard surface and divided into fine powder before being insufflated in “bumps”, “lines”, or “rails”. Devices used as aid in insufflation are known as “tooters”. Anything small and hollow, such as straws cut short, can serve as a tooter.
This achieves the greatest bioavailability, 100%, in shortest span of time, since drug is directly administered into bloodstream saving time and reduced bioavailability that occurs with drug absorption from site of drug administration into bloodstream. Resultant rush is intense and rapid. Risk of contracting blood-borne infections is greatest.
“Speedball”, a mixture of cocaine with heroin used intravenously is a popular and dangerous method of cocaine ingestion. It claims credit for many deaths, including celebrities like John Belushi, Chris Farley ,Mitch Hedberg, River Phoenix and Layne Staley.
- ADME Pharmacokinetics:
Absorption, Distribution, Metabolism and Excretion of Cocaine.
Before beginning discussion about pharmacokinetics or ADME of cocaine, table below summarizes the relationship of route of administration with onset of action, time taken to achieve peak effect, duration of action and half life. (Clarke, 1986)
Route of administration
Peak effect (min.)
Absorption refers to movement of drug from site of administration into bloodstream.As with any drug, absorption of cocaine depends on various factors and varies considerably with them. Factors which influence drug absorption include; drug formulation, route of administration, lipid solubility, pH of the medium, blood supply and surface area available for absorption. As evident from tabulated figures above, cocaine differs greatly in onset of action varying between 7 seconds up to 10 minutes from one route of administration to another. This is a factor of absorption of drug which depends on route of administration. Each route is separately discussed below in greater details. (Clarke, 1986).
Orally administered cocaine:
Cocaine induces vasoconstriction in vessels supplying oral mucosa and resultant reduction in blood supply slows down its absorption by decreasing surface area from which drug is absorbed. Therefore when orally administered, drug is slowly absorbed into bloodstream, taking roughly 30 minutes. Absorption is also incomplete; roughly one third of administered dose is absorbed. Due to slow absorption, onset of action is also delayed and peak effect is, however, not achieved until about 50-90 minutes after administration. Effect is, however, longer lasting, roughly 60 minutes after attainment of peak effect.
Another factor affecting absorption of orally administered cocaine is pH of the stomach. As previously mentioned, stomach acid hydrolyzes cocaine, resulting in inadequate and incomplete absorption. To improve absorption it is common practice to take cocaine along with an alkaline liquid to neutralize acidic pH.
Insufflations results in coating of the mucosa covering sinuses with cocaine, from where it is absorbed. Absorption is similar to that from oral cavity, cocaine induced vasoconstriction beneath mucosa results in slow and incomplete absorption (30-60%). Efficiency of absorption increases with concentration of drug. According to a study, time taken to reach peak effect via this route of administration averages 14.6 minutes.
Injected cocaine is directly administered into bloodstream eliminating need for absorption. According same study, as mentioned for insufflation, time taken to reach peak effect of cocaine through injection averaged 3.1 minutes, roughly five times less than time for insufflation.
Smoking crack delivers large quantities of the drug to the lungs, resultant absorption is rapid and effects created are comparable to intravenous administration. These effects, which are felt almost immediately after smoking, are intense and last for 5-10 minutes. According to Perez-Reyes et al, 1982, volunteers who smoked 50 mg of cocaine base in a controlled study experiment achieved rapidly elevated plasma cocaine level compared to intravenous cocaine administration.
Following absorption into bloodstream, cocaine is distributed, via blood, to all body tissues including vital organs like brain, lungs, liver, heart, kidneys and adrenals. It crosses both blood-brain and placental barrier. Being lipid soluble, it easily traverses biological membranes via simple diffusion. It is believed to accumulate in brain and adipose tissue with repeated administration, owing to its lipid nature. In an experiment, distribution and kinetics of cocaine in human body were studied using Positron Emission Topography (PET) technique with radioactively labeled (carbon-11) cocaine on 14 healthy male subjects. Rate of uptake and clearance were found to vary among organs. Following results were obtained for time, in minutes, taken by radioactively labeled cocaine to reach peak value in following organs:
Lungs: 45 seconds.
Heart and Kidneys: 2-3 minutes.
Adrenals: 7-9 minutes.
Liver: 10 minutes.
Liver, which is the key site for metabolism of cocaine is where distribution is most sluggish, increasing the half-life of cocaine. The Journal of Nuclear Medicine ( 1992 )
As already mentioned, cocaine is primarily metabolised in liver. It is estimated to get metabolized within two hours of administration. Half-life varies between 0.7 - 1.5 hours (Clarke, 1986), depending on route of administration among various other factors. There are three possible routes for bio-transformation of cocaine.
- Ester linkages in cocaine are hydrolyzed by plasma pseudocholinesterases and hepatic enzymes, human liver carboxylesterase form 1 (hCE-1)and human liver carboxylesterase form 2 (hCE-2). Benzoyl group is eliminated to produce ecgonine methyl ester. This is the major route for metabolism of cocaine.
- A secondary route, suggested by Fleming et al. 1990, proposes spontaneous hydrolysis, possibly non-enzymatic, followed by demethylation to produce benzoylecgonine.
- N-demethylation of cocaine is a minor route which leads to formation of norcocaine.
Final degradation of metabolites yields ecgonine.
Principal inactive metabolites are; benzoylecgonine, ecgonine methyl ester, and ecgonine itself. Norcocaine is an active metabolite and may reveal itself in acute intoxication.
Metabolism of cocaine may be influenced by a number of factors:
- Alcohol:When cocaine is co-administered with alcohol a compound called Cocaethylene is formed. Cocaethylene is associated with an increased risk of liver damage and premature death.
- Liver disease.
- Aged men.
- Congenital cholinesterase deficiency.
In all the aforementioned conditions, except alcohol, rate of cocaine metabolism is reduced, leading to elevated levels and duration of action of cocaine, enhancing its harmful effects of on the body. Following is a schematic representation of metabolic pathways of cocaine.
According to Andrew (1997) have found that the continuous use of alcohol with cocaine produce cocaethylene which is similar in the action of cocaine but it has more blood stream concentration by three to five times than cocaine as a result of its high half life. It's much attractive to be used for abuse as a result of slower removal from the body. Different types of side effects are associated with cocaethylene like liver damage, seizure and immuno compromised functioning . Cocaethylene has more possibility for sudden death by 18 - 25 times than using cocaine alone .
Butyrylcholinesterase (BChE) has been implicated as being important in metabolism of cocaine, even though it has limited capacity to fully hydrolyze cocaine. BChE is specially essential for cocaine detoxification. A lot of research has been done to study the effect of employing this enzyme in cocaine detoxification and in anti-cocaine medications. The rate at which human BChE hydrolyzes cocaine is slow; however, scientists at Eppley Institute and Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, have developed a mutant (A328Y) of human butyrylcholinesterase, which promises four fold greater efficiency in accelerating cocaine metabolism.
- Elimination or excretion:
1-9% of cocaine is excreted unaltered in urine along with metabolites, ecgonine methyl ester, benzoylecgonine, and ecgonine. Unchanged cocaine may also be eliminated through GI tract and/or be excreted in saliva. Most of the parent drug is eliminated from plasma within 4 hours after administration but metabolites may remain detectable for up to 144 hours after administration. Elimination of cocaine via kidneys is enhanced by acidification of urine. As already mentioned, cocaine easily traverses placental barrier, and the active metabolite, norcocaine is believed to persist in amniotic fluid for up to 5 days. In lactating mothers, cocaine and benzoylecgonine are excreted into maternal milk and can be detected up to 36 hours after administration. In smokers, cocaine is rapidly eliminated through exhalation of vapor. Ambre J et.al (1988)
In an experiment, the effects of chronic oral cocaine administration in healthy volunteer subjects with a history of cocaine abuse were investigated. There were sixteen daily sessions of oral cocaine administration while subjects were kept in a controlled clinical ward. In every session subjects received five equal doses of oral cocaine at one hour interval. Throughout sessions, cocaine was administered in ascending doses from an initial dose of 100 mg (500 mg/day) up to 400 mg (2 g/day), increasing by 25 mg/dose/session (125 mg/session). Urine specimens were collected throughout the study while plasma and saliva specimens were collected periodically during the dosing sessions and during the one-week withdrawal phase at the end of the study. Specimens were analyzed for cocaine and metabolites by solid-phase extraction followed by gas chromatographic-mass spectrometric analysis in the SIM mode. Half-lives of urinary elimination for cocaine and metabolites were determined by constructing ARE (amount remaining to be excreted) plots. Result that was obtained yielded two phases of urinary elimination of cocaine and its metabolites. An initial elimination phase during withdrawal which was similar to the elimination pattern observed after acute dosing, and a terminal phase.
Results were as follows:
Mean plasma cocaine elimination half-life: 1.5 ± 0.1 h.
Mean salivary cocaine elimination half-life: 1.2 ± 0.2 h.
Mean urinary cocaine elimination half-life: 4.1 ± 0.9 h.
Mean urinary cocaine elimination half-life: 19 ± 4.2 h.
A terminal elimination phase was also observed for cocaine metabolites with half-life estimates ranging from 14.6 to 52.4 h, which greatly exceeded previous estimates from studies of acute cocaine administration. This experiment shows that with chronic use, cocaine accumulates in the body with resultant prolonged terminal elimination phase for itself and its metabolites.
Like any pharmacokinetic feature of a drug, elimination may also be influenced by various factors. Since renal elimination is major route for cocaine excretion, state of renal function is essential determinant of efficiency of elimination. Patients with poor renal function are much more likely to develop toxicity than those with properly functioning kidneys. Also, as already mentioned, acidification of urine accelerates the elimination of cocaine from the body. Drummer O.H et.al ( 2001)
- Pharmacodynamics of cocaine:
Mechanism of action.
Cocaine mediates its actions through two basic mechanisms:
- Inhibition of re-uptake of monoamines; dopamine, nor adrenalin, and serotonin.
- Blockade of sodium channels.
Blockade of sodium channels: Membrane stabilizing effect.
As previously stated, a major breakthrough in field of surgery was discovery of cocaine and establishment of its use as a local anesthetic. All local anesthetics achieve their effect by same mechanism, known as membrane stabilizing effect. They achieve this by blocking the voltage - gated sodium channels in neuronal membranes. Figure 1.0 shows the action of cocaine on sodium channels.
Nerves carry impulses in the form of action potentials. Conduction of action potential involve a wave of depolarization, followed by repolarization, to travel along the nerve fiber. Depolarization, movement of membrane potential away from resting potential, is achieved through opening of voltage gated sodium channels and consequent influx of sodium. Local anesthetics reversibly reduce the rate of depolarization and repolarization by blocking these voltage gated sodium channels and eventually, impulse conduction is completely obliterated. Since local anesthetics prevent depolarization of membranes, membrane potential stays near resting levels; this is why it is called membrane stabilizing effect.
Local anesthetic drugs more readily target the "open" sodium channels, thus onset of neuronal blockade is faster in neurons that are rapidly firing. This is referred to as state dependent blockade.Local anesthetic action of cocaine is pH dependant. Potency and rate of action tends to decrease with the pH.
Inhibition of re-uptake of monoamines; dopamine, nor adrenalin, and serotonin.
Image above, taken from web, clearly demonstrates the action of cocaine (shown as yellow block in the figure) on dopamine re-uptake. Figure on the left shows normal process of synaptic transmission from a dopaminergic nerve terminal. Dopamine is secreted by the nerve terminal into synaptic cleft and subsequently binds to its receptor on post synaptic membrane. This is followed by its re-uptake via dopamine re-uptake transporter on neuronal membrane back into nerve terminal where it is degraded by MAO (Monoamine oxidase) into monoamines.
Figure on right shows similar synapse, in presence of cocaine. Cocaine binds to dopamine re-uptake transporter, forming a complex and blocking the re-uptake of dopamine back into nerve terminal greatly increasing the concentration of neurotransmitter in synaptic space, as evident by the picture.
A brain signaling pathway of particular interest for cocaine addiction research includes dopaminergic neurons originating in ventral tegmentum and terminating in nucleus accumbens. This pathway, believed to function as reward center, meaning it gets activated when a person experiences gratification of his/her needs in form of food or intimate desires. Cocaine administration has been shown to display activity in this reward center.
Action on adrenergic and serotonin receptors is similar. In case of serotonin, multiple receptors are believed to be involved including 5HT-3 and 5HT-2.
Peripherally, cocaine potentiates actions of noradrenaline, and produces the typical ‘fight or flight' sympathetic response of tachycardia, hypertension, pupillary dilatation and peripheral vasoconstriction. Physiological actions of cocaine are therefore achieved indirectly through potentiation of action of dopamine and other monoamines.
One possible mechanism for cocaine - induced cerebrovasospasm was, however, demonstrated in an experiment that was designed to study effect and possible mechanism of action of cocaine on cerebrovascular tissues. Results were as follows.
Acute exposure caused vasospasm in isolated canine basilar and middle cerebral arteries in a dose-dependant manner, but not in mesenteric arteries. Sensitivity to cocaine was higher in isolated canine basilar arteries compared to middle cerebral. Vasospasms remained unaffected by addition of a variety of amine antagonists, an opiate antagonist andan N-MDA receptor antagonist. However, haloperidol, indomethacin, verapamil and excessof Mg2+ as well as removal of Ca2+ completely preventedcocaine induced vasospasms. Intracellular free Ca2+ levels in cultured cerebral vascular muscle cells were rapidly elevated by cocaine to 50% over initial resting level.
Results suggest a direct action of cocaine on cerebral vasculature by promoting calcium influx and elevating intracellular calcium levels in cerebral vascular muscle cells, which may be modulated by magnesium. Circulation. ( 1999 )
According to data from the Lancet, cocaine is second most addictive and second most harmful of twenty drugs. Cocaine's effect on central nervous system as a stimulant has already been pointed out with respect to its effect on brain's reward center. Its stimulant effect may persist for several minutes or hours depending upon the dosage of cocaine taken, purity, and method of administration.
Cocaine toxicity can be broadly classified into two sub headings:
Acute cocaine poisoning:
Cocaine remains the chief candidate claiming credit for visits to the emergencydepartment (ED). A majority of acute cocaine toxicitycases involve young, habitual, adult cocaine users and oftenpresent with a range of cardiac, neurological, gastrointestinal(GI) or renal symptoms. Aside from alcohol and tobacco, cocaine is the most common cause of drug-related ED visits in the United States, accounting for nearly twice the number of reports to the Drug Abuse Warning Network (DAWN) as does marijuana or hashish, the second leading cause. Patients who present to the ED with cocaine toxicity often have a combination of other drugs along with cocaine in their system. The combined use of alcohol and cocaine is the most common reason for drug-related ED visits in the United States and may be the major cause of drug-related deaths. The toxicities of cocaine are far-ranging. They include sudden death, acute medical and psychiatric illness, infectious complications, reproductive disturbances, trauma, criminal activities and societal disruption, including child neglect and abuse and lost job productivity.
Complications of cocaine use can be broadly classified into:
Medical complications of cocaine, in general, reflect the intense sympathomimetic activities of cocaine.
Psychiatric complications include acute anxiety or panic and paranoid psychosis.
Cardiovascular complications include arrhythmias and sudden death, acute myocardial infarction, myocarditis, dissecting aneurysm and bowel infarction. Vascia Gabriella et.al ( 2002 )
Neurological complicationsinclude seizure, intracerebral hemorrhage and brain injury due to hyperthermia and/or seizures, and headache.
Initial signs of cocaine stimulation include; hyperactivity, agitation, hypertension, tachycardia and intense euphoria. Latter withers away as cocaine gets metabolized, leaving person in a state of discontentment and craving for more. It may be accompanied by amplification of intimate desires. Side effects that include, twitching, psychological disturbances, hallucinations, tachycardia and impotency, usually increase with frequent usage, and may also occur as a consequence of excessive dosage.
Particularly alarming for patients with existing cardiac problems are potentially fatal tachyarrhythmias and marked hypertensive state that can result from cocaine overdose. Experimental injection of acute toxic doses in mice reveals grand-mal seizures which are followed by depression of respiratory and circulatory centers in medulla. Death may result as a consequence of respiratory failure, stroke, or myocardial infarction. Most acute cocaine-related nontraumatic deaths are consequence of tachydysrhythmias. Other causes of sudden death associated with cocaine use include stroke, subarachnoid hemorrhage, hyperthermia, and the consequences of agitated delirium.
Cocaine is highly pyrogenic, stimulation of adrenergic system and increased muscular activity leads to greater heat production than can be eliminated from the system. Inhibition of heat dissipation results from intense vasoconstriction. Resulting hyperthermia can reach levels at which muscle death occurs. Dying muscles release myoglobin leading to myobloginuria which, unless controlled, may lead to acute renal failure.
Mood elevating action of cocaine, mediated via potentiation of mainly dopaminergic transmission in nucleus accumbens, the pleasure center of brain, ceases as cocaine gets metabolized to inactive products and as dopamine gets depleted in neuronal spaces, a process known as tachyphylaxis. Tachyphylaxis tends to produce, what we previously referred to as state of discontentment after the initial high, referred to as “crash”. The "crash" is accompanied with muscle spasms throughout the body, also known as the "jitters", muscle weakness, headaches, dizziness, and suicidal thoughts. These symptoms may not be experienced by every cocaine user. However, mostly users experience some or all of these “crash” symptoms.
Studies suggest that cocaine use during pregnancy may induce premature labor. In case of acute cocaine intoxication, any non - emergency surgical procedures should be delayed until sings of acute cocaine intoxication have disappeared, but this may not be possible in obstetric patients where acute cocaine intoxication may cause fetal distress and placental abruption. Cocaine can therefore be related to recreational habit of mother for which her fetus pays the price. Also, cocaine use during pregnancy may result in persistent behavioral abnormalities in the newborn. Animal studies show behavioral and neurochemical alterations in offspring that were exposed to cocaine prenatally. The monoamine neurons, including those containing dopamine, appear and become operational prenatally and mature during early postnatal life. According to Journal of Neuroscience ( 2007 ).
It is therefore conceivable that exposure to cocaine during gestation may critically affect normal development and subsequently cause protracted postnatal neurochemical and behavioral changes. According to one study, low-dose intravenous cocaine administration to pregnant rabbits causes permanent structural alterations in dopamine-rich cerebral cortical areas, substantially reduced dopamine D1 receptor coupling to G(s)-protein, and deficits in cognitive function. Collected data suggested that prenatal exposure to cocaine causes a novel, long-lasting adaptive response in the subcellular distribution of D1 receptors, resulting in alterations in signaling capacity that have developmental and behavioral consequences. Ann N Y Acad Sci. ( 1998 )
The recent epidemic of cocaine abuse, especially among young individuals, has caused increasing concern about the potential hazards of prenatal cocaine exposure on the developing fetus and newborn. Although large-scale epidemiologic studies and long-term data are lacking, a review of the literature suggests strongly that the popular belief about the relative safety of cocaine is unfounded and that maternal cocaine abuse during pregnancy may be associated with increased perinatal morbidity and mortality. Pediatric Neuroscience ( 1989 ) .
Investigators have discovered that cocaine, in concentrations commonly sold on the streets, cause abnormal buildup of primitive proteins in heart muscle - a process that ultimately leads to heart enlargement and may result in sudden death. This study was published in July 2006 issue of the Journal of Cardiovascular Pharmacology. Dr. Henning and his colleagues used heart muscle cells from adult rat to discover that cocaine induces activity of enzyme calmodulin kinase II (CaMK). CaMK II is involved in increasing cytosolic concentration of calcium ions within cardiac muscle cells. The increase in calcium appears to be a key promoting factor for accumulation of primitive fetal proteins which are not a normal finding in adult cardiac muscle cells - a process that causes the muscles cells, and eventually the heart, to enlarge. Myocardial enlargement may also result in dysrrythmias and sudden death. Henning et.al (2006)
A study on acute neurologic and psychiatric complications associated with cocaine abuse conducted by the department of Neurology, University of California, School of Medicine, San Francisco, Daniel H. Lowenstein et.al, ( 1987 ) yielded following results. The report reviewed 996 emergency room visits and 279 hospital admissions of patients with complications of cocaine abuse seen at the San Francisco General Hospital between 1979 and 1986. In 143 cases, acute neurologic or psychiatric symptoms were the primary complaint. The major neurologic complications included one or more seizures (in twenty nine cases), focal neurologic symptoms or signs (twelve cases), headache (ten cases), and transient loss of consciousness (six cases). Psychiatric disturbances included agitation, anxiety, or depression (thirty three cases), psychosis and paranoia (twenty four cases), and suicidal ideation (eighteen cases). Daniel H. Lowenstein et.al, (1987). The most serious consequences were found in patients with prolonged seizures or strokes, those who jumped out of buildings, and those who attempted suicide by overdosing with other drugs. There was no correlation between the appearance of complications and the reported route of administration, the amount of cocaine used, or prior experience with cocaine. The number of patients who are seeking hospital attention for these or related complaints appears to be rising substantially. Cocaine abuse, regardless of the use pattern, is associated with a variety of potentially severe neurologic and psychiatric complications. Daniel H. Lowenstein et.al, ( 1987 )
Acute cocaine abuse can also induce coronary artery spasm leading to myocardial infarction in presence or in absence of susceptibility to it, for instance in cases like atherosclerosis or variant angina. This can happen in naïve users on first use or on any subsequent use irrelevant of state of myocardium on cocaine intake. Although greater risk in patients with angina pectoris. Madu EC et.al. (1999)
Following is a case report of crack-cocaine-associated aortic dissection in early pregnancy:
“Even though uncommon in pregnancy, aortic dissection is a potentially catastrophic vascular complication, occurring mainly in the late stages of pregnancy. Vascular events, including aortic dissection are recognized complications of crack-cocaine use. The authors reported a case of aortic dissection in early pregnancy related to crack-cocaine use. They believe that the combined effects of pregnancy and crack cocaine on the vasculature create the requisite milieu potentiating such catastrophic events as aortic dissection.” Madu EC et.al. (1999)
Also it has moderate to high dependence potential. The effective dose is much higher than either morphine or heroin, meaning a lot more quantity of drug needs to be taken to have that effect. In case of cocaine, tolerance develops rapidly, a process known as tachyphylaxis. Therefore with every dose a further mounting dose of drug is required to achieve “high”.
One report set out to study whether changes in patterns of cocaine use, characterized by widespread abuse of cocaine alkaloid, have altered the nature and severity of medical complications over the past decade. It was conducted by Rubin RB and Neugarten J of Department of Medicine, Montefiore Medical Center, Bronx, New York. They concluded that in early 1980s nearly all hospital admissions were accounted for by infections, almost invariably occurring secondary to intravenous drug use. Beyond 1987, there was a rapid hike in presentation of cardio vascular, neurological and psychiatric complications. Data indicated that changes in patterns of cocaine use have altered the nature and increased the severity of medical complications with a shift from infectious to cardiovascular, neurological and psychiatric complications which may be life-threatening and associated with substantial morbidity.
Cocaine abuse is a serious social problem that precipitates a significant number of emergency hospital encounters.
Chronic cocaine toxicity:
Chronic exposure to cocaine leads to adaptation of cerebral neurons to presence of overwhelming amounts of neurotransmitters in synaptic clefts as a compensatory mechanism. This occurs by a process known as up/down regulation of receptors. Receptors either reduce (down regulation) or escalate (up regulation) in numbers depending upon requirement. Otherwise, they may respond with a reduced sensitivity to its ligands, in case of cocaine, mainly dopamine.
Contrary to other drugs of abuse, cocaine withdrawal is not dangerous. Common complaints of quenchless appetite, malaise, insomnia, and unrelenting nasal discharge are often described. Heavy users may develop dysphoria and suicidal thinking, as already pointed out. Long term damage of dopaminergic neurons also occurs. Tolerance to euphoric feeling develops rapidly requiring larger dose of cocaine to produce same effect.
Withdrawal symptoms include: dysphoric mental state, lethargy, nightmares, sleep disorders (may present as insomnia or narcolepsy), impotency, elevated appetite, restlessness, and angst.
Other medical conditions have been link to cocaine abuse. It has been associated with 6 % greater predisposition to development of myocardial infarction compared to non-abusers. During the hour after cocaine is used, heart attack risk rises twenty four -fold. Risk of developing rare immune mediated connective tissue diseases, such as SLE(Systemic lupus erythematosus) may be enhanced tremendously. It is associated with risk of developing kidney diseases and renal failure, doubles the risk of hemorrhagic and ischemic strokes and years after being withdrawn from drug, noticeably shrunken attention span has been reported by old users who quit cocaine years ago. Trozak D, Gould W ( 1984 )
Chronic use of cocaine and other sympathomimetic drugs has been reported as risk factor for cerebral stroke. Implicated patho-physiological mechanisms are multi factorial. Chronic cocaine use is associated with extensive destruction of osteocartilaginous structures of nose, sinuses and palate. There is a published case where a 56 years old woman with hypertension and smoke abuse was admitted with a pontine paramedian infarction. Cranial resonance findings of midline destructive lesions lead to the suspicion of chronic cocaine consumption. The initial outcome was good but she was re-admitted nine months later with an extent pontomesencephalic infarction. Cocaine is therefore a risk factor for stroke and should not be considered only for young patients but also elder adults. Neurologia. ( 2008 )
As already mentioned in previous passage, the association between cocaine abuse and destruction of osteo cartilaginous structures of nose, sinuses and palate has been well established. Often these complications resemble other pathological conditions in clinical picture. Trimarchi, Matteo et.al. (2003)
From January 1991 to September 2001, twenty five patients with cocaine induced midline destructive lesions were observed at the Department of Otorhinolaryngology, of the University of Brescia. The diagnosis was based on physical and endoscopic evaluation, routine blood and urine analysis, radiological findings, and repeated biopsies of the nasal mucosa.Subjects'serum was analyzed by the antineutrophilic cytoplasmic antibody (ANCA) test using indirect immunofluorescence and by enzyme-linked immunosorbent assay for antibodies against proteinase 3 and myeloperoxidase. Results were as follows:
Septal perforation was present in all 25 patients, 16 of which (68%) also had partial destruction of the inferior turbinate. Hard palate reabsorption was observed in only six patients (24%); in two of these patients, the lesion also extended to the soft palate. Fourteen patients (56%) were positive by the immunofluorescence test (nine patients had a P-ANCA and five patients a C-ANCA pattern). Four patients (16%) with the P-ANCA pattern and all patients with the C-ANCA pattern also tested positive for anti-proteinase 3 antibodies. Trimarchi, Matteo et.al. (2003)
Therefore it can be concluded that any sinonasal inflammation involving the midline that persists or remains refractory to treatment may be the first manifestation of potentially lethal drug addiction. Cocaine abuse should be considered in the differential diagnosis of destructive lesions of the nasal cavity even in the presence of a positive ANCA test. Trimarchi, Matteo et.al. (2003)
Chronic side effects specific to route of administration:
Side effects from chronic smoking of cocaine include bloody sputum, dyspnea, pruritus, sore throat, pyrexia, diffuse alveolar infiltrates without effusions which may be hemorrhagic, chest pain, pulmonary trauma, asthma, hoarseness of voice, and influenza like symptoms. Cocaine enhances involuntary tooth grinding, known as bruxism, which deteriorates tooth enamel and lead to gingivitis.
Chronic intranasal usage can degrade intranasal septum, a cartilage covered by nasal mucosa which separates the two nostrils. In severe cases, septum may be completely obliterated.
- Detection of cocaine:
With cocaine's emergence over past two decades as a popular drug of abuse, and medical personnels gaining more knowledge about health hazards of and drug interactions of cocaine, it has become essential and quite common practise to detect cocaine in blood. As previously mentioned, surgeries are preferably avoided when systemic cocaine levels are notable.
Various laboratory techniques have been described for cocaine detection. Some laboratories utilize the enzyme linked immunoassays (ELISA) for initial screening followed by gas chromatography/mass spectrometry (GC/MS) as a confirmatory test for positive results. Others employ point of care screening test (POCT).
- Enzyme linked immunoassays:
It is a rapid test to screen serum sample for presence of cocaine and/or its metabolite benzoylecgonine (BZE).
Reagents required:1.) Label enzyme, usually glucose oxidase (GOD), a wide variety of enzymes have however been used for labeling including,
alkaline phosphatase, horseradish peroxidase (HRP) and
2.) 3,3′,5,5′-tetramethylbenzidine (TMB).
4.) Anti-BZE monoclonal antibodies.
Method is simple. First, BZE-conjugated labeling enzyme, incase of glucose oxidase, BZE conjugated glucose oxidase is produced. It is then added, along with specimen into a wells of 96-well microtest plate which has already been coated with anti-BZE monoclonal antibodies. Walls are then washed and treated with glucose (substrate for labeling enzyme), horse radish peroxidase (HRP), and TMB. Glucose oxidase oxidizes glucose and produces hydrogen peroxide, which is detected by horse radish peroxidase and tetramethylbenzidine (TMD). Latter serves as chromogen, which enables the color changes to develop and aids in identifying a reaction, if any should occur. Time for immune reaction to occur and color changes to develop averages about 12 minutes, according to some experimental studies. (Mitsune Yamaguchi et.al 2001)
Key principal of this screening test, performed these days, as evident by above passage, is determination of cocaine or benzoylecgonine levels in any specimen by first linking the substrate, BZE to labeling enzyme, reacting enzyme-linked material with specimen, and then assaying for enzyme activity by adding substrate of the enzyme. A chromogen, TMB in this case, is added to achieve color change upon reaction.
It is rapid, sensitive, simple, safe, and easily carried out anywhere, provided micro-plate readers are available. Does not require sterile techniques, therefore can be conducted in a clinical setting or in hospital, in case of a crisis, when specimen cannot be immediately transported to lab.
It's quite efficient, detecting very low levels of cocaine and benzoylecgonaine. Also, it negates the need to treat biological samples prior to test, like concentrating the samples etc, samples like hair can also be used directly without prior treatment of any sort, further speeding up the screening procedure.
It is not as accurate as gas chromatography /mass spectrometry. Although comparatively very simple, it may give a false positive result.
- Point of care screening testing (POCT):
POCT referrers to laboratory testing procedures that are performed, within clinical settings, by healthcare professionals, who are not trained laboratory technicians/ specialists, i.e. procedures which do not require special laboratory equipment or testing. A simple example would be device used to measure blood glucose by diabetics at home. It has been used in various settings for screening of illicit substance of abuse, but its main use rests with law enforcementand drug treatment centers.
In an experimental study, at St. Joseph's Research Institute, Paterson, New Jersey, in 2002, use of POCT in emergency department was evaluated. Annals of Clinical & Laboratory Science ( 2002 )
POCT device used was OnTrakTM and the specimens were simulataneously also screened through laboratory- based screening system, TriageTM . Following outcomes were obtained after conducting screening tests on 170 subjects:
- Excellent concordance among results obtained using two screening techniques. (97% agreement for cocaine; 99% agreement for marijuana,opiates, and amphetamines).
- Cost analysis showed at least 37.5% decrease in cost per analytewhen urine samples were tested by the POCT device, comparedto the laboratory-based screening system.
Point of care testing is therefore a reliable, cost-effective and rapid screening system. Quality of which has not yet been challenged, although it can be argued that machine can malfunction, man cannot, but for every day purposes, and in case of emergencies, POCT is worth healthcare professionals' trust.
- EMIT (Enzyme Multiplied Immunoassay Technique)
is an EIA used for rapidly assaying microamounts of drugs and substances in human biological fluids. It is a homogeneous, liquid phase assay that measures haptens for drug, hormone and metabolite determinations.
Adapted from Dade behring inc
The way an EMIT drug assay works begins with an excess of specific antibodies that bind with the drug being measured. This excess is added to the patient specimen. If molecules of the drug being tested for are present, the molecules bind immediately to the antibody sites. If this occurs, the enzyme-labeled drug is added to the mixture. Molecules of this enzyme-labeled drug fill any antibody binding sites not filled by molecules of the drug in the specimen. Since only free enzyme-labeled drug molecules can act on the substrate, enzyme activity is reduced. The amount of free enzyme left in the mixture determines the amount of substrate that is converted to a colored form from an uncolored one, in a given time period. The color change is then easily measured by a spectrophotometer. There are two basic test principles essential to the EMIT assay. The first is that the enzyme need to remain active after it binds to the compound being measured (hapten), and secondly when the hapten reacts with its specific antibody the enzyme activity of the hapten-enzyme conjugate is either reduced or inhibited. EMIT is unique from other EIAs in that reagent filtration is not required
EMIT vs. ELISA
EMIT and ELISA have many characteristics that separate them from each other. EMIT is mainly used in drug, hormone, and metabolite determinations. It measures haptens which are small molecules while ELISA measures macromolecules such as antigens and antibodies and is used for diagnosing infectious disease and immunoglobulins. EMIT is faster than ELISA but ELISA has greater sensitivity. Both of these EIAs have a long shelf life and can be done by personnel with only minimal training.
- Recent cocaine facts, issues and figures:
Drugs Misuse in Scotland: Findings From the 2006 Scottish Crime and Victimisation Survey:
The extent of drug use among adults aged 16-59 living in private household in Scotland were studied. Estimates 16 different drugs were provided for 3 different time periods.
Drugs were classified as follows:
Proportion of people who reported having taken any drugs or any Class A drugs ever, in the last year,
17 per cent of respondents reported having ever taken one or more Class A drugs, with 5 per cent have taken one or more Class A drugs in the last year, and 3 per cent having taken them in the last month .
In the 2006 survey, 57 per cent of those who had taken one or more Class A drugs in the last year had also taken one or more Class A drugs in the last month. Again, this suggests that the majority of those who had taken Class A drugs in the last year can be considered to be regular drug users.
Reported use of Class A drugs was h
Cite This Dissertation
To export a reference to this article please select a referencing stye below: