Cocaine Drug Abuse

Cocaine Drug Abuse Cocaine through the ages: from elixir to poison. Cocaine through ages: from elixir to poison. Abstract: 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. Its 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. Its 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 pot ential 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. Methodology: 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, cocaines 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 im pulses 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 Nicolà ¡s Monardes, in 1569, to induce â€Å"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 Pembertons 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 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: Discovery of cocaine, as local anesthetic, is claim to fame for Austrian ophthalmologist, Karl Koller. Kollers 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) Isolation: 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, a Ph.D. student at the University of Gà ¶ttingen in Germany, in 1859. Niemann wrote a dissertation describing steps of isolation titled, â€Å" ÃÅ"ber eine neue organische Base in den Cocablà ¤ttern† (On a New Organic Base in the Coca Leaves), which was published in 1969. F. Gaedcke (1855) Formal Chemical Name (IUPAC) for cocaine: (1R,5S)-methyl 8-methyl-3-(phenylcarbonyloxy)-8-azabicyclo[3.2.1]octane-2-carboxylate. Medicalisation and popularization: Ever since its discovery, cocaines 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) 1859s Montagezzis 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 Wà ¼rzburg, 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 frogs 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 Kollers demonstration of anesthetic properties of cocaine in 1884 was an important breakthrough establishing cocaines importance, medically when it was introduced in Germany as local anesthetic for eye surgery. (Altman Aj et.al 1985) Kollers discovery was later followed in 1985 by Leonard Cornings accidental demonstration of cocaines 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. 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 Doyles 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. Prohibition: 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 1970s 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. Modern Usage: 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. Addiction potential: 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: Smoking: 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. Oral: 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 stomachs 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. Insufflation: 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 â€Å"bumps†, â€Å"lines†, or â€Å"rails†. Devices used as aid in insufflation are known as â€Å"tooters†. Rolled up banknotes, hollowed-out pens, cut straws, pointed ends of keys, specialized spoons, long fingernails, and (clean) tampon applicators may all be used a tooters. Injection: 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. â€Å"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) Absorption: 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: 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. Injection: 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: 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. Distribution: 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 ) Metabolism: 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. Pregnancy. 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. Its 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. Cocaine are hydrolyzed by human BChE in a slow rate , however, in university of Nebraska medical center the scientist at molecular biology and biochemistry 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 metabolite can be found and presets for longer time up to 36 hours after the first administration and it will be found after they excreted into maternal milk. On the other hand, it will be eliminated very fast through exhalation or vapor when it is administrated through smokes. Ambre J et.al (1988) In an experiment, the investigations of chronic cocaine oral administration effects in those healthy volunteers having a history of cocaine abuse were continued. 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 session, the doses of cocaine were administrated by an elevating rate starting from 100 mg as an initial dose (500 mg/ day) reaching to 400 mg (2 g/day) by a rate of increase of 25 mg/ dose/ session (125 mg / session). Urine specimens were collected throughout the study while at the end of the study specimens like saliva and plasma were periodically collected during the one week withdrawal phase and during the dosing session. The analysis of cocaine and cocaine metabolite were carried out by solid phase extraction and followed by gas chromatographic mass spectrometric analysis in the SIM mode. ARE is defin ed as a method or plots used to calculate the Half-lives of urinary elimination for cocaine and cocaine metabolites which stand for ( the amount remaining to be excreted ) plots. The urinary elimination for cocaine and cocaines metabolites in the Result obtained yielded two phases. An initial elimination phase during withdrawal which was has the same elimination pattern observed after acute dosing, and a terminal phase. Results were as follows: Initial phase: 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. Terminal phase: 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. 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 make the onset of neuronal blockade faster especially in rapidly firing neurons when they target open sodium channels which is known 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-upta