Cocaine
Cocaine (from French: cocaïne, from Spanish: coca, ultimately from Quechua: kúka)[13] is a tropane alkaloid that acts as a central nervous system (CNS) stimulant. As an extract, it is mainly used recreationally, and often illegally for its euphoric and rewarding effects. It is also used in medicine by Indigenous South Americans for various purposes and rarely, but more formally, as a local anaesthetic or diagnostic tool by medical practitioners in more developed countries. It is primarily obtained from the leaves of two Coca species native to South America: Erythroxylum coca and E. novogranatense.[14][15] After extraction from the plant, and further processing into cocaine hydrochloride (powdered cocaine), the drug is administered by being either snorted, applied topically to the mouth, or dissolved and injected into a vein. It can also then be turned into free base form (typically crack cocaine), in which it can be heated until sublimated and then the vapours can be inhaled.[12]
For other uses, see Cocaine (disambiguation).Clinical data
kə(ʊ)ˈkeɪn
Coke, blow, snow, crack (in free base form)
Physical: Low Psychological: High[4]
High[5]
- AU: S8 (Controlled drug)
- BR: Class F1 (Prohibited narcotics)
- CA: Schedule I
- DE: Anlage III (Special prescription form required)
- NZ: Class A
- UK: Class A
- US: Schedule II[7]
- UN: Narcotic Schedules I and III
- By mouth: 33%[8]
- Insufflated: 60[9]–80%[10]
- Nasal spray: 25[11]–43%[8]
Seconds to minutes[12]
20 to 90 minutes[12]
C17H21NO4
303.358 g·mol−1
98 °C (208 °F)
187 °C (369 °F)
1.8g/L (22 °C)
Cocaine stimulates the reward pathway in the brain.[15] Mental effects may include an intense feeling of happiness, sexual arousal, loss of contact with reality, or agitation.[12] Physical effects may include a fast heart rate, sweating, and dilated pupils.[12] High doses can result in high blood pressure or high body temperature.[16] Onset of effects can begin within seconds to minutes of use, depending on method of delivery, and can last between five and ninety minutes.[12] As cocaine also has numbing and blood vessel constriction properties, it is occasionally used during surgery on the throat or inside of the nose to control pain, bleeding, and vocal cord spasm.[17]
Cocaine crosses the blood–brain barrier via a proton-coupled organic cation antiporter[18][19] and (to a lesser extent) via passive diffusion across cell membranes.[20] Cocaine blocks the dopamine transporter,[21] inhibiting reuptake of dopamine from the synaptic cleft into the pre-synaptic axon terminal; the higher dopamine levels in the synaptic cleft increase dopamine receptor activation in the post-synaptic neuron,[22][23] causing euphoria and arousal.[24] Cocaine also blocks the serotonin transporter and norepinephrine transporter, inhibiting reuptake of serotonin and norepinephrine from the synaptic cleft into the pre-synaptic axon terminal and increasing activation of serotonin receptors and norepinephrine receptors in the post-synaptic neuron, contributing to the mental and physical effects of cocaine exposure.[6]
A single dose of cocaine induces tolerance to the drug's effects.[25] Repeated use is likely to result in addiction. Addicts who abstain from cocaine may experience prolonged craving lasting for many months.[26][27] Abstaining addicts also experience modest drug withdrawal symptoms lasting up to 24 hours, with sleep disruption, anxiety, irritability, crashing, depression, decreased libido, decreased ability to feel pleasure, and fatigue being common.[28][15] Use of cocaine increases the overall risk of death, and intravenous use potentially increases the risk of trauma and infectious diseases such as blood infections and HIV through the use of shared paraphernalia. It also increases risk of stroke, heart attack, cardiac arrhythmia, lung injury (when smoked), and sudden cardiac death.[15][29] Illicitly sold cocaine can be adulterated with fentanyl, local anesthetics, levamisole, cornstarch, quinine, or sugar, which can result in additional toxicity.[30][31] In 2017, the Global Burden of Disease study found that cocaine use caused around 7,300 deaths annually.[32]
Opioid involvement in cocaine overdose deaths in the US. The pale green line is cocaine without any opioid (bottom line in 2017). The yellow line is cocaine and synthetic opioids other than methadone (top line in 2017).[65]
Delphic analysis regarding 20 popular recreational drugs based on expert opinion in the UK. Cocaine was ranked the 2nd in dependence and physical harm and 3rd in social harm.[66]
![Delphic analysis regarding 20 popular recreational drugs based on expert opinion in the UK. Cocaine was ranked the 2nd in dependence and physical harm and 3rd in social harm.[66]](http://upload.wikimedia.org/wikipedia/commons/thumb/7/73/Rational_harm_assessment_of_drugs_bar_plot.svg/504px-Rational_harm_assessment_of_drugs_bar_plot.svg.png)
Pharmacology
Pharmacokinetics
The extent of absorption of cocaine into the systemic circulation after nasal insufflation is similar to that after oral ingestion. The rate of absorption after nasal insufflation is limited by cocaine-induced vasoconstriction of capillaries in the nasal mucosa. Onset of absorption after oral ingestion is delayed because cocaine is a weak base with a pKa of 8.6, and is thus in an ionized form that is poorly absorbed from the acidic stomach and easily absorbed from the alkaline duodenum.[11] The rate and extent of absorption from inhalation of cocaine is similar or greater than with intravenous injection, as inhalation provides access directly to the pulmonary capillary bed. The delay in absorption after oral ingestion may account for the popular belief that cocaine bioavailability from the stomach is lower than after insufflation. Compared with ingestion, the faster absorption of insufflated cocaine results in quicker attainment of maximum drug effects. Snorting cocaine produces maximum physiological effects within 40 minutes and maximum psychotropic effects within 20 minutes. Physiological and psychotropic effects from nasally insufflated cocaine are sustained for approximately 40–60 minutes after the peak effects are attained.[103]
Cocaine crosses the blood–brain barrier via both a proton-coupled organic cation antiporter[18][19] and (to a lesser extent) via passive diffusion across cell membranes.[20] As of September 2022, the gene or genes encoding the human proton-organic cation antiporter had not been identified.[104]
Cocaine has a short elimination half life of 0.7–1.5 hours and is extensively metabolized by plasma esterases and also by liver cholinesterases, with only about 1% excreted unchanged in the urine.[12] The metabolism is dominated by hydrolytic ester cleavage, so the eliminated metabolites consist mostly of benzoylecgonine (BE), the major metabolite, and other metabolites in lesser amounts such as ecgonine methyl ester (EME) and ecgonine.[105][12] Further minor metabolites of cocaine include norcocaine, p-hydroxycocaine, m-hydroxycocaine, p-hydroxybenzoylecgonine (pOHBE), and m-hydroxybenzoylecgonine.[106] If consumed with alcohol, cocaine combines with alcohol in the liver to form cocaethylene.[12] Studies have suggested cocaethylene is more euphoric, and has a higher cardiovascular toxicity than cocaine by itself.[12]
Depending on liver and kidney functions, cocaine metabolites are detectable in urine between three and eight days. Generally speaking benzoylecgonine is eliminated from someone’s urine between three and five days. However, for high users of cocaine, benzoylecgonine can be detected in their urine within four hours after cocaine intake and remains detectable in concentrations greater than 150 ng/mL typically for up to eight days after cocaine was used.[107]
Detection of cocaine metabolites in hair is possible in regular users until after the sections of hair grown during the period of cocaine use are cut or fall out.[108]
Pharmacodynamics
The pharmacodynamics of cocaine involve the complex relationships of neurotransmitters (inhibiting monoamine uptake in rats with ratios of about: serotonin:dopamine = 2:3, serotonin:norepinephrine = 2:5).[109][15] The most extensively studied effect of cocaine on the central nervous system is the blockade of the dopamine transporter protein. Dopamine neurotransmitter released during neural signaling is normally recycled via the transporter; i.e., the transporter binds the transmitter and pumps it out of the synaptic cleft back into the presynaptic neuron, where it is taken up into storage vesicles. Cocaine binds tightly at the dopamine transporter forming a complex that blocks the transporter's function. The dopamine transporter can no longer perform its reuptake function, and thus dopamine accumulates in the synaptic cleft. The increased concentration of dopamine in the synapse activates post-synaptic dopamine receptors, which makes the drug rewarding and promotes the compulsive use of cocaine.[110]
Cocaine affects certain serotonin (5-HT) receptors; in particular, it has been shown to antagonize the 5-HT3 receptor, which is a ligand-gated ion channel. An overabundance of 5-HT3 receptors is reported in cocaine-conditioned rats, though 5-HT3's role is unclear.[111] The 5-HT2 receptor (particularly the subtypes 5-HT2A, 5-HT2B and 5-HT2C) are involved in the locomotor-activating effects of cocaine.[112]
Cocaine has been demonstrated to bind as to directly stabilize the DAT transporter on the open outward-facing conformation. Further, cocaine binds in such a way as to inhibit a hydrogen bond innate to DAT. Cocaine's binding properties are such that it attaches so this hydrogen bond will not form and is blocked from formation due to the tightly locked orientation of the cocaine molecule. Research studies have suggested that the affinity for the transporter is not what is involved in the habituation of the substance so much as the conformation and binding properties to where and how on the transporter the molecule binds.[113]
Sigma receptors are affected by cocaine, as cocaine functions as a sigma ligand agonist.[114] Further specific receptors it has been demonstrated to function on are NMDA and the D1 dopamine receptor.[115]
Cocaine also blocks sodium channels, thereby interfering with the propagation of action potentials;[116][74] thus, like lignocaine and novocaine, it acts as a local anesthetic. It also functions on the binding sites to the dopamine and serotonin sodium dependent transport area as targets as separate mechanisms from its reuptake of those transporters; unique to its local anesthetic value which makes it in a class of functionality different from both its own derived phenyltropanes analogues which have that removed. In addition to this, cocaine has some target binding to the site of the κ-opioid receptor.[117] Cocaine also causes vasoconstriction, thus reducing bleeding during minor surgical procedures. Recent research points to an important role of circadian mechanisms[118] and clock genes[119] in behavioral actions of cocaine.
Cocaine is known to suppress hunger and appetite by increasing co-localization of sigma σ1R receptors and ghrelin GHS-R1a receptors at the neuronal cell surface, thereby increasing ghrelin-mediated signaling of satiety[120] and possibly via other effects on appetitive hormones.[121] Chronic users may lose their appetite and can experience severe malnutrition and significant weight loss.
Cocaine effects, further, are shown to be potentiated for the user when used in conjunction with new surroundings and stimuli, and otherwise novel environs.[122]