Cocaine and crack Flashcards
History
Indigenous South Americans, the Quichua people, refer to cocaine as kuka.
The Erythroxylum coca plant is native to the Andes mountains and northern parts of the Amazon.
The indigenous population chewed the leaves or drank the tea to increase stamina and resist fatigue, as well as to limit altitude sickness.
It was also used as part of religious/mystical ceremonies.
Europeans invading South America and enslaving the local population identified that allowing them access to coca leaves made them more productive and compliant.
In 1565 Nicholas Monardes published the first description of cocaine in Europe.
In 1855 Albert Niemann isolated cocaine.
In 1880 it was listed in the US Pharmacopoeia.
In 1884, Sigmund Freud (Vienna) published ‘Über Coca’, which describes the history and use of coca. It was a kind of marketing pamphlet.
In 1884 Carl Koller identified local anaesthetic action of cocaine in animals and humans.
Cocaine was prescribed for toothaches, headaches, dyspepsia, gastrointestinal disorders, neuralgia, and melancholy around the turn of the 20th century.
Cocaine appeared in popular literature, including Arthur Conan Doyle’s ‘The Sign of Four’ (1890), one of the Sherlock novels. It described Sherlock, the highly logical hero, injecting cocaine and morphine.
Angelo Mariani started marketing a tonic in 1863, combining coca leaves with red wine. This was called ‘Vin Mariani’ and adverts claimed it would restore health, strength, energy and vitality. The alcohol increased cocaine content to ~200 mg/L. This tonic was endorsed by the Pope.
Vin Mariani apparently inspired Pemberton’s French wine coca (1885), which used a ‘pinch of coca leaves’ and caffeine from African kola nuts. When Georgia declared a prohibition on alcohol in the same year, a non-alcoholic, carbonated version was generated. This was Coca-Cola. This was marketed as the “intellectual beverage and temperance drink” during prohibition.
Recreational use of cocaine became popular in the early 20th century, leading to a ban in the United States in 1914.
The Medellin cartel, led by Juan Pablo Escobar, monopolised cocaine import and sale in the United States in the 1970s.
Formulations
There are multiple formulations of cocaine and ‘crack’.
The hydrochloride salt can be snorted (insufflated) as powder (bioavailability ~80%, Tmax ~45 min) or injected as an aqueous solution.
Crack is a cocaine base, prepared by neutralising the HCl salt with bicarbonate.
It has very limited aqueous solubility, so cannot be injected. It’s rock crystal that is heated and crackles; its vapours are smoked (bioavailability ~60%, Tmax ~6 min).
Crack therefore has a lower bioavailability but much more rapid onset of action.
Pharmacodynamics
Cocaine is a Nav channel inhibitor, providing local anaesthetic action.
Psychomotor stimulation occurs due to inhibition of neurotransmitter reuptake transporters.
It causes DAT/SLC6A3 dopamine transporter blockade. This increases extracellular dopamine levels, relevant in the nucleus accumbens.
- Cocaine can be used as a pharmacological tool to identify DAT receptors and investigate the dopamine reward pathway. PET and fMRI have been used to study cocaine’s effects on the brain.
It also inhibits NET/SLC6A2 and SERT/SLC6A4, leading to increased monoamine activity.
Effects
The subjective acute effects are hyperstimulation, reduced fatigue and mental alertness.
Objective effects include α1-AR mediated vasoconstriction, dilated pupils, hyperthermia and increased HR and BP.
The duration of action depends on the route of administration. The faster the absorption, the more intense the high but the shorter the duration of action: snorting high may last 15-30 min, while that from smoking may last 5-10 min.
Repeated use can reduce the duration of the high and increases the risk of addiction.
Some tolerance is seen, but sensitisation is also possible.
Binges, during which the drug is taken repeatedly and at increasingly high doses, may lead to:
- Increasing irritability, restlessness, and paranoia
- Full-blown paranoid psychosis - associated with changes in dopamine signalling in the prefrontal cortex.
- Cardiovascular complications, arrhythmias, heart attack, stroke
- Appetite reduction leading to malnourishment - often a result of drug-seeking behaviour causing a reduction in eating
- Nasal septum deterioration
Withdrawal is associated with a crash, which includes dysphoria, depression, anxiety, pain and cravings.
Cocaethylene
Concurrent consumption of cocaine and alcohol generates cocaethylene, which is even more euphoric and cardiotoxic than cocaine in animals.
This is formed by the enzyme carboxylesterase-1.
It tends to stick around, so it can be identified in the body long after consumption or after overdose-associated death.
Statistics and Cocaine-associated fatalities
Acute overdose mostly occurs due to peripheral actions of the drug resulting in myocardial infarction due to coronary artery vasoconstriction.
Repeated consumption causes endothelial damage and arrhythmias.
“Acute exhaustive mania” involves hyperthermia, delirium and agitation/aggression.
In the UK, powder cocaine is a lot more popular than crack. Crack cocaine is a lot more popular in the US than the UK, but the reasons for this are unknown.
Cocaine use in the UK has increased from ~3% in 1995 to ~10% in 2024.
In the EU in 2022, estimated lifetime use was 14.4 million out of ~450 million (3.2%).
There has been a sharp increase in cocaine-related deaths in the last 10 years.
The European Union Drugs Agency (EUDA) reported that 213 tonnes of cocaine were seized in Europe in 2020.
Most cocaine users (85%) are men.
The mean age of first use is 23 and mean age of first treatment entry 32.
The mean frequency of cocaine use is 4 days/week. Smoking and sniffing are the most common routes of administration (36 and 59%).
The expense (55-85 €/g) and low purity (54-68%) of cocaine contribute to its lower popularity in Europe compared to other drugs.
In the US, overdoses related to cocaine remained under 0.03% of the population between 2000 and 2015.
~2.2 m people (~6%) in the US use cocaine regularly. Of those, 1.5 million fit DSM-5 criteria for CUD.
There are 23 million users worldwide - disproportionate amount of users in the US.
There are no FDA-approved therapeutics for cocaine use disorder.
Vaccines have been attempted since 1990. This is an antibody which binds the cocaine and sequesters it in the bloodstream. However, none of these have been successful so far.
Humanised antibodies can be used for acute detoxification. This has been occasionally successful.
Treatment can also be achieved through enzymatic targeting with carboxylesterase-1 (CES1) using an engineered ‘cocaine hydrolase’ based on butyrylcholinesterase. This has amplified hydrolase function to metabolise cocaine faster.
