Saturday, 3 May 2014

Russia and its drug problems

Well, the country I talk about after Germany is Russia and the reason why is quite simple, they're a developing country that's got a real problem with drugs, especially alcohol and opioids.

Figure 1: Russia (highlighted)1

History

Russia's history can be traced back to the 12th Century AD (the 1100s) and was dominated for 200 years by Mongols. After this came Monarchy rule in which the country became known as the Russian Empire, which would persist until the Russian Revolution of 1905 which followed the Russo-Japanese war of 1904-1905. The Russian Revolution was mostly just strikes and military mutinies and never really became violent. It lead to formation of a parliament and the formation and signing of a constitution. Later, however, after repeated defeats in World War I by the Germans, riots broke out in Russia leading to the overthrow of the Russian Empire in 1917. Soon after the communists, led by Vladimir Lenin, took over and formed the Union of Soviet Socialist Republics (USSR). Losif Stalin came into power soon after and lead to the systematic execution of tens of millions of people. During these years a few years after his rein extensive nuclear testing took place under the supervision of the Soviets. They actually tested the largest nuke in human history, the so called "Tsar Bomba" (Царь-бомба) or, "The Emperor Bomb" which was detonated on the 30th of October 1961 and was equivalent to roughly 57 million tonnes of TNT. This nuke was detonated on the largest of Russia's Islands, Novaya Zemlya. Later in 1986 the Chernobyl Incident took place. Then in 1991 the USSR fell and Russia is now, officially, the Russian Federation.2
Figure 2: Russia with Novaya Zemlya labelled

Modern day
Figure 3: Prime Minister

Dmitry Medvedev

Nowadays Russia is the largest (by area) country on Earth (at approximately 1.8 times that of the U.S. and 2.2 times that of Australia) and has a population of 142,470,272 (compared to 318,892,103 for the U.S. and 22,507,617 for Australia); its population has been in decline since the soviet years, once being almost 300,000,000 and now being about half that. The population growth rate (or rather reduction rate) is -0.03%. They have a Prime Minister and President whom are currently Dmitry Medvedev and Vladimir Putin, respectively. Their human development index (HDI) is considered high but not high enough to be considered developed at 0.788. There is a decent degree of variation in salaries among its inhabitants, as is supported by its relatively high Gini coefficient of 41.7 (compared to 30.5 in Australia; although lower than the U.S.'s 45); although the average annual income is just $14,461. The national currency is the Russian Ruple. It covers nine different time zones, from UTC+3 (7 hours behind the East Coast of Australia) to UTC+12 (2 hours ahead of the East Coast of Australia; same time zone as New Zealand). About 11% of the population is below the poverty line and the unemployment rate is 5.8% (compared to 5.7% in Australia and 7.3% in the U.S.). 99.7% of the adult population can read and right (compared to 99% in Australia and the U.S.) and the mean years of schooling (from primary school to university) is about 14 years (compared to 17 years in the U.S. and 20 years in Australia).2
Figure 4: President
Vladimir Putin

The obesity rate in adults is 26.5% (compared to 33% in the U.S. and 26.8% in Australia) and the adult HIV/AIDS rate is 1% (compared to 0.1% in Australia and 0.6% in the U.S.). The mean life expectancy at birth is 70.16 years (compared to 82.07 years in Australia and 79.56 years in the U.S.). There is a twelve year life expectancy gap between the sexes, favouring women, compared to about 5 years in Australia and the U.S. About 54% of the population is female. Their physicians density (i.e. the percentage of doctors for the amount of people) is abnormally high at 4.31 per 1000 people (compared to 2.42 per 1000 people in the U.S. and 3.85 per 1000 people in Australia). Their standard medical degree is the M.D. Their official language is Russian. They also have one of the highest incarceration rates in the world at 0.4% (compared to just 0.13% for Australia and 0.71% for the U.S.).2


Less than half of the population are practising believers (of any religion), which is likely a relic of the Soviet Era. Their capital and largest city is Moscow which has a population of 10.5 million, followed by Saint Petersburg with a population of 4.5 million and Novosibirsk with a population of 1.4 million.2
Figure 5: Russia with three major cities labelled

Alcohol

Their furthermost drug problem would have to be alcohol, about 17% of males and 2.6% of females have a problem with alcohol. Their preferred drink is Vodka (not surprising seeing how they were the ones that created Vodka in the first place) and about 25% of male drinkers are binge drinkers. Many of the deaths associated with alcohol is due to drink driving or alcohol-induced violence. One in five (20%) deaths in men can be attributed to alcohol.3-5

Illicit drugs

This post originally started as a status on an opioid that's remarkably popular in Russia, which is called by the street name Krokodil, which is German for crocodile, so called because of the horrible wounds inflicted by the drug which resemble that of a large carnivorous beast, like a crocodile. The proper name for this drug is desomorphine which is shown in figure 3 and compared to the structures of morphine and heroin. Desomorphine's appeal is that it's readily synthesised from codeine and other legal and commonplace things, much like metamfetamine ("methamphetamine") from pseudoephedrine. Unfortunately, these commonplace things include petrol (gasoline to the Americans), paint thinner, iodine, hydrochloric acid, lighter fluid and red phosphorus are not exactly ideal as impurities as they're highly corrosive and/or toxic, especially when they're injected directly into a vein like desomorphine is. Even less fortunately, the crude product is seldom ever purified further by clandestine chemists in order to improve client safety. This likely contributes to its street name, krokodil, as it is well-known for its high degree of toxicity. About 100,000 Russians and 20,000 Ukrainians are believed to use krokodil regularly.6-9

Figure 6: Desomorphine and related compounds' structure
It was first developed as a therapeutic agent in 1932, in the hope that it might overcome some of the problems of morphine and related opioids. It fell short of these hopes, although it was found to possess a lower liability for causing nausea and respiratory depression (suppressed breathing rate; which is the side effect that limits the doses given for pretty much every opioid as this is the side effect that usually ends up killing people in cases of overdose) and it was later realised that it possessed a greater abuse liability when compared to other opioids. It was also discovered to be about 8-10 times more potent than morphine on a dose-by-dose basis. Despite this it was available in Switzerland until the year 1981, although for many of these years it was being used to treat a single patient with a very rare condition.8 Adverse effects associated with krokodil's impurities include:6
Figure 7: The legs of a Krokodil victim

  • Thrombosis (blood clots)
  • Gangrene (which might necessitate limb amputation)
  • Skin infections
  • Osteomyelitis (bone infection; this can lead to the potential loss of one's jaw if this is the bone affected)
  • Pneumonia
  • Septicaemia (blood poisoning)
  • Coronary artery burst (destruction of the artery supplying the heart)
  • Rotting gums leading to tooth loss
  • Speech impediments
  • Impaired motor skills
  • Memory impairment
  • Rotting noses, lips and ears
  • Death
  • Kidney/liver problems or even failure
  • Personality changes
  • Skin ulcers and sores. 
Despite the ease of synthesis desomorphine from readily available substances it is illegal in every English-speaking country worldwide, Australia (it's Schedule 9 if you're one of my fellow pharmacy students), the UK and the U.S. included. The reason why desomorphine has a higher abuse liability when compared to morphine and related opioids is actually quite simpleit's more fat soluble

See the blood in the brain and spinal cord and the blood in the rest of the body is separated by a protective barrier called the blood-brain barrier (BBB) which is composed of cells called astrocytes which allow only specific substances to pass through. Most of these substances are essential vitamins, minerals or other nutrients; these substances are actively, i.e. intentionally and specifically carried cross the BBB via proteins designed specifically to ferry these substances across the BBB. Some substances can cross the BBB by basically behaving like "ghosts" as they're able to pass straight through the astrocytes that make up the BBB without any help by transporter proteins by virtue of their fat solubility, as astrocytes are composed of layers of fat-like molecules called phospholipids. This is why most drugs are at least a little fat soluble as they need to be in order to cross into the inner components of cells and hence affect the different functions of cells.10,11 

Opioids need to be particularly fat soluble as they need to cross the BBB in order to elicit many of their therapeutic effects, although some opioids used to treat diarrhoea need not cross the BBB as their effects are mostly mediated in the rest of the body. They also have certain constraints on their chemical structures as they need to satisfy these constraints in order to bind to their receptor targets, as the receptor is like a lock and the opioid is the key—if the key doesn't fit the lock it won't produce the desired effect.
Figure 8: The μ Opioid Receptor
Opioids all need to "look like" (i.e. be an adequate key to pick the lock) the class of compounds synthesised, by the body, to bind to and activate (or unlock) the opioid receptors, namely, the endorphins. There are three different types of opioid receptor (which are assigned the Greek letters, μ, κ, δ; pronounced mu, kappa and delta, respectively and abbreviated MOR, KOR and DOR, respectively) and three different major classes of endorphins — the enkephalins (δ-favouring endorphins), the dynorphins (κ-favouring endorphins) and the μ-favouring endorphins such as β ("beta")-endorphin. Most opioids (including those that have similar structures to morphine) are significantly μ-favouring, in nature, with fairly minimal activity at the DOR, although some clinically significant (still fairly small) activity at the KOR. If you visually compare the following picture of the structure of β-endorphin with the picture of morphine and desomorphine you'll notice they all have a free (i.e. there's no nearby molecules obstructing it from poking into receptors) phenol group (which I have highlighted in the β-endorphin picture) and a nitrogen atom nearby and we believe that this is the key to their opioid effects. Most endorphins have a free phenol group (including the enkephalins and dynorphins) in close proximity to a nitrogen atom. Another property of opioids that seems to be important to their biologic activity is that they all have a region of the molecule that is highly fat soluble.10,11
Figure 9: β ("beta")-endorphin

The only real difference between desomorphine and morphine is that desomorphine has an extra two hydrogen molecules and is missing an alcohol group. This alcohol group is polar, that is, it makes the opioid more water soluble (and hence less fat soluble), hence if you remove this alcohol group you'll improve the fat solubility of the opioid without compromising on the opioid activity of the opioid as it's the phenol group that appears most important to its opioid activity. You might be asking why is heroin still able to produce such powerful opioid effects despite missing the phenol group and this is a good question. Heroin is what's called a prodrug, which basically means while it itself is unable to bind to the opioid receptors to any significant extent it is rapidly metabolised in the body into morphine and 6-monoacetylmorphine, which do possess the phenol group required for opioid activity. The reason why heroin manages to produce a greater degree of euphoria when compared to morphine is that heroin is more fat soluble and hence crosses the BBB faster than morphine can, hence producing a more intense peak in opioid-induced euphoria. Desomorphine is also more lipophilic but unlike heroin it's not a prodrug so its effects are perhaps even more rapid-onset and powerful.10,11

Reference list:

  1. FutureTrillionaire (18 March 2014). "File:Russian Federation (orthographic projection) - Crimea disputed.svg". Wikimedia Commons. Wikimedia Foundation. Retrieved 3 May 2014.
  2. "Russia" (PDF). The World Factbook. Central Intelligence Agency. 22 April 2014. Retrieved 3 May 2014.
  3. "Russian Federation (the)" (PDF). World Health Organization. United Nations. 2011. Retrieved 3 May 2014.
  4. Pridemore, WA (December 2002). "Vodka and violence: alcohol consumption and homicide rates in Russia." (PDF). American Journal of Public Health 92 (12): 1921–30. PMC 1447353. PMID 12453810.
  5. World Health Organization (2011). Global status report on alcohol and health. (PDF). Geneva, Switzerland: World Health Organization. ISBN 978-92-4-156415-1. Retrieved 3 May 2014.
  6. Gahr, M; Freudenmann, RW; Hiemke, C; Gunst, IM; Connemann, BJ; Schönfeldt-Lecuona, C (2012). "Desomorphine goes "crocodile".". Journal of Addictive Diseases 31 (4): 407–12. doi:10.1080/10550887.2012.735570. PMID 23244560.
  7. Gahr, M; Freudenmann, RW; Hiemke, C; Gunst, IM; Connemann, BJ; Schönfeldt-Lecuona, C (June 2012). ""Krokodil":revival of an old drug with new problems.". Substance Use & Misuse 47 (7): 861–3. doi:10.3109/10826084.2012.669807. PMID 22468632.
  8. Grund, JP; Latypov, A; Harris, M (July 2013). "Breaking worse: the emergence of krokodil and excessive injuries among people who inject drugs in Eurasia.". The International Journal on Drug Policy 24 (4): 265–74. doi:10.1016/j.drugpo.2013.04.007. PMID 23726898.
  9. Katselou, M; Papoutsis, I; Nikolaou, P; Spiliopoulou, C; Athanaselis, S (May 2014). "A "Krokodil" emerges from the murky waters of addiction. Abuse trends of an old drug.". Life Sciences 102 (2): 81–87. doi:10.1016/j.lfs.2014.03.008. PMID 24650492.
  10. Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8.
  11. Rang, HP; Dale, MM; Ritter, JM; Flower, RJ; Henderson, G (2012). "Chapter 41: Analgesic drugs". Pharmacology. (7th ed.). New York: Elsevier. ISBN 978-1-4377-1933-8.

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