Diamorphine Case Study

Diamorphine is an opioid produced over one hundred years ago by the acetylation of morphine. Diamorphine is twice as potent when compared to morphine, because it is a more lipophilic molecule, containing a partition coefficient of 280 (Suresh, 2013). The lipophilicity of diamorphine allows it to rapidly distribute across the blood-brain barrier, producing effects within seconds. Morphine cannot penetrate the blood brain barrier at that rate, because it contains two hydroxyl groupings within its structure, causing it to be lyophobic. When diamorphine reaches the central nervous system it immediately stimulates the brain by binding to opioid receptors, which produce pleasurable effects and provides pain relief by impairing the action of the central
nervous system (Zang, 2015).
Diamorphine is not used for medicinal purposes in the United States, because of the side effects that occur.
The body will quickly start to develop a tolerance to the drug and will be able to handle a larger dose. When an individual increases the dose administered it increases their susceptibility to an overdose (Zang, 2015). Long-term users bodies start to depend on diamorphine. When they stop taking the opioid after consistent use extreme withdrawal symptoms occur and tortures the body. Addiction is the principal withdrawal symptom and causes diamorphine users feel irresistible cravings for the drug.
The American Society of Addiction Medicine states that in 2014, the leading cause of accidental death within the United States was due to drug overdoses. Due to the rise in drug overdoses, many research facilities are conducting clinical trails that involve recreational diamorphine users and probable antidotes for overdoses. The importance for examining diamorphine within the biological system is to study how to suppress diamorphine addictions, prevent overdoses, and to study other drugs that block opioid receptors from producing withdrawals and
cravings.
A German scientist, Felix Hoffmann, who worked for Bayer Pharmaceutical Company, discovered Diamorphine in the late 1800’s. He acetylated morphine with the intention of creating codeine, a less potent compound than morphine (Current 2010). However, Hoffmann’s experiment produced diamorphine, an acetylated form of morphine that was two to three times more effective than morphine (Vonkeman, 2010). Morphine is a constitute of the seedpod of the South Asian opium poppy plant, Papaver somniferum (Kapoor,1995). In 1912, Bayer Pharmaceutical Company marketed this drug as a flu remedy for children and a pain reliever. Soon after the drug was widely used, people began to develop extreme side effects; addiction, intense euphoria, and withdrawals (Edwards, 2011). To prevent people from administering the addictive prescription drug, the Harrison Narcotics Tax Act was implemented to control the distribution of diamorphine in 1914. Ten years later, the United States Congress banned the sale of diamorphine and made it illegal for medicinal use (Current, 2010). Diamorphine mechanism of action occurs within seconds of intravenous administration. Diamorphine rapidly crosses the blood-brain barrier due to the acetyl groups, which increase the lipid solubility. Once the molecule has penetrated into the central nervous system it is broken down into two metabolites: 6-monoacetylmorphine (6-MAM) and 3-monoacetylmorphine. These metabolites are then further metabolized into morphine (Current, 2010). Morphine acts as an agonist for the opioid receptors, specifically the mu receptor subtype. Opioid receptors are a group of G protein coupled receptors and are located in the brain where pain and reward skills are monitored (McDonald, 2005). In a normal biological system, endorphins are endogenous opioids that bind to the mu opioid receptors. They are produced by the central nervous system to inhibit pain signals. The inhibition of pain leads to feelings of pleasure or euphoria (McDonald, 2005). The mu receptors mediate the release of the neurotransmitter gamma-aminobutyric acid (GABA) from the nerve terminals. GABA monitors the release of dopamine in the body. Dopamine is a neurotransmitter that controls the reward centers in the brain (Katzung, 2001). When dopamine is released into the synaptic cleft through exocytosis, it binds to its complementary receptor on the postsynaptic membrane located at the nerve terminal. The postsynaptic neuron will elicit a rewarding stimulus, which can lead to addiction (Katzung, 2001).
As the morphine metabolite of diamorphine competitively binds to the mu opioid receptor inhibits the release of GABA from the nerve terminal.
The deactivation of GABA allows an uncontrolled production of dopamine from the nerve terminal. Dopamine and its receptors reside in the ventral tegmental area of the brain. The accumulation of dopamine binding to the dopamine receptors produces immediate effects of reward and pleasure (Katzung, 2001). The reward pathway has a large effect on addictions occurring, because it causes continuous stimulation of nerve cells, leading to intense euphoric
feelings. The morphine metabolite is further metabolized in the liver by phase II glucuronidation, allowing easy elimination from the body (Smith, 2009). Glucuronidation converts the xenobiotic molecule into a more water-soluble compound, also known as a glucuronide. The main two glucuronides are morphine-6-glucuronide (M6G) and morphine-3-glucuroninde (M3G) (Kilpatrick, 2005). UDP-Glucuronosyltransferase-2B7 (UGT2B7) is the major metabolism enzyme that breaks down morphine into M6G and M3G (Smith, 2009). M6G and M3G are highly hydrophilic, preventing penetration through the blood-brain barrier. They will eventually be excreted through the urine (Kilpatrick, 2005).