ms637+Final+Paper

ms637 final paper Morphine and Its Effects In today’s society, there are many different types of opium present all of which are composed of the same alkaloids. What sets each of these apart from one another is the small fact that there are different proportions within each. Morphine, Codeine and Thebaine are all functionally related based on the fact that through methylation and oxidation, Morphine can be transformed into Thebaine [3]. The systematic (IUPAC) name given for Morphine’s structure is (5α,6α)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol, with a chemical formula of C17H19NO3 and a molecular mass of 285.34 g/mol (grams/mole). (5α,6α)-7,8-didehydro-4,5-epoxy-3-methylmorphinan-6-ol is the systematic (IUPAC) name for Codeine. With the chemical formula being C18H21NO3, and with a molar mass of 299.364 g/mol. Thebaine, also referred to as paramorphine, although similar in chemical structure, acts as a depressant rather than an analgesic and is regarded as highly toxic. Paramorphine’s, C19H21NO3, have an IUPAC name of 6,7,8,14-tetradehydro-4,5-didehydro-4,5α -epoxy-3,6-methylmorphinan, and a molar mass of 311.37 g/mol [3]. Of these three opioids, only morphine and codeine are used as prescribed medications [3].

Morphine and its derivatives act on specific receptors which recognize the drug, called opioid receptors. Opioid receptors are chemical-recognition proteins, highly specific, which are located on the membrane of a cell. However, these receptors/proteins are only activated once they come into contact with a certain chemical that binds to them, causing them to activate. There are three main types of opioid receptors with which morphine interacts with, which are: mu (μ), kappa (κ) and delta (δ) receptors [1, 3, 11]. The receptors were given these names based on the analgesic drug which activated the said receptor. The μ –receptor (MOR) was named mu because Morphine interacts with it; κ-receptor (KOR) interacts with Ketocyclazocine, and δ –receptors (DOR) interact with Deferens [1, 2]. Logically speaking, since the brain has opioid receptors, the brain must have a substance like opiate already being produced within the body. It has been found that there are small amounts of morphine in body tissue and fluids, this is also known as endogenous morphine [1]. There are six naturally occurring opioids in the brain, which are referred to as endorphins (morphine and endogenous). They are derived from peptides, which can be classified into several groups, one of which is the opioid-type peptide. They are formed from a chain of amino acids made in another region of the body. For each of these peptides, there are receptor sites in the brain and other areas of the body. Chains which are sixteen to thirty amino acids long are called endorphins, whereas the shorter chains which contain only five amino acids are called enkephalins [4, 6, 11, 19]. Enkephalins, also known as endogenous ligands and endorphins, function to adjust nociception within the body. Nociception is when the sensation of pain is monitored by the nociceptors, which monitors changes (mechanical, thermal and chemical). When and if these changes are greater than the given threshold, the noriceptor is stimulated and signal is transmitted to the brain and the sensation of pain is felt. However, when one is in a stressful or traumatic situation, there is a decrease in the pain response to the stimuli produced by the noriceptor [4]. Meaning that when one is in a traumatic situation or event, the body does not register the pain, but instead releases stimuli to counteract the pain [4], which is basically the same mechanism of action as morphine. The opioid receptors are all G-protein coupled receptors (GPCR) which are grouped to their effectors which are opioids. G-protein coupled receptors function by sensing a molecule approach the cell, and then activates a signal transduction which eventually then leads to cellular responses. Sometimes the peptide/receptor complex goes inside the cell where it starts kinases; other times the complex acts directly as a transcription factor. The peptide receptors generate effects through secondary messenger systems [4,12,15,18]. Even though the action in which it is accomplished is different, it has similar results to traditional neurotransmitters. The mu receptor is distributed throughout the limbic system, and is responsible for most of the effects of morphine. Not all opioids bind to mu receptors with the same affinity; those with the weakest attraction at the receptor have the greatest effect on the receptor. Morphine doesn’t have a strong attachment to the mu receptor but when it binds to it, the strong effect can be seen, it stimulates the receptor. Most of the analgesic and reinforcing effects of morphine are controlled by the mu receptor. Morphine is referred to as an agonist because it activates all three of these receptor sites (it initiates these receptors which then causes the analgesic effects to take place). Morphine functions by mimicking endorphins, which produce analgesic effects by several mechanisms. It is most commonly known that endorphins are released right after somebody has finished working out for the day. The endorphins which are released cause the individual to feel good about themselves. It is like a reward for working out, it makes them happy and the next day, that person will want to work out once more just so that they can feel good about themselves as they had the day before. Basically, it is like a analgesic affect for working out and getting into shape. They affect areas of the spinal cord that transmits a dull, burning pain, and they simultaneously block this sensory incoming information. When the body undergoes pain, the periaqueductal opioid receptors are activated and the pain is reduced. Periaqueductal is the area of the brain which is concerned with the perception of pain and contains many opioid receptors. The opioids cause some of their analgesic effects by stimulating the opioid receptors in the periaqueductal area of the brain. Due to the location of mu receptors in the ventral tegmental area, opioids also stimulate the mesolimbic dopamine (neurotransmitter) system which also controls pain tolerance/levels. The dopamine system functions when the neurotransmitter, dopamine, is released into the cleft when an action potential arrives (in the case it would be when the noriceptor is stimulated). After dopamine diffuses across the synapse and interacts with receptor sites, it is reabsorbed into the terminal bouton, where it is stored again in vesicles and recycled. This mechanism explains its role in addiction based on the fact that the brain normally makes new neurotransmitter receiving structures, the process of turning new experiences into learning. It is basically a function of experience. Since there are less stimuli to trigger there is upregulation. The increased number of receptors means that there is tolerance. There then is an increased sensitivity (addiction), an increased degradation of cell (tolerance) and an increased probability of receptors triggering a response. Dopamine accelerates this process, which may be the reason why people are addicted. The more neurotransmitters there are, the greater sense of pleasure that person feels. According to some studies, casual morphine abuse to addiction starts with the abuser’s very first doses. Drugs produce effects that make people want to continue to use them and cause life-long health problems. First there are pleasurable feelings, then dependence and addiction caused by the disruption of the dopamine neurotransmitter system.

In the spinal cord, morphine and its endogenous counterparts (endorphins and enkephalins), the neurons send axons to the spinal cord where they excite the neurons that convey pain signals from the body to higher levels of the brain. This process is done by direct inhibition and by stimulating other neurons that release endogenous opiates in the spinal cord. Morphine can block pain by stimulating cell in the periaqueductal gray and the spinal cord. In the first few days that morphine is used, before tolerance is developed, morphine creates a state of euphoria where one is in a constant state of content. However, as that individual keeps using morphine, he/she want it more and more because as soon as the “rush” wears off, they no longer feel the instant feeling of pleasure, the pain sets in again. In order for that person to again be at a state where the pain is bearable if not go, they take another dose of morphine. As this cycle continues, the daily dose of morphine gradually increases and eventually it reaches a peak where it plateaus off. When there is no morphine, the amount of enkephalin is higher, which means that that person is in withdrawal. However, over time the amount of morphine to enkephalin reaches a balanced state where they are in correct proportions with one another, this period is also known as the recovery period.

Side Effects Morphine, if not used correctly and under the supervision of a doctor, may cause many serious side effects such as: constipation, physical addiction, tolerance, Hepatitis C as well as overdosing which then leads to death. The physical addiction is basically when abusers feel as though they can’t function in daily life without it, as if it is another source of oxygen. It is as if morphine is needed to survive on a day-to day basis. This form of addiction is when the amount of enkephalin gradually decreases as the amount of morphine steadily increases, which is defined as tolerance and addiction. As one becomes tolerant a drug, they no longer feel the initial ‘high’ as they had in the beginning. In order to feel the initial ‘high’ once more, that individual would need a larger dosage of morphine. As the individual uses the drug more and more, the bigger the doses of morphine will be as well.

Withdrawal Withdrawal from morphine causes nausea, tearing, yawning, chills, and sweating which could last up to three days. This specific drug works in a way in which it activates the brain’s reward systems. The promise of reward is very intense, causing the individual to crave the drug and to focus his or her activities around taking morphine. The ability of morphine to strongly activate brain reward mechanisms and its ability to chemically alter the normal functioning of these systems can produce an addiction. The analgesic affects of morphine are so great that individuals’ who really believe that they cannot live without another dose, are able to make themselves physically sick. Morphine effects also reduce a person's level of consciousness, harming the ability to think or be fully aware of present surroundings. Withdrawal is linked with morphine addiction because it occurs shortly before the next dosage or a little after the last dose was administered.

Constipation It has been studied that Morphine causes constipation in individuals by diminishing gut motility. This is done because morphine inhibits the muscles in the individuals upper gut from functioning correctly, resulting in constipation. From a laboratory experiment which was performed in Italy, constipation mainly depends on the way the central nervous system (CNS) reacts based on the fact that it occurred only when a dosage of morphine was given to the mice intracerebroventricularly (i.c.v.). The research group was also able to conclude that in order to reverse the affects of morphine, L-arginine needed to be injected intraperitoneally. As mentioned earlier in this paper, morphine binds with the μ –opioid receptors in the bowel which in turn inhibits the muscles of the upper gut.

Hepatitis C The Hepatitis C Virus (HCV) is increasingly becoming a great concern to health officials as well as government officials these days. The growing number of HCV cases has been linked with individuals who were undergoing either morphine withdrawal or heroin withdrawal. The common thread seen throughout all the cases of HCV seen, was the fact that all of the users were injection drug users (IDUs). An individual who is going through an opioid withdrawal would most probably contract the Hepatitis C virus by injecting themselves with a needle which another individual would have already utilized. Another theory which was proposed is that HCV is contracted due to the fact the individuals have suppressed their immune systems for a prolonged period of time, that their chances of contracting a virus has exponentially increased. According to research performed, results confirmed the hypothesis that morphine withdrawal increases Hepatitis C virus replicon expression. When an individual undergoes morphine withdrawal, the cells have increased levels of Hepatitis C virus RNA. At the same time however, morphine withdrawal also inhibits the expression of Interferon α (INF- α). According to this same research group, human hepatic cells express interferon α which in turn stops Hepatitis C virus replicon expression. In summary, morphine withdrawal causes cells to have increased levels of Hepatitis C virus RNA and at the same time inhibits the expression of INF- α, which stops the Hepatitis C virus replicon expression [15].

Symptoms of Overdoses An overdose, intentionally or unintentionally, of Morphine can lead to hospitalization as well as death. Overdosing can lead to problems within the individuals’ gastrointestinal system (constipation/ nausea/ vomiting), nervous system (drowsiness/ coma/ seizures), heart and blood vessels (low blood pressure/ weak pulse), respiratory system (breathing difficulties/ shallow breathing/ slow and labored breathing/ not breathing) as well as their skin (bluish tint to the individuals’ nails and lips). If an overdose is suspected in any case, the individual should be rushed to the E.R. for immediate attention.

Tolerance Morphine, being an analgesic, is a drug which gives the user has intense feelings of pleasure and contentment. The user feels good about themselves, which means that they want to be in that state of mind all the time. After the initial effects of the rush wear off, there is a period of depression. In order to bypass that period, an abuser will take another dose of morphine to experience the rush once again, leading to constant use in order to feel that rush of pleasure, leading to addiction which eventually leads to tolerance. Morphine tolerance can be defined by this scenario. An individual starts using morphine so that they can heal from surgery without feeling the pain. As time goes on and their body starts to heal, that individual would not need to the same dosage as they had right after the surgery. The individual enjoys the feeling that morphine provides and continues to self-medicate even though there is no longer any need for prescription medications. Soon, they realize that the same amount they used to ingest does not provide the same feeling, so they increase the dosage. Over time, the individual begins to take large doses of morphine at one time so that they can have that feeling of contentment. This is an example of morphine tolerance building up. Over time, the individuals’ body no longer responds to the same dose so they have to increase the amount needed to achieve pleasure. If continued, the individuals’ tolerance will only continue to increase and will eventually result in an overdose or even death.

Working in a hospital pharmacy, it is a common practice to keep all the morphine-containing medications in the narcotics vault. Until now, there has always been the question, “What is the big deal? Why is there a need to go as far as to do a narcotics count two times a day?” With this research, the reasons behind this particularly odd behavior are now very understandable and warranted. Basically, in the body morphine mimics the function of endorphins, which result in individuals’ being in a state of bliss. Morphine binds to a μ –receptor which then undergoes a few chemical reactions which results in a state of analgesia for the individual. This prescriptive drug can either be taken orally, intramuscular injection, intravenous injection, sublingually, rectally, or as an injection into the epidural space. The mechanism of Morphine can be compared to that of Cocaine because of their similarities. The basic mechanism of action of Cocaine is the blockage of reuptake of Dopamine (stimulant) and Norepinephrine so that the transmitter stays in the cleft longer. Catecholamine neurotransmitters- Epinephrine, Norepinephrine and Dopamine- are made by the body from tyrosine, which is found in food. Tyrosine is converted into L-Dopa which is in turn converted into Dopamine which it utilized by dopaminergic neurons. Norepinephrine is created from some Dopamine, and Epinephrine is created from Norepinephrine. These catecholamines are stored in vesicles in the termine bouton. Here they are protected from two enzymes which destroy, one of which is MAO (monoamine oxidase.) The neurotransmitters are then released into the cleft where the action potential arrives and the analgesic effects start take place. Similarly to the side effects of morphine, cocaine’s side effects just as lethal. Cocaine sniffing can cause inflammation and ulcers of the mucous membranes in the nose. There can also be openings in the septum of the nose. The discomfort in the nose will be relieved by sniffing more cocaine (local anesthetic), causing for the abuser to sniff more cocaine. The more cocaine sniffed means the more money spent (financially unstable) and the deterioration of the mental health as well as physical health.

Each day, millions of people take painkillers for some reason or other. Either it is due to the fact that they were in a physically traumatic accident or to help ebb away the pain of a serious chronic disease. If not taken correctly, painkillers can cause lethal damage to an individual as well as the people around them. When one looks around, there are many who are uneducated about the effects of narcotics and what exactly they are capable of doing. Working in a hospital, I come into contact with many who are forced to admitted due to the fact that their ‘recreational activities’ hurt them or somebody that they love. Before I began this research paper I knew very little about morphine and nothing about its effects on the body. My basic understanding of it was that it was a mild painkiller which was available for purchase just about everywhere. After finishing this research project, I realized how important my job is as a Pharmacy intern is to the hospital. If the different doses of morphine’s were to mixed up in some unfortunate accident, which could lead to an unnecessary mishap in the hospital. Knowing the different mechanisms of actions and the effects it has on the body definitely help me put my job into perspective and really discover what I wanted to do with my career.

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