Drug Mechanisms and Reactions

Drug Mechanisms and Reactions Phase 1: Drug Metabolism The whole range of biochemical processes that occur within an organism, Metabolism consists both of anabolism and catabolism (the buildup and breakdown of substances, respectively). The biochemical reactions are known as metabolic pathways and involve enzymes that transform one substance into another substance, either breaking down a substance or building a new chemical substance. The term is commonly used to refer specifically to the breakdown of food and its transformation into energy. The liver is the principal site of drug metabolism. Although metabolism typically inactivates drugs, some drug metabolites are pharmacologically active sometimes even more than the parent compound. An inactive or weakly active substance that has an active metabolite is called a pro-drug, especially if designed to deliver the active moiety more effectively. Drugs can be metabolized by oxidation, reduction, hydrolysis, hydration, conjugation, condensation, or isomerization, whatever the process, the goal is to make the drug easier to excrete. The enzymes involved in metabolism are present in many tissues but generally are more concentrated in the liver. Drug metabolism rates vary among patients. Some patients metabolize a drug so rapidly that therapeutically effective blood and tissue concentrations are not reached, in others, metabolism may be so slow that usual doses have toxic effects. Individual drug metabolism rates are influenced by genetic factors, coexisting disorders (particularly chronic liver disorders and advanced heart failure), and drug interactions (especially those involving induction or inhibition of metabolism). For many drugs, metabolism occurs in two phases: Phase I reactions: Which involve formation of a new or modified functional group or cleavage, these reactions are nonsynthetic. Phase II reactions Which involve conjugation with an endogenous substance, these reactions are synthetic. Metabolites formed in synthetic reactions are more polar and more readily excreted by the kidneys (in urine) and the liver (in bile) than those formed in nonsynthetic reactions. Some drugs undergo only phase I or phase II reactions, thus, phase numbers reflect functional rather than sequential classification. Phase I Drug Metabolism Phase I metabolism includes oxidation, reduction, hydrolysis and hydration reactions, as well as other rarer miscellaneous reactions. Oxidations performed by the microsomal, mixed-function oxidase system (cytochrome P450-dependent) is considered separately because of its importance and the diversity of reactions performed by this enzyme system. Classification of Phase I Reactions: Oxidation Reduction Hydrolysis Hydration Dethioacetylation Isomerization Oxidations involving cytochrome P450 (the microsomal mixed-function oxidase) The mixed-function oxidase system found in microsomes (endoplasmic reticulum) of many cells (notably those of liver, kidney, lung and intestine) performs many different functionalisation reactions. CYP 450: The cytochrome P450(CYP) enzyme system consists of a superfamily of hemoproteins that catalyse the oxidative metabolism of a wide variety of exogenous chemicals including drugs, carcinogens, toxins and endogenous compounds such as steroids, fatty acids and prostaglandins. The CYP enzyme family plays an important role in phase-I metabolism of many drugs. The broad range of drugs that undergo CYP mediated oxidative biotransformation is responsible for the large number of clinically significant drug interactions during multiple drug therapy. All of these reactions require the presence of molecular oxygen and NADPH as well as the complete mixed-function oxidase system (cytochrome P450, NADPH-cytochrome P450 reductase and lipid). All reactions involve the initial insertion of a single oxygen atom into the drug molecule. A subsequent rearrangement and/or decomposition of this product may occur, leading to the final products formation. (i) Aromatic hydroxylation: This is a very common reaction for drugs and xenobiotics containing an aromatic ring. In this example the local anaesthetic and antidysrhythmic drug, lignocaine, is converted to its 3-hydroxy derivative. (ii) Aliphatic hydroxylation: Another very common reaction, e.g. pentobarbitone hydroxylated in the pentyl side chain. (iii) Epoxidation: Epoxides are normally unstable intermediates but may be stable enough to be isolated from polycyclic compounds (e.g. the precarcinogenic polycyclic hydrocarbons). Epoxides are substrates of epoxide hydrolase (discussed later), forming dihydrodiols, but they may also spontaneously decompose to form hydroxylated products or quinones. It has been suggested that epoxide formation is the first step in aromatic hydroxylation. (iv) Dealkylation: This reaction occurs very readily with drugs containing a secondary or tertiary amine, an alkoxy group or an alkyl substituted thiol. The alkyl group is lost as the corresponding aldehyde. The reactions are often referred to as N-, O- or S-dealkylations, depending on the type of atom the alkyl group is attached to. (v) Oxidative deamination: Amines containing the structure -CH(CH3)-NH2 are metabolised by the microsomal mixed-function oxidase system to release ammonium ions and leave the corresponding ketone. As with dealkylation, oxidative deamination involves an intermediate hydroxylation step with subsequent decomposition to yield the final products. The product of the oxidative deamination of EPI or NE is 3,4-didydroxyphenylclycoaldehyde (DOPGAL). DOPGAL is subject to reduction to the corresponding alcohol (3,4-dihydroxyphenylethylene glycol, DOPEG) or oxidation to the corresponding carboxylic acid (3,4-dihydroxymandelic acid, DOMA), the latter being the major pathway. (vi) N-oxidation: Hepatic microsomes in the presence of oxygen and NADPH can form N-oxides. These oxidation products may be formed by the mixedfunction oxidase system or by separate flavoprotein N-oxidases. The enzyme involved in N-oxidation depends on the substrate under study. Many different chemical groups can be N-oxidised including amines, amides, imines, hydrazines and heterocyclic compounds. (vii) S-oxidation: Phenothiazines can be converted to their S-oxides (sulfoxides (SÂ ¼O) and sulfones (Â ¼SÂ ¼O)) by the microsomal mixed-function oxidase system. (viii) Phosphothionate oxidation: The replacement of a phosphothionate sulfur atom with oxygen is a reaction common to the phosphothionate insecticides, e.g. parathion. The product paraoxon is a potent anticholinesterase and gives the potent insecticide action as well as the toxicity in humans. Oxidations not catalysed by cytochrome P450 (Non-Microsomal) A number of enzymes in the body not related to cytochrome P450 can oxidize drugs. (i) Alcohol Oxidation by Alcohol dehydrogenase: This enzyme catalyses the oxidation of many alcohols to the corresponding aldehyde and is localised in the soluble fraction of liver, kidney and lung cells. This enzyme uses NAD+ as co-factor and is a true dehydrogenase. (ii) Aldehyde oxidation: Aldehydes can be oxidised by a variety of enzymes involved in intermediary metabolism, e.g. aldehyde dehydrogenase, aldehyde oxidase and xanthine oxidase (the latter two being soluble metalloflavoproteins). (iii) Oxidation by Xanthine oxidase: This enzyme will metabolise xanthine-containing drugs, e.g. caffeine, theophylline and theobromine, and the purine analogues to the corresponding uric acid derivative. Metabolic Reduction (i) Azo- and nitro-reduction can be catalysed by cytochrome P450 (but can also be catalysed by NADPH-cytochrome P450 reductase). (ii) Ring cleavage: Epoxides can be converted back to the parent hydrocarbon, e.g. benzo(a)anthracene- 8,9-epoxide whereas some heterocyclic compounds can be ring cleaved by reduction. (iii) Reductive defluorination: Fluorocarbons of the halothane type can be defluorinated by liver microsomes in anaerobic conditions. Metabolic Hydrolysis Esters, amides, hydrazides and carbamates can readily be hydrolysed by various enzymes. (i) Ester hydrolysis: The hydrolysis of esters can take place in the plasma (nonspecific acetylcholinesterases, pseudocholinesterases and other esterases) or in the liver (specific esterases for particular groups of compounds). Procaine is metabolised by the plasma esterase, whereas pethidine (meperidine) is only metabolised by the liver esterase. (ii) Amide hydrolysis: Amides may be hydrolysed by the plasma esterases (which are so non-specific that they will also hydrolyse amides, although more slowly than the corresponding esters) but are more likely to be hydrolysed by the liver amidases. Ethylglycylxylidide, the N-deethylated phase 1 product of lignocaine, is hydrolysed by the liver microsomal fraction to yield xylidine and ethylglycine. (iii) Hydrazide and carbamate hydrolysis: Less common functional groups in drugs can also be hydrolysed, such as the hydrazide group in isoniazid or the carbamate group in the previously used hypnotic, hedonal. Factors Affecting Metabolism Many factors can affect liver metabolism, such as: In aging, the numbers of hepatocytes and enzyme activity declines. Diseases that reduce hepatic blood flow like heart failure or shock can also reduce the metabolic potential of the liver. Also the use of other drugs as well as dietary and environmental factors can influence liver metabolic function. Metabolism can also be altered due to a genetic deficiency of a particular enzyme. Differences in metabolism that result from functional genetic polymorphisms can be accommodated by knowing the frequency of different genotypes, and by modifying either the enzyme abundance (null alleles, for example, in the case of CYP2D6 poor metabolizers) or the intrinsic enzyme activity (for example, CYP2C9 variants). Data on developmental changes in the abundance and activity of different CYPs can also be incorporated into the models to predict hepatic clearance in neonates, infants and children. Conclusion Metabolism is the breakdown of Drugs inside the body, to disable their activity, forming inactive metabolites, however some drugs are either not affected by metabolism or activated by it, some even form toxic metabolites Examples: Imipiramine not affected by metabolism: Paracetamol produce Toxic Metabolite Metabolism occurs in two phases, Phase I Metabolism, and Phase II Metabolism. Phase I Metabolism converts the drug into metabolite by formation of a new functional group or modifying it, while phase II Metabolism or reactions involve conjugation with indigenous substance. Phase I Reactions Include: Oxidation, reduction, hydrolysis and hydration reactions, and other rare miscellaneous reactions. Oxidation can be divided into Microsomal or non Microsomal according to whether it involves mitochondrial CYP 450 enzymes. Oxidation involves: Microsomal Aromatic Hydroxylation, Aliphatic Hydroxylation, Epoxidation, Dealkylation, oxidative deamination, N- oxidation, S-oxidation and Phosphothionate oxidation. Non-Microsomal Alcohol Oxidation by Alcohol dehydrogenase, Aldehyde Oxidation and Oxidation by Xanthine oxidase. Reduction involves: Azo- and nitro-reduction, Ring cleavage, Reductive defluorination Hydrolysis involves: Ester hydrolysis, Amide hydrolysis, Hydrazide and carbamate hydrolysis

Analysis of Marrysong Dennis Scott Essay

Then Scott having to ‘chart’ – suggesting the creation of a map in order to discover his wife, this emphasises the exploration of this ‘new-found-land’. The poem suggests an unsure attitude, as we see in the first line, ‘year after year’ we don’t know whether this suggest a long, drawn out relationship that could become dull, or whether this means he is happy, and the year after year suggests commitment. Time takes a prominent role in the poem, with what is described as ‘year after year’ is then shortened to passing ‘seasons’ then shrunk still to an ‘hour’ until the shifting of moods becomes sudden, ‘suddenly she would change’. This suggests confusion within the relationship for Scott, as the changing of her attitudes becomes unexplainable and undetectable. This unpredictability leads us to the point of the heavy use of ‘enjambment’ in the first five lines, painting a vivid picture of uncertainty for Scott; conversely, as the poem progresses, we see a much more structured approach. On the contrary, the poem as a whole is generally lacking in structure. The constant use of caesurae, which breaks lines using pauses, denoted by commas and full stops. Also, the stutter of ‘[a]ll, all’’ disrupts the flow of the poem much like the punctuation mentioned. This disruptiveness also contributes to the uncertainty of Scott within the marriage. However, as we approach the concluding lines of the poem Scott evokes a discovery of certainty. He says ‘accepting her geography’ and stating that he ‘wondered’ which maybe suggests that he has no need to wander anymore. This final couplet also features a rhyming final two lines, which suggests stability and an atmosphere of certainty. The oxymoronic use of ‘jaunty helpless journey’ suggest that Scott is at his lover’s mercy; this is significant, as the whole poem conveys the idea that the woman dominates the relationship, and that Scott is exploring her and trying to figure her out. At the beginning of the poem we see that Scott says that she is under control by saying ‘under his eye’, this oxymoron features near to the end of the poem and, with numerous time frames being described in the lines between these two phrases, seems to suggest that after all this time he still has not been able to work her out or even gain control of their relationship. Conversely, this contrasts with the following two lines in which Scott is stated to have figured her out ‘find his way among the landscapes of her mind’. The fourth line, ‘in the walled anger of her quarried hurt’ takes a prominent role within the poem. The use of ‘walled’ and ‘quarried’ suggests an inescapable ‘territory’ into which Scott seems to be stuck. ‘Quarried’ also suggests that Scott is trying to unearth her personality, with ‘walled’ being the defensive behavior with which he does this. Love is a dangerous unreliable territory seems to be one of the main themes evoked by the poem. We see that Scott is continuously trying to gain power in the relationship. This seems to be unobtainable throughout the poem, however the title in itself reveals a childlike innocence about Scott; ‘Marrysong’ isn’t really a word, and sounds like a word a child would make up. It also evokes the bewildering nature of love and the complexity of marriage. Ovid: Ars Amatoria 1. 469-78 states that ‘dura tamen saxa’ (nonetheless, hard rocks) ‘molii cavantur aqua’ (are hollowed out by soft water). At one stage of the poem Scott states that one can see ‘cool water laughing where the day before there were stones in her voice’ – Scott maybe saying that the water hollowed out the rocks and overcame the rocks to make way for love. Furthermore, in relation to territory, Ovid states that ‘capta vides Pergama sero capita tamen’ (You can see that Troy was captured after a long delay, but she was captured in the end) relating to Scott claiming that his lover’s logic is like a territory needing to be explored, and the references of time relate to Ovid stating that Troy was captured ‘after a while’.

We Live For A Recreational Drug Culture - 1403 Words

We live in a recreational drug culture. According to Dr. Sam Richards, who is a well-known professor among Penn State students and academic society, it is widely accepted by society and by lawmakers that consumption of alcohol is reasonable for us and we should consume it. However, not many of us notice that fighting, vandalism, and rape occur because of that beverage (Richards). But what happens if everyone smokes marijuana instead of drinking alcohol? How did we come to the idea that marijuana is bad and alcohol is okay? Think about it. Growing up, everyone is told that, â€Å"Drugs are bad for you,† time and time again. Now as a kid you don’t really understand the reasoning behind it, but you listen to your authority figure regardless. People must first be aware of what Marijuana even is. The term Marijuana is originated from Mexican and Spanish words, mariguana and marihuana. Marijuana itself, comes from a widely cultivated Asian herb called hemp. The leaves and ot her parts of the hemp plant are smoked and provides a feeling of relaxation called â€Å"high†. Even though the substance does not have serious drawbacks, smoking it is still considered as a crime. The debate to legalize marijuana in the United States has been fought since it exist. There are many reasons for and against legalization, but the arguments for it outweigh the arguments against it. In this paper, I argue that marijuana should be legalized for three main reasons: Medical, economic and social benefits.Show MoreRelatedArgumentative Essay : The Legalization Of Marijuana1293 Words   |  6 PagesArgumentative Essay: The Legalization of Marijuana in the United States Should we legalize marijuana? That is an excellent question. First, we must explore the history of Cannabis. Cannabis was introduced to the United States in the 1600’s, first encouraged by the federal government for domestic hemp production, cannabis soon became a required crop for farmers to grow. Hemp was recognized for its medical benefits and was the main fiber used in industrial textiles. Marijuana thrived until the earlyRead MorePsychoactive Drugs And Its Effects On Human Consciousness1284 Words   |  6 PagesA psychoactive drug is any substance that can be used to change brain function. This resulting change is responsible for alterations in perception, mood, and consciousness. As long as man has had a basic grasp on understanding consciousness they have tried delving deeper and deeper into their own consciousness and not only grown a larger respect for just how deep they can go but have had experiences that have encouraged them to go deeper. Rock paintings and fossi l finds from as far back as 10,000Read MoreEssay about Amphetamines: Recreational or Instrumental1069 Words   |  5 PagesEveryone has his or her own opinion about drugs. Recreational drug use is using an illegal drug to get high. 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How Convinced Are You by This Explanation of the Contemporary Drug Situation?3093 Words   |  13 PagesCritically discuss what Howard Parker et al (1998) mean by the normalisation of recreational drug use. How convinced are you by this explanation of the contemporary drug situation? This essay is going to look at Howard Parker et al’s (1998) theory of ‘normalisation’ and critically evaluate whether or not it still relevant in contemporary society. The essay will begin by explaining the theory in relation to how and where it developed from. The essay will move on to focus on specific aspects suchRead MoreThe Issue Of Marijuana Legalization1712 Words   |  7 PagesMarijuana is still illegal in the eyes of the federal government but the states claim it is, in fact, legal for the states to openly practice recreational and medicinal usage of the drug. 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Epic of Beowulf Essay - An Epic Poem - 1656 Words

Beowulf: An Epic Poem To qualify as an epic poem, Beowulf reflects the values of the culture in which it was created. The Anglo-Saxon culture and the poem share many of the same values. They shared a heroic ideal that included loyalty, strength, courage, courtesy, and generosity. Like all epic poems Beowulf is a long narrative work that tells the adventures of a great hero and also reflects the values of the society in which it was written. Both Beowulf and the Anglo-Saxons believed in those qualities as an individual. The strongest ties of loyalty in their society were to kin and lord. A kingdom was only as strong as its war-leader king. In order to have loyal men, the King needed to repay them. In other words the men†¦show more content†¦They burnt and destroyed the monuments of Roman occupation and let the roads and cities fall into utter disrepair. As Gildas, a British monks, phrases it, the red tongue of flame licked up the whole land form end to end, till it slaked its horrid thirst in the western ocean (Allen, 47). Those characteristics are also seen in the epic poem of Beowulf. It is a story of savage pirates, clad in shirts of ring-armoire, and greedy of gold and ale. The noblest leader is he who builds a great hall, throws up open for his people to carouse in, and liberally deals out beer, and bracelets, and money at the feast. Much of which they received from the king. When Beowulf first killed Grendel, there was a large feast in Hrothgar’s hall, Herot. There the queen se rved ale, and the king gave Beowulf and his men treasures. Fighting and drinking are the men’s’ two delights. The joy of battle is warm in their hearts. They are fearless and greedy and not ashamed of living by the strong hand alone. These men were always loyal to their king in the time of need because they were rewarded in the end (Allen, 16). Beowulf was a member of the Geat tribe who is described by the poet as greater/And stronger than anyone anywhere in this world (Beowulf,** 195-196).Beowulf is bringing fourteen of his strongest men across the sea to aid Hrothgar. Hrothgar did not ask for help from Beowulf or anyone else, but this warrior takes it upon himself toShow MoreRelated Epic of Beowulf Essay - Armor in the Epic Poem, Beowulf944 Words   |  4 Pagesthe poem Beowulf      Ã‚  Ã‚   Armor mentioned in the poem Beowulf include helmets and chain mail. There are an incredible number of references to these battle-apparel in the poem, making this topic of armor a very relevant one to consider.    â€Å"Helmets are the most dramatic and often quoted item of armor found in Beowulf,† says Catherine M. Hills in â€Å"Beowulf and Archaeology.† Indeed, examining the poem, one finds copious references to helmets in just the first 400 lines of the poem: Read MoreThe Pessimism of Beowulf in the Epic Poem, Beowulf Essay2837 Words   |  12 Pages  Ã‚  Ã‚   Anticipation of catastrophe, doom, gloom are present in Beowulf rom beginning to end, even in the better half of the poem, Part I. Perhaps this is part of what makes it an elegy – the repeated injection of sorrow and lamentation into every episode. In his essay, â€Å"The Pessimism of Many Germanic Stories,† A. Kent Hieatt says of the poem Beowulf: The ethical life of the poem, then, depends upon the propositions that evil. . . that is part of this life is too much for the preeminent manRead More The Epic Poem - Beowulf Essay2255 Words   |  10 Pages   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Beowulf is an epic poem. Why? Because (1) it is a long narrative work that relates the adventures of a great hero and (2) it reflects the values of the Anglo-Saxon society in which it was written prior to 1000AD. This Old English poem in unrhymed, four-beat alliterative style narrates, through the course of about 3200 verses, the bold killing of two monsters, Grendel and his Mother, and a fire-dragon, as well as numerous other brave deeds in lesser detail, by Beowulf, â€Å"the strongestRead MoreThe Epic Poem, Beowulf - A Jungian Reading of Beowulf Essay774 Words   |  4 PagesA Jungian Reading of Beowulf  Ã‚  Ã‚  Ã‚        Ã‚   The epic poem, Beowulf, depicts the battles and victories of the Anglo-Saxon warrior Beowulf, over man-eating monsters. The noble defender, Beowulf, constantly fought monsters and beasts to rid the land of evil. The most significant of these monsters, Grendel, represents Beowulfs shadow, the Jungian archetype explored in the essay collection, Meeting the Shadow.    The character Grendel portrays the fallen self, which will assert itself violentlyRead More The Theme of the Epic Poem, Beowulf Essay979 Words   |  4 PagesThe Theme of Beowulf      Ã‚  Ã‚  Ã‚   Interpretations of Beowulf vary. In this essay I hope to state clearly some of the popularly mentioned themes running through the poem.    â€Å"Many critics feel that the speech of Hrothgar between lines 1700 and 1784 encapsulates the moral of the poem†¦.’He does not know the worse – till inside him great arrogance grows and spreads’† (Shippey 38). Hrothgar’s ominous words do come back to haunt the hero more than once. Beowulf is a braggart; he is proud, andRead More The Epic Poem, Beowulf - Vengeance and Revenge in Beowulf Essay1328 Words   |  6 PagesVengeance and Revenge in Beowulf    The oldest of the great lengthy poems written in English and perhaps the lone survivor of a genre of Anglo-Saxon epics, Beowulf, was written by an unknown Christian author at a date that is only estimated.   Even so, it is a remarkable narrative story in which the poet reinvigorates the heroic language, style, and values of Germanic oral poetry.   He intertwines a number of themes including good and evil, youth and old age, paganism and Christianity and theRead MoreEssay on The Perfect Ruler in the Epic Poem, Beowulf2623 Words   |  11 Pages     Ã‚  Ã‚  Ã‚   The classic poem Beowulf presents the concept of the perfect king/leader/ruler. This is presented in two modes: the ideal Germanic king and the ideal Christian king. Literary scholar Levin L. Schucking in â€Å"Ideal of Kingship† states: â€Å"I have already tried to prove that the author of Beowulf designed it as a kind of Furstenspiegel (â€Å"mirror of a prince†) – perhaps for the young son of a prince, a thought with which Heusler later agreed† (36). So the author of Beowulf had in mind a humanRead MoreBeowulf: An Anglo-Saxon Epic Poem Essay1356 Words   |  6 Pages The epic poem Beowulf, is a work of fiction and was composed sometime between the middle of the seventh and the end of the tenth century of the first millennium, in the language today called Anglo- Saxon or Old English. This story is a heroic narrative, more than three thousand lines long, concerning the deeds of the Scandinavian prince, also called Beowulf, and it stands as one of the foundation works of poetry in English. Beowulf is obviously a creation of the poet, through partial comparisonsRead More Women in the Epic of Beowulf and in Other Anglo-Saxon Poems Essay1909 Words   |  8 PagesThe Women in Beowulf and in Other Anglo-Saxon Poems      Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   Are women in these poems active equals of the men? Or are they passive victims of the men? The roles of the women in Beowulf and other Anglo-Saxon poems are not always stereotyped ones of passive homemaker and childbearer and peaceweaver, but sometimes ones giving freedom of choice, range of activity, and room for personal growth and development. Beowulf makes reference to Ingeld and his wife and the coming Heathobard feud:Read MoreBeowulf : An Epic Poem Derived From Old World Storytelling Traditions1090 Words   |  5 PagesMs. Michelle Boykin EH 203 (Fall 2015) First Essay: Beowulf October 5, 2015 Beowulf: An Epic Poem Derived from Old World Storytelling Traditions The classic poem Beowulf recorded by a monk during eleventh century A.D., and of unknown authorship, is thought to have been passed down over time through oral traditions of storytelling, popular during that period in history. Most likely the listeners and retellers of these types of these stories would have been warriors themselves, much like