Zidovudine for the Prevention of HIV Transmission

zidovudine for the Prevention of human immunodeficiency virus TransmissionIntroductionzidovudine is an antiretroviral drug which is a nucleoside reverse transcriptase inhibitor it is utilize as treatment with other antiretroviral drugs against the Human Immunodeficiency Virus. Additionally, zidovudine dejection be utilised as a means of reducing the find of transfer of HIV from a pregnant woman to her child. Furthermore, zidovudine is utilise in post exposure prophylaxis in order to lower the happen of being infected with HIV in people who have been open to the virus. (AHFS Drug In editionation, n.d.).Name Of Drug, Structure, Formula and Functional Groupszidovudine is also know as azidothymidine and, in short, AZT (Joint pharmacopeia Committee, 2010). The molecular strivingula of the increase is C10H13N5O4 (The Merck Index, n.d.) and zidovudine has a molecular weight of 267.25, as calculated utilize the ISIS ChemDraw package (Cambridge Soft, n.d.). Analysing the escalate sh ows that zidovudine is made up of a triiodothyronine convocation bonded to a 2,3-dideoxyribose convention with an attached azide companying. because the systematic refer of zidovudine is 3-azido-2, 3-dideoxythymidine (The Merck Index, n.d.), as the type O of the hydroxyl group on the 3 carbon of the ribose parry has been removed, giving 3-deoxyribose, and has been replaced with an azide group and the oxygen on the 2 carbon has also been removed.The azide group on the ribose ring is the reason why zidovudine acts as a nucleoside reverse transcriptase inhibitor (AHFS Drug Information, n.d.). In order for zidovudine to carry out its role, it essential be phosphorylated by an enzyme called thymidine kinase this is delinquent to the fact that reverse transcriptase includes the triphosphates produced into the HIV DNA chain being form during HIV replication. Consequently, by and by the triphosphate has been included, 5, 3-phosphodiester bonding in the DNA chain is not contingen t, because of azide group in the triphosphate, and wherefore DNA formation stubnot continue (Foye et al, 2008).Formulations and PackagingThe generic form of zidovudine is acquir competent as hard capsules (Electronic Medicines Compendium, n.d.) in two strengths of 100mg and 250mg (Joint pharmacopeia Committee, 2010). Both strengths atomic number 18 packaged in foil blister packs and bendable bottles and guide to be kept in these they have an expiry take in of 2 historic period from the time of manufacture (Electronic Medicines Compendium, n.d.).Zidovudine is also available under the brand name of Retrovir in the form of capsules, literal resolvent and injection solution (Joint Formulary Committee, 2010). All of the Retrovir formulations need to be kept below 30 degrees and in their original outer(a) boxes (Electronic Medicines Compendium, n.d.).The capsules are hard capsules (Electronic Medicines Compendium, n.d.) in strengths of 100mg and 250mg (Joint Formulary Committee , 2010) they have an expiry catch of five years from the date of manufacture and are packaged in a blister pack or a bottle (Electronic Medicines Compendium, n.d.).The verbal solution consists of a 50mg in 5ml dose (Joint Formulary Committee, 2010) and is packaged in an amber bottle made of glass. The oral solution has an expiry date of two years from the date of manufacture but should be accustomed of after the bottle has been opened for one month (Electronic Medicines Compendium, n.d.).The injection solution is available in the dose of 10mg per 1ml and is utilise for intravenous infusion (Joint Formulary Committee, 2010). It is packaged in a glass vial which is amber or clear in colour. The solution has an expiry date of three years after the date of manufacture however, once opened, it must be used straight away and any remaining solution disposed of (Electronic Medicines Compendium, n.d.).According to Martindale The fat Drug Reference (n.d.), all the formulations of zidovud ine need to be screen from sources of rest and need to be kept in air mean(a) containers.Stereochemistry and ConformationAs high faired in the diagram drawn using ISIS ChemDraw (Cambridge Soft, n.d.), zidovudine has a total of three chiral centres and therefore zidovudine has eight possible stereoisomers. The 1 carbon of the ribose ring is of the R configuration whereas the 3 and 4 carbons are of the S configuration (Novak et al, 2003). Zidovudine has a specific ocular rotation jimmy of +99 in water (Merck, n.d.) and and so rotates the planer of polarized light clockwise consequently zidovudine is optically active (Freeman, 2010). deductive reasoningZidovudine was made by Jerome Horwitz in 1964 (Weeks et al, 2010). It can be form from thymidine, however, this is a apostrophizely method and therefore a more cost effective technique is used to make zidovudine on a large scale by using D-Mannitol as the starting compound (Saunders, 2000). The process has been drawn below using ISISChemDraw (Cambridge Soft, n.d.) with reference to Top Drugs (2000).In the first interpret, a derivative of D-glyceraldehyde is formed from D-mannitol using acetone and a source of protons and refluxing. Lead (IV) acetate is then added. In the second stage a Wittig reaction is carried out and PH3P=CHCO2Et and methanol are added. In the third base step hydrochloric acid is added, producing a lactone. In the fourth stage the lactone is cheer and the azide group is added on through a Michael addition reaction. The reagents used to protect the lactone are t-Bu(Me)2SiCl, imidazole and dimethylformamide. The reagents for the Michael addition reaction are lithium azide, tetrahydrofuran, acetic acid and water. In the fifth stage the lactone is cut back to a lactol at minus 78 degrees using Diisobutylaluminium hydride and dichloromethane. The hydroxyl group is activated to form a sugar fair using acetic anhydride and pyridine. In the 6th step, Vorbruggen conditions are adopted and a condensation reaction is performed with the sugar intermediate and silylated thymine which produces alpha and beta anomers. The reagents are di-trimethylsilyl-thymine, trimethylsilyl trifluoromethanesulfonate and EDC. In the seventh step, the silyl protect group is taken off and the anomers are uncombined to obtain zidovudine. The reagents used in this step are n-Bu4N+F- and tetrahydrofuran (Saunders, 2000).Drug stability Potential sites of chemical instability and metabolismZidovudine decomposes greatly in the presence of light because of the azide group and the product formed from the breakdown is thymine. This is because two nitrogen atoms are removed from the azide group, forming nitrene. An insertion reaction takes place and aziridine is made. Water, as a nucleophile, attacks aziridine. The amide anion formed causes the thymine group to be nucleophilically displaced and so thymine is produced as the abasement product (Dunge et al, 2004). Therefore as zidovudine is mostly impacted by light it is advised that the assorted formulations of zidovudine are kept away from light sources (British Pharmacopoeia, 2010).Zidovudine has a bioavailability of 63%. This is due to the fact that zidovudine undergoes glucuronidation, giving zidovudine glucuronide which is more water soluble than zidovudine due to a sugar group being added, and is renally excreted (Burton et al, 2006). UDP-glucuronyl transferease is the enzyme which catalyses the reaction (Veal et al, 1995).Zidovudine can also be converted to 3-amino-3-deoxythymidine due to the azide group being reduced (Veal et al, 1995) 3-amino-3-deoxythymidine can affect the action of zidovudine against HIV and is possibly noxious (Burton et al, 2006).Lipinskis Rules For Orally Active DrugsAccording to Clarkes Analysis Of Drugs And Poisons (n.d.) the Log P look on of Zidovudine is 0.05 and the molecular weight is 267.25 as calculated on ISIS ChemDraw (Cambridge Soft, n.d.). Zidovudine has a total of two hydrogen bond donor sites and a total of nine hydrogen bond acceptor sites (Lipinski et al, 1997). As a result, zidovudine follows Lipinskis Rules of Five as it has a molecular weight of little than 500, a Log P value of little than 5, there are less than five hydrogen bond donor sites and there are less than ten hydrogen bond acceptor sites (Lipinski et al, 1997).As the Log P value of zidovudine is 0.05 (Clarkes Analysis Of Drugs And Poisons, n.d.) it can be seen that the drug is somewhat polar. Zidovudine contains aromatic and large aliphatic regions which are hydrophobic the polar vitrine arises from the hydroxyl group, an amide region, an ether link and azide group, which are all hydrophilic regions. Therefore as there is a slight imbalance of more hydrophilic groups to hydrophobic groups, zidovudine is slightly hydrophilic and slightly polar and therefore is water soluble and has less affinity to cross the lipid membranes (Bichenkova, 2010).pKa and ionization State At pH 2, 7.4 and 10 and SolubilityAccording to the international Agency for Research on Cancer (n.d.), the pKa value of Zidovudine is 9.68 and hence it is weakly acidic. Using the equation for the component of ionization, which has been derived from the Henderson-Hasselbalch equation, I am able to calculate the percentage amount of ionization of zidovudine at various pH values.The equation used consists of % ionization of an acid = 100/ 1 + antilog(pKa pH) (Freeman, 2010).At pH2, the equation lead read % ionization = 100/ 1 + antilog (9.68 2). This gives the value 2.0910-6 %. Hence it can be seen that in the stay only a very small amount of zidovudine will be ionized and generally it will be largely unionized. The percentage of zidovudine unionized at pH2 is 99.99% and hence as zidovudine is extremely unionized at pH 2, it will be absorbed from the last. At pH2 2.0910-6% of zidovudine is ionized as the azide group can be protonated (Chemicalize, n.d.).At pH 7.4 the calculation gives a value of 0.52%. Hence in the communication channel stream zidovudine will be largely unionized as the percentage of zidovudine that is unionized in the blood stream is 99.8%. In the bloodstream 0.52% of Zidovudine will be ionized as the azide group can deprotonate (Chemicalize, n.d.). As zidovudine is largely unionized at pH 7.4, it can be absorbed from the bloodstream into the CD4 cells where it carries out its role as an antiretroviral (Foye et al, 2008).At pH 10 a value of 67.63% is obtained. Therefore in basic conditions, zidovudine is largelyionized as the azide group is deprotonated and the amide group of thymine is deprotonated (Chemicalize, n.d.). The percentage of zidovudine unionized in the blood is 32.37%.Zidovudine is absorbed very quickly in the body (Burton et al, 2006) and this can be seen through the fact that zidovudine is greatly unionise in the stomach and blood stream and hence can quickly enter the CD4 cells in the blood (Foye et al, 2008).ConclusionAs zidovudine h as an azide group it is able to eat up HIV replication (Foye, 2008). Zidovudine follows Lipinskis Rules and hence is well absorbed in the body (Lipinski et al, 1997). As zidovudine has a pKa of 9.68, the drug can be absorbed from the stomach as it will be largely unionised in the stomach. This is also the case for the drug in the bloodstream and hence zidovudine can be taken up quickly by the cells and carry out its role as an antiretroviral despite being slightly polar. The bioavailability of zidovdine is limited however by the fact that some zidovudine is glucuronidated and hence is lost some zidovudine is also affected by the azide group being reduced as the product formed can affect zidovudines role as an antiretroviral and could be toxic (Burton et al, 2006). As zidovudine degrades in the presence of light, the drug is packaged in blister packs or waxy bottles and all formulations of the drug need to be kept out of light and in the packaging they came in (Electronic Medicines Compendium, n.d.).