Zidovudine for the Prevention of HIV Transmission

Zidovudine for the Prevention of HIV Transmission Presentation Zidovudine is an antiretroviral sedate which is a nucleoside invert transcriptase inhibitor; it is utilized as treatment with other antiretroviral drugs against the Human Immunodeficiency Virus. Moreover, zidovudine can be used as a methods for diminishing the danger of move of HIV from a pregnant lady to her youngster. Moreover, zidovudine is utilized in post introduction prophylaxis so as to bring down the opportunity of being contaminated with HIV in individuals who have been presented to the infection. (AHFS Drug Information, n.d.). Name Of Drug, Structure, Formula and Functional Groups Zidovudine is otherwise called azidothymidine and, to put it plainly, AZT (Joint Formulary Committee, 2010). The sub-atomic recipe of the compound is C10H13N5O4 (The Merck Index, n.d.) and zidovudine has a sub-atomic load of 267.25, as determined utilizing the ISIS ChemDraw bundle (Cambridge Soft, n.d.). Examining the compound shows that zidovudine is comprised of a thymine bunch clung to a 2,3-dideoxyribose bunch with a connected azide gathering. Along these lines the deliberate name of zidovudine is 3†²-azido-2, 3†²-dideoxythymidine (The Merck Index, n.d.), as the oxygen of the hydroxyl bunch on the 3 carbon of the ribose ring has been expelled, giving 3-deoxyribose, and has been supplanted with an azide gathering and the oxygen on the 2 carbon has additionally been evacuated. The azide bunch on the ribose ring is the motivation behind why zidovudine goes about as a nucleoside turn around transcriptase inhibitor (AHFS Drug Information, n.d.). With the end goal for zidovudine to complete its job, it must be phosphorylated by a compound called thymidine kinase; this is because of the way that converse transcriptase incorporates the triphosphates delivered into the HIV DNA chain being framed during HIV replication. Subsequently, after the triphosphate has been incorporated, 5, 3-phosphodiester holding in the DNA chain is beyond the realm of imagination, in light of azide bunch in the triphosphate, and accordingly DNA arrangement can't proceed (Foye et al, 2008). Definitions and Packaging The conventional type of zidovudine is accessible as hard cases (Electronic Medicines Compendium, n.d.) in two qualities of 100mg and 250mg (Joint Formulary Committee, 2010). The two qualities are bundled in foil rankle packs and plastic containers and should be kept in these; they have an expiry date of 2 years from the date of production (Electronic Medicines Compendium, n.d.). Zidovudine is additionally accessible under the brand name of Retrovirâ ® as cases, oral arrangement and infusion arrangement (Joint Formulary Committee, 2010). The entirety of the Retrovirâ ® definitions should be kept underneath 30 degrees and in their unique external boxes (Electronic Medicines Compendium, n.d.). The cases are hard cases (Electronic Medicines Compendium, n.d.) in qualities of 100mg and 250mg (Joint Formulary Committee, 2010); they have an expiry date of five years from the date of production and are bundled in a rankle pack or a jug (Electronic Medicines Compendium, n.d.). The oral arrangement comprises of a 50mg in 5ml portion (Joint Formulary Committee, 2010) and is bundled in a golden jug made of glass. The oral arrangement has an expiry date of two years from the date of production however ought to be discarded after the container has been opened for one month (Electronic Medicines Compendium, n.d.). The infusion arrangement is accessible in the portion of 10mg per 1ml and is utilized for intravenous implantation (Joint Formulary Committee, 2010). It is bundled in a glass vial which is golden or clear in shading. The arrangement has an expiry date of three years after the date of production be that as it may, when opened, it must be utilized immediately and any outstanding arrangement discarded (Electronic Medicines Compendium, n.d.). As per Martindale: The Complete Drug Reference (n.d.), all the details of zidovudine should be protected from wellsprings of light and should be kept in water/air proof holders. Stereochemistry and Conformation As featured in the chart drawn utilizing ISIS ChemDraw (Cambridge Soft, n.d.), zidovudine has an aggregate of three chiral focuses and henceforth zidovudine has eight potential stereoisomers. The 1 carbon of the ribose ring is of the R arrangement while the 3 and 4 carbons are of the S design (Novak et al, 2003). Zidovudine has a particular optical revolution estimation of +99â ° in water (Merck, n.d.) and thus pivots the plane of captivated light clockwise; therefore zidovudine is optically dynamic (Freeman, 2010). Combination Zidovudine was made by Jerome Horwitz in 1964 (Weeks et al, 2010). It tends to be framed from thymidine, in any case, this is an exorbitant strategy and hence a more financially savvy procedure is utilized to make zidovudine for a huge scope by utilizing D-Mannitol as the beginning compound (Saunders, 2000). The procedure has been drawn beneath utilizing ISIS ChemDraw (Cambridge Soft, n.d.) regarding Top Drugs (2000). In the primary stage, a subsidiary of D-glyceraldehyde is framed from D-mannitol utilizing CH3)2CO and a wellspring of protons and refluxing. Lead (IV) acetic acid derivation is then included. In the second stage a Wittig response is done and PH3P=CHCO2Et and methanol are included. In the third step hydrochloric corrosive is included, delivering a lactone. In the fourth stage the lactone is secured and the azide bunch is included through a Michael expansion response. The reagents used to secure the lactone are t-Bu(Me)2SiCl, imidazole and dimethylformamide. The reagents for the Michael expansion response are lithium azide, tetrahydrofuran, acidic corrosive and water. In the fifth stage the lactone is decreased to a lactol at less 78 degrees utilizing Diisobutylaluminium hydride and dichloromethane. The hydroxyl bunch is enacted to shape a sugar middle utilizing acidic anhydride and pyridine. In the 6th step, Vorbruggen conditions are received and a buildup response is performed with the sugar moderate 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 securing bunch is taken off and the anomers are uncombined to get zidovudine. The reagents utilized in this progression are n-Bu4N+F-and tetrahydrofuran (Saunders, 2000). Medication security: Potential destinations of substance shakiness and digestion Zidovudine deteriorates significantly within the sight of light in view of the azide gathering and the item shaped from the breakdown is thymine. This is on the grounds that two nitrogen particles are expelled from the azide gathering, framing nitrene. An inclusion response happens and aziridine is made. Water, as a nucleophile, assaults aziridine. The amide anion shaped causes the thymine gathering to be nucleophilically uprooted and henceforth thymine is created as the debasement item (Dunge et al, 2004). In this manner as zidovudine is generally influenced by light it is informed that the different details with respect to zidovudine are avoided light sources (British Pharmacopeia, 2010). Zidovudine has a bioavailability of 63%. This is because of the way that zidovudine experiences glucuronidation, giving zidovudine glucuronide which is more water dissolvable than zidovudine because of a sugar bunch being included, and is renally discharged (Burton et al, 2006). UDP-glucuronyl transferease is the protein which catalyzes the response (Veal et al, 1995). Zidovudine can likewise be changed over to 3-amino-3-deoxythymidine because of the azide bunch being diminished (Veal et al, 1995); 3-amino-3-deoxythymidine can influence the activity of zidovudine against HIV and is potentially harmful (Burton et al, 2006). Lipinskis Rules For Orally Active Drugs As per Clarkes Analysis Of Drugs And Poisons (n.d.) the Log P estimation of Zidovudine is 0.05 and the sub-atomic weight is 267.25 as determined on ISIS ChemDraw (Cambridge Soft, n.d.). Zidovudine has a sum of two hydrogen bond contributor locales and a sum of nine hydrogen bond acceptor destinations (Lipinski et al, 1997). Therefore, zidovudine observes Lipinskis Rules of Five as it has an atomic load of under 500, a Log P estimation of under 5, there are under five hydrogen bond contributor destinations and there are under ten hydrogen bond acceptor locales (Lipinski et al, 1997). As the Log P estimation of zidovudine is 0.05 (Clarkes Analysis Of Drugs And Poisons, n.d.) it tends to be seen that the medication is marginally polar. Zidovudine contains fragrant and enormous aliphatic areas which are hydrophobic; the polar character emerges from the hydroxyl gathering, an amide district, an ether connection and azide gathering, which are largely hydrophilic locales. Along these lines as there is a slight unevenness of increasingly hydrophilic gatherings to hydrophobic gatherings, zidovudine is somewhat hydrophilic and marginally polar and hence is water dissolvable and has less fondness to cross the lipid layers (Bichenkova, 2010). pKa and Ionization State At pH 2, 7.4 and 10 and Solubility As indicated by the International Agency for Research on Cancer (n.d.), the pKa estimation of Zidovudine is 9.68 and henceforth it is pitifully acidic. Utilizing the condition for the level of ionization, which has been gotten from the Henderson-Hasselbalch condition, I am ready to compute the rate measure of ionization of zidovudine at different pH esteems. The condition utilized comprises of: % ionization of a corrosive = 100/1 + antilog(pKa pH) (Freeman, 2010). At pH2, the condition will peruse % ionization = 100/1 + antilog (9.68 2). This gives the worth 2.0910^-6 %. Thus it tends to be seen that in the stomach just a modest quantity of zidovudine will be ionized and by and large it will be to a great extent unionized. The level of zidovudine unionized at pH2 is 99.99% and consequently as zidovudine is exceptionally unionized at pH 2, it will be assimilated from the stomach. At pH2 2.0910^-6% of zidovudine is ionized as the azide gathering can be protonated (Chemicalize, n.d.). At pH 7.4 the computation gives an estimation of 0.52%. Consequently in the circulation system zidovudine will be to a great extent unionized as the level of zidovudine that is unionized in the circulatory system is 9