Zidovudine for the Prevention of HIV Transmission

Zidovudine for the Prevention of HIV Transmission Presentation Zidovudine is an antiretroviral tranquilize which is a nucleoside turn around transcriptase inhibitor; it is utilized as treatment with other antiretroviral drugs against the Human Immunodeficiency Virus. Furthermore, zidovudine can be used as a methods for lessening the danger of move of HIV from a pregnant lady to her kid. Besides, zidovudine is utilized in post presentation 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.). Dissecting the compound shows that zidovudine is comprised of a thymine bunch clung to a 2,3-dideoxyribose bunch with a connected azide gathering. Accordingly the efficient 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 evacuated, giving 3-deoxyribose, and has been supplanted with an azide gathering and the oxygen on the 2 carbon has additionally been expelled. The azide bunch on the ribose ring is the motivation behind why zidovudine goes about as a nucleoside switch 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 opposite transcriptase incorporates the triphosphates created into the HIV DNA chain being shaped during HIV replication. Thusly, after the triphosphate has been incorporated, 5, 3-phosphodiester holding in the DNA chain is beyond the realm of imagination, in view of azide bunch in the triphosphate, and in this way DNA arrangement can't proceed (Foye et al, 2008). Plans 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 containers 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 assembling 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 container made of glass. The oral arrangement has an expiry date of two years from the date of assembling however ought to be discarded after the jug 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 imbuement (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 in any case, when opened, it must be utilized immediately and any residual arrangement discarded (Electronic Medicines Compendium, n.d.). As indicated by 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 compartments. 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 subsequently zidovudine has eight potential stereoisomers. The 1 carbon of the ribose ring is of the R design though the 3 and 4 carbons are of the S arrangement (Novak et al, 2003). Zidovudine has a particular optical revolution estimation of +99â ° in water (Merck, n.d.) and subsequently turns the plane of spellbound light clockwise; thusly zidovudine is optically dynamic (Freeman, 2010). Amalgamation Zidovudine was made by Jerome Horwitz in 1964 (Weeks et al, 2010). It tends to be framed from thymidine, be that as it may, this is an expensive strategy and consequently a more financially savvy method 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 subordinate of D-glyceraldehyde is shaped 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, creating a lactone. In the fourth stage the lactone is ensured and the azide bunch is included through a Michael expansion response. The reagents used to ensure 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 diminished to a lactol at short 78 degrees utilizing Diisobutylaluminium hydride and dichloromethane. The hydroxyl bunch is enacted to shape a sugar middle of the road utilizing acidic anhydride and pyridine. In the 6th step, Vorbruggen conditions are received and a buildup response is pe rformed with the sugar halfway 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 ensuring 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 soundness: Potential destinations of substance shakiness and digestion Zidovudine disintegrates extraordinarily within the sight of light as a result of the azide gathering and the item shaped from the breakdown is thymine. This is on the grounds that two nitrogen molecules are expelled from the azide gathering, shaping 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 dislodged and consequently thymine is delivered as the debasement item (Dunge et al, 2004). Consequently as zidovudine is for the most part influenced by light it is informed that the different plans 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 solvent than zidovudine because of a sugar bunch being included, and is renally discharged (Burton et al, 2006). UDP-glucuronyl transferease is the catalyst 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 perhaps 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 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 an aggregate of nine hydrogen bond acceptor destinations (Lipinski et al, 1997). Thus, zidovudine adheres to 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 benefactor 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 very well may be seen that the medication is marginally polar. Zidovudine contains sweet-smelling and huge aliphatic locales which are hydrophobic; the polar character emerges from the hydroxyl gathering, an amide area, an ether connection and azide gathering, which are on the whole hydrophilic areas. In this manner as there is a slight irregularity of increasingly hydrophilic gatherings to hydrophobic gatherings, zidovudine is somewhat hydrophilic and marginally polar and hence is water dissolvable and has less partiality 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 consequently 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 ascertain 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 very well may be seen that in the stomach just an exceptionally modest quantity of zidovudine will be ionized and for the most part it will be to a great extent unionized. The level of zidovudine unionized at pH2 is 99.99% and thus as zidovudine is exceptionally unionized at pH 2, it will be consumed 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 estimation gives an estimation of 0.52%. Subsequently 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