Zidovudine (AZT) was the first drug approved to treat HIV/AIDS. It works by inhibiting the reverse transcriptase enzyme of HIV, preventing it from replicating its DNA within human cells. AZT was approved by the FDA in 1987 and is often used in combination with other antiretrovirals. It is administered orally and can cause side effects like anemia, neutropenia, and lactic acidosis. AZT remains an important component of combination antiretroviral therapy due to its effectiveness against HIV.

1. ZIDOVUDINE
(AZT)

2. INTRODUCTION
 Zidovudine or AZT (azidothymidine) is the drug used to delay development of AIDS
(acquired immunodeficiency syndrome) in patients infected with HIV (human
immunodeficiency virus).
 AZT belongs to a group of drugs known as nucleoside reverse transcriptase inhibitors
(NRTIs).
 In 1987 AZT became the first drug to be approved by the U.S. Food and Drug
Administration for the purpose of prolonging the lives of AIDS patients.
 Since HIV is capable of mutating and thus of developing resistance to the drug. As a
result, it is often given, either orally or intravenously, in combination with at least two
or three other drugs in order to overcome drug resistance.

3. HISTORY
 Dr. George Hitchings began the research program at Wellcome Research
Laboratories in 1942 to search for antagonists of nucleic acid bases
 In 1964 zidovudine (AZT) was synthesized by Horwitz at the Michigan Cancer
Foundation as a potential anti-cancer agent but was shown to be ineffective.
 In 1974 zidovudine was reported to have activity against retroviruses
 It was subsequently re-screened as an antiviral when the AIDS epidemic hit
Western societies during mid 1980’s
 ZIDOVUDINE was approved by the FDA on March 19, 1987
 Retrovir, was the first approved HIV/AIDS drug

4. RETROVIR®
by BURROUGHS WELLCOME Co.
( samples in the museum’s collections)

5. Chemistry of Zidovudine

6. IUPAC Name: 1-[(2R,4S,5S)-4-azido-5-
(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-
2,4-dione
Also known as: Azido-thymidine, Retrovir, 3'-Azido-
3'-deoxythymidine, AZT, Compound S , etc.
Molecular Formula: C10H13N5O4
Molecular Weight: 267.24132
Physical properties: A white or brownish powder,
sparingly soluble in ethanol. It melts at about 1240
degree C
CHEMISTRY of ZIDOVUDINE

7. Nucleoside/Nucleotide Reverse Transcriptase
Inhibitors
 These were the first type of drug available to treat
HIV infection in 1987.
 NRTIs (also known as nucleoside analogues or nukes)
interfere with the action of an HIV protein called
reverse transcriptase, which the virus needs to make
new copies of itself.
 NRTIs are sometimes called the "backbone" of
combination therapy because most regimens contain
at least two of these drugs.

8. Antiretroviral Agents Currently Available (generic name/Trade name)
Nucleoside Analogues (NRTI’s):
 Zidovudine/Retrovir(AZT, ZDV)
 Didanosine/Videx, Videx EC (ddI)
 Zalcitabine/HIVID (ddC)
 Stavudine/Zerit (d4T)
 Lamivudine/Epivir (3TC)
 Abacavir/Ziagen (ABC)

9. MODE of ACTION

10. MODE of ACTION
 Zidovudine (ZDV), is an important drug used for treatment of HIV
infection. It belongs to the family of nucleoside analogue reverse
transcriptase inhibitors (NRTIs)
 It is structurally related to the endogenous nucleoside thymidine with an
azido group in place of the hydroxyl group at the 3' position of the
deoxyribose ring.
 Presence of azido group prevents formation of phosphodiester linkages
needed for DNA replication, causing chain termination.
This is the mechanism by which ZDV interferes with viral replication. The
effectiveness of ZDV in the treatment of HIV infection is due to its selective affinity for
HIV reverse transcriptase as opposed to human DNA polymerases.

12. Pharmacokinetics
Absorption Distribution Metabolism & Excretion

13.  Absorption:
Zidovudine is well absorbed from the gut and, at all dose levels studied, the
bioavailability was 60-70%.
 Distribution:
From studies with intravenous zidovudine, the mean terminal plasma half-life was
1.1 hours, the mean total body clearance was 27.1 ml/min/kg and the apparent
volume of distribution was 1.6 litres/kg.
In adults, the average cerebrospinal fluid/plasma zidovudine concentration ratio,
2 to 4 hours after dosing, was found to be approximately 0.5. Data indicate that
zidovudine crosses the placenta and is found in amniotic fluid and foetal blood.
Zidovudine has also been detected in semen and milk.
Plasma protein binding is relatively low (34 to 38%) and drug interactions
involving binding site displacement are not anticipated.

14.  Metabolism :
Zidovudine is primarily eliminated by hepatic conjugation to an inactive
glucoronidated metabolite. The 5'-glucuronide of zidovudine is the major
metabolite in both plasma and urine, accounting for approximately 50-80% of the
administered dose eliminated by renal excretion. 3'-amino-3'-deoxythymidine
(AMT) has been identified as a metabolite of zidovudine following intravenous
dosing.
 Excretion :
Renal clearance of zidovudine greatly exceeds creatinine clearance, indicating that
significant tubular secretion takes place

16. Pharmacodynamics

17.  Zidovudine triphosphate (ZDV-TP), pharmacologically active form of ZDV, inhibits
the activity of HIV-1 reverse transcriptase by competing with its natural
nucleotide counterpart thymidine triphosphate for incorporation into newly
synthesized viral DNA. Once incorporated, it leads to DNA chain termination and
stops further DNA synthesis.
 The efficacy of ZDV treatment in HIV infection attributed to its selective affinity
for HIV reverse transcriptase as against to human DNA polymerase, however
non-specific inhibition of mitochondrial DNA polymerase gamma results in
observed mitochondrial toxicity. Specifically interference of mitochondrial DNA
replication by ZDV-TP results in reducing mitochondrial DNA subsequently
leading to mitochondrial dysfunction with anaerobic respiration, lip atrophy,
myopathy and lactic acidosis with hepatosteatosis. These undesirable side-
effects are further potentiated in HIV-patients due to negative impact of HIV
infection on mitochondria. Due to these factors the package insert of ZDV
includes warnings for risk of haematological toxicity, myopathy and lactic
acidosis with hepatosteatosis a rare but life threatening mitochondrial toxicity.

18. Quantitative Analysis

19. Quantitative Analysis
 The determination of Zidovudine in bulk and pharmaceutical dosage forms
can be done simply by Reverse Phase HPLC method
 very few methods are reported for the assay of Zidovudine
 UV-3000 LABINDIA double beam with UV win5software, UV-VISIBLE
spectrophotometer with 1cm matched quartz cells. Schimadzu HPLC
equipped with SPD 20A UV-VIS detector and the column used was
SYMMETRY C18 (250*4.6mm, 5µ). The data acquisition was performed by
using LC solutions software.

20. Linearity plot for Zidovudine
Standard chromatogram

21. Spectroscopic Method
LAM: lamivudine
ZID: zidovudine

22.  A salt crystal of AZT, viewed under
polarized light

23. DOSAGE FORMS
Tablets Capsules Injections Syrups

24. AZT in oral, injectable, and suppository form
Dosage Forms
 Tablets: 300 mg,
 Capsules: 100 mg,
 Syrup: 10 mg/mL

26. DOSING
 ADULT : The recommended dosage (syrup, capsules, or tablets) is
maximum dosage 300 mg BID or 200 mg TID
 Paediatric : 4 weeks to <18 years
(It is not FDA approved for use in children <4 weeks of age. However, it has been studied in younger children.)
Weight 4 kg – 9 kg :12 mg/kg BID or 8 mg/kg TID (total daily dosage: 24
mg/kg/day)
Weight 9 kg – 30 kg : 9 mg/kb BID or 6 mg/kg TID (total daily dosage: 18
mg/kg/day)
Weight above 30 kg : Adult dosage
 There are no food restrictions (Take with or without food).

27. ADVERSE EFFECTS

28. a) Zidovudine has caused severe blood problems including a decrease in red
blood cells (anaemia) and white blood cells (neutropenia). They occur more
frequently in people with advanced HIV disease (AIDS).
 signs of anaemia:
 unusual tiredness,
 breathing problems,
 weakness,
 bluish fingernails/lips,
 pale skin.
 Low white blood cells can make you more likely to get serious (sometimes fatal)
infections:
 fever,
 chills,
 persistent cough,
 breathing problems,
 sore throat

29. b) It may cause muscle problems (myopathy) :
 wasting or decrease in muscle size,
 muscle weakness/pain/tenderness,
 weight loss)
c) Serious long-term side effects such as :
 mitochondrial toxicity
 lactic acidosis
 bone marrow toxicity
d) Other symptomatic side effects of ZIDOVUDINE include :
 loss of appetite,
 nausea,
 vomiting,
 malaise,
 Headache, weakness, and dizziness.

30. OVER-DOSAGE &
CONTRA-INDICATIONS

31.  Acute overdoses of zidovudine have been reported in paediatric patients and
adults.
 No specific symptoms or signs apart from those listed as adverse events such
as fatigue, headache, vomiting, and occasional reports of haematological
disturbances.
OVER DOSAGE
CONTRAINDICATIONS
contraindicated in patients who have had potentially life-
threatening allergic reactions (e.g., anaphylaxis, Stevens-Johnson
syndrome)

32. Use

33.  Maximal and durable suppression of viral replication to prevent
development of HIV, drug resistance and treatment failure
 Restoration/ preservation of immunologic function
 Reduction of HIV-related morbidity and mortality
 Improvement of the patient’s quality of life
 Prevention of onward transmission of HIV infection
 Used in combinaitons with other NRTIs as highly active Anti-retroviral
therapy (HAART).
Uses OF Zidovudine

34. Market Preparations

35. SN
o Brand Name Manufacturers Dosage
form Unit
1 Ziddivir Sain Medicament Pvt. Ltd. Tablet 100mg
2 Retrovir (300 mg) Glaxo Smithkline Pharmaceuticals Ltd. Capsule 300mg
3 Zydowin Zydus Vaccicare Capsule 300mg
4 Ziddivir (300 mg) Sain Medicament Pvt. Ltd. Capsule 300mg
5 Retrovir Glaxo Smithkline Pharmaceuticals Ltd. Tablet 100mg
6 Retrovir ( H ) Glaxo Smithkline Pharmaceuticals Ltd. Tablet 100mg
7 Viro-Z Ranbaxy Laboratories Ltd (Croslands) Capsule 100mg
8 Viro-Z (100 ml) Ranbaxy Laboratories Ltd (Croslands) Suspensio
n 5ml
9 Viro-Z (300 mg) Ranbaxy Laboratories Ltd (Croslands) Capsule 300mg
10 Zidine Emcure Pharmaceuticals Ltd. Tablet 300mg
11 Zido-H Genix Pharma Ltd Capsule 100mg
12 Zido-H (300 mg) Genix Pharma Ltd Capsule 300mg
13 Zidomax Alkem Laboratories Ltd (Cytomed) Capsule 100mg
14 Zidomax (300 mg) Alkem Laboratories Ltd (Cytomed) Tablet 300mg
15 Zidovex Citadel Aurobindo Biotech Ltd. (CABL) Capsule 100mg
16 Zidovex (300 mg) Citadel Aurobindo Biotech Ltd. (CABL) Capsule 300mg
17 Zidovir Cipla Limited Capsule 100mg
18 Zidovir Cipla Limited Syrup 5ml
19 Zidovir Cipla Limited Tablet 300mg
LIST OF MARKETED PRODUCTS (INDIA)

36. Brand Name Combination Generics Manufacturers Type
Retrovir (300 mg) Zidovudine Glaxo Smithkline Pharmaceuticals Ltd. Capsule
Zydowin Zidovudine Zydus Vaccicare Capsule
Ziddivir (300 mg) Zidovudine Sain Medicament Pvt. Ltd. Capsule
Combivir Zidovudine, Lamivudine Glaxo Smithkline Pharmaceuticals Ltd. Tablet
Cytocom Zidovudine, Lamivudine Alkem Laboratories Ltd (Cytomed) Tablet
Cytocom – N Zidovudine, Lamivudine, Nevirapine Alkem Laboratories Ltd (Cytomed) Tablet
Cytocom –E Zidovudine, Efavirenz, Lamivudine Alkem Laboratories Ltd (Cytomed) Kit
Duovir Zidovudine, Lamivudine Cipla Limited Tablet
Duovir Zidovudine, Lamivudine Cipla Limited Tablet
Duovir E Kit Zidovudine, Efavirenz, Lamivudine Cipla Limited Kit
OTHER COMBINATIONS

37. Thank You
THE END