Introduction to Zidovudine (AZT)
Zidovudine, also known by its former name azidothymidine (AZT) and brand name Retrovir, is a historically significant medication in the fight against Human Immunodeficiency Virus (HIV) [1.3.1]. Initially synthesized in the 1960s as a potential anti-cancer agent, it was repurposed in the 1980s after its potent activity against HIV was discovered [1.6.5]. Its approval marked a turning point, offering the first effective treatment to slow the progression of Acquired Immunodeficiency Syndrome (AIDS) [1.6.1]. While no longer a first-line agent in many treatment guidelines due to its side effect profile, it remains a crucial drug in specific contexts, such as preventing mother-to-child transmission [1.8.1, 1.9.5].
What is the classification of zidovudine?
The primary pharmacological classification of zidovudine is as a Nucleoside Reverse Transcriptase Inhibitor (NRTI) [1.2.1, 1.2.4]. This places it in a class of antiretroviral drugs that form the backbone of combination antiretroviral therapy (cART). As an NRTI, zidovudine is a synthetic analogue of thymidine, one of the natural nucleosides used to build DNA [1.3.1]. Its structure is similar enough to be recognized by viral enzymes but different enough to disrupt the viral replication process [1.2.5].
Mechanism of Action: How NRTIs Work
The function of zidovudine is directly tied to the lifecycle of HIV. After HIV infects a human cell (typically a CD4+ T-cell), it uses an enzyme called reverse transcriptase to convert its viral RNA into DNA—a process that is backward compared to normal cell function [1.3.3]. This newly formed viral DNA can then be integrated into the host cell's own DNA, turning the cell into a factory for producing more viruses [1.3.3].
Zidovudine interrupts this critical step:
- Cellular Activation: Once inside a human cell, zidovudine is phosphorylated by host cell enzymes into its active form, zidovudine triphosphate [1.5.3].
- Competitive Inhibition: This active form competes with the natural thymidine triphosphate for a spot in the growing viral DNA chain being built by the reverse transcriptase enzyme [1.5.3].
- Chain Termination: Zidovudine has an azido group at the 3' position of its deoxyribose ring, where a normal nucleoside would have a hydroxyl (-OH) group [1.3.1]. Once zidovudine is incorporated into the DNA chain, this azido group prevents the next phosphodiester bond from forming. This acts as a "chain terminator," effectively halting the elongation of the viral DNA [1.3.1].
By stopping reverse transcription, zidovudine prevents the virus from successfully replicating, thereby decreasing the amount of HIV in the blood (the viral load) [1.2.1].
Pharmacokinetics: Absorption, Metabolism, and Excretion
Zidovudine is rapidly absorbed after oral administration, with a bioavailability of about 60-70% [1.5.1]. It is widely distributed throughout the body and can cross the blood-brain barrier [1.5.2]. The primary route of elimination is through metabolism in the liver, where it is converted into an inactive glucuronide metabolite (GZDV) [1.3.5, 1.5.2]. Both the parent drug and its metabolite are then excreted by the kidneys [1.3.1]. The typical half-life of zidovudine is short, at approximately 1.1 hours [1.5.1].
Comparison with Other NRTIs
While zidovudine was groundbreaking, newer NRTIs have been developed with different efficacy and tolerability profiles [1.8.1].
| Feature | Zidovudine (AZT) | Lamivudine (3TC) | Tenofovir Disoproxil Fumarate (TDF) | Abacavir (ABC) |
|---|---|---|---|---|
| Primary Toxicity | Bone marrow suppression (anemia, neutropenia), myopathy [1.4.2, 1.5.3] | Generally well-tolerated; pancreatitis (rare) [1.8.1] | Kidney toxicity, bone density loss | Hypersensitivity reaction (HSR) linked to HLA-B*5701 gene [1.8.3] |
| Dosing Frequency | Twice daily [1.10.2] | Once or twice daily | Once daily | Once daily |
| Key Considerations | Requires regular blood count monitoring [1.3.3]. Antagonistic with Stavudine (d4T) [1.7.4]. | Active against Hepatitis B virus (HBV). | Active against HBV. Monitor renal function. | Requires genetic screening for HLA-B*5701 prior to use to prevent HSR. |
| Historical Role | First approved HIV drug [1.6.1] | A common partner drug for Zidovudine and other NRTIs. | Often a component of preferred first-line regimens [1.8.1]. | A component in many single-pill regimens. |
Adverse Effects and Management
The use of zidovudine has declined primarily due to its significant adverse effects [1.8.1]. The most critical is hematologic toxicity, specifically bone marrow suppression, which can lead to severe anemia (low red blood cells) and neutropenia (low white blood cells) [1.4.3, 1.4.4]. This risk is higher in patients with advanced HIV disease [1.4.4].
Other notable side effects include:
- Myopathy: Prolonged use can cause muscle pain, tenderness, and weakness [1.4.3, 1.5.3].
- Lactic Acidosis and Hepatomegaly: A rare but life-threatening mitochondrial toxicity that can occur with NRTIs, causing a buildup of lactic acid in the blood and an enlarged, fatty liver [1.4.3].
- Gastrointestinal Issues: Nausea, vomiting, and loss of appetite are common, especially when starting the medication [1.4.2].
- Other Effects: Headaches, malaise, and insomnia are also frequently reported [1.4.2, 1.5.3].
Patients taking zidovudine require regular monitoring of their complete blood count (CBC) to detect anemia or neutropenia early [1.3.3].
Resistance and Drug Interactions
Like all antiretrovirals, HIV can develop resistance to zidovudine through mutations in the reverse transcriptase enzyme [1.7.5]. To combat this, zidovudine is never used as a monotherapy but always in combination with other antiretroviral drugs from different classes [1.3.2, 1.10.5].
Zidovudine has several important drug interactions. Its hematologic toxicity can be worsened when co-administered with other bone marrow suppressive agents like ganciclovir [1.7.4]. Concomitant use with stavudine should be avoided as the two drugs can have an antagonistic relationship [1.7.4].
Conclusion
In summary, the classification of zidovudine is a nucleoside reverse transcriptase inhibitor (NRTI) [1.2.4]. As the first approved antiretroviral, it revolutionized HIV treatment by providing a mechanism to inhibit viral replication through DNA chain termination [1.3.1, 1.6.1]. While its significant toxicities, particularly bone marrow suppression, have relegated it from first-line therapy in favor of newer, better-tolerated NRTIs, its legacy and continued use in specific situations like perinatal transmission prevention underscore its enduring importance in pharmacology [1.8.1, 1.9.4].
Authoritative Link: For more detailed information, consult the Zidovudine page on NIH's StatPearls [1.10.2].
