Zidovudine

History of creation and general characteristics

The drug was synthesized in 1964 as an anticancer agent, but showed no efficacy in this capacity. Years later, the situation changed: in 1987, the drug was approved as the first specific agent to combat HIV infection.

Chemically, the compound is a synthetic analogue of the nucleoside thymidine. Its key structural feature is that in the deoxyribose molecule, the hydroxyl group at the 3'-position is replaced by a 3'-azido group.

Metabolism and mechanism of antiviral action

Upon entering the body, zidovudine undergoes three-stage phosphorylation to its active metabolite — zidovudine triphosphate. Since the human immunodeficiency virus lacks its own kinases, this process is carried out exclusively by host cellular enzymes.

During replication, the active metabolite competes with natural deoxythymidine for incorporation into the growing viral DNA chain. Once the drug is incorporated into the chain, DNA synthesis terminates because the absence of a hydroxyl group at the 3'-position prevents the attachment of the next nucleotide. The target for the drug is HIV reverse transcriptase.

Selectivity and spectrum of activity

The drug demonstrates selectivity, inhibiting the viral reverse transcriptase significantly more strongly than human DNA polymerases. Meanwhile, the mitochondrial isoform of the enzyme becomes the main target for adverse effects in the body.

• Spectrum of activity: infections caused by HIV-1 and HIV-2.
• Clinical scenarios: early stages of the disease, as well as prevention of transmission from mother to fetus (transplacental pathway).
• Dosage forms: tablets, capsules, oral solutions, and parenteral formulations.

Pharmacokinetics and elimination

Zidovudine is well absorbed from the gastrointestinal tract, but its bioavailability is about 65% due to the first-pass hepatic effect.

• Distribution: the active substance penetrates into almost all tissues and biological fluids, crossing the placental barrier and the blood-brain barrier (BBB).
• Elimination: excretion is carried out by the kidneys unchanged and in the form of glucuronide metabolites.

Safety profile and toxicity

Due to the specifics of its activation, zidovudine accumulates not only in infected but also in healthy cells, leading to adverse effects:

1. Hematotoxicity: suppression of replication in rapidly dividing tissues increases the risk of anemia and neutropenia.
2. Mitochondrial toxicity: disruption of DNA synthesis in mitochondria can cause myopathy.
3. Hepatotoxicity: hepatic steatosis and acidosis may occur.
4. Neurotoxic and general reactions: headache, insomnia, dyspepsia, fever, and skin rash, which are often transient in nature.

Class and exam questions

What else to study on this topic

• History of the drug's development as an anticancer agent
• Comparison of the activation mechanism of zidovudine and acyclovir
• Molecular mechanisms of mitochondrial toxicity
• The role of zidovudine in the prevention of mother-to-child HIV transmission
• Factors influencing bioavailability and presystemic metabolism

Other topics in the "Antivirals" section

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.