Zidovudine is chemically named azidothymidine and as such is a derivative of the nucleoside thymidine. Pharmacologically, it belongs to the reverse transcriptase inhibitors and as such is effective against intracellular replication of HIV. It is marketed by the pharmaceutical company GlaxoSmithKline.
What is zidovudine?
Zidovudine is now part of the combination therapy for HIV infection, along with other agents. The paths of science are sometimes unfathomable: in the 1960s, American researchers set to work inventing a new anti-cancer agent – out came a well-performing drug for AIDS. Today, zidovudine, along with other agents, is part of the combination therapy for HIV infection.
Pharmacologic action
The pharmacologic action of zidovudine is due to inhibition of nucleoside reverse transcriptase, an enzyme that HI viruses absolutely require for replication and pathogenicity. The Human Immunodeficiency Virus (HIV), which causes the disease AIDS (Acquired Immune Deficiency Syndrome), belongs to the so-called retroviruses. It uses RNA as its genetic material, not DNA, as is the case with many other life forms, such as humans. In order for HIV to be able to integrate into human cells and, as is usual with viruses, cause them to replicate its genetic material and thus help it to reproduce, it needs reverse transcriptase:
It transcribes viral RNA into DNA (normally this happens the other way around in biology, hence the term “reverse” in this case), which is then integrated into the normal course of cellular metabolism and used to read and make new proteins and thus new viruses. Zidovudine is converted intracellularly to its active form, zidovudine triphosphate, and then has a high affinity for the reverse transcriptase of retroviruses, including HIV-1 and HIV-2, but it must be remembered that other transcriptases that do their work in normal cellular metabolism are also blocked by the drug with lower affinity, which accounts for much of the side effects. As an antimetabolite, zidovudine triphosphate is incorporated into the DNA of the provirus in place of a thymidine building block and blocks further production at this site. The reverse transcriptase involved is blocked. In this way, however, zidovudine only inhibits the HI viruses newly penetrating a host cell – what is already integrated into the cell genome, on the other hand, remains unaffected. Therefore, the agent must also always be used in combination with others to truly comprehensively attack the viral infection.
Medical application and use
Zidovudine is usually used as part of a broad-based HIV therapy called HAART (highly active anti-retroviral therapy). This is because after about six months of zidovudine therapy alone, resistance usually develops on the part of the HI viruses, which mutate in several steps and make their reverse transcriptase insensitive to the drug. In combination with other drugs, this development of resistance is very difficult for the viruses, since they are attacked from several sides at the same time. A triple combination is usually used, usually two nucleoside reverse transcriptase inhibitors with a non-nucleoside reverse transcriptase inhibitor or with a protease inhibitor. The therapy must be closely monitored; in particular, viral load and CD4 cell count are important markers for the direct success of the therapy. Originally, such treatment was launched only at full-blown AIDS; nowadays, there is an increasing tendency to start therapy at earlier stages of infection.
Risks and side effects
Zidovudine has some side effects that can occur during long-term therapy. The fact that it was originally intended to be developed as a chemotherapy drug against cancer tumors already indicates that some side effects must be consistent with those of chemotherapy: Damage to the bone marrow is one of these, which can manifest itself as anemia as early as two to four weeks after the start of therapy and usually as neutropenia, or a drop in white blood cells, from the sixth to eighth week. Neurotoxic effects include, for example, headaches (in 50 percent of those treated), insomnia and psychological changes. Long-term therapy may also result in muscle pain.Gastrointestinal disturbances, fever and skin rash may also occur. Some drug interactions should also be considered, including ASA (aspirin) and morphine may interfere with the breakdown of zidovudine in the liver, resulting in increased drug concentrations. Other cytotoxic or bone marrow-suppressing drugs, of course, exacerbate the side effects of zidovudine.
