Lamivudine and Tenofovir

Classification and mechanism of action

The nucleoside reverse transcriptase inhibitor (NRTI) class includes synthetic analogues of natural nitrogenous bases required for DNA synthesis. Structurally, these drugs are divided into several subclasses:

• Thymidine analogues: stavudine.
• Guanine analogues: abacavir.
• Adenine analogues: didanosine.
• Cytidine analogues: zalcitabine, lamivudine, and emtricitabine.

The general mechanism of antiviral action for the entire class is completely identical to that of the reference drug, zidovudine. Upon penetrating the infected cell, these false nucleosides are recognized by the viral enzyme and used for viral DNA synthesis. The incorporation of the abnormal molecule prevents the attachment of the next nucleotide, leading to chain termination and reliably suppressing HIV replication.

Pharmacological profile of lamivudine

Lamivudine is a cytidine analogue distinguished among other drugs by its favorable safety profile. Its main advantage is that it has a significantly weaker inhibitory effect on host cell mitochondrial DNA polymerase. As a result, specific toxicity is reduced, and complications such as neutropenia occur only when therapeutic doses are exceeded.

The drug's pharmacokinetics are characterized by excellent absorption: oral bioavailability reaches 86%. Its relative safety allows lamivudine to be widely used in pediatrics—it is officially approved for treating children starting from 3 months of age.

The spectrum of the drug's antiviral activity includes not only the human immunodeficiency virus but also the hepatitis B virus. However, clinicians face a major challenge: drug resistance to lamivudine develops extremely rapidly. Consequently, monotherapy with this agent is strictly contraindicated. The drug is prescribed exclusively as part of combination therapy, most often combined with zidovudine or non-nucleoside reverse transcriptase inhibitors.

Tenofovir: the only nucleotide inhibitor

Tenofovir differs fundamentally from other members of the group. It is the only nucleotide (rather than nucleoside) reverse transcriptase inhibitor used in HIV therapy. Chemically, it is an acyclic nucleotide—an adenosine monophosphate analogue featuring an incomplete ribose ring.

Its mechanism of action unfolds in three consecutive steps:

1. Upon entering the cell, the drug undergoes phosphorylation and is converted into its active form, tenofovir diphosphate.
2. The resulting active metabolite directly competes with the natural substrate, endogenous deoxyadenosine monophosphate.
3. The false nucleotide is incorporated into the growing viral DNA chain, causing immediate chain termination and blocking further viral assembly.

The spectrum of tenofovir's activity is broad: it exhibits high activity against HIV-1, HIV-2, and hepatitis B virus. Unlike lamivudine, this drug is used primarily for treating adult patients.

General drawbacks and toxicity of the group

Despite the vital necessity of using abnormal nucleosides and nucleotides in HIV therapy, these drugs possess numerous side effects. The primary cause of toxicity lies in their adverse impact on normal host cellular processes.

Most drugs in this class (like the classic zidovudine) lack absolute selectivity. They can suppress mitochondrial DNA synthesis in healthy human cells. This interference with cellular energy metabolism leads to class-wide side effects, the most severe of which is pronounced myelosuppression (impaired hematopoiesis).

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Thymidine and guanine analogues (stavudine, abacavir)
• Mechanism of action of zidovudine as the reference drug
• Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
• Principles of combination therapy for HIV infection
• Mechanisms of myelosuppression during antiretroviral therapy

Other topics in the "Antivirals" section

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