Interferons

Classification and pharmacodynamics

There are three main types of interferons (IFNs), which differ in their producer cells, production stimuli, and predominant pharmacological effects:

• IFN-alpha (produced predominantly by leukocytes) and IFN-beta (synthesized by fibroblasts). The stimuli for their synthesis are viral infections and cytokines (IL-1, IL-2, tumor necrosis factor). These types are dominated by antiviral and antiproliferative activity. They actively stimulate the cytotoxicity of immunocompetent cells (macrophages, lymphocytes, killer cells).
• IFN-gamma (produced by T-lymphocytes and natural killer cells). It is produced in response to antigenic stimulation. Here, the immunomodulatory action comes to the fore, whereas the antiviral effect is weakly expressed.

Molecular mechanism of antiviral action

Interferon itself does not destroy the virus directly. The effect is realized at various stages of viral reproduction through a complex intracellular cascade of reactions:

1. The interferon molecule binds to specific receptors on the cell surface.
2. Induction of protein synthesis occurs — genes encoding protective effector enzymes are activated.
3. The synthesized proteins block the replication of viral DNA and RNA.

Key IFN-inducible enzymes:

• Oligoadenylate 2'-5' (A) synthetase — activates endoribonucleases that degrade single-stranded RNA (both viral and the cell's own). This enzyme is used as a marker of interferon biological activity.
• Protein kinase R — phosphorylates cellular enzymes involved in translation, leading to their inactivation and complete blockade of viral protein synthesis.

Main groups of drugs

Pharmacological agents are divided into natural (obtained from biological material — blood leukocytes) and recombinant (created by genetic engineering methods).

Natural preparations:

• Human leukocyte interferon (a mixture of IFN-alpha subtypes) — used intranasally for the prevention and treatment of influenza and ARVI.
• Lokferon — used topically for viral eye diseases.

Recombinant preparations (systemic and local):

• IFN-alpha-2a: Roferon-A (systemically for hepatitis B and C, myeloid leukemia, Kaposi sarcoma), Reaferon-ES, Ophthalmoferon (eye drops where IFN is combined with the antihistamine diphenhydramine).
• IFN-alpha-2b: Differs from 2a by the presence of the amino acid arginine at position 23. Includes parenteral forms (Altevir, Intron-A), oral forms (Reaferon-ES-Lipint), intranasal forms (Grippferon), and rectal suppositories (Genferon Light, Viferon).
• IFN-beta-1a: Rebif, Avonex. Used for multiple sclerosis, herpes, HPV, and hepatitis (often in combination therapy with ribavirin).

Pegylation and pharmacokinetics

Standard parenteral forms of interferons have a bioavailability of about 80%, are metabolized in the liver and kidneys, and their half-life ($t_{1/2}$) is only 3–8 hours.

To improve pharmacokinetic properties, pegylation is used — the attachment of a monomethoxypolyethylene glycol (PEG) molecule to the interferon molecule. This makes it possible to prolong the drug's action: $t_{1/2}$ increases to 80–90 hours. Due to this, pegylated interferons (Pegasys, PegIntron) can be administered subcutaneously only once a week. They are effective in treating hepatitis B and C, including cases of resistance to conventional interferons.

Safety profile

Interferon therapy is often accompanied by adverse reactions. The most frequent of these is flu-like syndrome, which occurs a few hours after injection. It manifests as fever (usually subsides after 12 hours), myalgia, arthralgia, headache, and dyspeptic disorders (nausea, vomiting, diarrhea).

Hematological toxicity is also characteristic (thrombocytopenia, neutropenia — especially frequent with the use of pegylated forms). Organotoxicity is possible: disorders of the central nervous system, cardiovascular system, development of nephritis, pneumonia, as well as hepatotoxic effects.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Differences in clinical indications between IFN-alpha-2a and IFN-alpha-2b preparations.
• Features of the use of interferons in oncology and oncohematology (Kaposi sarcoma, myeloid leukemia).
• Mechanisms of development of hematological toxicity when using pegylated interferons.
• The role of combination therapy (interferon-beta + ribavirin) in the treatment of viral infections.
• Pharmacodynamics of combined local preparations using Ophthalmoferon as an example.

Other topics in the "Antivirals" section

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