Commonly used drug for the treatment of herpetic diseases such as cold sores or shingles: a summary of the main characteristics of the drug, therapeutic indications, dosage and mechanism of action

 Introduction

Acyclovir is an acyclic analog of deoxyguanosine, a nucleoside present in the body necessary for DNA and cell duplication.

Before the discovery of aciclovir, DNA replication blocking drugs were used for anticancer therapy, a therapy that is toxic to all cells in the body because it is not very selective only for cancer cells.

The discovery of aciclovir has revolutionized the pharmacological treatment of viral diseases, the drug in fact selectively blocks the duplication of viral DNA without involving healthy human cells; this results in a good safety profile of the drug and few side effects.

However, acyclovir is a drug with a spectrum of action restricted only to viruses with a DNA genome (eg Herpes virus), and its improper use, such as suspension of therapy before completely resolving the infection, or its abuse. , can cause the development of drug-resistant mutated viruses. From pharmacological resistances persistent infections arise, more complex to treat, and which induce the patient to follow different pharmacological therapies, with more toxic drugs and more invasive administrations.

Viruses are pathogens that infect and replicate inside the cells of our body, which are smaller and different from bacteria in cellular structure and pathogenicity. They consist of genetic material that exists in the form of DNA or RNA, a protein coat, called a capsid, and in some cases an additional lipid coating that covers the capsid.

L'acyclovir (Aciclin®, Sanavir®, Zovirax®) is the reference drug for the treatment of herpetic diseases such as herpes simplex labialis (HSV-1) of the skin and mucous membranes, primary genital herpes simplex (HSV-2) and its relapses, for the prophylaxis of Herpes simplex infections in immunocompromised patients (suffering from AIDS or bone marrow transplant) and for the treatment of chickenpox and varicella zoster (shingles) in adults.

Acyclovir is available in topical application creams, which are useful for treating blisters caused by labial or genital herpes simplex. It is also available in tablets of 200 and 800 mg for oral therapy and in ampoules for intravenous administration following complications due to herpetic infection.

Undesirable effects

In some patients the administration of aciclovir caused the appearance of skin rashes, which disappeared upon discontinuation of therapy. Undesirable effects on the gastrointestinal system (nausea, vomiting and diarrhea) and on the central nervous system (headache, dizziness, confusion, hallucinations, convulsions) have rarely occurred.

Topical treatment

It is indicated for the treatment of genital and labial herpes simplex skin infections, both primary and recurrent infections.

Dosage: it must be applied 5 times a day at intervals of about 4 hours on the lesions or on the areas where they are developing. The treatment must continue for at least 5 days and up to a maximum of 10.

Oral treatment

For the treatment of infection with Herpes simplex:

therapy should be started if possible at the onset of the first symptoms; one 200 mg tablet is administered 5 times a day at intervals of approximately 4 hours, omitting the night dose. The treatment lasts for 5 days, but it may be necessary to prolong the therapy in case of severe primary infections. In severely immunocompromised patients (HIV-infected or following bone marrow transplantation), or in patients with impaired intestinal absorption, the dose can be doubled to 400 mg.

For the treatment of recurrent infections it is recommended to administer one 200 mg tablet per day every 6 hours.

For the treatment of infection with Varicella zoster:

one 800 mg tablet is administered daily, 5 times a day at intervals of approximately 4 hours. Treatment should be continued for 7 days. In immunocompromised patients, the hypothesis of administering the drug intravenously may be considered. Therapy should begin at the first appearance of symptoms.

Precautions: since clinical data on administration in pregnancy are limited, during this period the drug should only be administered if strictly necessary. Following oral administration of 200 mg of aciclovir 4 times a day, the presence of the drug was observed in breast milk, at concentrations equal to 0.6-4.1 times the corresponding plasma values, therefore it should be avoided. use of aciclovir during breastfeeding in order not to expose the infant to the drug.

Adequate hydration should be maintained during aciclovir therapy, as drug elimination occurs via the kidney. In patients with severe renal insufficiency it is important to adjust the dose to 200 mg administered twice daily with 12 hour intervals.

Intravenous treatment

Intravenous treatment with aciclovir is indicated for Herpes simplex and varicella zoster infections in immunocompromised patients, recurrent forms of varicella zoster and severe forms of primary genital herpetic disease in individuals with normal immune function, herpes simplex virus encephalitis and treatment of Herpes simplex infections in infants.

Pharmacological study: mechanism of action of acyclovir

Acyclovir is a prodrug of synthetic origin similar in structure to deoxyguanosine, in which pentose (2'-deoxy-D-ribose) is replaced with an acyclic unit (Fig. 1).

Fig.1 - Molecular structure of 2'-deoxyguanosine (left) and acyclovir (right)

Acyclovir, being a prodrug, must undergo a chemical transformation to carry out its pharmacological action; this happens inside the cell infected by the virus thanks to the action of an enzyme of viral origin called thymidine kinase (TK). Viral TK catalyzes a phosphorylation reaction of acyclovir, transforming it into acyclovir monophosphate. Acyclovir monophosphate undergoes further phosphorylation reactions, and is transformed first into di-, then into triphosphate by other cellular enzymes such as guanosine monophosphate kinase.

Healthy eukaryotic cells in our body also express the TK enzyme; however, this is not able to bind acyclovir due to the very low affinity for the prodrug, so that acyclovir is not transformed into the active form inside cells not infected by the virus. This explains the good selectivity of acyclovir and the low toxicity for healthy cells.

Activated acyclovir, in the form of acyclovir triphosphate, competes with the substrate of the viral enzyme DNA polymerase, deoxyguanosine triphosphate, forming an irreversible complex with the enzyme, blocking it. DNA polymerase plays a key role in viral replication, and blocking it prevents the virus from replicating its own genome and spreading to other cells.

Furthermore, acyclovir triphosphate, when integrated into viral DNA, in place of deoxyguanosine triphosphate, causes premature termination of DNA duplication, due to the lack of the hydroxyl group (OH) in the 3 ′ position of the sugar.