Anti-Herpes Virus Drugs

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Chapter: Essential pharmacology : Antiviral Drugs

Idoxuridine It is 5iodo2deoxyuridine (IUDR); acts as a thymidine analogue. It was the first pyrimidine antimetabolite to be used as antiviral drug. It competes with thymidine, gets incorporated in DNA so that faulty DNA is formed which breaks down easily


ANTIHERPES VIRUS DRUGS

 

Idoxuridine  It is 5iodo2deoxyuridine (IUDR); acts as a thymidine analogue. It was the first pyrimidine antimetabolite to be used as antiviral drug. It competes with thymidine, gets incorporated in DNA so that faulty DNA is formed which breaks down easily. It is effective only against DNA viruses and clinical utility is limited to topical treatment of Herpes simplex Keratitis, labial and genital herpes. However, because of low virus selectivity, higher local toxicity and rapid development of viral resistance, it has been superseeded by acyclovir.

 

Trifluridine and vidarabine are other pyrimidine antimetabolites effective against H. simplex.

 

Acyclovir

 

This deoxiguanosine analogue antiviral drug requires a virus specific enzyme for conversion to the active metabolite that inhibits DNA synthesis and viral replication.

 


 

Acyclovir is preferentially taken up by the virus infected cells. Because of selective generation of the active inhibitor in the virus infected cell and its greater inhibitory effect on viral DNA synthesis, acyclovir has low toxicity for host cells: a several hundredfold chemotherapeutic index has been noted.

 

Acyclovir is active only against herpes group of viruses; H. simplex type I is most sensitive followed by H. simplex type II > varicellazoster virus=EpsteinBarr virus; while cytomegalovirus (CMV) is practically not affected. Both H. simplex and varicellazoster virus have been found to develop resistance to acyclovir during therapy; the former primarily due to mutants deficient in thymidine kinase activity and the latter primarily by change in specificity of virus directed enzyme so that its affinity for acyclovir is decreased.

 

Pharmacokinetics

 

Only about 20% of an oral dose of acyclovir is absorbed. It is little plasma protein bound and is widely distributed attaining CSF concentration that is 50% of plasma concentration. It penetrates cornea well. Acyclovir is primarily excreted unchanged in urine, both by glomerular filtration and tubular secretion; plasma t½ is 2–3 hours. Renal impairment necessitates dose reduction.

 

ZOVIRAX 200 mg tab, 250 mg/vial for i.v. inj; CYCLOVIR 200 mg tab, 5% skin cream; HERPEX 200 mg tab, 3% eye oint, 5% skin cream; OCUVIR 200, 400, 800 mg tab, 3% eye oint, ACIVIRDT 200, 400, 800 mg tab. ACIVIR EYE 3% oint.

 

Use

 

Acyclovir is effective in patients with normal as well as deficient immune status.

 

1. Genital Herpes simplex: Generally caused by type II virus; can be treated by topical, oral or parenteral acyclovir depending on stage and severity of disease.

 

Primary disease: 5% ointment is applied locally 6 times a day for 10 days. This is effective only if started early and in mild cases. Late and more severe cases should receive oral therapy (1 g/day in 5 divided doses or 400 mg TDS for 10 days) in addition to local therapy. Both local and oral therapies afford symptomatic relief and rapid healing of lesions, but do not prevent recurrences.

 

Recurrent disease: Topical therapy is totally ineffective. Response to oral treatment is slow and incomplete; severe cases may be treated parenterally—5 mg/kg i.v. infused over 1 hr, repeated 8 hourly for 10 days. Suppressive oral therapy with 400 mg BD has been shown to prevent recurrences as long as given. It is recommended to stop treatment after 1 yr and ascertain whether the patient is still having recurrences; if so restart treatment. After prolonged therapy frequency of recurrences is reduced. Continuous acyclovir prophylaxis is generally advocated in patients with > 8 recurrences per year. However, suppressive therapy reduces, but does not toally prevent, disease transmission to sexual partner.

 

2. Mucocutaneous H. simplex is a type I virus disease, remains localized to lips and gums; does not usually require specific treatment, but acyclovir skin cream may provide some relief. Spreading lesions may be treated with 10 day oral acyclovir. Prophylactic oral therapy may prevent sun exposure related recurrences. The disease often gets disseminated in immunocompromised individuals and may be treated with oral or i.v. acyclovir (15 mg/kg/day) for 7 days, but recurrences are not prevented.

 

3. H. simplex encephalitis (type I virus): Acyclovir 10 to 20 mg/kg/8 hr i.v. for >10 days is the drug of choice. Treatment is effective only if started early: delay precludes salutary effect on mortality and neurological complications.

 

4. H. simplex (type I) keratitis: Acyclovir is equally effective as idoxuridine in superficial dendritic corneal ulcer, and may be better for deep stromal infections because of good corneal penetration. Though acyclovir eye ointment acts slower than idoxuridine eye drops, blindness can be prevented. The eye ointment should be applied 5 times daily till 3 days after healing.

 

5. Herpes zoster: The varicella-zoster virus is less susceptible to acyclovir. As such, higher doses are needed and it should be used only in immunodeficient individuals or in severe cases: 10 mg/ kg/8 hr i.v. for 7 days. Oral therapy with 800 mg 5 times daily is beneficial only if started early. It affords symptomatic relief and faster healing of lesions. Postherpetic neuralgia is not prevented, though its duration may be shortened. Acyclovir skin cream may be applied on herpetic ulcers.

 

6. Chickenpox: in patients with immunodeficiency and in neonates only calls for specific therapy. Acyclovir (15 mg/kg/day i.v. × 7 days) is the drug of choice: reduces fever, eruptions, hastens healing and prevents visceral complications.

 

Oral acyclovir 400 mg 4 times a day for 7 days given during the incubation period may abort chickenpox in susceptible contacts.

 

Adverse Effects

 

Topical: stinging and burning sensation after each application.

Oral: The drug is well tolerated; headache, nausea, malaise and some CNS effects are reported.

Intravenous: rashes, sweating, emesis and fall in BP occur only in few patients.

 

Dose-dependent decrease in g.f.r. is the most important toxicity; occurs especially in those with kidney disease; normalises on discontinuation of the drug.

 

Reversible neurological manifestations (tremors, lethargy, disorientation, hallucinations, convulsions and coma) have been ascribed to higher doses.

No teratogenic potential has been noted.

 

Valaciclovir It is an ester prodrug of acyclovir with improved oral bioavailability (55–70%) due to active transport by peptide transporters in the intestine. During passage through intestine and liver, it is completely converted to acyclovir in the first passage by esterases. Thus, higher plasma levels of acyclovir are obtained improving clinical efficacy in certain conditions; e.g. it is the drug of choice in herpes zoster. Valaciclovir is excreted in urine as acyclovir with a t½ of 3 hours.

 

Dose: For genital herpes simplex—first episode 0.5–1.0 g BD × 10 days; recurrent episode 0.5 g BD × 3 days; suppressive treatment 0.5 g OD × 6–12 months.

 

For orolabial herpes 2 g BD × 1 day; in immunocompromised patient 1 g BD × 5 days. For herpes zoster 1 g TDS × 7 days.

 

VALVIR 0.5 g, 1.0 g tabs.

 

Famciclovir It is an ester prodrug of a guanine nucleoside analogue penciclovir, which has good oral bioavailability and prolonged intracellular t½ of the active triphosphate metabolite. Like acyclovir, it needs viral thymidine kinase for generation of the active DNA polymerase inhibitor. Famciclovir inhibits H. simplex, H. zoster but not acyclovir-resistant strains. Some activity against hepatitis B virus (HBV) has been noted. It is used as an alternative to acyclovir for genital or orolabial herpes and herpes zoster. Early treatment of herpes zoster reduces the duration of post herpetic neuralgia, but not its incidence.

 

Dose: Genital herpes (1st episode) 250 mg TDS × 5 days; recurrent cases 250 mg BD for up to 1 year. Herpes zoster and orolabial herpes 500 mg TDS for 7–10 days.

 

FAMTREX 250, 500 mg tabs.

 

Famciclovir is a less active alternative to lamivudine in chronic hepatitis B, but not in resistant cases. Side effects are headache, nausea, loose motions, itching, rashes and mental confusion.

 

Ganciclovir It is an analogue of acyclovir which is active against all herpes viruses including H. simplex, H. zoster,

EB virus and cytomegalovirus (CMV). It is more active than acyclovir against CMV. The active triphosphate metabolite of ganciclovir attains much higher concentrations inside CMV infected cells. The plasma t½ of ganciclovir is 2–4 hrs, but that of its triphosphate inside CMV infected cells is > 24 hrs. These factors account for its high activity against CMV infections. CMV can develop ganciclovir resistance by mutation.

 

Systemic toxicity of ganciclovir is high (bone marrow depression, rash, fever, vomiting, neuropsychiatric disturbances) and use is restricted to severe CMV infections (pneumonia/colitis) in immunocompromised (AIDS, transplant recipient) patients. Intravenous infusion of 10 mg/kg/day has prevented blindness in AIDS patients with CMV retinitis. Ganciclovir therapy has been found to lower HBV titre in chronic hepatitis B.

 

Foscarnet It is a simple straight chain phosphonate unrelated to any nucleic acid precursor which inhibits viral DNA polymerase and reverse transcriptase. It is active against H. simplex (including strains resistant to acyclovir), CMV (including ganciclovir resistant ones) and HIV. Viral resistance to foscarnet is minimal. However, viral selectivity of foscarnet is low. Oral absorption is poor. Its t½ is 4–8 hours, and it is not metabolised.

 

Toxicity of foscarnet is high: damages kidney— produces a renal diabetes like condition, acute renal failure can also occur. Anaemia, phlebitis, tremor, convulsions and other neurological as well as constitutional symptoms due to hypocalcaemia are frequent. Administered by i.v. infusion, foscarnet has been used for:

 

1. CMV retinitis and other CMV infections in AIDS patients; efficacy is similar to ganciclovir, but includes resistant cases.

 

2. Acyclovir-resistant mucocutaneous H.  simplex  type and varicella-zoster infections in AIDS patients. When used to treat associated CMV/H. simplex/

 

Varicella-zoster infection in AIDS patient, it decreases HIV viral titre, but is not used primarily for HIV infections.

 

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