Acyclovir and Valacyclovir

Acyclovir can be applied topically as a cream to treat cutaneous and mucosal infections. This drug can also be administered systemically, either orally or intravenously in severe, acute infections. 

Valacyclovir (Valtrex) is the precursor or prodrug of acyclovir.89 When administered orally, valacyclovir is converted to acyclovir in the intestinal tract and liver. This conversion typically results in the eventual appearance of higher levels of acyclovir in the bloodstream, because valacyclovir is absorbed more readily from the gastrointestinal tract than acyclovir.42 Thus, administration of valacyclovir is a more effective way to achieve the therapeutic effects of acyclovir when these drugs are orally administered.42 

Mechanism of Action. Acyclovir inhibits viral DNA replication by inhibiting the function of the DNA polymerase enzyme.42 This drug is taken into virus-infected cells and converted to acyclovir triphosphate by an enzyme known as viral thymidine kinase 42 The phosphorylated drug directly inhibits the function of the viral DNA polymerase, thus impairing the replication of viral genetic material. The virus also incorporates the drug into viral DNA strands, which halts further production of DNA because of the presence of a false nucleic acid.42 

The antiviral specificity of acyclovir is due to the drug s higher affinity for viral DNA polymerase rather than the analogous enzyme in human cells42 Also, the first step in the phosphorylation of acyclovir is greatly accelerated in virus-infected cells versus healthy cells. Hence, the amount of the activated (phosphorylated) form of acyclovir is much greater in the cells that really need it—that is, cells infected with the virus. 

Adverse Effects. Topical application of acyclovir may produce local irritation of cutaneous and mucosal tissues. Prolonged systemic administration of acyclovir or valacyclovir may cause headaches, dizziness, skin rashes, and gastrointestinal problems (nausea, vomiting, diarrhea). 

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THERAPEUTIC USES In immunocompetent persons, the clinical benefits of acyclovir and valacyclovir are greater in initial HS V infections than in recurrent ones, which typically are milder. These drugs are particularly useful in immunocompromised patients because these individuals experience more frequent and more severe HSV and VZV infections. Since VZV is less susceptible than HSV to acyclovir, higher doses must be used for treating varicella or zoster infections. Oral valacyclovir is as effective as oral acyclovir in HSV infections and more effective for treating herpes zoster. 

Agents Interfering with Viral Nucleic Acid Replication (Table 43.3) Acyclovir and Valacyclovir... 

Bacterial and fungal complications in chemical peels are rare, since phenol is bacteriocidal and fungacidal. Patients with positive history of herpes simplex infection can be treated proph-ylactically with acyclovir or valacyclovir during the healing phase for 10 days. 

Absorption/Distribution - Valacyclovir is rapidly absorbed and is rapidly and nearly completely converted to acyclovir and L-valine by first-pass metabolism. The absolute bioavailability of acyclovir after administration of valacyclovir is 54.5%. 

Three oral nucleoside analogs are licensed for the treatment of HSV and VZV infections acyclovir, valacyclovir, and famciclovir. They have similar mechanisms of action and similar indications for clinical use all are well tolerated. Acyclovir has been the most extensively studied it was licensed first and is the only one of the three that is available for intravenous use in the United States. Comparative trials have demonstrated similar efficacies of these three agents for the treatment of HSV but modest superiority of famciclovir and valacyclovir for the treatment of herpes zoster. Neither valacyclovir nor famciclovir has been fully evaluated in pediatric patients thus, neither is indicated for the treatment of varicella infection. 

Valacyclovir is the L-valyl ester of acyclovir (Figure 49-2). It is rapidly converted to acyclovir after oral administration via first-pass enzymatic hydrolysis in the liver and intestine, resulting in serum levels that are three to five times greater than those achieved with oral acyclovir and approximate those achieved with intravenous acyclovir. Oral bioavailability is 54-70%, and cerebrospinal fluid levels are about 50% of those in serum. Elimination half-life is 2.5-3.3 hours. 

Fig. 1 Chemical structures of penciclovir, acyclovir, ganciclovir, and valacyclovir...

Oral acyclovir and oral valacyclovir are similar in efficacy and safety for the treatment of HZO. Oral valacyclovir may be more effective in reducing pain from postherpetic neuralgia. 

There is evidence that femciclovir is similar to acyclovir in efficacy, safety, and side effects for the treatment of HZO. In addition, lamciclovir and valacyclovir are comparable in efficacy and safety when treating herpes zoster in immimo-competent patients. A large prospective study provided evidence that famciclovir therapy significantly decreases (twofold) the duration of postherpetic neuralgia when compared with a placebo. When femciclovir was compared with acyclovir in treating immunocompromised patients, the treatments showed a similar efficacy and safety profile. 

There are two approaches to management of recurrent episodes episodic or chronic suppressive therapy. " Episodic therapy is initiated early during the course of the recurrence, preferably at the onset of prodromal symptoms, but no more than 24 hours after the appearance of lesions. In most patients, appreciable effects on symptomatology are not seen. Patients with prolonged episodes of recurrent infection or severe symptomatology are most likely to benefit from episodic therapy. Table 115-10 lists the recommended acyclovir, famciclovir, and valacyclovir suppressive regimens. Because of the relative mildness and brevity of recurrent infections, parenteral administration of acyclovir usually is not justifiable. ... 

In immunocompromised patients with mucocutaneous HSV infection, intravenous acyclovir (250 mg/vtf every 8 hours for 7 days) shortens healing time, duration of pain, and the period of virus shedding. Oral acyclovir (800 mg five times per day) and valacyclovir (1000 mg twice daily) for 5-10 days are also effective. Recurrences are common after drug cessation and may require long-term suppression. In those with very localized labial or facial HSV infections, topical acyclovir may provide some benefit. Intravenous acyclovir may be beneficial in viscerally disseminating HSV in immunocompromised patients and in patients with HSV-infected bum wounds. 

In older adults with localized herpes zoster, oral acyclovir (800 mg five times daily for 7 days) reduces pain and healing times if initiated within 72 hours of rash onset. Treatment of zoster ophthalmicus reduces ocular complications. Prolonged acyclovir and concurrent prednisone for 21 days speed zoster healing and improve quality-of-life compared with either therapy alone. Valacyclovir (1000 mg three times daily for 7 days) provides more rapid relief of zoster-associated pain than acyclovir in adults over 50 with zoster. 

Newer drugs— famciclovir and valacyclovir are approved for HSV infection and are similar to acyclovir in mechanism. They may have activity against strains resistant to acyclovir, but not TK strains. They have a longer t 2 than acyclovir. 

The antiherpes drugs include acyclovir, ganciclovir, and foscarnet. Famciclovir and valacyclovir are j newer dmgs very similar to acyclovir. All inhibit viral DNA polymerase. Acyclovir and ganciclovir do so j by first being phosphorylated by viral enzymes. As well as acting as a polymerase inhibitor, acyclovir 1 triphosphate is incorporated into the vital DNA, where it acts as a chain terminator. The mechanisms I of action, activities, clinical uses, and adverse effects are discussed. 

Indinavir is an inhibitor of HIV protease and has no significant effect on reverse transcriptase. Note that initial monophosphorylation by viral thymidine kinase is not only a characteristic of the activation of acyclovir but also of its congeners famciclovir and valacyclovir. The answer is (B). 

While infection is rare after any type of peel, it tends to result more frequently after medium and deep peels. It is not the infection per se that is problematic, but rather the associated scarring that can ensue. If bacterial, fungal or viral infection is suspected, empiric therapy should be started after a culture is taken. Infections can be bacterial (most commonly staphylococci and streptococci), viral (herpes simplex) and fungal (Candida). Patients with positive history of herpes simplex infection should be treated prophylacticaUy with acyclovir or valacyclovir until full reepithehalization is achieved. 

Prophylactic acyclovir, valacyclovir or famvir is given to patients with a history of recurrent herpes simplex, starting a day before the procedure and continuing for 10 days until full re-epithelialization is achieved. 

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