This document discusses acyclovir and valacyclovir, two antiviral drugs used to treat herpesvirus infections. It describes their mechanism of action, pharmacokinetics, antiviral spectrum, resistance, clinical uses, adverse effects, contraindications, drug interactions, and dosages. Acyclovir works by inhibiting herpesvirus DNA polymerase and acting as a chain terminator during viral DNA replication. Valacyclovir is a prodrug of acyclovir that is converted to the active form in the body, improving its bioavailability. Both drugs are effective at treating herpes simplex virus and varicella zoster virus infections.

1. CHAPTER 10 CHEMOTHERAPEUTIC DRUGS
AN EASY APPROACH TO FATEH PHARMACOLOGY 1
ANTI - VIRAL DRUGS
VIRAL INFECTION AND DISEASE
Viruses are obligate intracellular parasites that use many of the host cell’s
biochemical mechanisms and products to sustain their viability. A mature virus
(virion) can exist outside a host cell and still retain its infective properties. However,
to reproduce, the virus must enter the host cell, take over the host cell’s mechanisms
for nucleic acid and protein synthesis, and direct the host cell to make new viral
particles.
CHEMOTHERAPY VIRAL INFECTIONS:
CLSSIFICATION OF THE ANTI- MALRIAL DRUGS:
 On the basis of mechanism of action it is classified into six classes, these are
given as under;
A). Drugs inhibiting adsorption & penetration of susceptible cells
1). Gamma globulins:
2). Adamantanamines:
e.g. Amantadine, Rimantadine, Tromantadine HCl.
B). Drugs inhibiting early protein synthesis
e.g. guanidine, Hydroxybenzylbenzimidazole.
C). Drugs inhibiting Nucleic acid synthesis
1). Pyrimidine & purine Analogues:
e.g. 5-Fluorouracil, 5-Bromouracil, Idoxuridine, Cytarabine, Trifluridine,
Vidarabine, Acyclovir, Ganciclovir & Zidovudine etc.
2). Others:
e.g. Ribavirin, Foscarnet, Phosphonoacetic acid.
D).Drugs inhibiting late protein synthesis
e.g. Methisazone, Fluorophenylalanine, Puromycin.
E). Drugs inhibiting assembly or release of viral particles
e.g. Puromycin, Rifampin, Floxuridine.
F). Drugs inhibiting both nucleic acid & protein synthesis
e.g. Interferons
DRUGS INHIBITING NUCLEIC ACID SYNTHESIS
ACYCLVIR ( Aciclovir®)
VALACYCLOVIR ( ®)
INTRODUCTION:
Acyclovir is an acyclic guanine nucleoside analog that lacks a 3'-hydroxyl on the side
chain. Valacyclovir is the L-valyl ester prodrug of acyclovir.
STRUCTURE:

2. CHAPTER 10 CHEMOTHERAPEUTIC DRUGS
AN EASY APPROACH TO FATEH PHARMACOLOGY 2
PHARMACOKINETICS:
PARAMETER VALUE
Route of administration Oral
Metabolism In Liver
Bio-availability
Excretion In urine
Half Life 3 -4 hours
Protein binding capacity 20%
Valacyclovir is rapidly and completely converted to acyclovir by intestinal and
hepatic first-pass metabolism. The bioavailability of acyclovir following oral
valacyclovir dosing is three to five times that resulting from oral acyclovir
administration and is comparable to that of intravenous acyclovir.
Acyclovir absorption is variable and incomplete following oral administration. It is
about 20% bound to plasma protein and is widely distributed throughout body tissues.
Significant amounts may be found in amniotic fluid, placenta, and breast milk.
Acyclovir is both filtered at the glomeruli and actively secreted. Most of
the dose is excreted in the urine as unchanged drug; a small portion is excreted as an
oxidized inactive metabolite. The plasma half-life of acyclovir is 3 to 4 hours in
patients with normal kidney function and up to 20 hours in patients with renal
impairment.
PHARMACODYNAMICS:
Mechanism of action:
The active metabolite of acyclovir inhibits herpesvirus DNA replication in two ways.
Acyclovir triphosphate acts as a competitive inhibitor for the incorporation of
deoxyguanosine triphosphate (dGTP) into the viral DNA. In addition, acyclovir that is
incorporated into viral DNA acts as a chain terminator because it lacks the 3 hydroxy
group necessary for further chain elongation. Viral DNA polymerase becomes
irreversibly bound to an acyclovir-terminated DNA chain and is unavailable for
further replicative activity. The effect of acyclovir on host cell DNA synthesis is
much smaller than its effect on the viral enzyme. Concentrations of acyclovir signifi-
cantly beyond the therapeutic range are required to inhibit host cell growth.

3. CHAPTER 10 CHEMOTHERAPEUTIC DRUGS
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Figure: mechanism of action
ANTIVIRAL SPECTRUM:
Acyclovir's clinically useful antiviral spectrum is limited to herpesviruses. In
vitro, acyclovir is most active against HSV-1, approximately half as active against
HSV-2, a tenth as potent against VZV and Epstein-Barr virus (EBV), and least active
against cytomegalovirus (CMV) and human herpesvirus (HHV-6). Uninfected
mammalian cell growth generally is unaffected by high acyclovir concentrations.
RESISTANCE:
In HSV and VZV, the most common mechanism of resistance to acyclovir involves;
 Mutations that result in decreased thymidine kinase activity.Therefore, these viral
mutants exhibit cross-resistance to other antiviral agents that require thymidine
kinase activation, such as famciclovir, ganciclovir, and valacyclovir.
 A rare mechanism of acyclovir resistance involves decreased affinity of viral
DNA polymerasefor the drug.

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CLINICAL USES:
1. It is used in herpes genitalis infection
2. it is used in herpes simplex encephalitis
3. it is used in neonatal herpatic dissemination.
4. It is used prophylactically before bone marrow transplants to protect against
severe herpes lesions during post-transplant immunosuppression.
Valacyclovir demonstrates efficacy similar to that of acyclovir but requires less
frequent oral dosing. While indicated for the treatment of herpes zoster and the
treatment and suppression of HSV, it is not approved for use in immunocompromised
individuals or for the therapy of disseminated herpes zoster.
ADVERSE EFFECTS:
1. Topical application: It causes local discomfort & pruritus.
2. Oral therapy: It causes nausea, vomiting, diarrhea & headache. With
valacyclovir also occur thrombotic thromocytopenia purpura in patients with
AIDS.
3. IV therapy: It causes thrombophlebitis, rash, nephrotoxicity, neurological
reactions and hives.
CONTRA-INDICATIONS:
Aside from drug hypersensitivity, there are no absolute contraindications to the use of
acyclovir and valacyclovir. Adjustment of drug dosage is required in patients with
renal impairment. A potentially fatal disorder, thrombotic thrombocytopenic purpura
hemolytic uremic syndrome, has been reported in immunocompromised individuals.
Animal studies have demonstrated no teratogenic or embryotoxic effects of
valacyclovir and acyclovir. Although there are no large, controlled studies of the
safety of these drugs in pregnant women, a prospective epidemiological registry of
acyclovir use during pregnancyshowed no increase in the incidence of common birth
defects.
DRUG INTERACTIONS:
The potential for drug interactions, particularly with other drugs that are actively
secreted by the proximal tubules, should be considered.
 Probenecid has been shown to inhibit the renal clearance of acyclovir.
 Cyclosporine and other nephrotoxic agents may increase the risk of renal
toxicity of acyclovir.
DOSAGE:
Topical ………………… 5% Ointment
Oral …………………… 200mg five times daily
IV ……………………... 15mg/kg/day