• Acyclovir is an analogue of 2'-deoxyguanosine. (J222.340.w1)
• Valacyclovir is the L-valine ester of acyclovir which is given orally as a prodrug which is then converted to acyclovir in the body. (J549.30.w1)

White crystalline solid. (B567.99.w99)

Sodium salt: more than 100 mg/mL at 25 °C. (B567.99.w99)

• Acyclovir is phosphorylated in cells infected with herpes simplex virus or varicella-zoster virus. The first phosphorylation step is carried out by a thymidine kinase specific to these viruses, following which the second and third phosphorylations are carried out by cellular enzymes. (B135.49.w49, B567.99.w99)
  • Phosphorylation by viral thymidine kinase is 30 - 100 times as fast as phosphorylation by host cell kinase. (B135.49.w49, B560.14.w14)
• Acyclovir triple phosphate is a potent alternative-substrate inhibitor, competing with dGTP (deoxyguanosine triphosphate) to be bound to the herpesvirus DNA polymerase and incorporated into viral DNA. One incorporated, viral DNA-polymerase-associated 3'-exonuclease is unable to excise the drug, and the viral polymerase cannot add another deoxyribonucleoside triphosphate onto the chain following acyclovir because the acyclovir does not have a 3'-hydroxyl. (B560.14.w14) therefore the chain is terminated (viral DNA production is stopped). (B560.14.w14, B567.99.w99)
• Additionally, it is possible for the DNA polymerase plus a deoxynriboucleoside triphosphate to become trapped in a reversible dead-end complex with the acyclovir-terminated primer. (B560.14.w14, B567.99.w99)
  • Acyclovir triphosphate inhibits herpesvirus DNA polymerase 10 - 30 times more than it inhibits host cell DNA polymerase. B567.99.w99
• This is an analogue of 2'-deoxyguanosine. It is active following metabolism to acyclovir triphosphate. The first phosphorylation step is catalysed by thymidine kinase in HSV-infected (and VZV-infected) cells, while the second and third phosphorylation steps are catalysed by cellular enzyme. Acyclovir triphosphate competes with 2'-deoxyguanosine triphosphate as a substrate for viral DNA polymerase and is inserted into the replicating viral DNA; synthesis of the viral DNA then stops. (J222.340.w1)

Associated Techniques

• Potently active against herpes simplex virus Type 1, herpes simplex virus type 2 and varicella zoster virus. (B567.99.w99)
• Moderately active against Herpes simiae (B virus). (B567.99.w99)
• Limited activity against human cytomegalovirus. (B567.99.w99)

• In the treatment of herpes simplex and varicella-zoster virus infections. 

Humans

• In the treatment/suppression of mucocutaneous herpes simplex infections in immunocompromised individuals. (B567.99.w99)
• Treatment of initial/recurrent genital herpes infections, and chronic suppression of infection in individuals with frequent recurrent genital herpes. (B567.99.w99)
• Treatment of varicella-zoster infection (in immunocompetent and immunosuppressed individuals). (B567.99.w99)
• Treatment of herpes simplex encephalitis. (B567.99.w99)
• Treatment of herpes zoster. (B567.99.w99)
• Less effective in the treatment of Epstein-Barr virus or cytomegalovirus. (B553.44.w44)

In psittacines: 

Used experimentally; decreased mortality following herpesvirus infection, if given before the onset of clinical signs. (B553.44.w44) 

• Reduced activity against viral mutants with either:
  • Reduced virus-specific thymidine kinase. Occurs in vivo in patients with very poor endogenous immunity recieving prolonged courses of acyclovir. (B567.99.w99)
  • Altered DNA polymerase with a lower binding affinity to acyclovir triphosphate. Very rare in vivo. (B567.99.w99)

• About 20% (based on an oral dose of 200 mg in humans). (B567.99.w99)
• 15 - 30%; may decrease with increasing dose. (B553.44.w44)
• Oral bioavailability is 10-20%. (J222.340.w1)

• "Volume of distribution approximates total body water." (B553.44.w44)
• Concentrations of acyclovir in CSF and in aqueous humour are about a third to one-half those in plasma. B553.44.w44

• Low - about 22 - 33%; (B567.99.w99) 9 - 33%. (B553.44.w44)

• Mainly via the kidneys, as unchanged drug (71 - 99% excreted in urine, human studies with labelled drug). (B567.99.w99)
  • Excreted by glomerular filtration and tubular excretion, as indicated by a higher renal clearance than occurs for creatinine. (B567.99.w99)
• Some metabolism: following intravenous dosing, about 10% of the dose was converted to the metabolite 9-carboxymethoxymethylguanine and about 2% to the metabolite 8-hydroxy-9-(2-hydroxyethoxymethyl)-guanine. (B567.99.w99)

• In humans with normal renal function, average total body clearance about 300 mL/minute/1.73 m²; terminal half-life about 3.0 hours. (B567.99.w99)
• Plasma half-life 2-3 hours (J222.340.w1); 2.5 - 3.5 hours. (B553.44.w44)
  • Intracellular half-life of the triphosphate is 1 - 2 hours (in vitro data). (J222.340.w1)
• Note: in humans with chronic renal failure, average total body clearance about 29 mL/minute/1.73 m²; terminal half-life about 19.0 hours. (B567.99.w99)

• Sterile powder to be reconstituted for intravenous use. (B135.49.w49, B567.99.w99)
• 200 mg capsule. (B135.49.w49, B567.99.w99)
• 400 mg tablets, 800 mg tablets. (B135.49.w49, B567.99.w99)
• 200 mg/5 mL oral suspension. (B135.49.w49, B567.99.w99)
• 5% topical (non-ophthalmic) ointment. (B567.99.w99)
• 3% ophthalmic ointment. (B567.99.w99)

• Note: reduced dosages may be required in individuals with renal impairment, in whom the drug may accumulate. (B567.99.w99)

• Contraindicated in individuals showing hypersensitivity to the drug or to components in its formulation. (B567.99.w99)

• Adverse effects in humans include:
  • Reversible nephropathy due to crystallisation of the drug in the renal tubules. This normally occurs only after intravenous administration. It is uncommon and can be managed by giving fluids at 1 litre per gram of acyclovir, infusing the dose at a rate of no more than 6 mg/mL, over one hour, and reducing the dose in individuals with renal insufficiency (as indicated by creatinine clearance). (J222.340.w1)
  • Gastrointestinal disturbance. This is an uncommon direct effect of the drug and can be managed by reducing the drug dose if necessary. (J222.340.w1)
  • Irritation at the site of injection; phlebitis. (B553.44.w44, J222.340.w1)
    • Due to the high pH of the drug in solution (pH 11). Prevented by ensuring the drug is given intravenously, without extravasation. (J222.340.w1)
  • Rash as a rare idiosyncratic reaction. If moderate to severe, it may be necessary to discontinue the drug. (J222.340.w1)
  • Encephalopathy as a rare reaction precipitated by renal failure or by other drugs with adverse effects on the CNS. Treated by discontinuing use of the drug. (J222.340.w1)

• Little toxicity to human cells not infected with one of the herpesviruses. (B567.99.w99)

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