Review of Pharmacology - 9E (2015)

Review of Pharmacology
viral particles are released (with the help of neuraminidase) and cause infection of
other cells. Drugs can act at any of these steps to inhibit viral replication.
Chemotherapy B: Antimicrobials for Specific Conditions
584
Fig. 14.1: Mechanism of action of
anti-viral drugs
Acyclovir is drug of choice for H.
Simplex encephalitis
Ganciclovir is the drug of choice
for CMV infections including
retinitis.
Cidofovir has wide-spectrum
antiviral activities against:
– HSV
– CMV
– Papilloma virus
– Polyomavirus
– Pox virus
– Adeno virus
Anti Herpes Drugs
Most of these drugs are antimetabolites and inhibit viral DNA polymerase after bioactivation
by kinases.
Acyclovir and its Congeners
It is a guanosine analogue active against herpes simplex virus (HSV-1 and 2) and varicella
zoster virus (VZV). Acyclovir is not active against CMV infections. It is activated first by a virus
specific kinase (thymidine kinase) to form acyclovir monophosphate (virus develops resistance due
to mutation of this kinase) and then by host kinases to form acyclovir triphosphate. This
product competitively inhibits the action of DNA polymerase (by competing with GTP) and also
gets incorporated into the DNA and causes chain termination. It can be used topically, orally or
intravenously. It has very short t 1/2
and requires multiple daily dosing. It is primarily excreted
by kidneys. It is used for the treatment of mucocutaneous and genital herpes and also for the
prophylaxis of herpes infections in AIDS and immunocompromised patients. Parenteral
administration for serious herpes infections cause nephrotoxicity and neurotoxicity (altered
sensorium, tremor, myoclonus, delirium, seizures etc.) as principal dose limiting toxicities
but it does not cause bone marrow suppression. Mycophenolate (immunosuppressant) potentiates
antiherpes activity of acyclovir and related drugs by depleting intracellular GTP. It is essential
to maintain hydration while the patient is on acyclovir therapy because dehydration increases
its nephrotoxic potential. Valacyclovir has a long half life and gets converted to acyclovir by
hepatic metabolism. Famciclovir is a prodrug that gets converted to penciclovir (also developed
as a separate drug) and acts via similar mechanism.
Ganciclovir
It is active against CMV and HSV and acts by inhibiting DNA polymerase. First phosphorylation
step in this case also is virus specific. Ganciclovir is used only intravenously whereas
valganciclovir has good oral absorption. Ganciclovir is the drug of choice for CMV infections
including retinitis. Dose limiting adverse effect is myelosuppression. Its bone marrow
suppressive action is additive to other myelosuppressive drugs like zidovudine. CNS side
effects (headache to convulsions) also occur quite commonly.
Cidofovir
It is activated exclusively by host cell kinases and is active against HSV, CMV, adenovirus
and papilloma virus. Its diphosphate product has prolonged t 1/2
. Dose limiting toxicity is
nephrotoxicity. Probenecid and i.v. saline can decrease nephrotoxicity. Ocular toxicity
including uveitis and iritis is another complication. It is considered as a potential human
carcinogen.
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