Материал: 2016_Kaplan_USMLE_Step_1_Lecture_Notes_Pharmacology

Learning Objectives

Answer questions about anti-herpetics and other antiviral agents

Describe the appropriate treatment of HIV

Solve problems concerning fusion inhibitors

Many antiviral drugs are antimetabolites that resemble the structure of naturally occurring purine and pyrimidine bases or their nucleoside forms. Antimetabolites are usually prodrugs requiring metabolic activation by host-cell or viral enzymes—commonly, such bioactivation involves phosphorylation reactions catalyzed by kinases.

λ Site of action:

Protease inhibitors

Figure V-3-1. Sites of Antiviral Drug Actions

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Section V λ Antimicrobial Agents

Table V-3-1. Mechanism of Action of Antiviral Drugs

ANTIHERPETICS

Acyclovir

λMechanisms of action:

–Monophosphorylated by viral thymidine kinase (TK), then further bioactivated by host-cell kinases to the triphosphate

–Acyclovir-triphosphate is both a substrate for and inhibitor of viral DNA polymerase

–When incorporated into the DNA molecule, acts as a chain terminator because it lacks the equivalent of a ribosyl 3′ hydroxyl group

–Resistance possibly due to changes in DNA polymerase or to decreased activity of TK

–>50% of HSV strains resistant to acyclovir completely lack thymidine kinase (TK– strains)

Figure V-3-2. Common Mechanism for “ovirs” and NRTIs

λActivity and clinical uses:

−Activity includes herpes simplex virus (HSV) and varicella-zoster virus (VZV)

−There are topical, oral, and IV forms; has a short half-life

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Chapter 3 λ Antiviral Agents

−Reduces viral shedding in genital herpes; ↓ acute neuritis in shingles but has no effect on postherpetic neuralgia

−Reduces symptoms if used early in chickenpox; prophylactic in immunocompromised patients

λSide effects:

−Minor with oral use, more obvious with IV

−Crystalluria (maintain full hydration) and neurotoxicity (agitation, headache, confusion—seizures in OD)

−Is not hematotoxic

λNewer drugs—famciclovir and valacyclovir are approved for HSV infec-

tion and are similar to acyclovir in mechanism. They may have activity against strains resistant to acyclovir, but not TK– strains. They have a longer t1/2 than acyclovir.

Ganciclovir

λMechanisms of action:

−Similar to that of acyclovir

−First phosphorylation step is viral-specific; involves thymidine kinase in HSV and a phosphotransferase (UL97) in cytomegalovirus (CMV)

−Triphosphate form inhibits viral DNA polymerase and causes chain termination

−Resistance mechanisms similar to acyclovir

λActivity and clinical uses:

−HSV, VZV, and CMV

−Mostly used in prophylaxis and treatment of CMV infections, including retinitis, in AIDS and transplant patients—relapses and retinal detachment occur

λSide effects:

−Dose-limiting hematotoxicity (leukopenia, thrombocytopenia), mucositis, fever, rash, and crystalluria (maintain hydration)

−Seizures in overdose

Foscarnet

λMechanisms and clinical uses:

–Not an antimetabolite, but still inhibits viral DNA and RNA polymerases

–Uses identical to ganciclovir, plus > activity versus acyclovir-resistant strains of HSV

λSide effects:

–Dose-limiting nephrotoxicity with acute tubular necrosis, electrolyte imbalance with hypocalcemia (tremors and seizures)

–Avoid pentamidine IV (→↑ nephrotoxicity and hypocalcemia)

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