Материал: 2016_Kaplan_USMLE_Step_1_Lecture_Notes_Pharmacology

Chapter 3 λ Antiviral Agents

Chapter Summary

General Principles

λAntiviral drugs are often antimetabolites that are structural analogs of purine or pyrimidine bases or their nucleoside forms. Many are prodrugs to be activated by host or viral enzymes. The steps in viral replication and the main sites of action of such antiviral drugs are illustrated in Figure V-3-1.

λTable V-3-1 summarizes the mechanisms of action of the major antiviral drugs.

Antiherpetics

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

Reverse Transcriptase Inhibitors

λNucleoside reverse transcriptase inhibitors (NRTIs) are used in most drug regimes to treat HIV infections. Commonly two NRTIs are used together with a protease inhibitor.

λThe mechanisms, biodisposition, and adverse effects associated with zidovudine (AZT) use are described. The other nucleotide RTIs act almost identically. The NRTIs and their adverse effects are summarized in Table V-3-2.

λNonnucleoside inhibitors of reverse transcriptase (NNRTIs) and a nucleotide RTI are also used in combinations for treatment in an HIV-positive patient.

Protease Inhibitors (PIs)

λHIV aspartate protease has a unique dipeptide structure that has been used as a target for protease inhibitory drugs.

λRitonavir is the most commonly used protease inhibitor. Adverse effects of this group are discussed.

Fusion Inhibitors

λ Enfuvirtide and maraviroc block the entry of HIV into cells.

Integrase Inhibitors

λRaltegravir inhibits HIV integrase and prevents integration of the viral genome into host DNA.

(Continued )

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Section V λ Antimicrobial Agents

Chapter Summary (cont’d )

Other Antivirals

λZanamivir and oseltamivir inhibit influenza viruses A and B neuraminidase, promoting viral clumping and decreasing the chance of penetration. Ribavirin becomes phosphorylated and inhibits IMP dehydrogenase and RNA polymerase. It is used to treat respiratory syncytial virus, influenza A and B,

Lassa fever, Hantavirus, and as an adjunct to alpha-interferons in hepatitis C. The mechanisms, clinical uses, and side effects of these drugs are considered. Hepatitis C therapies are rapidly changing, however. Sofosbuvir is popular in many regimens while simepravir is also being used.

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Learning Objectives

Demonstrate understanding of drugs for malaria and helminthic infections

OVERVIEW

Table V-4-1. Major Protozoal Infections and the Drugs of Choice

ANTIMALARIAL DRUGS

λClinical uses:

−Chloroquine-sensitive regions

ºProphylaxis: chloroquine +/– primaquine

ºBackup drugs: hydroxychloroquine, primaquine, pyrimethaminesulfadoxine

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Section V λ Antimicrobial Agents

λ Specific treatment:

Table V-4-2. Treatment of Chloroquine-Sensitive Malaria

−Chloroquine-resistant regions

ºProphylaxis: mefloquine; backup drugs: doxycycline, atovaquoneproguanil

ºTreatment: quinine +/– either doxycycline or clindamycin or pyrimethamine

λSide effects:

−Hemolytic anemia in G6PD deficiency (primaquine, quinine)

−Cinchonism (quinine)

DRUGS FOR HELMINTHIC INFECTIONS

λMost intestinal nematodes (worms)

−Albendazole (↓ glucose uptake and ↓ microtubular structure)

−Pyrantel pamoate (NM agonist → spastic paralysis)

λMost cestodes (tapeworms) and trematodes (flukes)

−Praziquantel (↑ Ca2+ influx, ↑ vacuolization)

Chapter Summary

λTable V-4-1 lists the major types of protozoal infections and the drugs of choice for their treatment, with various relevant comments.

λTable V-4-2 lists the drugs of choice used against the various forms of malaria, and information is given about treatment and prophylaxis of malaria. Chloroquine-sensitive or -resistant areas are listed separately.

λThe drugs used to treat helminthic infections are listed, and their mechanisms of action are noted.

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