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Katzung & Trevor's Pharmacology: Examination & Board Review, 12e

Chapter 49: Antiviral Agents

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Which statement about the mechanisms of action of antiviral drugs is accurate?

(A) Acyclovir has no requirement for activation by phosphorylation

(B) Ganciclovir inhibits viral DNA polymerase but does not cause chain termination

(C) Increased activity of host cell ribonucleases that degrade viral mRNA is one of the actions of interferon-α

(D) The initial step in activation of foscarnet in HSV-infected cells is its phosphorylation by thymidine kinase

(E) The reverse transcriptase of HIV is 30–50 times more sensitive to inhibition by fosamprenavir than host cell DNA polymerases

Acyclovir is activated by host cell kinases. Like acyclovir, ganciclovir inhibits viral DNA polymerase and causes chain termination. However, foscarnet inhibits viral DNA polymerase without requiring bioactivation. Fosamprenavir is the prodrug of amprenavir, an inhibitor of HIV protease; it has no significant effect on reverse transcriptase. The answer is C.

A 30-year-old male patient who is HIV-positive and symptomatic has a CD4 count of 250/µL and a viral RNA load of 15,000 copies/mL. His treatment involves a 3-drug antiviral regimen consisting of zidovudine, didanosine, and ritonavir. The patient is taking acyclovir for a herpes infection and ketoconazole for oral candidiasis. He now complains of anorexia, nausea and vomiting, and abdominal pain. His abdomen is tender in the epigastric area. Laboratory results reveal an amylase activity of 220 U/L, and a preliminary diagnosis is made of acute pancreatitis.

If this patient has acute pancreatitis, the drug most likely to be responsible is

(A) Acyclovir

(B) Didanosine

(C) Ketoconazole

(D) Ritonavir

(E) Zidovudine

Gastrointestinal problems occur with most antiviral drugs used in HIV-positive patients, and acute pancreatitis has been reported for several reverse transcriptase inhibitors. However, didanosine’s most characteristic adverse effect is a dose-limiting acute pancreatitis. Other risk factors that are relative contraindications to didanosine are advanced AIDS, hypertriglyceridemia, and alcoholism. The answer is B.

In the further treatment of this patient, the drug causing the pancreatitis should be withdrawn and replaced by

(A) Atazanavir

(B) Cidofovir

(C) Foscarnet

(D) Lamivudine

(E) Ribavirin

Symptomatic AIDS patients should be treated with a HAART regimen regardless of a relatively high CD4 count or a relatively low HIV RNA load. Because didanosine must be discontinued, lamivudine would be a good NRTI replacement. Use of a second protease inhibitor (eg, atazanavir) with a single reverse transcriptase inhibitor could be as effective as regimens that include 2 reverse transcriptase inhibitors, although there may be an increased possibility of drug interactions. Atazanavir use is associated with electrocardiographic PR-interval prolongation, which may be exacerbated by other causative agents such as the calcium channel blocker verapamil which an older patient might be taking for angina. The answer is D.

In an accidental needlestick, an unknown quantity of blood from an AIDS patient is injected into a resident physician. The most recent laboratory report on the AIDS patient shows a CD4 count of 20/µL and a viral RNA load of greater than 10⁷ copies/mL. The most appropriate course of action regarding treatment of the resident is to

(A) Determine whether HIV transmission has occurred by monitoring the patient’s blood

(B) Treat with a single high dose of zidovudine

(C) Treat with full doses of zidovudine for 4 weeks

(D) Treat with single doses of zidovudine and indinavir

(E) Treat with zidovudine plus lamivudine plus ritonavir for 4 weeks

The viral RNA titer in the blood from the AIDS patient in this case is very high, and this needlestick must be considered as a high-risk situation. Although full doses of zidovudine for 4 weeks have been shown to have prophylactic value, in high-risk situations combination regimens are favored. Optimal prophylaxis in this case might best be provided by the combination of zidovudine with lamivudine (basic regimen), plus the addition of protease inhibitors (expanded regimen). The answer is E.

A patient with AIDS has a CD4 count of 45/µL. He is being maintained on a 3-drug regimen of indinavir, didanosine, and zidovudine. For prophylaxis against opportunistic infections, he is also receiving cidofovir, fluconazole, rifabutin, and trimethoprim-sulfamethoxazole.

The drug most likely to suppress herpetic infections and provide prophylaxis against CMV retinitis in this patient is

(A) Fluconazole

(B) Cidofovir

(C) Indinavir

(D) Rifabutin

(E) Trimethoprim-sulfamethoxazole

Ganciclovir (not listed) has been the most commonly used drug for prevention and treatment of CMV infections in the immunocompromised patient. However, cidofovir is also very effective in CMV retinitis and has good activity against many strains of HSV, including those resistant to acyclovir. The answer is B.

The dose of indinavir in this patient may need to be increased above normal. This is because

(A) Fluconazole slows gastric emptying

(B) Ganciclovir increases the renal clearance of indinavir

(C) Gastric absorption is inhibited by fluconazole

(D) Rifabutin increases hepatic drug metabolism

(E) Sulfamethoxazole increases indinavir plasma protein binding

Drug interactions can be severe in the immunocompromised patient because many of the drugs administered can influence the pharmacokinetic properties of other drugs. Rifabutin, like rifampin, acts as an inducer of several isoforms of hepatic cytochrome P450. This action can result in an increased clearance of other drugs, including indinavir. The answer is D.

A 27-year-old nursing mother is diagnosed as suffering from genital herpes. She has a history of this viral infection. Previously, she responded to a drug used topically. Apart from her current problem, she is in good health. Which drug to be used orally is most likely to be prescribed at this time?

(A) Amantadine

(B) Foscarnet

(C) Ritonavir

(D) Trifluridine

(E) Valacyclovir

Three of the drugs listed (foscarnet, trifluridine, valacyclovir) are active against strains of herpes simplex virus. Foscarnet is not used in genital infections (HSV-2) because clinical efficacy has not been established, it has poor oral bioavailability, and the drug causes many toxic effects. Trifluridine is used topically but only for herpes keratoconjunctivitis (HSV-1). Valacyclovir is converted to acyclovir by first-pass metabolism in the intestine and liver. The answer is E.

Oral formulations of this drug should not be used in a pregnant AIDS patient because they contain propylene glycol. One of the characteristic adverse effects of the drug is hyperpigmentation on the palms of the hands and soles of the feet, especially in African-American patients.

(A) Amprenavir

(B) Emtricitabine

(C) Efavirenz

(D) Fosamprenavir

(E) Zalcitabine

Three of the drugs listed should be avoided, or used with extreme caution, in the pregnant patient. Oral forms of amprenavir and emtricitabine both contain propylene glycol, a potentially toxic compound. Efavirenz has caused fetal abnormalities in pregnant monkeys and should be avoided during the first 8 weeks of pregnancy. However, one of the distinctive adverse effects of emtricitabine is hyperpigmentation. The answer is B.

Which of the following statements about interferon-α is false?

(A) At the start of treatment, most patients experience flu-like symptoms

(B) Indications include treatment of genital warts

(C) It is used in the management of hepatitis B and C

(D) Lamivudine interferes with its activity against hepatitis B

(E) Toxicity includes bone marrow suppression

Lamivudine is used in monotherapy of HBV infections and does not oppose the beneficial effects of interferon-α when both agents are used together in the treatment of hepatitis B. The answer is D.

More than 90% of this drug is excreted in the urine in intact form. Because its urinary solubility is low, patients should be well hydrated to prevent nephrotoxicity. Which drug is described?

(A) Acyclovir

(B) Efavirenz

(C) Indinavir

(D) Trifluridine

(E) Zidovudine

Acyclovir is eliminated in the urine by glomerular filtration and by active tubular secretion, which is inhibited by probenecid. Nephrotoxic effects, including hematuria and crystalluria, are enhanced in patients who are dehydrated or who have preexisting renal dysfunction. Adequate hydration is equally important in the case of indinavir because it causes nephrolithiasis. However, more than 80% of a dose of indinavir is eliminated via hepatic metabolism. Trifluridine is used topically to treat herpes keratoconjunctivitis. The answer is A.

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Chapter 49: Antiviral Agents

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Chapter 49: Antiviral Agents

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