48
C H A P T E R
Antifungal Agents
Fungal infections are difficult to treat, particularly in the
immunocompromised or neutropenic patient. Most fungi
are resistant to conventional antimicrobial agents, and rela-
tively few drugs are available for the treatment of systemic
fungal diseases. Amphotericin B, the azoles (fluconazole,
Alter cell Block beta-glucan
membrane permeability synthesis
Azoles Polyenes Terbinafine Echinocandins
DRUGS FOR SYSTEMIC
FUNGAL INFECTIONS
A. Amphotericin B
Amphotericin B continues to be an important drug for the treat-
ment of systemic fungal infections. However, several azoles and
echinocandins are proving to be just as effective in some systemic
mycoses with less risk of toxic effects.
1. Classification and pharmacokinetics—Amphotericin B is
a polyene antibiotic related to nystatin. Amphotericin is poorly
÷
absorbed from the gastrointestinal tract and is usually adminis-
tered intravenously as a nonlipid colloidal suspension, as -
a lipid
complex, or in a liposomal formulation. The drug is widely dis-
tributed to all tissues except the central nervous system (CNS).
Elimination is mainly via slow hepatic metabolism; the half-life is
approximately 2 weeks. A small fraction of the drug is excreted in
the urine; dosage modification is necessary only in extreme renal
dysfunction. Amphotericin B is not dialyzable.
404
itraconazole, ketoconazole, and voriconazole), and the echi-
nocandins are the primary drugs used in systemic infections.
They are selectively toxic to fungi because they interact with
or inhibit the synthesis of ergosterol, a sterol unique to fungal
cell membranes.
Drugs acting on fungi
Block nucleic Disrupt
acid synthesis microtubule functions
Flucytosine Griseofulvin
2. Mechanism of action—The fungicidal action of ampho-
tericin B is due to its effects on the permeability and transport
EI
properties of fungal membranes. Polyenes are molecules with both
hydrophilic and lipophilic characteristics (ie, they are amphipathic).
They bind to ergosterol, a sterol specific to fungal cell membranes,
and cause the formation of artificial pores (Figure 48–1). Resistance,
though uncommon, can occur via a decreased level of or a struc-
tural change in membrane ergosterol.
3. Clinical uses—Amphotericin B is one of the most important
drugs available for the treatment of systemic mycoses and is often
used for initial induction regimens before follow-up treatment
with an azole. It has the widest antifungal spectrum of any agent
and remains the drug of choice, or codrug of choice, for most
systemic infections caused by Aspergillus, Blastomyces, Candida
albicans, Cryptococcus, Histoplasma, and Mucor. Amphotericin B
is usually given by slow intravenous infusion, but in fungal
meningitis intrathecal administration, though dangerous, has
been used. Local administration of the drug, with minimal

Fungal cell
DNA, RNA
synthesis
–
Flucytosine
Squalene Ergosterol
– Terbinafine
Squalene epoxide Lanosterol
FIGURE 48–1 Targets of antifungal drugs. Except for flucytosine (and possibly griseofulvin, not shown), all available antifungal
drugs target the fungal cell membrane or cell wall. (Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology,
12th ed. McGraw-Hill, 2012: Fig. 48–1.)
toxicity, has been used in treatment of mycotic corneal ulcers
and keratitis.
4. Toxicity
a. Infusion related—Adverse effects related to intravenous
infusion commonly include fever, chills, muscle spasms, vomit-
ing, and a shock-like fall in blood pressure. These effects may
be attenuated by a slow infusion rate and by premedication with
f-
antihistamines, antipyretics, meperidine, or glucocorticoids.
b. Dose limiting—Amphotericin B decreases the glomerular
filtration rate and causes renal tubular acidosis with magnesium
and potassium wasting. Anemia may result fromo
-
decreases in the
renal formation of erythropoietin. Although concomitant saline
-
infusion may reduce renal damage, the nephrotoxic effects of
the drug are dose-limiting. Dose reduction (with lowered toxicity)
is possible in some infections when amphotericin B is used with
e-
-
flucytosine. Liposomal formulations of amphotericin B have
reduced nephrotoxic effects, possibly because of decreased binding
of the drug to renal cells.
c. Neurotoxicity—Intrathecal administration of amphotericin
-
B may cause seizures and neurologic damage.
B. Flucytosine (5-Fluorocytosine [5-FC])
1. Classification and pharmacokinetics—5-FC is a pyrimidine
-
antimetabolite related to the anticancer drug 5-fluorouracil
- -
(5-FU). It is effective orally and is distributed to most body
CHAPTER 48 Antifungal Agents 405
Fungal cell membrane and cell wall
Proteins
β-glucans
Chitin
Cell membrane
bilayer
β-glucan
Amphotericin B, synthase
nystatin
–
– Azoles Echinocandins
tissues, including the CNS. The drug is eliminated intact in
the urine, and the dose must be reduced in patients with renal
impairment.
2. Mechanism of action—Flucytosine is accumulated in fungal
cells by the action of a membrane permease and converted by
cytosine deaminase to 5-FU, an inhibitor of thymidylate synthase
(Figure 48–1). Selective toxicity occurs because mammalian cells
have low levels of permease and deaminase. Resistance can occur
rapidly if flucytosine is used alone and involves decreased activity
of the fungal permeases or deaminases. When 5-FC is given with
amphotericin B, or triazoles such as itraconazole, emergence of
resistance is decreased and synergistic antifungal effects may occur.
3. Clinical uses—The antifungal spectrum of 5-FC is narrow;
its clinical use is limited to the treatment, in combination
with amphotericin B or a triazole, of infections resulting from
Cryptococcus neoformans, possibly systemic candidal infections,
and chromoblastomycosis caused by molds.
4. Toxicity—Prolonged high plasma levels of flucytosine cause
reversible bone marrow depression, alopecia, and liver dysfunction.
C. Azole Antifungal Agents
1. Classification and pharmacokinetics—The azoles used
for systemic mycoses include ketoconazole, an imidazole, -
and the triazoles fluconazole, itraconazole, posaconazole,
-
406 PART VIII Chemotherapeutic Drugs
isavuconazole, and voriconazole. Oral bioavailability is variable
(normal gastric acidity is required). Fluconazole, posaconazole,
isavuconazole, and voriconazole are more reliably absorbed via
the oral route than the other azoles. Most triazoles are avail-
able in both oral and intravenous formulations. The drugs are
distributed to most body tissues, but with the exception of
fluconazole, drug levels achieved in the CNS are very low. Liver
metabolism is responsible for the elimination of ketoconazole,
e
itraconazole, posaconazole, and voriconazole. Inducers of drug-
metabolizing enzymes (eg, rifampin) decrease the bioavailability
of itraconazole. Fluconazole is eliminated by the kidneys, largely
in unchanged form.
2. Mechanism of action—The azoles interfere with fungal cell
membrane permeability by inhibiting the synthesis of ergosterol.
These drugs act at the step of 14α-demethylation of lanosterol,
which is catalyzed by a fungal cytochrome P450 isozyme. With
increasing use of azole antifungals, especially for long-term
prophylaxis in immunocompromised and neutropenic patients,
resistance is occurring, possibly via changes in the sensitivity of
÷
the target enzymes.
3. Clinical uses
a. Ketoconazole—Because it has a narrow antifungal spectrum
and causes more adverse effects than other azoles, ketoconazole is
now rarely used for systemic mycoses. The drug is not available
in parenteral form. However, ketoconazole continues to be used
for chronic mucocutaneous candidiasis and is also effective against
dermatophytes.
b. Fluconazole—Fluconazole is a drug of choice in esophageal
and oropharyngeal candidiasis and for most infections caused by
Coccidioides. A single oral dose usually eradicates vaginal candidia-
sis. Fluconazole is the drug of choice for treatment and secondary
prophylaxis against cryptococcal meningitis and is an alternative
drug of choice (with amphotericin B) in treatment of active dis-
ease due to Cryptococcus neoformans. The drug is also equivalent to
amphotericin B in candidemia.
c. Itraconazole—This azole is currently the drug of choice for
systemic infections caused by Blastomyces and Sporothrix and for
subcutaneous chromoblastomycosis. Itraconazole is an alternative
agent in the treatment of infections caused by Aspergillus, Coccidioides,
Cryptococcus, and Histoplasma. In esophageal candidiasis, the drug
is active against some strains resistant to fluconazole. Itraconazole
is also used extensively in the treatment of dermatophytoses, espe-
cially onychomycosis.
d. Voriconazole—Voriconazole has an • even wider spectrum of
fungal activity than itraconazole. It is a codrug of choice for treat-
ment of invasive aspergillosis; some studies report greater efficacy
than amphotericin B. Voriconazole is an alternative drug in candi-
demia with activity against some fluconazole-resistant organisms,
and in AIDS patients has been used in the treatment of candidal
-
esophagitis and stomatitis.
e. Posaconazole—The• broadest-spectrum triazole, posaconazole
has activity against most species of Candida and Aspergillus. It is
A
the only azole with activity against Rhizopus, one of the agents of
mucormycosis, and is used for prophylaxis of fungal infections
during cancer chemotherapy and in salvage therapy in invasive
aspergillosis.
f. Isavuconazole—Isavuconazole is a triazole with an antifungal
spectrum similar to posaconazole. Preliminary evidence suggests it
is better tolerated than posaconazole.
4. Toxicity—Adverse effects of the azoles include vomiting, diarrhea,
rash, and sometimes hepatotoxicity, especially in patients with
preexisting liver dysfunction. Ketoconazole is a notorious inhibitor
⇐
of hepatic cytochrome P450 isozymes and may increase the plasma
levels of many other drugs, including cyclosporine, oral hypoglycemics,
phenytoin, and warfarin. Inhibition of cytochrome P450 isoforms
by ketoconazole interferes with the synthesis of adrenal and gonadal
-
I
steroids and may lead to gynecomastia, menstrual irregularities, and
infertility. The other azoles are more selective inhibitors of fungal
cytochrome P450. Although they are less likely than ketoconazole
to cause endocrine dysfunction, their inhibitory effects on liver
drug-metabolizing enzymes have resulted in drug interactions.
Voriconazole causes immediate but transient visual disturbances
including blurring of vision of unknown cause in more than 30%
of patients. Based on animal studies voriconazole is a class D drug in
terms of pregnancy risk. Visual dysfunction has not been reported
with posaconazole, but the drug is an inhibitor of CYP3A4, increas-
ing the levels of cyclosporine and tacrolimus.
SKILL KEEPER: INHIBITORS OF CYTOCHROMES
P450 (SEE CHAPTERS 4 AND 61)
Ketoconazole has the unenviable reputation of association
with multiple drug interactions because of its inhibition of
cytochromes P450 involved in drug metabolism.
1. List drugs that are metabolized by enzymes inhibited by
ketoconazole.
2. List other drugs that inhibit hepatic cytochromes P450.
The Skill Keeper Answers appear at the end of the chapter.
D. Echinocandins
1. Classification and pharmacokinetics—Caspofungin is
an echinocandin, the first of a novel class of antifungal agents.
-
Other echinocandins include anidulafungin and micafungin.
Used intravenously, the drugs distribute widely to the tissues
and are eliminated largely via hepatic metabolism. Caspofungin
has a half-life of 9–12 h. The half-life of micafungin is slightly
longer, and that of anidulafungin is 24–48 h.
I
2. Mechanism of action—The echinocandins have a unique
fungicidal action, inhibiting the synthesis of β(1-3)-glucan, a criti-
cal component of fungal cell walls.
3. Clinical uses—Caspofungin is used for disseminated and
mucocutaneous Candida infections in patients who fail to

respond to amphotericin B and in the treatment of mucormycosis.
Anidulafungin is used for esophageal and invasive candidiasis.
Micafungin is used for mucocutaneous candidiasis and for pro-
phylaxis of Candida infections in bone marrow transplant patients.
4. Toxicity—Echinocandins are well tolerated. Infusion-related
-
effects of caspofungin include headache, gastrointestinal distress,
-
fever, rash, and flushing (histamine release). Micafungin also
causes histamine release and elevates blood levels of the immuno-
suppressant drugs cyclosporine and sirolimus. Combined use of
echinocandins with cyclosporine may elevate liver transaminases.
SYSTEMIC DRUGS FOR
MUCOCUTANEOUS
FUNGAL INFECTIONS
Drugs used orally in the treatment of dermatophytoses include
griseofulvin, terbinafine, and several azole antifungals.
A. Griseofulvin
1. Pharmacokinetics—Oral absorption of griseofulvin depends
on the physical state of the drug—ultra-micro-size formulations,
which have finer crystals or particles, are more effectively
absorbed—and is aided by high-fat foods. The drug is distrib-
uted to the stratum= corneum, where it binds to keratin. Biliary
excretion is responsible for its elimination.
2. Mechanism of action—Griseofulvin interferes with microtu-
bule function in dermatophytes and may alsoF- inhibit the synthesis
-
and polymerization_ of nucleic acids. Sensitive dermatophytes take
up the drug by an energy-dependent mechanism, and resistance
can occur via decrease in this transport. Griseofulvin is fungistatic.
3. Clinical uses and toxicity—Griseofulvin is notx active -
topically.xThe oral formulation of the drug is indicated for der-
-
matophytoses of the skin and hair, but has been largely replaced
by terbinafine and the azoles. Adverse effects include headaches,
mental confusion, gastrointestinal irritation, photosensitivity,
and changes in liver function. Griseofulvin should not be used in
patients with porphyria. Griseofulvin decreases the bioavailability
of warfarin, resulting in decreased anticoagulant effect, and it also
causes disulfiram-like reactions with ethanol.
B. Terbinafine
I
1. Mechanism of action—Terbinafine and naftifine inhibit a
fungal enzyme, squalene epoxidase (Figure 48-1). This causes
F-
accumulation of toxic levels of squalene, which can interfere
with ergosterol synthesis. Terbinafine is fungicidal.
2. Clinical uses and toxicity—Terbinafine is available in both
oral and topical forms. Like griseofulvin, terbinafine accumulates
in keratin, but it is much more effective than griseofulvin in ony-
chomycosis. Adverse effects include gastrointestinal upsets, rash,
CHAPTER 48 Antifungal Agents 407
headache, and taste disturbances. Terbinafine does not inhibit
cytochrome P450.
C. Azoles
The azoles other than voriconazole and posaconazole are com-
monly used orally for the treatment of dermatophytoses. Pulse or
intermittent dosing with itraconazole is as effective in onychomy-
coses as continuous dosing because the drug persists in the nails
for several months. Typically, treatment for 1 week is followed by
3 weeks without drug. Advantages of pulse dosing include a lower
incidence of adverse effects and major cost savings. Topical forms
of various azoles are also available for use in dermatophytoses.
TOPICAL ANTIFUNGAL THERAPY
A number of antifungal drugs are used topically for superficial
infections caused by C albicans and dermatophytes. Nystatin is a
polyene antibiotic (toxicity precludes systemic use) that disrupts
-
fungal membranes by binding to ergosterol. Nystatin is com-
monly used topically to suppress local Candida infections and has
been used orally to eradicate gastrointestinal fungi in patients with
impaired defense mechanisms. Other topical antifungal agents
that are widely used include the azole compounds miconazole,
clotrimazole, and several others.
QUESTIONS
1. Interactions between this drug and cell membrane compo-
nents can result in the formation of pores lined by hydro-
philic groups present in the drug molecule.
(A) Caspofungin
(B) Flucytosine
(C) Griseofulvin
(D) Nystatin
(E) Terbinafine
2. A 14-year-old patient has experienced severe headache
and double vision for a month. His temperature is 38.6°C
(101.5°F). His CSF culture was positive for cryptococcal
antigen. Which of the following drugs would be appropriate
to treat this patient systemically (not intrathecally)?
(A) Amphotericin B
(B) Fluconazole
(C) Itraconazole
(D) Ketoconazole
(E) Nystatin
Questions 3–5. A 37-year-old woman with leukemia was
undergoing chemotherapy with intravenous antineoplastic drugs.
During treatment, she developed a systemic infection from an
opportunistic pathogen. There was no erythema or edema at the
catheter insertion site. A white vaginal discharge was observed.
After appropriate specimens were obtained for culture, empiric
antibiotic therapy was started with gentamicin, nafcillin, and
ticarcillin intravenously. This regimen was maintained for 72 h,
during which time the patient’s condition did not improve
significantly. Her throat was sore, and white plaques had appeared
in her pharynx. On day 4, none of the cultures had shown any
408 PART VIII Chemotherapeutic Drugs

bacterial growth, but both the blood and urine cultures grew out 10. Regarding the clinical use of liposomal formulations of
Candida albicans. amphotericin B, which statement is accurate?
(A) Amphotericin B affinity for these lipids is greater than
3. At this point, the best course of action is to affinity for ergosterol
(A) Continue current antibiotics and start griseofulvin (B) Less expensive to use than conventional amphotericin B
(B) Continue current antibiotics and start amphotericin B (C) More effective in fungal infections because they increase
(C) Stop current antibiotics and start itraconazole tissue uptake of amphotericin B
(D) Stop current antibiotics and start amphotericin B (D) They decrease the nephrotoxicity of amphotericin B
(E) Stop current antibiotics and start terbinafine (E) They have a wider spectrum of antifungal activity than
conventional formulations of amphotericin B
4. If amphotericin B is administered, the patient should be pre-
medicated with
(A) Diphenhydramine
(B) Ibuprofen ANSWERS
(C) Prednisone 1. The polyene antifungal drugs amphotericin B and nystatin
(D) Any or all of the above are amphipathic molecules that can interact with ergos-
(E) None of the above terol in fungal cell membranes to form artificial pores.
5. Candida is a major cause of nosocomial bloodstream infec- In these structures, the lipophilic groups on the drug
tion. The opportunistic fungal infection in this patient could molecule are arranged on the outside of the pore, and the
have been prevented by administration of hydrophilic regions are located on the inside. The fungi-
(A) Caspofungin cidal action of the polyenes derives from this interaction,
(B) Flucytosine which results in leakage of intracellular constituents. The
(C) Nystatin answer is D.
(D) Voriconazole 2. The classes of antifungal drugs that have activity against
(E) None of the above Cryptococcus are the polyenes (amphotericin B formulations),
the azoles, and flucytosine. Fluconazole is the best-absorbed
Questions 6–7. A 28-year-old man living on the East Coast was member of the azole group and the only one that readily pen-
transferred by his employer to California for several months. On etrates into cerebrospinal fluid. Amphotericin would work if
his return, he complains of having influenza-like symptoms with it were delivered intrathecally. The answer is B.
fever and a cough. He also has red, tender nodules on his shins. 3. The antibiotic regimen should be stopped immediately, since
His physician suspects that these symptoms are due to coccidioi- the condition of the patient did not improve after 3 d of such
domycosis contracted during his stay in California. treatment, the cultures were negative for bacteria, and the
clinical picture suggested that the patient had a fungal infec-
6. This patient should be treated immediately with tion. This was subsequently confirmed by blood culture. The
(A) Amphotericin B answer is D.
(B) Caspofungin
(C) Ketoconazole 4. Infusion-related adverse effects of amphotericin B include
(D) Terbinafine chills and fevers (the “shake and bake” syndrome), muscle
(E) None of these drugs spasms, nausea, headache, and hypotension. Analgesic-
antipyretics, antihistamines, and glucocorticoids all have
7. Which is the drug of choice if this patient is suffering from been shown to be helpful. The administration of a 1-mg test
persistent lung lesions or disseminated disease caused by dose of amphotericin B is sometimes useful in predicting
Coccidioides immitis? the severity of infusion-related toxicity. The answer is D.
(A) Amphotericin B 5. In the case of opportunistic candidal infections in the
(B) Flucytosine immunocompromised patient, no prophylactic drugs have
(C) Itraconazole been shown to be clinically effective. Prophylaxis against
(D) Micafungin other fungi may be effective in some instances, including
(E) Terbinafine suppression of cryptococcal meningitis in AIDS patients
8. Which drug is least likely to be effective in the treatment of with fluconazole. However, prophylactic use of azoles may
esophageal candidiasis if it is used by the oral route? contribute to the development of fungal resistance. The
(A) Clotrimazole answer is E.
(B) Griseofulvin 6. A travel history can be important in the diagnosis of fungal
(C) Ketoconazole disease. If this patient has a fungal infection of the lungs, it is
(D) Itraconazole probably due to C immitis, which is endemic in dry regions
(E) Nystatin of the western United States. Pulmonary symptoms of coc-
cidioidomycosis are usually self-limiting, and drug therapy
9. Serious cardiac effects have occurred when this drug was is not commonly required in an otherwise healthy patient.
taken by patients using the antihistamines astemizole or Tender red nodules on extensor surfaces constitute a good
terfenadine prognostic sign. Erythema nodosum is a delayed hypersensi-
(A) Amphotericin B tivity response to fungal antigens. No organisms are present
(B) Griseofulvin in the lesions, and it is not a sign of disseminated disease. The
(C) Ketoconazole answer is E.
(D) Terbinafine
(E) Voriconazole
 CHAPTER 48 Antifungal Agents 409

7. In progressive or disseminated forms of coccidioidomycosis,
systemic antifungal drug treatment is needed. Until recently,
amphotericin B was the recommended therapy, but flucon-
azole or itraconazole are now generally preferred. Note that
the risk of dissemination is much greater in African Americans
(10% incidence) and in pregnant women during the third
trimester. The answer is C.
8. Griseofulvin has no activity against C albicans and is not
effective in the treatment of systemic or superficial infections
caused by such organisms. “Swish and swallow” formula-
tions of clotrimazole and nystatin have been used commonly.
Most of the azoles are effective in esophageal candidiasis. The
answer is B.
9. Ketoconazole was the first oral azole introduced into clinical
use, but it has a greater propensity to inhibit human cyto-
chrome P450 enzymes than other azoles and is no longer
widely used in the United States. Cardiotoxicity may occur
when ketoconazole is used by patients taking astemizole or
terfenadine as a result of the ability of ketoconazole to inhibit
their metabolism via hepatic cytochromes P450. The answer
is C.
10. Liposomal formulations of amphotericin B result in decreased
accumulation of the drug in tissues, including the kidney.
As a result, nephrotoxicity is decreased. With some lipid
formulations, infusion-related toxicity may also be reduced.
Lipid formulations do not have a wider antifungal spectrum;
their daily cost ranges from 10 to 40 times more than the
conventional formulation of amphotericin B. The answer is D.
SKILL KEEPER ANSWERS: INHIBITORS
OF CYTOCHROMES P450
(SEE CHAPTERS 4 AND 61)
1. A sampling of commonly used drugs with cytochrome
P450-mediated metabolism inhibited by ketoconazole
(and to a much lesser extent by other azoles) includes
chlordiazepoxide, cisapride, cyclosporine, didanosine,
fluoxetine, loratadine, lovastatin, methadone, nifedipine,
phenytoin, quinidine, tacrolimus, theophylline, verapamil,
warfarin, zidovudine, and zolpidem.
2. Other drugs that inhibit hepatic cytochromes P450
include chloramphenicol, cimetidine, clarithromycin,
disulfiram, erythromycin, ethanol, ethinyl estradiol,
fluconazole, furanocoumarins (in grapefruit juice),
isoniazid, itraconazole, MAO inhibitors, phenylbutazone,
and secobarbital.

CHECKLIST

When you complete this chapter, you should be able to:

❑ Describe the mechanisms of action of the azole, polyene, and echinocandin antifungal
drugs.
❑ Identify the clinical uses of amphotericin B, flucytosine, individual azoles, caspofungin,
griseofulvin, and terbinafine.
❑ Describe the pharmacokinetics and toxicities of amphotericin B.
❑ Describe the pharmacokinetics, toxicities, and drug interactions of the azoles.
❑ Identify the main topical antifungal agents.
410 PART VIII Chemotherapeutic Drugs

DRUG SUMMARY TABLE: Antifungal Drugs

Drug/Drug Pharmacokinetics
Class Mechanism of Action Clinical Applications & Interactions Toxicities

Amphotericin B Binds to ergosterol in
fungal cell membranes,
forming leaky pores
Candidemia and infections
caused by Aspergillus,
Blastomyces, Cryptococcus,
Histoplasma, Mucor, etc
Multiple forms, IV for systemic Nephrotoxicity is dose-
infections (liposomal forms limiting, additive with other
ocular/bladder infections reactions (chills, fever, muscle
spasms, hypotension)

Azoles Inhibit fungal P450-dependent Aspergillosis (voriconazole) Various topical and oral Ketoconazole is rarely used
Ketoconazole enzymes blocking ergosterol forms for dermatophytoses in systemic fungal infections
Fluconazole (itraconazole, fluconazole) Oral, parenteral forms for owing to its inhibition of
Itraconazole occur with long-term use mycoses (fluconazole, hepatic and adrenal P450s
Posaconazole itraconazole, posaconazole,
Voriconazole drugs in candidemia and voriconazole) but may cause GI upsets and
Isavuconazole infections caused by Most azoles undergo
Aspergillus, Blastomyces, hepatic metabolism visual disturbances and is
Cryptococcus, and class D risk in pregnancy
Histoplasma in urine unchanged

CNS penetration (fungal

meningitis)

Echinocandins Inhibit β-glucan synthase Treatment of candidemia Gastrointestinal distress,

Caspofungin decreasing fungal cell wall increases levels of flushing from histamine
Micafungin synthesis  as salvage therapy in nifedipine and cyclosporine release 
Anidulafungin aspergillosis
drug interactions 

Flucytosine Inhibits DNA and RNA Synergistic with Oral; enters cerebrospinal Bone marrow suppression
polymerases amphotericin B in
candidemia and
cryptococcal infections

Terbinafine Inhibits epoxidation of Mucocutaneous fungal GI upsets, headache

Naftifine (weeks)
accumulation is toxic to fungi keratin
 49
C H A P T E R

Antiviral Agents

The replication of viruses depends on synthetic processes of
the host cell. Antiviral drugs can exert their actions at several
stages of viral replication including viral entry, nucleic acid
synthesis and integration, late protein synthesis, and process-
ing, as well as in the final stages of viral packaging and virion
release (Figure 49–1). Most of the drugs active against herpes
viruses (HSV) and many agents active against human immuno-
deficiency virus (HIV) are antimetabolites, structurally similar
to naturally occurring compounds. The selective toxicity of
antiviral drugs usually depends on greater susceptibility of viral
enzymes to their inhibitory actions than host cell enzymes.
One of the most important trends in viral chemotherapy,
especially in the management of HIV infection, has been the
introduction of combination drug therapy. This can result in
greater clinical effectiveness in viral infections and can also
prevent, or delay, the emergence of resistance.

Antiviral agents

Drugs for Drugs for HIV Drugs for Drugs for

herpes influenza HBV and HCV

Acyclovir INF-α
Fusion Protease Amantadine
Ganciclovir Lamivudine
inhibitor inhibitors Zanamivir
Foscarnet Boceprevir
Sofosbuvir
Reverse transcriptase Ribavirin
inhibitors

Integrase strand
Nucleosides Nonnucleosides transfer inhibitors

ANTIHERPES DRUGS
Most drugs active against herpes viruses are antimetabolites bio-
activated via viral or host cell kinases to form compounds that
inhibit viral DNA polymerases.
A. Acyclovir (Acycloguanosine)
1. Mechanisms—Acyclovir is a guanosine analog active against
-
herpes simplex virus (HSV-1, HSV-2) and varicella-zoster virus
(VZV). The drug is activated initially by the viral kinase to form
acyclovir triphosphate, which interferes with viral synthesis in
2 ways. It acts as a competitive substrate for DNA polymerase,
and it leads to chain termination after its incorporation into viral
DNA (Figure 49–2). Resistance of HSV can involve changes in
viral DNA polymerase. However, many resistant strains of HSV
(TK – strains) lack thymidine kinase, the enzyme involved in the
initial viral-specific phosphorylation of acyclovir. Such strains
are cross-resistant to famciclovir, ganciclovir, and valacyclovir.

411
412 PART VIII Chemotherapeutic Drugs

Blocked by
enfuvirtide (HIV), Blocked by
docosanol (HSV), amantadine,
maraviroc (HIV), rimantadine
palivizumab (RSV) (influenza)

Viral Penetration
attachment
and entry Uncoating
Blocked by
interferon-alfa
(HBV, HCV)

Blocked by NRTIs,
Mammalian Nucleic acid NNRTIs (HIV),
cell synthesis Nucleoside/nucleotide
Blocked by analogs (HSV, HBV)
neuraminidase
inhibitors Packaging
(influenza) and Integration
assembly (retroviruses)
Viral Transcription
release
Viral protein
synthesis Blocked by INSTIs (HIV)

Blocked by PIs
(HIV, HCV)

FIGURE 49–1 The major sites of antiviral drug action. Note: interferon-alfas are speculated to have multiple sites of action on viral
replication. (Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 14th ed. McGraw-Hill, 2018: Fig. 49–1.)

2. Pharmacokinetics—Acyclovir can be administered by

the topical, oral, and intravenous routes. Because of its short
Virus-specified

=
Acyclovir Monophosphate half-life, oral administration requires multiple daily doses of
penciclovir enzymes acyclovir. Renal excretion is the major route of elimination of
ganciclovir (eg, thymidine
kinase, UL97) acyclovir, and dosage should be reduced in patients with renal
impairment.
Host
Trifluridine kinases 3. Clinical uses and toxicity—Oral acyclovir is commonly
cidofovir used for the treatment of mucocutaneous and genital herpes
lesions (Table 49–1) and for prophylaxis in AIDS and in other
Diphosphate immuno-compromised patients (eg, those undergoing organ
transplantation). The oral drug is well tolerated but may cause
gastrointestinal (GI) distress and headache. Intravenous admin-
t

istration is used for severe herpes disease, including encephalitis,

Triphosphate
-

and for neonatal HSV infection. Toxic effects with parenteral

administration include delirium, tremor, seizures, hypotension, and
Foscarnet
nephrotoxicity. Acyclovir has no significant toxicity on the bone
Incorporation into Competitive inhibition marrow.
viral DNA of viral DNA polymerase

4. Other drugs for HSV and VSV infections—Several newer

Chain Inhibition of viral agents have characteristics similar to those of acyclovir. Valacyclovir
termination DNA synthesis is a prodrug converted to acyclovir by hepatic metabolism after oral

FIGURE 49–2 Mechanism of action of antiherpes agents.
(Reproduced, with permission, from Katzung BG, editor: Basic &
Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 49–3.)
I
administration and reaches plasma levels 3–5 times greater than those
achieved by acyclovir. Valacyclovir has a longer duration of action
#=
than acyclovir. Penciclovir undergoes activation by viral thymidine
kinase, and the triphosphate form inhibits DNA polymerase but
 CHAPTER 49 Antiviral Agents 413

TABLE 49–1 Important antiviral drugs. C. Cidofovir

1. Mechanisms and pharmacokinetics—Cidofovir is a phos-
Alternative or Adjunctive phonate and is activated exclusively by host cell kinases. The
Virus Primary Drugs Drugs
active diphosphate inhibits DNA polymerases of HSV, CMV,
CMV Ganciclovir, Cidofovir, foscarnet, fomivirsen adenovirus, and papillomavirus (HPV). Because phosphoryla-
valganciclovir tion does not require viral kinase, cidofovir is active against
HSV, VZV Acyclovira Cidofovir, foscarnet, vidarabine many acyclovir and ganciclovir-resistant strains. Resistance is
due to mutations in the DNA polymerase gene. The drug is
HBV IFN-α, lamivudine Adefovir dipivoxil, entecavir, given intravenously and undergoes renal elimination. Dosage
lamivudine, telbivudine
should be adjusted in proportion to creatinine clearance and full
HCV IFN-α, sofosbuvir Ledipasvir, grazoprevir, hydration must be maintained.
ribavirin

Influenza A Oseltamivir Amantadine, rimantadine, 2. Clinical uses and toxicity—Cidofovir is effective in CMV
zanamivir retinitis, in mucocutaneous HSV infections, including those
resistant to acyclovir, and in genital warts. Nephrotoxicity is the
Influenza B Oseltamivir Zanamivir
-
major dose-limiting toxicity of cidofovir, additive with other
a
Anti-HSV drugs similar to acyclovir include famciclovir, penciclovir, and valacyclovir; nephrotoxic drugs including amphotericin B and aminoglycoside
IFN-α, interferon-α.
antibiotics.

does not cause chain termination. Famciclovir is a prodrug converted

D. Foscarnet

I#
to penciclovir by first-pass metabolism in the liver. Used orally in
genital herpes and for herpes zoster, famciclovir is well tolerated and is
similar to acyclovir in its pharmacokinetic properties. None of the acy-
clovir congeners has activity against TK– strains of HSV. Docosanol
is an aliphatic alcohol that inhibits fusion between the HSV envelope
and plasma membranes. It prevents viral entry and subsequent
replication. Used topically, docosanol shortens healing time.
1. Mechanisms—Foscarnet is a phosphonoformate derivative
that does not require phosphorylation for antiviral activity.
Although it is not an antimetabolite, foscarnet inhibits viral RNA
polymerase, DNA polymerase, and HIV reverse transcriptase.
Resistance involves point mutations in the DNA polymerase
gene.

2. Pharmacokinetics—Foscarnet is given intravenously and

B. Ganciclovir
penetrates well into tissues, including the CNS. The drug under-
1. Mechanisms—Ganciclovir, a guanine derivative, is triphos- goes renal elimination in direct proportion to creatinine clearance.
phorylated to form a nucleotide that inhibits DNA polymerases
of cytomegalovirus (CMV) and HSV and causes chain termina-
3. Clinical uses and toxicity—The drug is an alternative for
tion. The first phosphorylation step is catalyzed by virus-specific
prophylaxis and treatment of CMV infections, including CMV
enzymes in both CMV-infected and HSV-infected cells. CMV
retinitis, and has activity against ganciclovir-resistant strains of
resistance mechanisms involve mutations in the genes that code
this virus. Foscarnet←
inhibits herpes DNA polymerase in acyclovir-
for the activating viral phosphotransferase and the viral DNA
resistant strains that are thymidine kinase–deficient and may
polymerase. Thymidine kinase-deficient HSV strains are resis-
suppress such resistant herpetic infections in patients with AIDS.
tant to ganciclovir.
Adverse effects are severe and include nephrotoxicity (30% inci-
dence) with disturbances in electrolyte balance (especially hypo-
2. Pharmacokinetics—Ganciclovir is usually given intrave-
calcemia), genitourinary ulceration, and CNS effects (headache,
nously and penetrates well into tissues, including the eye and the
hallucinations, seizures).
central nervous system (CNS). The drug undergoes renal elimina-
tion in direct proportion to creatinine clearance. Oral bioavailabil-
ity is less than 10%. An intraocular implant form of ganciclovir E. Other Antiherpes Drugs
can be used in CMV retinitis. Valganciclovir, a prodrug of gan- 1. Vidarabine—Vidarabine is an adenine analog and has activ-

=
-

ciclovir, has high oral bioavailability and has decreased the use of
intravenous forms of ganciclovir (and also of intravenous cidofovir
and foscarnet) in end-organ CMV disease.
3. Clinical uses and toxicity—Ganciclovir is used for the
prophylaxis and treatment of CMV retinitis and other CMV
infections in immunocompromised patients. Systemic toxic
effects include leukopenia, thrombocytopenia, mucositis, hepatic
dysfunction, and seizures. The drug may cause severe neutropenia
when used with zidovudine or other myelosuppressive agents.
-
ity against HSV, VZV, and CMV. Its use for systemic infec-
tions is limited by rapid metabolic inactivation and marked
toxic potential. Vidarabine is used topically for herpes keratitis
but has no effect on genital lesions. Toxic effects with systemic
use include GI irritation, paresthesias, tremor, convulsions, and
hepatic dysfunction. Vidarabine is teratogenic in animals.
2. Idoxuridine and trifluridine—These pyrimidine analogs are
used topically in herpes keratitis (HSV-1). They are too toxic for
systemic use.
414 PART VIII Chemotherapeutic Drugs
3. Fomivirsen—Fomivirsen is an antisense oligonucleotide that
binds to mRNA of CMV, inhibiting early protein synthesis. The
⇐
drug is injected intravitreally for treatment of CMV retinitis.
Cross-resistance between fomivirsen and other anti-CMV
agents has not been observed. Concurrent systemic anti-CMV
therapy is recommended to protect against extraocular and con-
tralateral retinal CMV disease. Fomivirsen causes iritis, vitreitis,
increased intraocular pressure and changes in vision.
ANTI-HIV DRUGS
The primary drugs effective against HIV are antimetabolite inhib-
itors of viral reverse transcriptase and inhibitors of viral aspartate
protease (Table 49–2). The current approach to treatment of
infection with HIV is the initiation of treatment with 3 or more
antiretroviral drugs, if possible, before symptoms appear. Such
combinations usually include nucleoside reverse transcriptase
inhibitors (NRTIs) together with inhibitors of HIV protease (PI).
Highly active antiretroviral therapy (HAART) involving drug
e- 02€ €
combinations can slow or reverse the increases in viral RNA load
that normally accompany progression of disease. In many AIDS
patients, HAART slows or reverses the decline in CD4 cells and
decreases the incidence of opportunistic infections.
Drug management of HIV infection is subject to change.
Updated recommendations can be obtained at the following
websites: AIDSinfo, http://aidsinfo.nih.gov; and NPIN, https://
npin.cdc.gov.
A. Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
To convert their RNA into dsDNA, retroviruses require virally
encoded RNA-dependent DNA polymerase (reverse transcriptase).
Mammalian RNA and DNA polymerases are sufficiently distinct
to permit a selective inhibition of the viral reverse transcriptase.
NRTIs are prodrugs converted by host cell kinases to triphos-
phates, which not only competitively inhibit binding of natural
nucleotides to the Deoxyribonucleotide triphosphate (dNTP)-
binding site of reverse transcriptase but also act as chain termi-
nators via their insertion into the growing DNA chain. Because
NRTIs lack a 3′-hydroxyl group on the ribose ring, attachment of
TABLE 49–2 Major antiretroviral drugs.
Subclass Prototype Other Significant Agents
Nucleoside reverse Zidovudine Abacavir, didanosine,
transcriptase emtricitabine, lamivudine,
inhibitors stavudine, zalcitabine
Nonnucleoside Delavirdine Efavirenz, etravirine,
reverse transcriptase nevirapine, rilpivirine, tenofovir
inhibitors
Protease inhibitors Indinavir Amprenavir, atazanavir,
darunavir, lopinavir, nelfinavir,
ritonavir, saquinavir, tipranavir
CCR-5 antagonist Maraviroc  
Fusion inhibitor Enfuvirtide  
the next nucleotide is impossible. Resistance emerges rapidly when
NRTIs are used as single agents via mutations in the pol gene;
cross-resistance occurs but is not complete.
1. Abacavir—A guanosine analog, abacavir has good oral
-
bioavailability and an intracellular half-life of 12–24 h. HIV
resistance requires several concomitant mutations and tends to
develop slowly. Hypersensitivity reactions, occasionally fatal,
occur in 5% of HIV patients.
2. Didanosine (ddI)—Oral bioavailability of ddI is reduced °
by food and by chelating agents. The drug is eliminated by the
kidney, and the dose must be reduced in patients with renal dys-
function. Pancreatitis is dose-limiting and occurs more frequently
in alcoholic patients and those with hypertriglyceridemia. Other
adverse effects include peripheral neuropathy, diarrhea, hepatic
dysfunction, hyperuricemia, and CNS effects.
3. Emtricitabine—Good oral bioavailability and renal elimina-
tion with long half-life permit once-daily dosing of emtricitabine.
Because of the propylene glycol in the oral solution, the drug is
contraindicated in pregnancy and young children and in patients
with hepatic or renal dysfunction. Common adverse effects of the
drug include asthenia, GI distress, headache, and hyperpigmenta-
tion of the palms and/or the soles.
4. Lamivudine (3TC)—Lamivudine is 80% bioavailable by the
oral route and is eliminated almost exclusively by the kidney. In
addition to its use in HAART regimens for HIV, lamivudine
is also effective in hepatitis B infections. Dosage adjustment is
needed in patients with renal insufficiency. Adverse effects of
lamivudine are usually mild and include GI distress, headache,
insomnia, and fatigue.
5. Stavudine (d4T)—Stavudine has good oral bioavailability
and penetrates most tissues, including the CNS. Dosage adjust-
ment is needed in renal insufficiency. Peripheral neuropathy is
dose-limiting and -increased with coadministration of didanosine
=
-
or zalcitabine. Lactic acidosis with hepatic steatosis occurs more
frequently with stavudine than with other NRTIs.
6. Tenofovir—Although it is a nucleotide, tenofovir acts like
NRTIs to competitively inhibit reverse transcriptase and cause
chain termination after incorporation into DNA. Tenofovir also
has activity against HBV (see below). Oral bioavailability of teno-
I
fovir is in the 25–40% range, the intracellular half-life is more than
60 h, and the drug undergoes renal elimination. Tenofovir may -
impede the renal elimination of acyclovir and ganciclovir. Adverse
effects include GI distress, asthenia, and headache; rare cases of
acute renal failure and Fanconi’s syndrome have been reported.
7. Zalcitabine (ddC)—Zalcitabine has a high oral bioavailability.
Dosage adjustment is needed in patients with renal insufficiency
and nephrotoxic drugs (eg, amphotericin B, aminoglycosides)
increase toxic potential. Dose-limiting peripheral neuropathy is
the major adverse effect of ddC. Pancreatitis, esophageal ulcer-
ation, stomatitis, and arthralgias may also occur.

8. Zidovudine (ZDV)—Formerly called azidothymidine (AZT),
zidovudine is active orally and is distributed to most tissues,
including the CNS. Elimination of the drug involves both hepatic
metabolism to glucuronides and renal excretion. Dosage reduction
is necessary in uremic patients and those with cirrhosis. The primary
toxicity of zidovudine is bone marrow suppression (additive with
other immunosuppressive drugs) leading to anemia and neutropenia,
which may require transfusions. GI distress, thrombocytopenia,
headaches, myalgia, acute cholestatic hepatitis, agitation, and
insomnia may also occur. Drugs that may increase plasma levels
of zidovudine include azole antifungals and protease inhibitors.
Rifampin increases the clearance of zidovudine.
9. NRTIs and lactic acidosis—NRTI agents, taken alone or in
combination with other antiretroviral agents, may cause lactic
acidemia and severe hepatomegaly with steatosis. Risk factors include
obesity, prolonged treatment with NRTIs, and preexisting liver
dysfunction. Consideration should be given to suspension of NRTI
treatment in patients who develop elevated aminotransferase levels.
B. Nonnucleoside Reverse Transcriptase
Inhibitors (NNRTIs)
NNRTIs bind to a site on reverse transcriptase different from the
binding site of NRTIs. Nonnucleoside drugs do not require phos-
phorylation to be active and do not compete with nucleoside tri-
phosphates. There is no cross-resistance with NRTIs. Resistance
from mutations in the pol gene occurs very rapidly if these agents
are used as monotherapy.
1. Delavirdine—Drug interactions are a major problem with
delavirdine, which is metabolized by both CYP3A4 and CYP2D6.
Its blood levels are decreased by antacids, ddI, phenytoin,
rifampin, and nelfinavir. Conversely, the blood levels of delavirdine
are increased by azole antifungals and macrolide antibiotics.
Delavirdine increases plasma levels of several benzodiazepines,
nifedipine, protease inhibitors, quinidine, and warfarin. Delavirdine
causes skin rash in up to 20% of patients, and the drug should be
avoided in pregnancy because it is teratogenic in animals.
2. Efavirenz—Efavirenz can be given once daily because of its
long half-life. Fatty foods may enhance its oral bioavailability.
Efavirenz is metabolized by hepatic cytochromes P450 and is
frequently involved in drug interactions. Toxicity of efavirenz
includes CNS dysfunction, skin rash, and elevations of plasma
cholesterol. Efavirenz is one of the NNRTI agents recommended
for use in pregnancy, but should be initiated after the first 8 weeks
due to birth defects observed in a primate study at doses similar to
those used in humans.
3. Etravirine—Etravirine is approved for treatment-experienced
HIV patients, and may be effective against HIV strains resistant
to other drugs in the group. The drug causes rash, nausea, and
diarrhea. Elevations in serum cholesterol, triglycerides, and trans-
aminase levels may occur. Etravirine is a substrate as well as an
inducer of CYP3A4 and also inhibits CYP2C9 and CYP2C19 and
may be involved in significant drug-drug interactions.
CHAPTER 49 Antiviral Agents 415
4. Nevirapine—Nevirapine has good oral bioavailability, pen-
etrates most tissues including the CNS, has a half-life of more
than 24 h, and is metabolized by the hepatic CYP3A4 isoform.
The drug is used in combination regimens and is effective in pre-
venting HIV vertical transmission when given as single doses to
mothers at the onset of labor and to the neonate. Hypersensitivity
reactions with nevirapine include a rash, which occurs in 15–20%
of patients, especially females. Stevens-Johnson syndrome and
a life-threatening toxic epidermal necrolysis have also been
reported. Nevirapine blood levels are increased by cimetidine and
macrolide antibiotics and decreased by enzyme inducers such as
rifampin.
5. Rilpivirine—Rilpivirine is a highly protein-bound diaryl-
pyrimidine with a long half-life of 50 h. Its oral bioavailability is
dependent on an acid gastric environment for optimal absorption;
thus antacids and H2-receptor antagonists should be separated in
time and proton pump inhibitors are contraindicated. Rilpivirine
is one of the NNRTI agents recommended for use in pregnancy.
-
Rilpivirine is primarily metabolized by CYP3A4, and drugs that
induce or inhibit CYP3A4 may thus affect the clearance of rilpiv-
irine. The most common adverse effects associated with rilpivirine
therapy are rash, depression, headache, insomnia, and increased
serum aminotransferases. Increased serum cholesterol and fat
redistribution syndrome have also been reported. Higher doses
have been associated with QTc prolongation.
C. Protease Inhibitors
The assembly of infectious HIV virions is dependent on an aspar-
tate protease (HIV-1 protease) encoded by the pol gene. This viral
enzyme cleaves precursor polyproteins to form the final structural
proteins of the mature virion core. The HIV protease inhibitors are
designer drugs based on molecular characterization of the active
site of the viral enzyme. Resistance is mediated via multiple point
mutations in the pol gene; the extent of cross-resistance is variable
depending on the specific protease inhibitor. Protease inhibitors
(PIs) have important clinical use in AIDS, most commonly in
combinations with reverse transcriptase inhibitors as components
of HAART. All of the PIs are substrates and inhibitors of CYP3A4
with ritonavir having the most pronounced inhibitory effect. The
PIs are implicated in many drug-drug interactions with other anti-
retroviral agents and with commonly used medications.
1. Atazanavir—This is a PI with a pharmacokinetic profile that
permits once-daily dosing. Oral absorption of atazanavir requires
=
an acidic environment—antacid ingestion should be separated by
12 h. The drug penetrates cerebrospinal and seminal fluids and
undergoes biliary elimination. Adverse effects include GI distress,
peripheral neuropathy, skin rash, and hyperbilirubinemia. Pro-
longation of the QTc interval may occur at high doses. Unlike
most PIs, atazanavir does not appear to be associated with dyslip-
idemias, fat deposition, or a metabolic syndrome. However, it is a
potent inhibitor of CYP3A4, CYP2C9, and UGT1A1.
2. Darunavir—This drug is used in combination with ritonavir
-
or cobicistat in treatment-experienced patients with resistance to
-
416 PART VIII Chemotherapeutic Drugs
other PIs. The drug is a substrate of CYP3A4. GI adverse effects
=
and rash occur, and liver toxicity has been reported. Darunavir
contains a sulfonamide moiety and should be used with caution
-
in patients with sulfonamide allergy.
3. Fosamprenavir—Fosamprenavir is a prodrug, forming -
-
amprenavir via its hydrolysis in the GI tract. The drug formulation
y
includes propylene glycol and should not be used in children or
in pregnant women. Fosamprenavir is often used in combination
with low-dose ritonavir. The= absorption of amprenavir is impeded
=
by fatty foods. Amprenavir undergoes hepatic metabolism and is
both an inhibitor and an inducer of CYP3A4. The drug causes
GI distress, paresthesias, and rash, the latter sometimes severe
enough to warrant drug discontinuation. Cross-allergenicity may
occur with sulfonamides.
4. Indinavir—Oral bioavailability of indinavir is good except in
the presence of food. Clearance is mainly via the liver, with about
10% renal excretion. Adverse effects include nausea, diarrhea,
thrombocytopenia, hyperbilirubinemia, and nephrolithiasis. To
reduce renal damage, it is important to maintain good hydration.
Insulin resistance may be more common with indinavir than other
PIs. Indinavir is a substrate for and an inhibitor of the cytochrome
P450 isoform CYP3A4 and is implicated in drug interactions.
Serum levels of indinavir are increased by azole antifungals and
decreased by rifamycins. Indinavir increases the serum levels of
antihistamines, benzodiazepines, and rifampin.
5. Lopinavir/ritonavir—In this combination, a subtherapeutic
dose of ritonavir acts as a =
pharmacokinetic enhancer (“booster”)
-
by inhibiting the CYP3A4-mediated metabolism of lopinavir.
Patient compliance is improved owing to lower pill burden and
the combination is usually well tolerated.
6. Nelfinavir—This PI is characterized by increased oral absorp-
tion in the presence of food, hepatic metabolism via CYP3A4, and
a short half-life. As an inhibitor of drug metabolism, nelfinavir has
been involved in many drug interactions. Adverse effects include
diarrhea, which can be dose-limiting. The drug has the- most
a-
favorable safety profile of the PIs in pregnancy.
7. Ritonavir—Oral bioavailability is good, and the drug should
be taken with meals. Clearance is mainly via the liver, and dosage
reduction is necessary in patients with hepatic impairment. The
most common adverse effects of ritonavir are GI irritation and a
bitter taste. Paresthesias and elevations of hepatic aminotransferases
and triglycerides in the plasma also occur. Drugs that increase the
activity of the cytochrome P450 isoform CYP3A4 (anticonvul-
sants, rifamycins) reduce serum levels of ritonavir, and drugs that
inhibit this enzyme (azole antifungals, cimetidine, erythromycin)
elevate serum levels of the antiviral drug. Ritonavir inhibits the
metabolism of a wide range of drugs, including erythromycin,
dronabinol, ketoconazole, prednisone, rifampin, and saquinavir.
Subtherapeutic doses of ritonavir inhibit the CYP3A-mediated
metabolism of other protease inhibitors (eg, indinavir, lopinavir,
saquinavir); this is the rationale for PI combinations that include
ritonavir because it permits the use of lower doses of the other
protease inhibitor.
8. Saquinavir—Original formulations of saquinavir had low and
erratic oral bioavailability. Reformulation for once-daily dosing in
combination with low-dose ritonavir has improved efficacy with
decreased GI side effects. The drug undergoes extensive first-pass
metabolism and functions as both a substrate and inhibitor of
CYP3A4. Adverse effects of saquinavir include nausea, diarrhea,
dyspepsia, and rhinitis. Saquinavir plasma levels are increased by
azole antifungals, clarithromycin, grapefruit juice, indinavir, and
ritonavir. Drugs that induce CYP3A4 decrease plasma levels of
saquinavir.
9. Tipranavir—This is a newer drug used in combination with
ritonavir in treatment-experienced patients with resistance to
other PIs. The drug is a substrate and inducer of CYP3A4 and also
induces P-glycoprotein transporters, possibly altering GI absorp-
tion of other drugs. For example, increased blood levels of the
HMG-CoA reductase inhibitors (eg, lovastatin) may occur, thus
increasing the risk for myopathy and rhabdomyolysis. GI adverse
effects, rash, and liver toxicity have been reported.
10. Effects on carbohydrate and lipid metabolism—The
use of PIs in HAART drug combinations has led to the develop-
ment of disorders in carbohydrate and lipid metabolism. It has
been suggested that this is due to the inhibition of lipid-regulating
proteins, which have active sites with structural homology to that
of HIV protease. The syndrome includes hyperglycemia and insu-
lin resistance or hyperlipidemia, with altered body fat distribu-
tion. Buffalo hump, gynecomastia, and truncal obesity may occur
with facial and peripheral lipodystrophy. The syndrome has been
observed with PIs used in HAART regimens, with an incidence
of 30–50% and a median onset time of approximately 1 year
duration of treatment. Atazanavir does not appear to be associated
with dyslipidemia or hyperglycemia.
D. Entry and Fusion Inhibitors
1. Maraviroc—HIV-1 infection begins with attachment of
an HIV envelope protein called gp120 to CD4 molecules on
-
surfaces of helper T cells and other antigen-presenting cells
such as macrophages and dendritic cells. The attachment
of many HIV strains involves a transmembrane chemokine
receptor CCR5 (ie, CCR5-tropic HIV strains). This receptor,
=
a human protein, is the target for maraviroc, which blocks
viral attachment. Although resistance has occurred, there is
-
minimal cross-resistance with other antiretroviral drugs. Note
that CXCR4-tropic HIV is not affected by maraviroc so tropic
testing of the virus is key.
Maraviroc is used orally and has good tissue penetration. It is a
substrate for CYP3A4, and dosage adjustments may be needed in
the presence of drugs that induce or inhibit this enzyme. Adverse
effects of maraviroc include cough, diarrhea, muscle and joint
pain, and increases in hepatic transaminases.

2. Enfuvirtide—Enfuvirtide is a synthetic 36-amino-acid peptide.
The drug binds to the gp41 subunit of the viral envelope gly-
coprotein, preventing the conformational changes required for
the fusion of the viral and cellular membranes. There is no
cross-resistance with other anti-HIV drugs, but resistance may
occur via mutations in the env gene. Enfuvirtide is administered
subcutaneously in combination with other anti-HIV agents in
previously drug-treated patients with persistent HIV-1 replication
despite ongoing therapy. Its metabolism via hydrolysis does not
involve the cytochrome P450 system. Injection site reactions and
hypersensitivity may occur. An increased incidence of bacterial
pneumonia has been reported.
E. Integrase Strand Transfer Inhibitors (INSTs)
Raltegravir is a pyrimidine derivative that binds integrase, an
enzyme essential to replication of both HIV-1 and HIV-2, inhib-
iting strand transfer. As a result, integration of reverse-transcribed
HIV DNA into host cell chromosomes is inhibited. The drug
has been used mainly in treatment-naïve HIV patients, usually in
combination regimens. The drug is metabolized by glucuronida-
tion and is not affected by agents that induce or inhibit hepatic
cytochromes P450. However, if used with rifampin, which
induces UDP-glucuronosyltransferase, the dose of raltegravir
should be doubled. Adverse effects include nausea, dizziness, and
fatigue. An increase in creatinine kinase has been reported, with
potential for myopathy or rhabdomyolysis. Dolutegravir and
elvitegravir are similar.
ANTI-INFLUENZA AGENTS
A. Amantadine and Rimantadine
=#
1. Mechanisms—Amantadine and rimantadine inhibit an early
step in replication of the influenza A (but not influenza B) virus
(Figure 49–1). They prevent uncoating by binding to a proton
channel that is required at the onset of infection to acidify the
virus core. Acidification of the core activates viral RNA tran-
scriptase. Adamantine-resistant influenza A virus mutants are
now common.
2. Clinical uses and toxicity—These drugs are prophylactic
-
against influenza A virus infection and can reduce the dura-
tion of symptoms if given within 48 h after contact. However,
adamantine-resistant influenza A virus mutants including H3N2
strains causing seasonal influenza in the United States have
increased dramatically in the last 2–3 years. The H1N1 strain
responsible for the recent pandemic that contain genes derived
from both avian and porcine influenza viruses is also resistant to
the adamantines. Fortunately, there is minimal cross-resistance
to the neuraminidase inhibitors. Toxic effects of these agents
include GI irritation, dizziness, ataxia, and slurred speech.
Rimantadine’s activity is no greater than that of amantadine,
but it has a olonger half-life and requires no dosage adjustment
-
in renal failure.
CHAPTER 49 Antiviral Agents 417
B. Oseltamivir and Zanamivir
1. Mechanisms—These drugs are inhibitors of neuraminidases
produced by influenza A and B and are currently active against
both H3N2 and H1N1 strains. These viral enzymes cleave sialic
acid residues from viral proteins and surface proteins of infected
cells. They function to promote virion release and to prevent
clumping of newly released virions. By interfering with these
actions, neuraminidase inhibitors impede viral spread. Decreased
susceptibility to the drugs is associated with mutations in viral
neuraminidase, but worldwide resistance remains rare.
2. Clinical use and toxicity—Oseltamivir is a prodrug used
I
orally, activated in the gut and the liver. Zanamivir is adminis-
tered intranasally. Both drugs decrease the duration of influenza
symptoms and are more effective if used within 24 h after onset
of symptoms. Taken prophylactically, oseltamivir significantly
decreases the incidence of influenza. GI symptoms may occur
with oseltamivir; zanamivir may cause cough and throat discom-
fort and has induced bronchospasm in asthmatic patients.
AGENTS USED IN VIRAL HEPATITIS
The agents available for use in the treatment of infections caused
by hepatitis B virus (HBV) are suppressive rather than curative.
The primary goal of drugs used for infections caused by hepatitis
C virus (HCV) is viral eradication. The drugs available include
interferon-α (IFN-α), lamivudine, adefovir dipivoxil, entecavir,
telbivudine, tenofovir, ribavirin, and sofosbuvir.
A. IFN-`
1. Mechanisms—IFN-α is a cytokine that acts through host
-
cell surface receptors increasing the activity of Janus kinases
(JAKS). These enzymes phosphorylate signal transducers and
activators of transcription (STATS) to increase the formation of
antiviral proteins. The selective antiviral action of IFN-α is pri-
marily due to activation of a host cell ribonuclease that prefer-
entially degrades viral mRNA. IFN-α also promotes formation
of natural killer cells that destroy infected liver cells.
2. Pharmacokinetics—There are several forms of IFN-α with
minor differences in amino acid composition. Absorption from
intramuscular or subcutaneous injection is slow; elimination of
IFN-α is mainly via proteolytic hydrolysis in the kidney. Conven-
tional forms of IFN-α are usually administered daily or 3 times
a week. Pegylated forms of IFN-α conjugated to polyethylene
glycol can be administered once a week.
3. Clinical uses—Interferon-α is used in chronic HBV as an
individual agent or in combination with other drugs. When
used in combination with ribavirin, the progression of acute
HCV infection to chronic HCV is ←
-
reduced. Pegylated IFN-α
together with ribavirin is superior to standard forms of IFN-α in
chronic HCV. Other uses of IFN-α include treatment of Kaposi’s
sarcoma, papillomatosis, and topically for genital warts.
418 PART VIII Chemotherapeutic Drugs
4. Toxicity—Toxic effects of IFN-α include GI irritation, a flu-
like syndrome, neutropenia, profound fatigue and myalgia, alope-
cia, reversible hearing loss, thyroid dysfunction, mental confusion,
and severe depression. Contraindications include pregnancy.
B. Adefovir Dipivoxil
1. Mechanisms—Adefovir dipivoxil is the prodrug of adefovir,
which competitively inhibits HBV DNA polymerase and results
in chain termination after incorporation into the viral DNA.
2. Pharmacokinetics and clinical use—Adefovir has good
oral bioavailability unaffected by foods. Dose reductions are
required in renal dysfunction.
Adefovir suppresses HBV replication and improves liver his-
tology and fibrosis. However, serum HBV DNA reappears after
cessation of therapy. Adefovir has activity against lamivudine-
resistant strains of HBV.
3. Toxicity—Nephrotoxicity is dose-limiting. Lactic acidosis and
severe hepatomegaly with steatosis may also occur.
C. Entecavir
Entecavir inhibits HBV DNA polymerase. Effective orally, the
← the DAAs are the HCV-encoded proteins that are vital to the repli-
drug undergoes renal elimination in part via active tubular secre-
tion. Clinical efficacy is similar to that of lamivudine and there is
cross-resistance between the 2 drugs. The drug causes headache,
dizziness, fatigue, and nausea.
D. Lamivudine
This nucleoside inhibitor of HIV reverse transcriptase (see prior dis-
cussion) is active in chronic HBV infection. Lamivudine has a longer
intracellular half-life in HBV-infected cells than in HIV-infected
cells and thus can be used in lower doses for hepatitis than for HIV
infection. Used as monotherapy, lamivudine rapidly suppresses
HBV replication and is remarkably nontoxic.
E. Ribavirin
1. Mechanisms—Ribavirin inhibits the replication of a wide
range of DNA and RNA viruses, including influenza A and B,
parainfluenza, respiratory syncytial virus (RSV), paramyxovi-
ruses, HCV, and HIV. Although the precise antiviral mecha-
nism of ribavirin is not known, the drug inhibits guanosine
triphosphate formation, prevents capping of viral mRNA, and
can block RNA-dependent RNA polymerases.
2. Pharmacokinetics and clinical uses—Ribavirin is effective
orally (avoid antacids) and is also available in intravenous and
aerosol forms. It is eliminated by the kidney, necessitating dose
reductions in renal dysfunction. Ribavirin is used adjunctively
- catalytic site of NS5B, and are activated within the hepatocyte
with IFN-α in chronic HCV infection in patients with com-
pensated liver disease. Monotherapy with ribavirin alone is not
effective. Early intravenous administration of ribavirin decreases
mortality in viral hemorrhagic fevers. Despite its alleged activity
against RSV, ribavirin has been shown to have no benefit in treat-
ment of RSV infections, although it is still recommended by some
authorities in immunocompromised children.
3. Toxicity—Systemic use results in dose-dependent hemolytic
anemia. Aerosol ribavirin may cause conjunctival and bronchial
irritation. Ribavirin is a known human teratogen and is absolutely
contraindicated in pregnancy.
F. Newer Drugs for HBV
Telbivudine, a nucleoside analog, is phosphorylated by cellular
kinases to the triphosphate form, which inhibits HBV DNA
polymerase. The drug is at least as effective as lamivudine in
chronic HBV infections and is similar in terms of its safety profile.
Tenofovir, an antiretroviral drug, is also approved for chronic
HBV infection and is active against lamivudine- and entecavir-
resistant strains. Sofosbuvir inhibits RNA polymerase in HCV,
alone or in combination with interferon or ribavirin and achieves
very high cure rates (90–95%). Boceprevir is a protease inhibitor
in HCV and is used in combination with ribavirin.
G. Treatment of Hepatitis C Infection
There are four current classes of direct-acting antiviral agents
(DAAs): nonstructural protein (NS) 3/4A protease inhibitors,
NS5B nucleoside polymerase inhibitors, NS5B non-nucleoside
polymerase inhibitors, and NS5A inhibitors. The main targets of
cation of the virus (Figure 49–1). The safety profiles of all the com-
bination regimens are generally excellent, with adverse events of
mild severity and very low rates of discontinuation due to adverse
events in clinical trials in the absence of concurrent ribavirin use.
1. NS5A Inhibitors—The NS5A protein plays a role in both
=
-
viral replication and the assembly
-
of HCV; however, the exact
mechanism of action of the HCV NS5A inhibitors remains
unclear.
Daclatasvir is used in combination with sofosbuvir for treat-
- -
ment of HCV genotypes 1, 2, and 3. It may be taken with
-
or without food and does not require adjustment for renal or
hepatic impairment. Daclatasvir is generally well tolerated. The
most common adverse effects in patients receiving daclatasvir/
sofosbuvir were headache and fatigue, usually mild or moderate
in severity.
Daclatasvir is primarily metabolized through CYP3A metabolism
and should not be given with inducers or inhibitors of this enzyme.
Elbasvir, ledipasvir, ombitasvir, and velpatasvir are similar.
2. NS5B RNA Polymerase Inhibitors—NS5B is an RNA-
dependent RNA polymerase involved in post-translational pro-
cessing that is necessary for replication of HCV.
Nucleoside/nucleotide analogs (eg, sofosbuvir) target the
through phosphorylation to nucleoside triphosphate, which com-
petes with nucleotides, resulting in chain termination. Non-nucle-
oside analogs (eg, dasabuvir) act as allosteric inhibitors of NS5B.
3. NS3/4A Protease Inhibitors—NS3/4A protease inhibitors
are inhibitors of the NS3/4A serine protease, an enzyme involved
in post-translational processing and replication of HCV.

Grazoprevir is a potent, pan-genotypic protease inhibitor,
reversibly binding to HCV NS3/4A protease. It is distinct from
earlier-generation protease inhibitors due to its pan-genotypic
activity, as well as activity against some of the major resistance-
associated variants (R155K and D168Y) resulting in failure with
first-generation protease inhibitors. It is only available in combi-
nation with elbasvir for treatment of HCV genotypes 1 and 4. It is
partially eliminated by oxidative metabolism, primarily by CYP3A
and is mostly eliminated in the feces. Elbasvir/grazoprevir should
not be administered to patients with moderate or severe hepatic
impairment, or in conjunction with organic anion transporting
polypeptide 1B1/3 (OATP1B1/3) inhibitors, strong inducers or
Questions 5 and 6. A patient with AIDS has a CD4 count of
inhibitors of CYP3A, or efavirenz. The most commonly reported
45/µL. He is being maintained on a 3-drug regimen of indinavir,
side effects during therapy with elbasvir/grazoprevir were fatigue,
didanosine, and zidovudine. For prophylaxis against opportunistic
headache, and nausea. Elevations in serum aminotransferases may
infections, he is also receiving cidofovir, fluconazole, rifabutin,
occur. Paritaprevir and simeprevir are similar.
and trimethoprim-sulfamethoxazole.
QUESTIONS
1. 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
Questions 2 and 3. 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.
2. If this patient has acute pancreatitis, the drug most likely to
be responsible is
(A) Acyclovir
(B) Didanosine
(C) Ketoconazole
(D) Ritonavir
(E) Zidovudine
3. 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
CHAPTER 49 Antiviral Agents 419
4. 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 regard-
ing 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
5. 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
6. 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
7. A 27-year-old nursing mother is diagnosed as suffering from
genital herpes. She has a history of this viral infection. Previ-
ously, 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
8. Oral formulations of this drug should not be used in a preg-
nant AIDS patient because they contain propylene glycol.
One of the characteristic adverse effects of the drug is hyper-
pigmentation 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
9. 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
420 PART VIII Chemotherapeutic Drugs

10. 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
ANSWERS
1. Acyclovir is activated by host cell kinases. Like acyclovir,
ganciclovir inhibits viral DNA polymerase and causes chain
termination. However, foscarnet inhibits viral DNA poly-
merase 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.
2. 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.
3. Symptomatic AIDS patients should be treated with a HAART
regimen regardless of a relatively high CD4 count or a rela-
tively low HIV RNA load. Because didanosine must be dis-
continued, 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 prolon-
gation, 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.
4. 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.
5. Ganciclovir (not listed) has been the most commonly used drug
for prevention and treatment of CMV infections in the immu-
nocompromised patient. However, cidofovir is also very effec-
tive in CMV retinitis and has good activity against many strains
of HSV, including those resistant to acyclovir. The answer is B.
6. 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 clear-
ance of other drugs, including indinavir. The answer is D.
7. 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 effi-
cacy 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.
8. Three of the drugs listed should be avoided, or used with
extreme caution, in the pregnant patient. Oral forms of ampre-
navir and emtricitabine both contain propylene glycol, a poten-
tially 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.
9. 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.
10. 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 nephro-
lithiasis. However, more than 80% of a dose of indinavir is
eliminated via hepatic metabolism. Trifluridine is used topi-
cally to treat herpes keratoconjunctivitis. The answer is A.

CHECKLIST

When you complete this chapter, you should be able to:

❑ Identify the main targets for antiviral action in viral replication.
❑ Describe the mechanisms of action of antiherpes drugs and the mechanisms of HSV
and CMV resistance.
❑ List the main pharmacokinetic properties and toxic effects of acyclovir, ganciclovir,
cidofovir, and foscarnet.
❑ Describe the mechanisms of anti-HIV action of zidovudine, indinavir, and enfuvirtide.
❑ Match a specific antiretroviral drug with each of the following: to be avoided in
pregnancy; hyperpigmentation; neutropenia; pancreatitis; peripheral neuropathy;
inhibition of P450; severe hypersensitivity reaction; injection site reactions.
❑ Identify the significant properties of 4 drugs active against HBV and HCV.
❑ Identify the significant properties of an anti-influenza drug acting at the stage of viral
uncoating and another acting at the stage of viral release.
 CHAPTER 49 Antiviral Agents 421

DRUG SUMMARY TABLE: Antivirals & Antiretrovirals

Mechanism Pharmacokinetics
Drug Class of Action Clinical Applications & Interactions Toxicities

ANTIVIRAL DRUGS
Antiherpes drugs
Acyclovir Activated by viral Treatment and prophylaxis Acyclovir: Topical, oral, Oral forms cause nausea,
Valacyclovir (prodrug) thymidine kinase (TK) for HSV-I, HSV-2, and VZV - diarrhea, and headache
Penciclovir to forms that inhibit None of these drugs is -
Famciclovir (prodrug) viral DNA polymerase active against TK– strains cyclovir: Oral and CNS toxicity

Drugs for cytomegalovirus

Ganciclovir Viral activation of
Valganciclovir ganciclovir to form
Cidofovir inhibiting DNA
Foscarnet polymerase; no viral
bioactivation of
cidofovir and foscarnet
Treatment of CMV
infections in immuno-
suppression (eg, AIDS) and
organ transplantation
Ganciclovir: Oral, IV, intra-
ocular forms
Ganciclovir: Bone marrow
suppression, hepatic and
neurologic dysfunction
CNS effects and electrolyte
imbalance

Antihepatitis drugs
Interferon-α (IFN-α) Degrades viral RNA via Suppressive treatment of IFN-α: Parenteral IFN-α: Alopecia, myalgia,
Adefovir-dipivoxil activation of host cell HBV (all drugs except riba- - depression, flu-like syndrome
Entecavir RNAse (IFN-α - vudine, sofosbuvir, and Adefovir: Lactic acidosis, renal
Lamivudine tion of HBV polymerase HCV (sofosbuvir, ribavirin and hepatic toxicity
Telbivudine - +/– IFN-α) Inhalational Ribavirin: Anemia, teratogen
Ribavirin viral actions (ribavirin)
Sofosbuvir

Anti-HCV drugs
Daclatasvir NS5A inhibitors HCV (part of combination Oral Headache, fatigue
Elbasvir regimen)
Ledipasvir
Ombitasvir
Velpatasvir

Dasabuvir NS5B RNA pol HCV (part of combination Oral Nausea, insomnia
Sofosbuvir inhibitors regimen)

Grazoprevir NS3/4A protease HCV (part of combination Oral Headache, fatigue, nausea
Paritaprevir inhibitors regimen) Sulfa-allergies for simeprevir
Telaprevir
Boceprevir
Simeprevir

Anti-influenza drugs
Amantadine Amantadine and M2 blockers virtually Oral forms except Oseltamivir & Peramivir:
Rimantadine rimantadine: block of zanamivir (inhalational) Gastrointestinal effects
Oseltamivir M2 proton channels prophylaxis vs most Delirium in pts w active
Zanamivir current flu strains and influenza
Peramivir zanamivir inhibit shorten symptoms Zanamivir: Bronchospasm in
neuraminidase asthmatics

(Continued )
422 PART VIII Chemotherapeutic Drugs

DRUG SUMMARY TABLE: Antivirals & Antiretrovirals (Continued )

Mechanism Pharmacokinetics
Drug Class of Action Clinical Applications & Interactions Toxicities

ANTIRETROVIRAL DRUGS
Nucleoside/nucleotide reverse transcriptase inhibitor (NRTIs)a
Abacavir Inhibit HIV reverse Duration of action usually Zidovudine: Bone Most NRTIs are not
Didanosine transcriptase after marrow suppression extensively metabolized by
Emtricitabine phosphorylation by undergo renal elimination hepatic enzymes such as the
Lamivudine cellular enzymes especially, didanosine, P450 isoforms, so they have few
Stavudine emtricitabine, lamivudine, interactions that concern their
Tenofovir common, but stavudine, tenofovir, and zalcitabine: Peripheral pharmacokinetic characteristics
Zalcitabine incomplete zidovudine neuropathy
Zidovudine

Nonnucleoside reverse transcriptase inhibitors (NNRTIs)

Delavirdine Inhibit HIV reverse All current NNRTIs are Delavirdine, nevirapine: Inducers of P450 isozymes
Efavirenz - metabolized via P450 Rash, increased liver (eg, phenytoin, rifampin) and
Etravirine phorylation required inhibitors (eg, azoles, PIs) alter
Nevirapine may induce formation of Teratogenic
Rilpivirine between NNRTIs but CYP3A4, but inhibits other etravirine
not with NRTIs P450s

Protease inhibitors (PIs)b

Atazanavir Inhibit viral protein Elimination mainly via Atazanavir, fosamprenavir, Ritonavirc and other PIs can
Darunavir metabolism by P450 lopinavir, nelfinavir, inhibit P450 metabolism of
Fosamprenavir resistance between PIs saquinavir: GI distress many drugs including anti-
Indinavir common substrates and inhibitors histamines, antiarrhythmics,
Lopinavir of P450 Peripheral neuropathy HMG-CoA reductase inhibi-
Nelfinavir Fosamprenavir is a tors, oral contraceptives and
Ritonavir prodrug forming - sedative-hypnotics
Saquinavir amprenavir, a substrate nemia and nephrolithiasis Drugs known to induce or
Tipranavir and inducer of P450 inhibit P450 isoforms may alter
the plasma levels of PIs

Entry inhibitors
Enfuvirtide Block fusion between
Maraviroc viral and cellular mem-
branes (enfuvirtide)
antagonist (maraviroc)
Extrahepatic hydrolysis of Enfuvirtide: Hypersensitivity Inducers and inhibitors of P450
enfuvirtide (subcutaneous alter elimination of maraviroc
- joint pain, diarrhea, and
lism (maraviroc) increased liver enzymes

Integrase inhibitors Block viral integrase of Metabolized by UGT1A1 GI upset and headache Inducers and inhibitors of P450
Dolutegravir HIV-1 & HIV-2 alter elimination of dolutegravir,
Elvitegravir only UGT1A1
Raltegravir
CYP interactions
a
NRTIs, nucleoside/nucleotide reverse transcriptase inhibitors: Risk of lactic acidosis with hepatic steatosis is characteristic of the group. Zalcitabine (ddC; dideoxycytidine) is no longer
marketed, and regimens containing zidovudine (AZT; azidothymidine), ddI (didanosine), or stavudine (d4T) are infrequently recommended as first-line regimens.
b
PIs, protease inhibitors: Risk of hyperlipidemia, fat maldistribution, hyperglycemia, and insulin resistance is characteristic of the group, with exception of atazanavir.
c
Ritonavir is a potent inhibitor of the CYP3A4 isoform of P450, an action used to advantage in “boosting” effects of other PIs. Drug-drug interactions between PIs and many other
medications occur commonly.