Download Chapter 8 outline

Chapter 8:
Antifungal and Antiviral Agents
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Chapter 8 Outline

Antifungal and Antiviral Agents


Antifungal Agents
Antiviral Agents
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2
Antifungal and Antiviral Agents


Haveles (p. 102)
Antibiotics and antiinfectives are effective
against a certain spectrum of organisms:
bacteria, protozoa, rickettsia, trichomonads,
amoebas, and spirochetes

They are not effective against either fungal or viral
infections
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3
Antifungal Agents



Nystatin
Imidazoles




Haveles (pp. 102-106)
Clotrimazole
Ketoconazole
Other imidazoles
Other antifungal agents


Amphotericin B
Griseofulvin
cont’d…
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4
Antifungal Agents


Fungal infections are not frequently
encountered in the dental practice


Haveles (p. 102)
When present, they are often difficult to treat
They are more likely to occur in patients who
are immunocompromised, and they can
become chronic
cont’d…
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5
Antifungal Agents


They can be divided into those that affect
primarily the skin and mucosa and those that
affect the whole body


Haveles (pp. 102-103) (Tables 8-1, 8-2)
Mucosal lesions may be treated with a topical or
systemic antifungal agent
Two common groups are the candida-like and
tinea


Mucocutaneous candidal infections are managed with
nystatin, clotrimazole, ketoconazole, or fluconazole
Tinea affects the skin and produces athlete’s foot,
“jock itch,” and ringworm; managed both with
prescription and over-the-counter medications
cont’d…
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6
Antifungal Agents


Systemic mycoses produced by fungi include
aspergillosis, blastomycosis,
coccidioidomycosis, cryptococcosis,
histoplasmosis, mucormycosis, and
paracoccidioidomycosis


Haveles (pp. 102-103, 106) (Figs. 8-1, 8-2)
Chromomycosis, mycetoma, and sporotrichosis
may progress to deep mycotic infections
These serious infections are medical
management situations

Amphotericin B and miconazole are used to treat
them
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7
Nystatin



Haveles (pp. 103-104)
A polyene macrolide antibiotic produced by
Streptomyces noursei
Mechanism of action involves binding to sterols
in the fungal cell membrane


This action produces an increase in membrane
permeability
Bacteria do not contain sterols in their cell membrane,
therefore nystatin is not effective against these
organisms
cont’d…
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8
Nystatin

Not absorbed from the mucous membranes
or through intact skin


Taken orally, it is poorly absorbed from the
gastrointestinal (GI) tract
Fungicidal and fungistatic against a variety of
yeasts and fungi
cont’d…
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9
Nystatin

Adverse reactions are minor and infrequent


Applied topically or taken orally, little absorption
occurs
With higher doses, nausea, vomiting, and diarrhea
have occasionally occurred
cont’d…
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10
Nystatin


Haveles (pp. 103-104) (Table 8-1)
Used for both treatment and prevention of
oral candidiasis in susceptible cases


Candida albicans is a frequent inhabitant of the
oral cavity; only under unusual conditions does it
produce disease
Affected patients are often immunocompromised
cont’d…
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11
Nystatin


Haveles (p. 103) (Table 8-1)
For treatment of oral candidiasis; available as
an aqueous suspension containing 50%
sucrose

Swish, swirl, and spit or swallow 5 ml four times
daily
• The suspension should remain in the mouth for 2 minutes
for the best effect
cont’d…
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12
Nystatin

Nystatin pastilles (contain sugar)



15 minutes to dissolve, bathing lesions in
antifungal agent for a longer period
Used four times daily
The products are used for between 10 and
14 days or for 48 hours after the symptoms
have subsided and cultures have returned
negative
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13
Examples


Haveles (p. 103) (Table 8-1)
Nystatin (Mycostatin, Nilstat, others)
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14
Imidazoles


Haveles (pp. 104-105)
Several imidazoles useful in dentistry include
clotrimazole, miconazole, fluconazole, and
itraconazole
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15
Clotrimazole


Haveles (p. 104)
A synthetic antifungal agent available as a
slowly dissolving, sugar-containing lozenge for
oral use

Mechanism of action involves alteration of cell
membrane permeability
 Spectrum of action is primarily against the Candida
species
 Most common adverse reactions involve the GI tract,
including abdominal pain, diarrhea, and nausea
cont’d…
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16
Clotrimazole

Indicated for the local treatment of
oropharyngeal candidiasis

Usual adult dose is one lozenge five times daily for 10 to
14 days or for 48 hours after symptoms have cleared
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17
Ketoconazole


Alters cellular membranes and interferes with
intracellular enzymes



Haveles (pp. 104-105)
Interferes with synthesis of ergosterol, a cellular
component of fungi
Pharmacokinetics: an acidic environment is
required for adequate systemic absorption
Spectrum: effective against a wide variety of
fungal infections

Indicated for systemic fungal infections, including
blastomycosis, candidiasis, coccidioidomycosis, and
histoplasmosis
cont’d…
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18
Ketoconazole


Haveles (p. 105)
Adverse reactions of ketoconazole




GI effects: the most frequent adverse reactions
are nausea and vomiting
Hepatotoxicity effects: the most serious adverse
reaction; thought to be idiosyncratic
Other effects: headache, dizziness, drowsiness,
photophobia, skin rash or pruritus, and insomnia
Pregnancy and nursing considerations: can
produce syndactyly, oligodactyly, dystocia, and
embryotoxicity
cont’d…
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19
Ketoconazole


Haveles (p. 105)
Drug interactions


Many, because an acidic environment is required,
agents that alter the amount of stomach acid could
theoretically reduce the absorption of
ketoconazole
ketoconazole inhibits the CYP P-450 3A4 hepatic
microsomal isoenzyme, which can produce drug
interactions with many other drugs also
metabolized by this isoenzyme
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20
Uses of Ketoconazole


Dental: indicated for treatment and
management of mucocutaneous and
oropharyngeal candidiasis (oral thrush)


Haveles (p. 105)
Used only after topical antifungal agents have been
ineffective or its believed they will be ineffective
Medical: indicated for treatment of candidiasis,
histoplasmosis, and paracoccidioidomycosis

Used to treat recalcitrant cutaneous
dermatophytoses such as tinea corporis, tinea cruris,
tinea versicolor, and seborrheic dermatitis
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21
Dose of Ketoconazole


Dose for treatment of Candida is 200 to 400 mg
orally daily



Haveles (p. 105)
Used for at least 2 weeks; 6 to 12 months may be
required for chronic mucocutaneous candidiasis
Available for topical administration in a 2%
aqueous vehicle (cream) for tinea or candidal
infections
A shampoo is used twice weekly for dandruff, a
condition caused by the fungus
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22
Other Imidazoles


Haveles (p. 105)
Other imidazoles are used to treat certain
fungal infections

Fluconazole prevents the synthesis of ergosterol
in the fungal cell membrane by inhibiting fungal
cytochrome P-450 enzymes
• Indicated for the treatment of oropharyngeal and
esophageal candidiasis, and serious systemic fungal
infections
cont’d…
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23
Other Imidazoles


Haveles (p. 105)
Itraconazole is used for blastomycosis,
histoplasmosis, and aspergillosis

The first antifungal effective in the treatment of
onychomycosis of the toenail or fingernail
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24
Examples of Antifungal Agents


Haveles (p. 103) (Table 8-1)
Fluconazole (Diflucan)
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25
Other Antifungal Agents


Haveles (pp. 105-106)
Amphotericin B


Used in the treatment of many serious systemic fungal
infections
Because of side effects it is nicknamed
“amphoterrible”
cont’d…
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26
Other Antifungal Agents

Amphotericin B

An amphoteric polyene macrolide antibiotic
produced by Streptomyces nodosus
• Binds to the sterols in the fungus cell membrane, altering
membrane permeability
• Spectrum includes many fungi such as certain strains of
Aspergillus, Paracoccidioides, Coccidioides,
Cryptococcus, Histoplasma, Mucor, and Candida
• Also effective against the protozoa Leishmania
cont’d…
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27
Other Antifungal Agents


Haveles (p. 106)
Amphotericin B


Adverse reactions are wide ranging and potentially
serious, but it is often the only effective treatment
for certain serious systemic fungal infections
Many potentially serious drug interactions
cont’d…
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28
Other Antifungal Agents


Haveles (p. 106)
Griseofulvin



An antibiotic produced by Penicillium griseofulvum
Disrupts the cells mitotic spindle structure and
arrests cell division in metaphase
Preferentially deposited in diseased keratin
precursors (hair, nails, skin)
cont’d…
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29
Other Antifungal Agents


Haveles (p. 106)
Griseofulvin

Spectrum includes tineas (e.g. ringworm),
Trichophyton, Microsporum, and Epidermophyton
but does not include Candida organisms
 Adverse reactions include headache, GI complaints,
and overgrowth of Candida organisms in the oral
cavity
 Hypersensitivity reactions include urticaria,
photosensitivity, and lupus-like reactions
 Indicated for treatment of susceptible infections of
the skin, hair, and nails
 The drug is deposited only in growing tissues
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30
Antiviral Agents


Herpes simplex





Haveles (pp. 106-111)
Acyclovir
Docosanol 10%
Penciclovir
Famciclovir
Acquired immunodeficiency syndrome (AIDS)

Nucleoside reverse transcriptase inhibitors
 Nonnucleoside reverse transcriptase inhibitors
 Protease inhibitors
 Combinations
 Other antiviral agents
cont’d…
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31
Antiviral Agents


Treatment of viral infections has posed the
greatest problem of all infectious organisms



Haveles (pp. 106-108) (Fig. 8-3; Table 8-3)
Viruses are obligate intracellular organisms
The herpes virus is of the most interest to the
dental health care worker
Symptoms of AIDS are also seen clinically in
the mouth
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32
Herpes Simplex


Haveles (p. 107) (Fig. 8-4; Color Plates 1 and 2)
Herpes viruses are associated with “cold
sores”

Most antiviral agents are either purine or
pyrimidine analogues that inhibit deoxyribonucleic
acid (DNA) synthesis
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33
acyclovir (Zovirax)


Haveles (p. 107)
A purine nucleoside


The triphosphate form exerts its antiviral action on
herpesviruses by interfering with DNA polymerase
and inhibiting DNA replication
It is much less toxic to normal cells because it is
preferentially taken up by infected cells
cont’d…
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34
acyclovir (Zovirax)


Pharmacokinetics


Haveles (p. 107)
Taken orally; between 15% and 30% is absorbed;
widely distributed throughout the body and
excreted primarily unchanged in the urine
Spectrum

Herpesviruses, including herpes simplex types 1
and 2, varicella zoster, Epstein-Barr, Herpesvirus
simiae (B virus), and cytomegalovirus
cont’d…
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35
acyclovir (Zovirax)


Haveles (p. 107)
Adverse reactions

Topical administration: produces burning, stinging,
or mild pain in about one third of patients
 Oral administration: headache (13%) is one of the
most common; other central nervous system
(CNS) and GI effects
 Parenteral administration: local reactions at the
injection site are the most common
cont’d…
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36
acyclovir (Zovirax)


Haveles (pp. 107, 109)
Uses

Topical
• Indications include initial herpes genitalis and limited non–
life-threatening initial and recurrent mucocutaneous herpes
simplex virus 1 and 2 (HSV-1 and HSV-2) in
immunocompromised persons

Oral
• Indicated for treatment of initial herpes genitalis and
management of recurrent herpes genitalis infections in both
immunocompromised and nonimmunocompromised patients

Injectable
• Used for severe initial herpes genitalis infections in the
nonimmunocompromised patient
cont’d…
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37
acyclovir (Zovirax)


Haveles (p. 109)
Dose


Oral adult dose for treatment of initial genital
herpes is 200 mg every 4 hours while the patient
is awake, five times daily for 10 days
Acyclovir has not been shown to effectively treat
herpes labialis in topical, tablet, or capsule
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38
Docosanol 10%


Haveles (p. 109)
Available topically and without a prescription

Has been shown to decrease healing time by
about a half day in patient with recurrent orolabial
herpes when started within 12 hours of the
appearance of prodromal symptoms
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39
Penciclovir


Haveles (p. 109)
Available topically

Shown to reduce both the duration of the lesion
and the pain of the lesions on the lips and face
associated with both primary and recurrent herpes
simplex
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40
Famciclovir


Haveles (p. 109)
Famciclovir and valacyclovir are prodrugs
that are converted to penciclovir and acyclovir
as they pass through the intestinal wall

Indicated in the treatment of recurrent episodes of
genital herpes, for treatment of acute localized
varicella-zoster infections
 Ganciclovir is indicated for serious
cytomegalovirus retinitis in immunocompromised
patients
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41
Acquired Immunodeficiency
Syndrome


Haveles (pp. 109-110) (Tables 8-4, 8-5)
Antiretroviral agents are used in combinations
called “cocktails” to manage AIDS

They include nucleoside reverse transcriptase
inhibitors (NRTIs), nonnucleoside reverse
transcriptase inhibitors (NNRTIs), and protease
inhibitors
 The usual combination includes one choice from
each of the three groups
cont’d…
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42
Acquired Immunodeficiency
Syndrome

Opportunistic infections often occur in
patients with AIDS

They may be taking various antiinfective agents to
prevent tuberculosis, Pneumocystis carinii
pneumonia, herpes infections, and candidiasis
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43
Nucleoside Reverse
Transcriptase Inhibitors


Haveles (pp. 109-110)
Zidovudine is converted into zidovudine
triphosphate and then incorporated into DNA
polymerase so that synthesis of viral DNA is
terminated


Azidothymidine (AZT) is well absorbed orally,
metabolized by the liver, and excreted by the
kidneys
Distributed to most body tissue
cont’d…
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44
Nucleoside Reverse
Transcriptase Inhibitors




Toxicity of AZT is related to bone marrow
depression
CNS effects include headache, agitation and
insomnia
Oral manifestations reported include taste
perversion, edema of the tongue, bleeding gums,
and mouth ulcers
Acetaminophen, indomethacin, and aspirin can
inhibit AZT’s glucuronidation and potentiate the
toxicity of both drugs
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45
Nonnucleoside Reverse
Transcriptase Inhibitors


Haveles (p. 110)
Nevirapine, an NNRTI, is specific for human
immunodeficiency virus type 1 (HIV-1)


These agents inhibit the same enzymes as the
nucleoside analogues but do not require
bioactivation
Adverse reactions include CNS effects, rash, GI
effects, and elevated liver function tests
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46
Protease Inhibitors


Haveles (p. 110)
Saquinavir prevents the cleavage of viral
protein precursors needed to generate
functional structural proteins in and
modulation of reverse transcriptase activity,
preventing the maturation of HIV-infected
cells

Protease inhibitors can interfere with the action of
HIV infected cells, whereas the previous two
groups of drugs cannot
cont’d…
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47
Protease Inhibitors



Adverse reactions include rash, hyperglycemia,
and paresthesias
GI adverse reactions include pain, diarrhea, and
vomiting
Oral adverse reactions involve buccal mucosa
alteration
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48
Combinations


Haveles (p. 110)
The combinations of drugs used to manage
HIV or AIDS are constantly changing

Normally, patients with HIV will be taking an NRTI,
an NNRTI, and a protease inhibitor
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49
Examples of Drugs Used to Treat
Human Immunodeficiency Virus


Nucleoside analogues






didanosine (ddl) (Videx)
lamivudine (3TC) (Epivir)
stavudine (d4T) (Zerit)
zalcitabine (ddC) (Hivid)
zidovudine (AZT, ZVD) (Retrovir)
Nonnucleoside Analogs



Haveles (p. 109) (Table 8-4)
delavirdine (Rescriptor)
nevirapine (NVP) (Viramune)
Protease Inhibitors




indinavir (Crixivan)
nelfinavir (Viracept)
ritonavir (Norvir)
saquinavir (Invirase, Fortovase)
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50
Other Antiviral Agents


Haveles (pp. 110-111)
amantadine (Symmetrel): inhibits the
penetration of the absorbed virus into the
host’s cells or inhibits the uncoating of the
influenza A viruses


Side effects include nausea, dizziness,
lightheadedness, and insomnia
Can be used to prevent or for treatment to reduce
symptoms of influenza A viruses
cont’d…
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51
Other Antiviral Agents


Haveles (pp. 110-111)
Interferons

A large group of endogenous proteins that have
antiviral, cytotoxic, and immunomodulating action
• Recombinant DNA technology now produces interferons
cont’d…
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52
Other Antiviral Agents


Haveles (p. 111)
Interferons

Adverse reactions vary, a flulike syndrome,
consisting of myalgias, fatigue, headache, and
arthralgia occurs in many patients
• Other side effects include CNS effects, GI tract effects,
and rash
• Oral effects include taste changes, reactivation of herpes
labialis, and excessive salivation
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53
Examples of Interferons










Haveles (p. 110) (Table 8-6)
alfa-2a (Roferon-A)
peginterferon alfa-2a (Pegasys)
peginterferon alfa-2a with ribavirin (Copegus)
alfa-2b (Intron-A)
peginterferon alfa-2b (PEG-Intron)
peginterferon alfa-2b plus ribavirin (Rebetol)
alfa-n3 (Alferon N)
beta-1a (Avonex)
beta-1b (Betaseron)
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54