CHEMOTHERAPY II

ANTIFUNGAL AGENTS
Fungal Infection
 Fungi are also called mycoses.
 A fungus is a colorless plant that lacks chlorophyll.
 They are eukaryotic organisms and possess cell wall.
 The cell wall is made up of chitin and the cell membrane is made up
of Ergosterol.
 Fungi are heterotroph, they acquire their food by absorbing dissolved
molecules typically secreting digestive enzymes into their
environment.
 Fungi that cause disease in humans may be yeast-like or mold-like;
the resulting infections are called mycotic infections or fungal
infections.
 Fungal infections are iatrogenic/drug induced and they
majorly occur in immunocompromised people
receiving immunosuppressants.
 Fungal infections range from superficial skin infections
to life-threatening systemic infections.
 Systemic fungal infections are serious infections that
occur when fungi gain entrance into the interior of the
body.
CLASSIFICATIONS
AZOLE ANTIFUNGALS

 Azole antifungals are made up of two different classes of drugs

 Imidazoles
 Triazoles
 They have similar mechanisms of action and spectra of activity
but different pharmacokinetics and therapeutic uses.
 Imidazoles are given topically for cutaneous infections.
 Triazoles are given systemically for the treatment or prophylaxis
of cutaneous and systemic fungal infections.
THERAPEUTIC ACTION
 They have broad spectrum of action with minimal adverse reactions.
 They are fungicidal, they block the formation of egosterol.
 Azoles are either binding to sterols and cause cell death or interfering with cell
replication.
INDICATION
 Treatment for candidiasis, cryptococcal meningitis, systemic mycoses, aspergillosis,
among others.
Children
 They are more sensitive to the effects of antifungals so more severe adverse
reactions may be expected from them.
 Only fluconazole, ketoconazole, terbinafine, and griseofulvin have established
pediatric doses.
 Topical agents are avoided on open or draining areas to avoid systemic absorption.
Also, occlusive dressings, including tight diapers, should be avoided over the
affected areas.
Adults
 This age group widely use over-the-counter antifungals and it should be
emphasized to them that antifungals can be very toxic so usage is only justified
when causative organism is identified.
 Pregnant and lactating women should be advised that usage of this drug
should only be in situations where the benefits clearly outweigh the risks.
 As for women of childbearing age, barrier contraceptives should be employed.
Lastly, antifungals should not be used over open or draining areas as this can
facilitate systemic absorption.
Older adults
 They are more susceptible to the adverse effects of the drug, especially those
with hepatic and renal dysfunction. In such cases, doses are needed to be
lowered.
PHARMACOKINETICS

Route Onset Peak Duration

Oral Slow 1-2 h 2-4 d

IV Rapid 1h 2-4 d

T1/2: 30 h
Metabolism: liver
Excretion: kidney (urine)
CONTRAINDICATION
 Hepatic dysfunction. Ketoconazole, fluconazole, posaconazole, and terbinafine can cause
serious hepatic toxicity. Patients are carefully monitored for bone
marrow suppression and GI and liver toxicity if using these drugs, particularly
posaconazole.
 Endocrine or fertility problems. Ketoconazole is absolutely contraindicated in patients
with this condition because of its effects on these processes. Fluconazole can be the
alternative drug but it can cause liver and/or renal toxicity. Caution is exercised.
 Pregnancy and lactation. Not known whether most azoles cross placenta or enter
breastmilk. However, terbinafine is known to do so.
 Patients taking drugs that can prolong QTc interval. Voriconazole and these drugs can
worsen condition and can cause ergotism if taken with ergot alkaloids.
ADVERSE EFFECTS
 GI: liver toxicity
 Severe effects on a fetus or a nursing babies
 All azoles are teratogenic
DRUG INTERACTIONS
 Cyclosporine, digoxin, oral hypoglycemics, warfarin,
oral anticoagulants, phenytoin: increased serum levels of these drugs when
ketoconazole and fluoconazole are also being taken by the patient. The two
drugs strongly inhibit CYP450 enzyme system.
 Statins, triazolam, midazolam, pimozide, dofetilide: serious cardiac effects
together with itraconazole
 Ergot alkaloids: ergotism if taken with posaconazole and voriconazole
NURSING CONSIDERATION
 Check culture and sensitivity reports to ensure that this is the drug
of choice for this patient.
 Ensure that patient receives full course of antifungals as prescribed
(may take up to 6 months for chronic infection), to get the full
beneficial effects.
 Monitor IV sites to ensure that phlebitis or infiltration does not
occur.
 Provide safety measures (e.g.side rails and assistance with
ambulation, antipyretics for fever and chills, temperature regulation
for fever, etc.) to protect the patient if CNS effects (e.g. confusion,
disorientation, numbness) occur.
 Provide small, frequent, nutritious meals if GI upset is severe.
Monitor nutritional status and arrange a dietary consultation as
needed to ensure nutritional status.
 Advise patient to report sore throat, unusual bruising
or bleeding, or yellowing of eyes and skin, all of which could
indicate hepatic toxicity; or severe nausea and vomiting, which
could interfere with nutritional state and slow recovery.
 Educate client on drug therapy to promote understanding and
compliance.
TOPICAL AZOLES
INDICATION
 They are used to treat oral, vulvovaginal, cutaneous candidiasis.
They are also used to treat T. corporis, cruris and capitis
infection.
 Miconazole is more efficacious than other topical azoles.
 The half-life is 1-6 hours.
 Treatment ranges from 2-6 months based on the area of
infection.
SYSTEMIC AZOLES- Ketoconazole

 Oral ketoconazole has historically been used for the treatment of

systemic fungal infections but is rarely used today due to the risk of
severe liver injury, adrenal insufficiency, and adverse drug
interactions.
PHARMACOKINETICS
 They are well absorbed orally and metabolized by liver.
 They are well absorbed through out the body but does not enter CSF.
 It is a potent CYP 450 inhibitor.
INDICATION
 It is used in the treatment of
 systemic candidiasis
 Vaginal moniliasis
 Deep micotic infections
 Cryptococcal infections
 Coccidioiodo infections
ADVERSE DRUG REACTIONS
 It inhibits enzymes useful for sterol synthesis.
 Decreased production of testosterone leading to impotency,
loss of hair, oligozoospermia and gynaecomastia.
 Menstrual irregularities
 hepatotoxicity
 TRIAZOLE- Fluconazole
 Most of its spectrum are limited to yeast and some dimorphic fungi
PHARMACOKINETICS
 It is orally well absorbed, crosses the BBB and up to 90% is excreted unchanged in
urine.
 It has high affinity towards fungal lanosreol.
INDICATION
 It is used for prophylaxis against invasive fungal infections in recipients of bone
marrow transplants.
 It is also the drug of choice for cryptococcus neoformans after induction therapy
with amphotericin B and flucytosine and is used for the treatment of candidemia
and coccidioidomycosis.
 It is commonly used as a single-dose oral treatment for vulvovaginal candidiasis.
ITRACONAZOLE
PHARMACOKINETICS
 It is orally well absorbed.
 IV can be given in serious infections.
INDICATION
 It is used for the treatment of
 fluconazole resistant fungal meningitis
 Histoplamosis
 Blastomycoses
 Sporotrichosis
 Mucormycosis
 Coccidioiodomycosis
 paracoccidioiodomycosis
ADVERSE REACTION
 Nausea
 Vomiting, rash hypokalemia
 Hypertension
 Edema
 Headache
 hepatoxicity
CONTRAINDICATION
 It has a negative ionotropic effect and should be avoided in patients with
evidence of ventricular dysfunction, such as heart failure.
POSACONAZOLE
 Newer and most costliest of all the azoles
 Limited use due to increased cost
 It is available as an oral suspension, oral tablet, or IV
formulation
 It is commonly used for the treatment and prophylaxis of
invasive candida and aspergillus infections in severely
immunocompromised patients.
 It is a CYP inhibitor.
VORICONAZOLE
 It has replaced amphotericin B as the drug of choice for invasive
aspergillus.
 It is also approved for the treatment of invasive candidiasis, as
well as serious infections caused by scedosporium and fusarium
species.
 Adverse effects are similar to those of the other azoles; however,
high trough concentrations are associated with visual and
auditory hallucinations and an increased incidence of
hepatotoxicity.
Echinocandin Antifungals
• Echinocandin antifungals include anidulafungin, caspofungin, and micafungin.
THERAPEUTIC ACTION
• Inhibiting glucan synthesis. Glucan is an enzyme that is present in the fungal cell
wall but not in human cell walls. Fungal cell wall cannot be formed if glucan is
destroyed.
INDICATIONS
• Treatment of candidemia and other forms of Candida infection
• Treatment of invasive aspergillosis in patients who do not respond or are
intolerant to other therapies
• Prophylaxis of Candida infections in patients with hematopoietic stem cell
transplant
PHARMACOKINETICS

Route Onset Peak Duration

Anidulafungin IV Rapid N/A N/A

T1/2: 40-50 h
Metabolism: liver
Excretion: colon (feces)

Caspofungin IV Rapid N/A N/A

T1/2: 9-11 h, then 6-48 h, then 40-50 h

Metabolism: liver
Excretion: kidney (urine)

Micafungin IV Rapid N/A N/A

T1/2: 14-17 h
Metabolism: liver
Excretion: kidney (urine)
 Due to large molecular weight of echinocandins, they have poor
oral bioavailability and are administered by intravenous infusion
 Also, their large structures limit penetration into cerebrospinal
fluid, urine, and eyes. In plasma, they have a high affinity to
serum proteins
CONTRAINDICATIONS
• Anidulafungin. May cross placenta and enter breastmilk. Caution
is also used in the presence of hepatic impairment.
• Caspofungin. It is embryotoxic in animal studies and known to
enter breast milk.
• Micafungin. Should only be used in pregnant and lactating
patients if benefits clearly outweigh the risks.
ADVERSE EFFECTS
• GI: hepatic toxicity
• Serious hypersensitivity reactions, particularly with micafungin
• Immunological: bone marrow depression
DRUGI INTERACTIONS
• Cyclosporine: concurrent use with caspofungin is contraindicated
NURSING CONSIDERATION
 Ensure that this is the drug of choice for this patient.
 Ensure that patient receives full course of antifungals as
prescribed to get the full beneficial effects.
 Monitor IV sites to ensure that phlebitis or infiltration does not
occur.
 Provide safety measures (e.g.side rails and assistance with
ambulation, antipyretics for fever and chills, temperature
regulation for fever, etc.) to protect the patient if CNS effects
(e.g. confusion, disorientation, numbness) occur.
 Provide small, frequent, nutritious meals if GI upset is severe.
Monitor nutritional status and arrange a dietary consultation as
needed to ensure nutritional status.
 Advise patient to report sore throat, unusual bruising
or bleeding, or yellowing of eyes and skin, all of which could
indicate hepatic toxicity; or severe nausea and vomiting, which
could interfere with nutritional state and slow recovery.
 Educate client on drug therapy to promote understanding and
compliance.
Topical Antifungals
 Topical antifungals are used to treat a variety of mycoses of skin
and mucous membranes. Some systemic antifungals have topical
forms.
 Fungi causing these mycoses are called dermatophytes.
THERAPEUTIC ACTION
 Altering the cell permeability of the fungus, causing prevention
of replication and fungal death.
TERBINAFINE
 Oral terbinafine is the drug of choice for treating dermatophyte onychomycoses
(fungal infection of nails, therapy requires 3 months)
 Topical terbinafine is used to treat tinea pedis, tinea corporis(ring worm) and tinea
cruris (infection of the groin). Treatment duration is usually 1 week.
PHARMACOKINETICS
 Bioavailability is only 40% due to first pass metabolism
 It is highlyprotein bound and is deposited in the skin, nails, and adipose tissues
 It accumulates in breast milk and should not be given to nursing mothers
 A prolonged terminal half lide of 200 to 400 hours may reflect the slow release from
the tissues
ADVERSE EFFECTS
 GI disturbances (diarrhea, dydpepsia, and nausea)
 Headache
 Rash
 Taste and visual disturbances have been reported, as
well as transient elevations in serum hepatic
transaminases
GRISEOFULVIN
 It is obtained from Streptomyces griseus
PHARMACOKINETICS
 Well absorbed orally
 Absorption is enhanced in the presence of lipophilic substances
 Accumulation is enhanced in tissues made up of keratin such as
skin, nails, hair
 Can prevent further spread but cannot treat already infected
keratinocytes
THERAPEUTIC ACTION
INDICATION
 It is used to treat dermatophytes of the scalp and hair
 It is fungistatic and requires a long duration of treatment (6 to 12
months for onychomycosis)
 For the treatment of T. unguium and T. corporis
ADVERSE REACTION
 Rash
 Nausea
 Vomiting
 Diarrhea
 Mild hepatotoxicity
NYSTATIN
CICLOPIROX
TOLNAFTATE
NURSING CONSIDERATION
 Check culture and sensitivity reports to ensure that this is the drug of
choice for this patient.
 Ensure that patient receives full course of antifungals as prescribed to get
the full beneficial effects.
 Instruct patient in the correct method of administration, depending on
the route, to improve effectiveness and decrease the risk of adverse
effects.
 Troches should be dissolved slowly in the mouth.
 Vaginal suppositories, creams, and tablets should be inserted high into the vagina
with the patient remaining recumbent for at least 10-15 minutes after insertion.
 Topical creams and lotions should be gently rubbed into the affected area after it
has been cleansed with soap and water and patted dry. Occlusive bandages should
be avoided.
 Advise patient to stop the drug if a severe rash occurs, especially if it is
accompanied by blisters or if local irritation and pain are very severe. This
development may indicate drug sensitivity or worsening of condition being
treated.
 Educate client on drug therapy to promote understanding and compliance.