ANTIFUNGAL DRUGS

An antifungal drug is a medication used to treat fungal infections such as athlete's

foot, ringworm, candidiasis (thrush), serious systemic infections such as

cryptococcal meningitis etc.

 Mode of action;
Antifungals work by exploiting differences between mammalian and fungal
cells to kill the fungal organism without dangerous effects on the host.

Unlike bacteria, both fungi and humans are eukaryotes.

Thus fungal and human cells are similar at the molecular level.

This makes it more difficult to find or design drugs that target fungi without
affecting human cells.

Consequently, many antifungal drugs cause side-effects.

Some of these side-effects can be life-threatening if the drugs are not used
properly.
 Precaution

Apart from side-effects like liver-damage or effects on estrogen levels , many

medicines can cause allergic reactions in people. For example, the azole group of
drugs is known to cause anaphylaxis.

There are also many drug interactions. For example, the azole antifungals such
as ketoconazole or itraconazole can be both substrates and inhibitors of the P-
glycoprotein, which (among other functions) excretes toxins and drugs into the
intestines

Azole antifungals also are both substrates and inhibitors the cytochrome P450
family CYP3A4, causing increased concentration when administering, for example,
calcium channel blockers, immunosuppressants, chemotherapeutic drugs,
benzodiazepines, tricyclic antidepressants, macrolides and SSRIs.
 Classes;
1) Polyene antifungals
 The polyene antimycotics bind with sterols in the fungal cell membrane,
principally ergosterol.
 Animal cells contain cholesterol instead of ergosterol and so they are much
less susceptible.
 As a polyene's hydrophobic chain is shortened, its sterol binding activity is
increased. Therefore, further reduction of the hydrophobic chain may result in it
binding to cholesterol, making it toxic to animals.
 Examples include; F R A N N C
o Nystatin
o Amphotericin B
o Candicin
o Natamycin
o Rimocidin
o Filipin
2) Azole Antifungals; Imidazole, triazole, and thiazole antifungals;
 Azole antifungal drugs inhibit the enzyme cytochrome P450 CYP51 and
14α-demethylase; the enzyme necessary to convert lanosterol to ergosterol.
 Depletion of ergosterol in fungal membrane disrupts the structure and many
functions of fungal membrane leading to inhibition of fungal growth
Imidazoles;
Miconazole
Ketoconazole
Clotrimazole
Econazole
Bifonazole
Isoconazole
Griseofulvin
G M C BIKE AZOLE
 Triazoles;
Newer, less toxic and more effective. These include;
Fluconazole
Itraconazole
Isavuconazole
Ravuconazole
Posaconazole
Voriconazole
Terconazole
V I P FIR T

Thiazoles;
Example include;
Abafungin
3) ; Allylamines
 Allylamines inhibit squalene epoxidase, another enzyme required for ergosterol
synthesis: examples include; B A T
o Terbinafine
o Amorolfine
o Naftifine
o Butenafine

4) Echinocandins;
 Echinocandins inhibit the synthesis of glucan in the cell wall, probably via the
enzyme 1,3-β glucan synthase: examples include; C A M
o Anidulafungin
o Caspofungin
o Micafungin
5) Others;
 Benzoic acid – has antifugal properties but must be combined with a
keratolytic agent such as salicylic acid (as in Whitfield's Ointment)
 Other examples include;
o Ciclopirox – most useful against Tinea versicolour
o Tolnaftate
o Flucytosine or 5-fluorocytosine – an antimetabolite
o Griseofulvin – binds to polymerized microtubules and inhibits fungal
mitosis
o Haloprogin – discontinued due to side effects
Anti-dandruff shampoos;

Antifungal drugs (such as ketoconazole) are often found in anti-dandruff

shampoos.

The antifungal drugs inhibit the yeast Malassezia globosa which encourages

seborrhoeic dermatitis and tinea versicolor.

Polyene antifungals
Nystatin
 Nystatin is a polyene antifungal drug to which many molds and yeast infections
are sensitive, including Candida spp.
 Due to its toxicity profile, there are currently no injectable formulations of this
drug.
 Nystatin may however be safely given orally as well as applied topically due to
its minimal absorption through mucocutaneous membranes such as the gut and
the skin.
 Mechanism of action;
Like amphotericin B and natamycin, nystatin binds to ergosterol, a major
component of the fungal cell membrane.
When present in sufficient concentrations, it forms pores in the membrane that
lead to K+ leakage and death of the fungus.
Ergosterol is fairly unique to fungi, so the drug does not have such
catastrophic
effects on animals.
Uses
Cutaneous, vaginal, mucosal and esophageal Candida infections usually
respond well to treatment with nystatin. Cryptococcus is also sensitive to
Nystatin in vitro.
Treating neonatal oral thrush is restricted to those over the age of one month
(miconazole is an appropriate alternative for younger babies).
Nystatin is often used as prophylaxis in patients who are at risk for fungal
infections, such as AIDS patients with a low CD4+ count and patients receiving
chemotherapy.
It is prescribed in units, with doses varying from 100,000 (for oral infections)
to 1 million (for intestinal ones).
As it is not absorbed from the gut, it is safe for oral use and does not have
problems of drug interactions.
Amphotericin B

Amphotericin B is a polyene antifungal drug, often used intravenously for

systemic fungal infections.

Its name originates from the chemical's amphoteric properties. Two

amphotericins, Amphotericin A and Amphotericin B are known, but only B is

used clinically because it is significantly more active in vivo.

Currently the drug is available as plain Amphotericin B,

Uses;
Oral preparations of Amphotericin B are used to treat thrush; these are virtually
nontoxic, in contrast to typical IV doses ( i.e. 0.25, 0.5, 0.75 mg / kg b.w per day).
One of the main intravenous uses is in treating various systemic fungal infections
(e.g. in critically ill, comorbidly infected or immunocompromised patients),
including cryptococcal meningitis.
Amphotericin B is also commonly used in tissue culture to prevent fungi from
contaminating cell cultures.
It is usually sold in a concentrated solution, either on its own or in combination
with the antibiotics penicillin and streptomycin.
Another IV use is as a drug of last resort in otherwise untreatable parasitic
protozoan infections such as visceral leishmaniasis and primary amoebic
meningoencephalitis.
Mechanism of action
As with other polyene antifungals, amphotericin B associates with ergosterol,
the main component of fungal cell membranes, forming a transmembrane
channel that leads to monovalent ion (K+, Na+, H+, Cl-) leakage, which is the
primary effect leading to fungal cell death.
The actual mechanism of action may be more complex and multi-faceted.
Mechanism of toxicity
Mammalian and fungal membranes both contain sterols, a primary membrane
target for amphotericin B.
Because mammalian and fungal membranes are similar in structure and
composition, this is one mechanism by which amphotericin B causes cellular
toxicity.
Amphotericin B molecules can form pores in the host membrane as well as the
fungal membrane. This impairment in membrane barrier function can have lethal
effects.
Amphotericin administration is limited by infusion-related toxicity.
Side effects
Amphotericin B is well-known for its severe and potentially lethal side effects.
Very often a serious acute reaction after the infusion (1 to 3 hours later) is noted
consisting of high fever, shaking chills, hypotension, anorexia, nausea, vomiting,
headache, dyspnoea, and tachypnea, drowsiness, generalized weakness.
This reaction sometimes subsides with later applications of the drug and may in
part be due to histamine liberation.
In order to decrease the likelihood and severity of the symptoms, initial doses
should be low and increased slowly.
Acetaminophen, pethidine, diphenhydramine and/or hydrocortisone have all
been used to treat or prevent the syndrome, but the prophylactic use of these
drugs is often limited by the patient's condition.
Intravenously administered Amphotericin B has also been associated with
multiple organ damage in therapeutic doses. These include;
Nephrotoxicity
Electrolyte imbalances (e.g. hypokalemia and hypomagnesemia)
 Hepatotoxicity (up to and including fulminant liver failure)
Anemia and other blood dyscrasias (leukopenia, thrombocytopenia)
Cardiac arrhythmias (including ventricular fibrillation
Skin reactions, including serious forms, are also possible.
Interactions
Flucytosine : Toxicity of Flucytosine increased. Use lower dose of
Amphotericin B. Amphotericin B may also facilitate entry of Flucystosine into
the fungal cell by interfering with the permeability of the fungal cell membrane.
Diuretics and Cisplatin : Increased renal toxicity and increased risk of
hypokalemia
Corticosteroids : Increased risk of hypokalemia
Other nephrotoxic drugs : Increased risk of serious renal damage.
Foscarnet, Ganciclovir, Tenofovir, Adefovir : Risk of hematological and renal
side-effects of Amphotericin B increased.
2) Azole antifungals; (Imidazole, triazole, and thiazole)
Imidazoles;
Miconazole;
 Miconazole is an imidazole antifungal agent.
 It is commonly applied topically (to the skin) or mucus membranes to cure
fungal infections.
 It works by inhibiting the synthesis of ergosterol, a critical component of
fungal cell membranes.
 It can also be used against certain species of Leishmania protozoa (which
are a type of unicellular parasite), as these also contain ergosterol in their
cell membranes.
 In addition to its antifungal and antiparasitic actions, it also has some
limited antibacterial properties
 Indications

Miconazole is mainly used externally for the treatment of athlete's foot,

ringworm and jock itch. oral or vaginal thrush

Internal application is used for (yeast infection).

In addition the oral gel may also be used for the lip disorder angular cheilitis.

It has an advantage over nystatin in the treatment of neonatal oral thrush in
that

nystatin is only used in infants over the age of one month; but note the

possibility for drug interactions.

 Side effects

Unlike nystatin, some miconazole is absorbed by the intestinal tract when used

orally (and possibly if used vaginally) which may lead to drug interactions.

Of note may be interactions with anticoagulants, phenytoin, terbinafine, some

newer atypical antipsychotics, ciclosporin and some statins used to treat

hypercholesterolemia.
Cheilitis
Oral candidiasis on the tongue and soft palate.
Candida balanitis
Moniliasis
Moniliasis
 Ketoconazole
Ketoconazole is a synthetic antifungal drug used to prevent and treat skin

fungal infections,

It inhibits growth of dermatophytes and yeast species such as Candida albicans

especially in HIV/AIDS immune compromised patients.

 Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream,

and oral tablet.

Ketoconazole is very lipophilic, which leads to accumulation in fatty tissues.

The less toxic and more effective triazole compounds fluconazole and

itraconazole have largely replaced ketoconazole for internal use.

Ketoconazole is best absorbed at highly acidic levels, so antacids or other

causes

of decreased stomach acid levels will lower the drug's absorption when taken

orally.
 Usage

Ketoconazole is usually prescribed for topical infections such as athlete's foot,

ringworm, candidiasis (yeast infection or thrush), jock itch, tinea versicolor and

mycetoma.

The side-effects of ketoconazole are sometimes used to treat non-fungal

problems. These include;

a)The decrease in testosterone caused by the drug makes it useful for

treating prostate cancer and for preventing post-operative erections

following penile surgery.

b)The suppression of glucocorticoid synthesis, where it is used in the

treatment of Cushing's disease.

 Ketoconazole can be prescribed as a 200 mg pill, a 2% cream, a 2% gel, a 2%

foam, 1% or 2% shampoo for the treatment of dandruff / seborrhoeic dermatitis.

The anti-dandruff shampoo is designed for people who have a more serious

case of dandruff where symptoms include, but are not limited to constant

non-stop flaking, and severe itchiness.

Ketoconazole may have a stimulatory effect on hair growth. Ketoconazole

shampoo (Nrizoal shampoo) has shown to be beneficial in men suffering from

androgenic alopecia and has been shown to work just as well as

minoxidil 2% in men with androgenic alopecia.

It is a pregnancy category C drug because animal testing has shown it to

cause

teratogenesis in high dosages.

 Mechanism of action

Ketoconazole is structurally similar to imidazole, and interferes with the fungal

synthesis of ergosterol, a constituent of cell membranes, as well as certain

enzymes.

As with all azole antifungal agents, ketoconazole works principally by inhibition

of an enzyme, cytochrome P450 14-alpha-demethylase (P45014DM). This

enzyme is in the sterol biosynthesis pathway that leads from lanosterol to

ergosterol.

Fluconazole and itraconazole have been found to have a greater affinity for

fungal cell membrane than ketoconazole, and thus lower doses of these azoles

are required to kill fungi.

 Clotrimazole
Clotrimazole is an antifungal medication commonly used in the treatment of
fungal infections of both humans and animals; such as vaginal yeast infections,
oral thrush, ringworm and athlete's foot.

Indications and formulations

It is commonly available as a cream, pessaries and also ear drops for ear
infection.
Potential for drug interactions with oral clotrimazole exists, as it is a potent,
specific inhibitor of cytochrome P450 oxidase and may alter the metabolism of
other drugs.
Side effects include occasional localised irritation of the skin with a mild burning
sensation, redness and itching.
 Griseofulvin
Griseofulvin is an antifungal drug that is administered orally. It is used to treat
fungal infections of the skin (commonly known as ringworm) and nails.
It is derived from the mold Penicillium griseofulvum.
Mechanism of action
The drug binds to tubulin, interfering with microtubule function, thus inhibiting
Mitosis hence dermatophyte growth.
It also binds to keratin in keratin precursor cells and makes them resistant to
fungal infections.
Griseofulvin is used to treat the following fungal infections:
oTinea capitis (ringworm of the scalp)
oTinea corporis (ringworm of the body)
oTinea pedis (athlete's foot)
oTinea unguium (onychomycosis)
oTinea cruris (ringworm of the thigh & perineum)
oTinea barbae (barber's itch)
It is a cytochrome p450 enzyme inducer hence the potential reduction in the
effectiveness of oral contraceptives etc.
 Adverse effects

Confusion teratogenicity
Considered unsafe for those with Disulfiram-like/anti-abuse-like
Porphyria reaction with alcohol
Diarrhea Sensitivity to prolonged sun
Dizziness exposure
Fatigue Skin rashes
Headache Swelling
Itching Tingling in the hands or feet
Loss of taste sensation Upper abdominal pain
Nausea
Vomiting
Oral thrush (yeast infection of the
mouth)
 Triazoles;
Fluconazole
 Fluconazole is a triazole antifungal drug used in the treatment
and prevention of superficial and systemic fungal infections.

Mode of action
 Like other imidazole- and triazole-class antifungals, fluconazole
inhibits the fungal cytochrome P450 enzyme 14α-demethylase.
 This inhibition prevents the conversion of lanosterol to
ergosterol, an essential component of the fungal cytoplasmic
membrane.
 Fluconazole is primarily fungistatic
Fluconazole is active against the following micro-organisms:

oBlastomyces dermatitidis

oCandida spp. (except C. krusei and C. glabrata)

oCoccidioides immitis

oCryptococcus neoformans

oHistoplasma capsulatum

oEpidermophyton spp.

oMicrosporum spp.

oTrichophyton spp.
 Pharmacokinetics

Fluconazole is almost completely absorbed within two hours.

Bioavailability is not significantly affected by the absence of stomach acid.

Concentrations measured in the urine, tears and skin are approximately 10

times

the plasma concentration, while saliva, sputum and vaginal fluid concentrations

are approximately equal to the plasma concentration

Standard dose range of between 100 mg and 400 mg per day.

The elimination half-life of fluconazole follows zero order kinetics and only 10%

of elimination is due to metabolism, the remainder is excreted in urine and sweat.

Patients with impaired renal function will be at risk of overdose as well as

patients taking drugs such as warfarin.

 Indications

Fluconazole is indicated for the treatment and prophylaxis of fungal infections

where other antifungals have failed or are not tolerated (e.g. due to adverse

effects), including;

oCandidiasis caused by susceptible strains of Candida

oTinea corporis, tinea cruris or tinea pedis

oOnychomycosis

oCryptococcal meningitis

oFluconazole can be used first-line for the following indications:

Coccidioidomycosis

Cryptococcosis

Histoplasmosis

Prophylaxis of candidiasis in immunocompromised people

Adverse effects

 Adverse drug reactions associated with fluconazole therapy include:

a) Common (≥1% of patients): skin rash, headache, dizziness, nausea,

vomiting, abdominal pain, diarrhea, and/or elevated liver enzymes

b) Infrequent (0.1–1% of patients): anorexia, fatigue, constipation

c) Rare (<0.1% of patients): oliguria, hypokalaemia, paraesthesia, seizures,

alopecia, Stevens-Johnson syndrome, thrombocytopenia, other blood
dyscrasias, serious hepatotoxicity including hepatic failure,
anaphylactic/anaphylactoid reactions

d) Very rare: prolonged QT interval, torsades de pointes

 Fluconazole is in the FDA pregnancy risk category C.

 Drug interactions

Fluconazole is an inhibitor of the human cytochrome P450 system, particularly the

isozymes CYP2C9 and CYP3A4.

In theory, therefore, fluconazole decreases the metabolism and increases the

concentration of any drug metabolised by these enzymes.

Additionally, its potential effect on QT interval increases the risk of cardiac

arrhythmia if used concurrently with other drugs that prolong the QT interval.
 Itraconazole
Pharmacology
Itraconazole is a triazole antifungal agent that may be given orally or
intravenously.
It inhibits the fungal cytochrome P450 oxidase-mediated synthesis of ergosterol.
Because of its ability to inhibit cytochrome P450 3A4, caution should be used
when considering interactions with other medications.
Itraconazole is available as capsules or as an oral solution. The dose is 200 mg
once a day, to 400 mg in severe infection.
Itraconazole may be taken with orange juice or cola, as absorption is also
improved by acid. Absorption of itraconazole is impaired when taken with an
antacid, H2-blocker or proton pump inhibitor.
In intravenous dosing, four doses of itraconazole 200 mg are given 12 hours
apart,
before changing the dose to once daily.
Indication

Itraconazole has a broader spectrum of activity than fluconazole

(but not as broad as voriconazole or posaconazole).

It is also prescribed for systemic infections such as aspergillosis, candidiasis and

cryptococcosis where other antifungal drugs are inappropriate or ineffective.

In particular, it is active against aspergillus, which fluconazole is not. It is also

used in blastomycosis, histoplasmosis and onychomycosis.

Itraconazole is over 99% protein bound and has virtually no penetration into

cerebrospinal fluid, therefore it should never be used to treat meningitis or other

central nervous system infections.

 Adverse effects of itraconazole;
Include:
onausea
ovomiting
oabdominal pain
ofatigue
oloss of appetite
oyellow skin (jaundice)
oyellow eyes
oitching
odark urine
opale stool
 3) Allylamines;
Terbinafine
 Terbinafine hydrochloride is a synthetic allylamine antifungal.

 It is highly lipophilic in nature and tends to accumulate in skin, nails, and fatty
tissues.

Pharmacology

 Terbinafine hydrochloride is available as a white fine crystalline powder.

 Like other allylamines, terbinafine inhibits ergosterol synthesis by inhibiting

squalene epoxidase, an enzyme that is part of the fungal cell membrane
synthesis pathway.

 Because terbinafine prevents conversion of squalene to lanosterol,

ergosterol cannot be synthesized. This is thought to change cell membrane
permeability, causing fungal cell lysis.
 Indications

Terbinafine is mainly effective on the dermatophytes group of fungi.

As a 1% cream or powder it is used for superficial skin infections such as jock
itch

(Tinea cruris), athlete's foot (Tinea pedis) and other types of ringworm

(Tinea corporis).

Oral 250mg tablets are often prescribed for the treatment of onychomycosis of

the toenail or fingernail due to the dermatophyte (Tinea unguium). Fungal nail

infections are located deep under the nail in the cuticle to which topically applied

treatments are unable to penetrate in sufficient amounts.

Adverse effects include;

oHepatotoxicity (rarely)

oInduction or exacerbation of subacute cutaneous lupus erythematosus.

SLE Malar Rash
SLE Malar Rash
SLE Malar Rash
SLE Scarring Alopecia
SLE Associated Alopecia
Alopecia
SLE Discoid Rash
Localized Chronic Cutaneous Lupus
 Butenafine
Pharmacology

Butenafine hydrochloride is an odourless white crystalline powder

Like the allylamine antifungals, butenafine works by inhibiting the synthesis of

ergosterol by inhibiting squalene epoxidase,

Indications

Butenafine is indicated for the topical treatment of tinea (pityriasis) versicolor

due to M. furfur, as well as athlete’s foot (Tinea pedis), ringworm (Tinea

corporis) and jock itch (Tinea cruris)

It has superior fungicidal activity against this group of fungi when compared to

that of terbinafine, naftifine, clotrimazole, and tolnaftate.

Butenafine is typically available as a 1% topical cream.

 Other Antifungals
Flucytosine
Flucytosine, or 5-fluorocytosine, a fluorinated pyrimidine analogue, is a
synthetic

antimycotic drug.

It is structurally related to the cytostatic fluorouracil.

 It is available in oral and in some countries also in injectable form.

The drug is dispensed in capsules of 250 mg and 500 mg strength.

The injectable form is diluted in 250 mL saline solution to contain

2.5 g in total (10 mg/mL).

Mechanisms of action
Two major mechanisms of action have been elucidated:
a) One is that the drug is intrafungally converted into the cytostatic fluorouracil that
undergoes further steps of activation and finally interacts as
5-fluorouridinetriphosphate with RNA biosynthesis and disturbs the building of
certain essential proteins.
b) Conversion into 5-flourodeoxyuridinemonophosphate which inhibits fungal DNA
synthesis.
 Pharmacokinetics;
Flucytosine is well absorbed (75 to 90%) from the gastrointestinal tract.
Intake with meals slows the absorption,
Following an oral dose of 2 grams peak serum levels are reached after
approximately 6 hours.
The drug is eliminated by renal route as unchanged drug (90% of an oral dose)
and only traces are metabolized and excreted in the feces.
Periodic measurements of serum levels are recommended for all patients and are
a must in patients with renal damage.
 Indications;

Oral flucytosine is indicated for the treatment of serious infections caused by

susceptible strains of Candida, Cryptococcus neoformans or Chromomycosis

(chromoblastomycosis)

Flucytosine must not be used as a sole agent in life-threatening fungal infections

due to relatively weak antifungal effects and fast development of resistance, but

rather in combination with amphotericin B and/or azole antifungals such as

fluconazole or itraconazole.

Minor infections such as candidal cystitis may be treated with flucytosine alone.

Treatment with slow intravenous infusions for no more than a week is also a

therapeutic option, particular if the disease is life-threatening.

 Contraindications and cautions

All patients receiving flucytosine should be under strict medical supervision.

Hematological, renal and liver function studies should be done frequently during

therapy (initially daily, twice a week for the rest of treatment).

Patients with preexisting bone marrow depression and liver impairment should be

treated with caution.

Patients with renal disease should receive flucytosine cautiously and in reduced

doses. Guidelines for proper dosing exist. Serum level determinations are

mandatory in these patients.

Hypersensitivity to flucytosine is an absolute contraindication.

Flucytosine has been found to be teratogenic; pregnant women should be given

flucytosine only if the potential benefits exceed the potential harm to the fetus.
 Side effects
Bone marrow depression (anemia, leukopenia, pancytopenia, or even rarely
agranulocytosis) may occur.
Aplastic anemia has also been seen. Bone marrow toxicity can be irreversible and
may cause death, particular in immunocompromised patients.
GI toxicity may be severe or rarely fatal and consists of anorexia, abdominal
bloating, abdominal pain, diarrhea, dry mouth, duodenal ulcer, GI hemorrhage,
nausea, vomiting, and ulcerative colitis.
Liver function: Elevations of liver enzymes and bilirubin, hepatic dysfunction and
jaundice
Renal function: Increased BUN and serum creatinine have been noted.
Adverse central nervous system effects are frequent and include; confusion,

hallucinations, psychosis, ataxia, hearing loss, headache, paresthesia,

parkinsonism, peripheral neuropathy, vertigo and sedation.

Skin reactions: Rash, pruritus, and photosensitivity have all been noticed.

Anaphylaxis: Sometimes cases of anaphylaxis consisting of diffuse erythema,

pruritus, conjunctival injection, fever, abdominal pain, edema, hypotension and

bronchospastic reactions are observed.

Scleritis
Scleritis
 Dosage

The recommended daily dose is 50 to 150 mg/kg of bodyweight orally, divided

in

four equal doses every six hours.

If problems exist to swallow a complete single dose, the dose may be given in

several partial amounts over 15 minutes.

The dose for intravenous infusions is 50 mg/kg infused over 20 to 40 minutes

every six hours.

The duration of treatment depends on the clinical situation, but generally does

not exceed seven days.