3. Imidazoles and triazoles
• Mechanism of action:
– Imidazoles and triazoles on fungi is inhibition of 14-α-sterol
demethylase and impair the biosynthesis of ergosterol in
cytoplasmic membrane and accumulates the 14-αmethylsterols. These methylsterols may disrupt the close
packing of acyl chains of phospholipids, impairing the functions/
inhibit the growth of the fungi.
– Some azoles (e.g., clotrimazole) directly increase permeability of
the fungal cytoplasmic membrane- topical use.
• Resistance:
– Azole resistance (clinical failure) observed in HIV infection and
oropharyngeal or esophageal candidiasis. The primary
mechanism of resistance in C. albicans is accumulation of
mutations in ERG11, the gene coding for the 14-a-sterol
demethylase. Increased production of 14-a-sterol demethylase
is another potential cause of resistance.
4. Clotrimazole
• It is effective in the topical treatment of tinea infections like
ringworm.
• Absorption of clotrimazole is less than 0.5% after application to the
intact skin; from the vagina, it is 3% to 10%.
• The small amount absorbed is metabolized in the liver and excreted
in bile.
• ADR:
clotrimazole
on
the
skin
may
cause
stinging, erythema, edema, vesication, desquamation, pruritus, and
urticaria. When it is applied to the vagina, about 1.6% of recipients
complain of a mild burning sensation, and rarely of lower
abdominal cramps, a slight increase in urinary frequency, or skin
rash. No systemic toxicity is seen after topical use.
• Dose: 1% lotion, cream, powder; 100 mg vaginal tab.
5. Econazole
It is similar to clotrimazole. Effective in
dermatophytosis, otomycosis and oral thrush.
Dose: 1% oint, 150 mg vaginal tab
Miconazole
highly efficacious (>90% cure rate) drug for
tinea, pityriasis
versicolor, otomycosis, cutaneous and
vulvovaginal candidiasis.
ADR: Irritation after cutaneous application is
infrequent. No systemic adverse effects are seen.
Dose: 2% gel, 2% powder and solution; 2%
vaginal gel
6. Ketoconazole (KTZ)
• First orally effective broad-spectrum antifungal drug, useful in
both dermatophytosis and deep mycosis.
• It has been replaced by itraconazole for the treatment of all
mycoses
• Ketoconazole sometimes is used to inhibit excessive
production of glucocorticoids in patients with Cushing's
syndrome
• PK-PD: Elimination of KTZ is dose dependent: t1/2 varies from
11/2 to 6 hours. Penetration in CSF is poor: not effective in
fungal meningitis. However, therapeutic concentrations are
attained in the skin and vaginal fluid.
• ADR: Ketoconazole is much less toxic than AMB, most
common side effects are nausea and vomiting.
Gynaecomastia, loss of hair and libido, and oligozoospermia
may be the manifestations.
7. Ketoconazole (KTZ)
• Interaction: H2 blockers, proton pump inhibitor and antacids
decrease the oral absorption of KTZ. Ketoconazole inhibits
cytochrome P450, especially CYP3A4, and raises the blood
levels
of
several
drugs
including
phenytoin, digoxin, diazepam, cyclosporine, warfarin, etc..
• Use:
– Effective in dermatophytosis, monilial vaginitis, Systemic
mycosis
– KTZ is occasionally used in dermal leishmaniasis and kala azar
– High-dose KTZ has been used in Cushing's syndrome to decrease
corticosteroid production.
8. Fluconazole
• It is a water-soluble triazole having a wider range of activity
than KTZ. It has good cerebrospinal fluid penetration.
• PK: Fluconazole is 94% absorbed; oral bioavailability is not
affected by food or gastric pH. It is primarily excreted
unchanged in urine with a t1/2 of 25-30 hr. Fungicidal
concentrations are achieved in nails, vagina and saliva;
penetration into brain and CSF is good. Dose reduction is
needed in renal impairment.
• ADR: Mostly nausea, vomiting, abdominal pain, rash and
headache. Elevation of hepatic transaminase has been noted
• in AIDS patients.
• Use:
vaginal
candidiasis,
oropharyngeal
candidiasis,
disseminated candidiasis, cryptococcal/ coccidioidal meningitis;
eye drop is useful in fungal keratitis.
• Dose: 150- 200 mg weekly for 1-12 months; 0.3% eye drops.
9. Itraconazole
•
•
•
•
It has a broader spectrum of activity than KTZ or fluconazole.
It is fungistatic, but effective in immunocompromised patients.
Its structurally closely related to the imidazole (ketoconazole).
Steroid hormone synthesis inhibition is absent in itraconazole,
and serious hepatotoxicity is rare.
• PK: Accumulates in vaginal mucosa, skin and nails, but
penetration into CSF is poor. T1/2 varies from 30-64 hours.
Itraconazole is metabolized in the liver and it is substrate for
and a potent inhibitor of CYP3A4.
10. ltraconazole
• ADR: Dizziness, pruritus, headache and hypokalaemia.
Itraconazole is not carcinogenic but is teratogenic in rats, and is
contraindicated for the treatment of onychomycosis during
pregnancy or for women contemplating pregnancy (category C).
• Serious hepatotoxicity has rarely led to hepatic failure and
death.
• Use: Vaginal candidiasis, dermatophytosis, onychomycosis
• Dose: 100, 200-400 mg cap
11. Voriconazole
• Voriconazole is the second generation triazole used for
systemic fungal infections.
• Pk: The recommended dosage is 400 mg/d. The drug is well
absorbed orally, and metabolism is predominantly in liver.
• ADR: Observed toxicities include rash and QTc
prolongation, elevated hepatic enzymes. Visual disturbances
are common, occurring in up to 30% of patients receiving
voriconazole, and include blurring and changes in color vision
or brightness. These visual changes usually occur immediately
after a dose of voriconazole and resolve within 30 minutes.
12. TERBINAFINE
• Terbinafine is a synthetic allylamine that is available in an oral
formulation and is used at a dosage of 250 mg/d.
• It is used in the treatment of dermatophytoses, especially
onychomycosis .
• PK:
– Approximately 75% of oral terbinafine is absorbed, but only 5%
or less from unbroken skin. First pass metabolism further
reduces oral bioavailability.
– lt is lipophilic, widely distributed in the body, strongly plasma
protein bound and concentrated in sebum, stratum corneum and
nail plates.
– It is inactivated by metabolism and excreted in urine (80%) and
faeces (20%); elimination t1/2 of 11-16 hr is prolonged to 10 days
after repeated dosing.
13. TERBINAFINE
• MOA: Terbinafine inhibits the fungal enzyme squalene
epoxidase. This leads to the accumulation of the sterol
squalene, which is toxic to the organism.
• ADR:
– Adverse effects are rare, consisting primarily of
gastrointestinal upset and headache.
– Topical terbinafine can cause
erythema, itching, dryness, irritation, urticaria and rashes.
• Dose: One tablet given daily for 12 weeks achieves a cure rate
of up to 90% for onychomycosis and is more effective than
griseofulvin or itraconazole.
14. Antimetabolite – Flucytosine (5-FC)
• It is a pyrimidine antimetabolite (inactive as such)
• After fungal uptake, it is converted into 5-fluorouracil and
then to 5-fluorodeoxyuridylic acid which is an inhibitor of
thymidylate synthesis.
• 5-FC is narrow spectrum fungistatic.
• ADR: Toxicity of 5-FC is lower than that of AMB. Dose
dependent bone marrow depression. Liver dysfunction is
mild and reversible.
• Therapy with 5-FC is generally limited to first 2 weeks of AMB
regimen to avoid its bone marrow toxicity.
15. OTHER TOPICAL ANTIFUNGALS
Drug
Use
Dose
Tolnaftate
drug for tinea
cruris and tinea corporis for 1-3 weeks
1% lotion/ cream
Ciclopirox
olamine
newer drug effective in tinea infections,
pityriasis versicolor and dermal candidiasis;
used for onychomycosis, vaginal candidiasis
1% cream, 1% topical
solution, 1% vaginal
cream
Undecylenic
acid
It is fungistatic. Used for tinea pedis, nappy
rash and tinea cruris
Benzoic acid
It has antifungal and antibacterial property. It
is fungistatic-weaker than tolnaftate. On
hyperkeratotic lesions, it is used in
combination with salicylic acid
Butenafine
Efficacy in tinea cruris/ corporis/pedis
is similar to that of topical terbinafine
1% cream; apply locally
once/ twice daily.
Quiniodochlor
Weak antifungal and antibacterial activity. It
has been used for dermatophytosis, mycosis
barbae, seborrhoeic dermatitis, infected
eczema, furunculosis and pityriasis versicolor
3% / 4% / 8% cream
Sodium
thiosulfate
weak fungistatic, active against Malassezia
furfur
Karpin Lotion 20%.
20. Visceral leishmaniasis (VL)/ kala-azar/ black fever/ Dumdum fever
caused by protozoan parasites of the Leishmania genus.
This disease is the second-largest parasitic killer in the
world (after malaria), responsible for an estimated 500,000
infections each year worldwid
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