These drugs are used for superficial or deep systemic fungal
Fungal infection termed as mycoses.
FUNGI AND FUNGAL INFECTION:
Fungi are Eukaryotic cells. They possess mitochondria, nuclei & cell
They have rigid cell walls containing chitin as well as polysaccharides,
and a cell membrane composed of ergosterol.
While bacterial cells are prokaryotic. So, antibacterial agents can exhibit
In contrast, similarity between fungal & mammalian cells makes
Antifungal drugs non-selective.
Thus, Antifungal drugs are in general more toxic than antibacterial
Exampels of Fungi:
Clinically important fungi may be classified into four main types:
2.yeast like fungi that produce a structure resembling a
3.filamentous fungi with true mycelium(Aspergillus fumigatus)
4.Dimorphic fungi that,depending on nutritional consraints,may grow as
either yeasts or filamentous fungi(histoplasma capsulatum)
1) Superficial fungal infections can be classified into
Infection of hair,skin,nails
Most commonly caused by Trichophyton,Microsporum or
Epidermophyton,giving rise to various types of ‘ring worm’ or tine.
Yeast like organisam may infect the mucous membranes of the mouth
or vagina(thrush) or the skin.
2) Systemic fungal infection:
paracoccidomycosis;thses are the primary infections.
Involve the internal organs
- Amphotericin B(AMB)
systemic – Ketoconazole
5) β-glucan synthase inhibitors:
Other topical agents:
Action of antifungal agents:
Polyenes, triazoles, and imidazoles target ergosterol destroying
the cell membrane’s integrity.
Allylamines inhibit ergosterol synthesis.
flucytosine inhibit DNA/RNA synthesis.
griseofulvin inhibit fungal cell mitosis preventing cell proliferation
It is the drug of choice used in the treatment of the systemic
mycoses although it is toxic.
It is sometimes used in combination with flucytosine to decrease
the toxicity of amphotericin B.
It binds with ergosterol(component of fungal cell membrane)
AMB-ergosterol complex alter the membrane permeability
creates pore in the membrane
pores allows the leakage of inracellular ions,amino acid &
i.v.(t½ - 24 hours)
some is excreted by kidney
does not readily pass the blood brain barrier
extensively bound to plasma proteins, and is distributed
throughout the body. However, amphotericin B does cross the
placenta; some is also eliminated via the bile. Liposomal
preparations of amphotericin B are available and have shown
topically applied for ,
oral,vaginal, cutaneous candidasis
leishmaniasis:it is a reserve drug for resistant cases of kala azar
and mucocutaneous leishmaniasis.
Infusion related: fever,chills,aches ,nausea,vomiting and
dyspnoea and can be alleviated partly by pretreatment with
NSAIDs,antihistamines,meperidine and adrenal steroids.
• Nephrotoxicity includes reduce g.f.r,acidosis, hypokalemia and
inability to concentrate urine.
• anemia:it is due to bone marrow depression(decrease
• CNS toxicity:occurs only on intrthecal injection –
Alternative Formulations to Decrease Toxicity
LIPID amphotericin B formulations in use
Amphotericin B Lipid Complex: (ABLC; Abelcet®)
Amphotericin B Colloidal Dispersion: (ABCD; Amphocil® or
Liposomal Amphotericin B:(L-AMB; Ambisome®)
It is similar in structure to amphotericin and same mechanism
No absorption from the mucous membranes of the body or from
Use limited to candida infection of skin,git,mucous membrane
B. Hetrocyclic benzofuran:
It is isolated from Penicillium griseofulvum and cure infections due to
dermatophytes(ringworm) when administered orally.
It is ineffective against candida albicans.
It interacts with microtubules of miotic spindle and with cytoplasmic
disorientation of miotic microtubules and interfere in the mitosis
inhibit the growth of fungal hyphae.
It is very low water soluble drug,low absorption,absorption
improved by taking with fatty meals and microfine the drug
It induces warfarin metabolism and reduces efficacy of oral
It is pyrimidine analogue related to the chemotherapeutic agent 5-FU
This permeates the fungal cell wall and converts into 5-FU
phosphorylation of 5-FU and formation of UDP and UTP
which inhibits to thymidylate synthesis
inhibitn the DNA and RNA synthesis
inghibit fungal cell grpwth
Bone marrow depression
In cyptococcosis its synergistic action with AMB is utillized to reduce the
total dose of the more toxic latter dose.
Inhibit the fungal cytochrome P450 enzyme lanosterol 14-methylase
impair ergosterol synthesis
membrane abnormalities in fungus.
Orally used for mucocutaneous candidiasis or dermatophytoses.
• Variable oral absorption, dependent on pH (often given with cola or
• T1/2 = 7-10 hours
• Protein binding > 99%
• Hepatic, bile and kidney elimination
Decrease androgen production and displace testoterone from protein
binding sites gynaecomastia,loss of libido and oligospermia.
Menstrual irregularities in female.
Dose-related inhibition of CYP P450 .
Potent inhibitor of cytochrome P450 3A4
Rifampin and phenytoin decrease ketoconazole levels
Ketoconazole increases cyclosporin, warfarin and terfenadine levels.
Drugs that increase gastric pH will decrease blood levels of
Antacids, omeprazole, H2 blockers
Fluconazole is clinically important because of its lack of the
endocrine side effects of ketoconazole, and its excellent penetrability
into the CSF & ocular fluids.
Water soluble having wider range of activity than Ketoconazol
Drug of choice in fungal meningitis
Non-albicans Candida species more likely to exhibit primary
Sporotrichosis (This fungal disease usually affects the skin, although
other rare forms can affect the lungs, joints, bones, and even the brain).
Posaconazole & Ravuconazole:
• For Invasive candidiasis, and aspergillosis infections
• Only orally available
• Inhibits CYP3A4
• Adverse effects include: GI effects, dizziness, cardiac arrhythmias,
abnormal liver function
Very popular local azoles are – Clotrimazole, Econazole and
(For Tinea, Ring worm, Athlete’s foot, otomycosis, oral, cutaneous &
Mechanism of action is same as that of Ketoconazole i.e. ergosterol
inhibition by inhibiting CYP450
Clotrimazole is favoured in vaginitis because of long lasting residual
effect and once daily dosing
Miconazole causes frequently vaginal irritation & pelvic cramp.
Available as lotion, cream, powder, vaginal tablet etc.
inhibit the enzyme squalene epoxidase
inhibit synhesis of ergosterol.
Possible superior to greiseofluvin in onchomycoses.
GI distress,rash,headache,possible hepatotoxicity.
5. β-glucan synthase inhibitors:
Metabolized by hydrolysis and N-acetylation
Not inhibitor/inducer/substrate of CYP
Enzymes induced by carbamazepine, cyclosporine, dexamethasone,
efavirenz, nelfinavir, nevirapine, phenytoin, rifampin
Substrate 3A4 minor; weak inhibitor of 3A4
Increased levels of nifedipine
Increased monitoring for toxicity and dosage adjustment needed.
Not inhibitor/inducer/substrate of CYP
Degrades at normal pH and condition to an open-ringed peptide
6.Other topical agents:
All these drugs are used in dermatophytosis.
Effective drug fof tinea cruris and tinea corporis.
It causes little irritation and is better than other topical agents.
2) Ciclopirox olamine:
It used in tinea infections,pityriasis versicolor , dermal candidiasis
and vaginal candidiasis.
3) Undecylenic acid:
It used for tinea pedis,nappy rash and tinea cruris.
Used in combination with its zinc salt.
4) Benzoic acid:
Used in combination with salicyclic acid,its kerolytic action helps to
remove the infected tissue and promotes the penetration of benzoic
acidinto the lesion.
Used in dermatophytosis,mycosis barbae,seborrhoeic dermatitis,
infected eczematricomonas vaginitis.
6) Sodium thiosulphate:
It is effective in pityriasis versicolor.
Moving into the cell:
Fungi must synthesize Met, Ile, Thr.
Iron importation mechanism
Fungi must scavenge for iron inside host
Siderophores bind soluble iron with high affinity
Actively transported through cell wall
Summary of Treatments
Amphotericin B +
Flucytosine followed by
Saturate solution of
1)Tripathi KD.Essentials of medical pharmacology,Jaypee brother
medical publisher,5th edition(2005),p.p:715-724
2)Rang H.P.,Dale M.M,Ritter J.M.,Flower R.J.,Churchill livingstone
3) Goodman and Gilman, The pharmacological basis of therapeutics, 11th