ANTIFUNGAL DRUGS

PREPARED BY : JIPSY FALDU

M.PHARM SEM - ɪɪ

SUBJECT NAME : AP- ɪɪ

GUIDED BY : DR.DEVANG B.SHETH

B.K.MODY GOVT.PHARMACY COLLEGE,RAJKOT

CONTENT
o TYPES OF ANTIFUNGAL INFECTIONS
o CLASSIFICATION
o Mechanism of action
o Recent advances of antifungal drug
o GTU questions
o References

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FUNGAL INFECTION IN HUMANS-MYCOSIS
o Major Types of Mycoses
o Superficial infections
o Affecting skin, nails, scalp or mucous membrane.

o Systemic infections
o Affecting deeper tissues and organs.

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Superficial fungal infections
o It can be classified into-
 dermatomycoses - onychomycosis
Tinea capitis
- They are most commonly caused by Trichophyton, Microsporum or Epidermophyton.

 oral and vulvovaginal candidiasis.

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Systemic infections
o Candidiasis ,
o Cryptococcal meningitis,
o Pulmonary Aspergillosis,
o Leading cause of death in immunocompromised patients, recipients of bone marrow
transplants.

o Rhinocerebral mucormycosis

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Classification- Antibiotics
●
Amphotericin B
polyenes ●
Nystatin
●
Hamycin

●
Caspofungin
Echinocandins ●
micafungin
●
Anidulafungin

Heterocyclic ●
Griseofulvin
benzofuran

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Classification- Azoles

Imidazoles- ●

●
Clotrimazole
Econazole
miconazole
(topical)
●

●
oxiconazole

imidazoles– ●
ketoconazole
(systemic)
Triazoles ●

●
Fluconazoles
Itraconazoles
voriconazoles
(systemic)
●

●
posaconazole

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Antimetabo ●
Flucytosine (5- fc)
lite

allylamine ●
terbinafine

Other
●
Tolnaftate
●
Undecylenic acid
●
Benzoic acid
●
Butenafin

topical agent
●
Sod.thiosulfate
●
Olamine
●
quiniodochlor

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Mechanism of action

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 Amphotericin B
o Amphotericin B is a naturally occurring polyene antifungal produced by
streptomyces nodosus.
o Amphotericin B is an amphoteric polyene macrolide (polyene =containing
many double bonds; macrolide = containing a large lactone ring of 12 or more
atoms).
o In spite of its toxic potential , amphotericin B remains the drug of choice for
the treatment of several life threatening mycoses.

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MOA OF Amphotericin B

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 Antifungal spectrum & clinical use

o Amphotericin B remains the antifungal agent with the broadest spectrum of action.
o It has activity against the clinically significant yeasts, including Candida albicans and
Cryptococcus neoformans;
o the organisms causing endemic mycoses, including Histoplasma capsulatum, Blastomyces
dermatitidis, and Coccidioides immitis; and the pathogenic molds, such as Aspergillus fumigatus
and the agents of mucormycosis.
o Some fungal organisms such as Candida lusitaniae and Pseudallescheria boydii display intrinsic
amphotericin B resistance.
o Owing to its broad spectrum of activity and fungicidal action, amphotericin B remains a useful
agent for nearly all life-threatening mycotic infections, although newer, less toxic agents have
largely replaced it for most conditions.

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o Local or topical administration of amphotericin B has been used with success.
o Mycotic corneal ulcers and keratitis can be cured with topical drops as well as by direct subconjunctival
injection.
o Fungal arthritis has been treated with adjunctive local injection directly into the joint.
o Candiduria responds to bladder irrigation with amphotericin B, and this route has been shown to produce
no significant systemic toxicity.
o Amphotericin B can be applied topically for oral, vaginal and cutaneous candidiasis and otomycosis.
o It is the most effective drug for various types of systemic mycoses and is the gold standard of antifungal
therapy.
o in Febrile neutropenia
o Leishmaniasis : AMB is the most effective drug for -
resistant cases of kala azar and mucocutaneous leishmaniasis.

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AMB in Recent Advances in the Management of Mucormycosis
o  LFAB have evolved as the cornerstone of primary therapy for mucormycosis.
o Posaconazole may be useful as salvage therapy, but it cannot be recommended as primary therapy for
mucormycosis on the basis of available data.
o Preclinical and limited retrospective clinical data suggest that combination LFAB-echinocandin
therapy may improve survival during mucormycosis.
o Combination therapy with LFAB and the iron chelator, deferasirox, also improved outcomes in
animal models of mucormycosis.

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 Recommended
Drug Advantages Disadvantages
dosage
AmB 1.0–1.5 mg/kg/day >5 Decades clinical experience; inexpensive; only Highly toxic; poor
licensed agent for the treatment of mucormycosis CNS penetration

LAmB 5–10 mg/kg/day Less nephrotoxic than AmB; better CNS penetration Expensive
than AmB and ABLC improved outcomes vs. AmB in
murine models and a retrospective clinical review

ABLC 5–7.5 mg/kg/d Less nephrotoxic than AmB; murine and retrospective More nephrotoxic
clinical data suggest benefit of combination therapy than LAmB possibly
with echinocandins less efficacious than
other options as
monotherapy,
particularly for CNS
infection

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Pharmacokinetics
o AMB nearly insoluble in water and is therefore prepared as a colloidal suspension of
amphotericin B and sodium deoxycholate for intravenous injection.
o Amphotericin B is poorly absorbed from the gastrointestinal tract
o About 60% of AMB is metabolized in the liver.
o The drug is widely distributed in most tissues, but only 2–3% of the blood level is reached in
cerebrospinal fluid, thus occasionally necessitating intrathecal therapy for certain types of
fungal meningitis.
o The terminal elimination t½ is 15 days.
o Excretion occurs slowly both in urine and bile.

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Adverse effects
A. Infusion-Related Toxicity
o Infusion-related reactions are nearly universal and consist of
o fever, chills, muscle spasms, vomiting, headache, and hypotension
B. Cumulative Toxicity
o Renal damage is the most significant toxic reaction
o nephrotoxicity usually occurs in the setting of prolonged administration (>4 g cumulative
dose).
o anemia due to reduced erythropoietin production by damaged renal tubular cells.

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 Caspofungin

o These are a new class of potent semisynthetic antifungal antibiotics with a complex cyclic
lipopeptide structure, which stand out due to their low toxicity compared to AMB.
o It is the first and the prototype member of the class .
o It is active mainly against Candida and Aspergillus.
o Semisyntetic lipopeptide synthesized from the fermentation product of Glarea lozoyensis.
o It is active in vitro against a wide variety of fungi and it has proved effective in the
treatment of candidiasis.
o and forms of invasive aspergillosis that are refractory to amphotericin.

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MOA of caspofungin

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 Pharmacokinetics
o Caspofungin is not absorbed orally,so it has to be infused i..v.
o It is distributed into tissues, but does not enter CSF.
o Metabolism is extensive and metabolites are excreted in urine as well as faeces with a plasma
t½ of 10 hours.
o Catabolism is largely by hydrolysis & n- acetylation .
o Mild and moderate hepatic insufficiency increases the AUC by 55% & 76% respectively

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Therapeutic use
o Caspofungin is approved for initial therapy of deeply invasive candidiasis & as salvage
therapy for patients with invasive aspergillosis who are failing or intolerant of approved
drugs, such as AMB formulations or voriconazole.
o Approval for salvage therapy of aspergillosis.
o Caspofungin is also approved for esophagal candidiasis.
o It is used in treatment of persistently febrile neutropenic patients with suspected fungal
infections.

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 Adverse effect
o An acute febrile reaction some times attends the i.v. infusion of caspofungin, as does
phlebitis of the injected vein.
o Rashes
o vomiting,
o dyspnoea,
o Hypokalemia
o and joint pain may occur.

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 Griseofulvin
o It was one of the early antibiotics extracted from Penicillium griseofulvum.
o Griseofulvin is fungistatic for most dermatophytes, including Epidermophyton,
Trichophyton, Microsporum, etc., but not against Candida and other fungi causing deep
mycosis

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MOA of griseofulvin

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 Pharmacokinetics
o The absorption of griseofulvin from g.i.t. is somewhat irregular because of its very low
water solubility.
o The plasma half-life is 24 h, but it is retained in the skin for much longer.
o Griseofulvin is largely metabolized, primarily by methylation, and excreted in urine.
o Dose :
o The recommended daily dose of griseofulvin is 2.3 mg/kg for children 500 mg to 1 g for
adults.

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Adverse effects
o Toxicity of griseofulvin is low and usually not serious.
o Headache is the commonest complaint, followed by g.i.t. disturbances.
o CNS symptoms and peripheral neuritis are occasional.
o Rashes, photoallergy may warrant discontinuation.
o Gynaecomastia is reported.
o Transient leukopenia and albuminuria are infrequent.

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Therapeutic use
o Griseofulvin is used orally only for dermatophytosis.
o On getting deposited in the skin through circulation, it prevents fungal invasion of keratin.
o It is effective in athletes foot.

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Flucytosine
o It is a pyrimidine antimetabolite which is
inactive.
o After uptake into fungal cells, it is converted
into 5-Fc.
o it is a narrow spectrum fungistatic, active
against Cryptococcus neoformans, Torula,
Chromoblastomyces and a few strains of
Candida.

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Fungal resistance
o Flucytosine is used alone for cryptococcosis & candidiasis.
o In isolates of cryptococcus & candida species, secondary drug resistance has been
accompanied by a change in the minimal inhibitory concentration from < 2.5 µg/ml to
360 µg/ml.
o The mechanism for this resistance can be loss of the permease necessary for cytosine
transport or decreased activity of cytosine deaminase.

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Pharmacokinetics
o Flucytosine is absorbed rapidly and well from GI tract.
o It is widely distributed in the body.
o The peak plasma concentration in patients with normal renal function is ~70-80 µg/ml
o T1/2 of the drug is 3-6 hours in normal individuals.
o Flucytosine concentration in CSF is ~ 65-90 % of that found simultaneously in the
plasma.

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 Therapeutic use
o Rapid development of resistance limits its utility in deep mycosis.
o its synergistic action with AMB is utilized to reduce the total dose of the more toxic latter
drug.
o Therapy with 5-FC is generally limited to first 2 weeks of AMB regimen to avoid its
bone marrow toxicity.
o An all oral regimen of flucytosine + fluconazole also has been advocated for the therapy
of AIDS patients.

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 Adverse effect
o Toxicity of 5-FC is lower than that of AMB.

o It consists of dose-dependent bone marrow depression and gastrointestinal disturbances, particularly enteritis and
diarrhoea.
o Liver dysfunction is mild and reversible.
o leukopenia
o Thrombocytopenia
o Hematological disorder
o Other untoward effects- including rash
-nausea
-vomiting
-diarrhea

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Azole antifungals
o These are presently the most extensively used antifungal drugs.
o The azoles are a group of synthetic, fungistatic agents with a broad spectrum of activity
based on the imidazole or triazole nucleus.
o Which share the same antifungal spectrum and mechanism of action.
o The systemic triazoles are metabolized more slowly and have less effect on human
sterol synthesis than the imidazoles.

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MOA of azole antifungal

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 clotrimazole
o It is effective in the topical treatment of tinea infections like ringworm.
o clotrimazole used only for topical application.
o 60–100% cure rates are reported with 2–4 weeks application on a twice daily schedule.
o imazole interferes with amino acid transport into the fungus by an action on the cell
membrane.
o It is active against a wide range of fungi, including candidal organisms
o These drugs are sometimes combined with anti-inflammatory glucocorticoids

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Pharmacokinetics
o Absorption of clotrimazole is < 0.5 % after application to the intact skin from the
vagina, it is 3-10%.
o Fungicidal concentrations remain in the vagina for as long as 3 days after application of
the drug.
o The small amount absorbed is metabolized in the liver and excreted in bile.
o In adults, an oral dose of 200 mg/day will give rise initially to plasma concentrations of
0.2-0.35 µg/ml.

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Therapeutic use
o Clotrimazole is available as a 1% cream, lotion, powder, aerosol solution .
o 1% or 2% vaginal cream or vaginal tablets
o On the skin applications are made twice a day.
o For oropharyngeal candidiasis, troches are to be dissolved slowly in the mouth five
times a day for 14 days.
o Topical clotrimazole cures dermatophyte infections.

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Adverse effect
o It may cause stinging
o Erythema
o Edema
o Vesication
o Urticaria
o Mild burning sensation
o And rarely of lower abdominal cramps
o By the oral route clotrimazole can cause GI irritation

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Ketoconazole
o Ketoconazole was the first azole that could be given orally to treat systemic fungal
infection.
o It is useful in both dermatophytosis and deep mycosis.

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Pharmacokinetics
o It is well absorbed from the gastrointestinal tract.
o The oral absorption of KTZ is facilitated by gastric acidity because it is more soluble at
lower pH .
o It is inactivated in the liver and excreted in bile and in urine.
o Its plasma t1/2 is 8 hr.
o Penetration in CSF is poor therefore not effective in fungal meningitis.

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Therapeutic use
o It is the first orally effective broad-spectrum antifungal drug.
o It’s useful in both dermatophytosis and deep mycosis.
o Used as a lotion or shampoo, KTZ is quite effective in seborrhoea of scalp and dandruff.
o Though effective in monilial vaginitis, oral therapy (for 5–7 days) with KTZ is reserved
for recurrent cases or those not responding to topical agents.

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 Adverse effect
o The main hazard of ketoconazole is liver toxicity.
o Other side effects - gastrointestinal disturbances
pruritus.

o Inhibition of adrenocortical steroid and testosterone synthesis has been recorded with high
doses, the latter resulting in gynaecomastia in some male patients.
o There may be adverse interactions with other drugs - Ciclosporin and astemizole

o all interfere with cytochrome P450 drug - metabolizing enzymes, causing increased plasma
concentrations of ketoconazole or the interacting drug or both. Rifampicin, histamine
o H2 receptor antagonists and antacids decrease the absorption of ketoconazole.

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 Itraconazole
o This orally active triazole antifungal has a broader spectrum of activity than KTZ or
fluconazole; includes some moulds like Aspergillus.
o Some fluconazole resistant Candida are susceptible.
o It is fungistatic, but effective in immunocompromised patients.
o This synthetic triazole is an equimolar racemic mixture of four diastereoisomers , each
possessing three chiral centers.
o The structure is similar to that of the imidazole ketoconazole.

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 Pharmacokinetics
o Oral absorption of itraconazole is variable.
o It is enhanced by food and gastric acid.
o Itraconazole is highly protein bound, has a large volume of distribution (10 L/Kg),
accumulates in vaginal mucosa, skin and nails.
o but penetration into CSF is poor.
o It is largely metabolized in liver by CYP3A4.
o an active metabolite is produced which is excreted in faeces; t½ varies from 30–64 hours.

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Therapeutic use
o Itraconazole is the preferred azole antifungal for most systemic mycosis .
o It is superior to fluconazole for histoplasmosis, blastomycosis, sporotrichosis and is the drug of
choice for the rare fungal infections— paracoccidioidomycosis and chromomycosis.
o It also affords some relief in aspergillosis.
o A dose of 200 mg OD/BD with meals is used for 3 months or more.
o useful in Vaginal candidiasis.
o Onychomycosis

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Adverse effect
o Though rare, the most serious are hepatoxicity and Stevens–Johnson syndrome.
o Gastrointestinal disturbances,
o headache
o allergic skin reactions
o Drug interactions as a result of inhibition of cytochrome P450 enzymes occur.

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Recent advances in antifungal drugs
Generic Brand Name MOA New Indication Approval
Name Date
Ibrexafunrp BREXAFEM Inhibits for the treatment of adult and
(1→3)-β-D-
E glucan postmenarchal pediatric females June 1, 2021
synthase with VVC. 

olorofim F 90131 a reversible the treatment of invasive mold November

inhibitor of
the enzyme infections. 2019
dihyroorotate
dehydrogenas
e (DHODH)

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Generic Brand Name MOA New Indication Approval
Name Date

Rezafungin CD101 IV inhibit cell For the treatment of In 2016

wall
formation, candidemia and invasive
specifically candidiasis.
1,3-β-D-
glucan
synthesis.

Anidulafungin Eraxis, Ecalta inhibition of use in esophageal candidiasis and In 2006

(1→3)-β-D- candidemia
glucan
synthase

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GTU questions
o Write a note on ketoconazole.
o Describe the pharmacology of Amphotericin B.

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 References

o Laurence Brunton, Bruce A. Chabner, Bjorn Knollman, Goodman And Gilman’s The
Pharmacological Basics of Therapeutics; Twelfth Edition, McGraw Hill Education 2011, Section 7,
Chapter 57, pg: 1572- 1590.
o Bertram G . Katzung ,basic & clinical pharmacology, fourteenth edition, Lange medical
Publications 1984 , Section 8,chapter 48, pg : 853-862
o Rang H.P., Dale M.M., Ritter J.M., Moore P.K., “Pharmacology” 7th Edition, Churchill Livingston,
2012, Section 5, Chapter 52, pg no: 649- 654.
o KD Tripathi, “Essential of Medical Pharmacology” 7th Edition, Jaypee brothers Medical Publishers
(P) Ltd., 2013, Section 12, Chapter 57, pg no: 787-797.

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