ANTIMYCOTIC AGENTS

AND THEIR PROPERTIES

BY
MAWULI ATIEMO
Central University College, Accra
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 INTRODUCTION
• Mycosis is term for infections caused by fungi
and the study of fungal infections is referred to
as mycology.
• Antimycotics agents are drugs used to treat
fungal infections.
• Fungi are free-living micro-organisms that
exist as yeasts (single-cell, round fungi),
molds (multicellular filamentous fungi), or a
combination of the two (so-called dimorphic
fungi)
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 Main groups of fungi
• Yeast e.g. Cryptococcus neoformans
• Yeast – like fungi that produces a s’ture
resembling a mycelium e.g. Candida
albicans
• Filamentous fungi (Molds) with true
mycelium e.g. Aspergillus fumigatus
• ‘Dimorphic’ fungi e.g. Histoplasma
capsulatum

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 CHARACTERISTICS
• eukaryotic -
• Saprophytic - feed on dead organisms
• Rigid cell walls containing chitin as well as
polysaccharides
• Cell membrane composed of ergosterol (Cholesterol for
mammalians)
• Phylogenetic similarity with humans - homologous
metabolic pathways for energy production, protein
synthesis and cell division.
• Most fungi have detoxification system that modifies
antifungal agents.
• Greater difficulty in developing selective antifungal
agents than in developing selective antibacterial agents

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 SUSCEPTIBILITY
• surgical and intensive care unit (ICU) patients
• patients with prostheses
• patients with compromised immune defenses e.g. HIV
• immunosuppressive therapy
• the extensive use of broad-spectrum antibiotics and
steroids
• the wider use of long-term intravenous
• cancer chemotherapy
• the successes of organ transplantation
• Diabetics and pregnant women etc.

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 Diagnosis
• Traditional methods
culture-base method
direct examination of specimens under light
microscopy
• focus of modern mycology
polymerase chain reaction (PCR),
western blot
antigen detection (serology)
identification of fungal metabolites

Because these techniques are still investigational, they must be

performed in parallel with traditional culture-base method.

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 Types of mycoses
• 4 main groups
1. Systemic or deep mycoses – when internal
systems are infected
2. Subcutaneous mycoses – when skin, fascia
and bone are infected
3. Cutaneous mycoses – epidermis, hair or
nails are involved e.g. Athlete’s foot
4. Superficial mycoses – outermost layer of
epidermis and hair.

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 Class of Antimycotic Agents
• Characteristics of ideal Antimycotic
Agent:
1. broad spectrum of action
2. low drug toxicity
3. multiple routes of administration
4. excellent penetration into the CSF,
urine and bone
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 Cellular Targets of Antimycotic Agents

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Cellular Targets of Antimycotic Agents
• Currently antifungal agents act on distinct
molecular targets.
1. Flucytosine inhibits fungal DNA synthesis
2. Griseofulvin (Penicillium griseofulvum) inhibits
fungal mitosis by disrupting mitotic spindles.
3. Allylamines, Benzylamines, imidazoles and
triazoles inhibit the ergosterol synthesis
pathway in the ER.
4. Polyenes (Amphotericin B) bind to ergosterol
in the fungal membrane and thereby disrupt
plasma membrane integrity.
5. Echinocandins (caspofungin, micafungin &
anidulafungin) inhibit fungal cell wall synthesis.
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 Inhibitors of Fungal Nucleic acid
synthesis: Flucytosine
• Mechanism
• Flucytosine enters the fungal cell via a
transmembrane cytosine permease.
• Inside the cell, cytosine deaminase converts
flucytosine to 5-fluorouracil (5 – FU), which is
subsequently converted to 5 – fluorodeoxyuridylic
acid monophosphate (5 – FdUMP).
• 5 – FdUMP inhibits thymidylate synthase and
thereby blocks the conversion of deoxythymidylate
(dTMP).
• In the absence of dTMP, DNA synthesis is
inhibited.
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 Flucytosine cont.
• Clinical App- Limited to candidiasis,
cryptococcosis and chromomycosis
• P’kinetics – Easily penetrate CNS. Renal
excretion
• Contraindication – Pregnancy
• Adverse Effects - bone narrow suppression
(leading to leukopenia and thrombocytopenia),
GIT disturbance( nausea, vomiting, diarrhea),
cardiotoxicity and hepatic dysfunction
• Coadministration with Amphotericine B reduces
the likelihood of the emergence of resistance to
Flucytosine
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Inhibitors of fungal mitosis: Griseofulvin
• Mechanism - Binds to tubulin and a microtubule –
associated protein, thereby disrupting assembly of
the mitotic spindle thereby disrupting cell division.

• P’kinetics -
– Absorption – Enhanced if drug is taken with fatty
meal. Nearly complete but varies with particle
size.
– Distribution – about 84% bound to plasma
proteins
– Metabolism – Metabolized in the liver .
Elimination t1/2 is 9-24hrs
– Excretion – urine (1%), faeces(36%), sweat
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 Cont.
• Clinical App.- Fungal infection of the skin, hair, or nail
due to Trichophyton, Microsporum, or Epidermophyton.
Not effective against yeast & dimorphic fungi.
• Contra – indications: severe liver ds, lupus
erythematosus, pregnancy
• Adverse effects – 1.CNS (headache, lethargy, vertigo,
blurred vision)
2. GIT (dry mouth, flatulence, oral candidiasis)
3.Haematological (leukopenia, neutropenia)
4.Angioedema, 5. exfoliative dermatitis.
• Interactions – Fulcin induces C. P450 enzyems
1. increases metabolism of anticoagulants e.g warfarin,
2. reduces the efficacy of oral contraceptives

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Inhibitors of 14α – Sterol Demethylase:
Imidazoles & Triazoles
• Mechanism - Inhibit ultimate conversion of lanosterol
to ergosterol by inhibiting 14α – sterol demethylase;
the resulting decrease in ergosterol synthesis and
accumulation of 14α –methyl sterols disrupt the
tightly packed acyl chains of the phospholipids in the
fungal membrane.
• Include:1. Imidazoles – Ketoconazole, Clotrimazole,
Miconazole
2. Triazoles – Fluconazole, Itraconazole

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 Ketoconazole
• Indications – Systemic mycoses, serious chronic resistant
mucocutaneous candidiasis, chronic resistant vaginal candidiasis,
resistant dermatophyte inf. of skin or fingernails, prophylaxis of mycoses in
immunosuppressed patients.
• P’kinetics –
• Absorption – oral bioavailability is 75%
• Distribution – 90% bound to plasma protein
• Metabolism – in the liver
• Elimination t1/2 - biphasic 2hrs & terminal t1/2 of 8hrs.
GIT absorption of oral Ketoconazole depends on conversion of the drug to
a salt in the acidic env’t of the stomach.
• Excretion – faeces as metabolites & unchanged drug, urine 13%
Contra indication – Achlorhydria patients, patients on bicarbonates,
antacids, H2- blockers, or PPI, pregnancy
Interactions – Isoniazid, Rifampicin ↓s plasma conc.
Anticoagulant effect enhanced by Ketoconazole.
12/08/21 ↑s plasma conc. Antidiabetics
Group 4 ( sulfonylureas). 16
 Fluconazole
• Most widely used antifungal. Hydrophilic azole available in both oral or
i.v. preps
• Indication – vaginal candidiasis, systemic candidiasis, cryptococcal
meningitis, prophylaxis of fungal inf. in immunocompromised patients
following cytotoxic chemotherapy or radiotherapy.
• P’kinetics –
• Absorption- Well absorbed p.o. Bioavailability is nearly 100% from oral
route but . Not affected by gastric PH unlike Ketoconazole.
• Distribution – Concentrations in the CSF 50 – 90% of plasma conc.
Protein binding is only about 12%.
• Metabolism – Partially in the liver. Elimination t1/2 of 30hrs
• Excretion – about 61-88% unchanged in urine and 11% as metabolites.
• Contra – indication- pregnancy, hypersensitivity to Fluconazole
• Adverse effect – GIT (nausea, vomiting, abdominal pain), Hepatic
disorders, Steven- Johnson syndrome, CNS ( headache, seizures)
• Interactions-↑s levels of Amitriptyline, Cyclosporine, Phenytoin, Warfarin
↓s levels & effect of Fluconazole by Carbamazipine,
12/08/21 Phenobarbital, Isoniazid.
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 Inhibitors of Ergosterol synthesis pathway
( Inhibitors of Squalene Epoxidase)
• Mechanism - Inhibit conversion of squalene to
lanosterol by inhibiting squalene epoxidase.
• E.g. - Allylamines (terbinafine & naftifine) &
Benzylamines ( butenafine
TERBINAFINE
• Indications- Dermatophyte infs. of skin & nails,
ringworm inf. (Tinea pedis, T. cruris & T. corporis.)
• Terbinafine – available in both oral & topical preps.
• Topically Allylamines and Benzylamines are more
effective than topical azoles against common
Dermatophyte, esp. Tinea pedis. They are
however, less effective than topical azoles against
Candida skin infections.
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 Terbinafine cont.
• P’kinetics –
Absorption - 40% bioavailability after oral admin.
Distribution- 99% bound to plasma proteins.
Metabolism- 1st pass metabolism in liver
Elimination t1/2 approx. 22 - 26hrs
Excretion – up to 70% in urine and 20% in faeces

• Contra-indication: renal/hepatic failure, pregnancy

• Adverse effect – hepatotoxicity, Steven-Johnson syndrome,

neutropenia

• Interactions- 1. Cimetidine + Terbinafine = ↑s plasma levels

2. Rifampicin + Terbinafine = ↓s plasma levels
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Inhibitors of fungal membrane stability: Polyenes

• Mechanism - Bind to ergosterol and form pores that alter fungal

membrane permeability and stability.
• E.g. Amphotericin B & Nystatin- natural pdts from streptomyces spps
• Amphotericin B – used to be most effective drug for systemic mycoses.
• P’kinetics – Highly insoluble. Supplied as buffered deoxycholate
colloidal suspension. Poorly absorbed 4m GIT. Admin i.v preferred.
90% bound to tissues sites, 10% bound to plasma protein
• Distribution- CSF, vitreous humour and amniotic fluid.
• Adverse effect- Toxicity of Ampho B limits it clinical use. 3 main effects-
1.systemic rxns (hypotension, fever and chills)
2. renal toxicity (nephrotoxicity)
3. haematological effects ( decreased prdxn of erythropoietin)
• Interactions- Nephrotoxic drugs like aminoglycosides and
cyclosporine ↑s plasma levels
• Amphotericin B in liposomes or lipid formulations reduces nephrotoxicity.
(prevent exposure to proximal tubule)
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 Nystatin
• Indication- topical candidiasis involving the
skin, vaginal mucosa and oral mucosa
• P’kinetics –
• Absorption – Insignificant orally. Not
absorbed systemically after topical admin
• Excretion – as unchanged drug in faeces.
• Adverse effect- Rashes, oral irritation,
nausea, vomiting, diarrhoea at high doses.

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 Inhibitors of fungal wall synthesis:
Echinocandins
Mechanism - Noncompetitively inhibit synthesis of β – (1,3) –
D – glucans (cell wall chitins), which leads to disruption of
cell wall integrity.
• They include caspofungin, micafungin and anidulafungin.
Indications- in vitro and in vivo antifungal activity against
Candida and Aspergillus spps.
• All 3 Echinocandins are fungicidal against Candida spps. ( C.
glabrata & C. krusei) and fungistatic against Aspergillus
spps.
• Available only in parenteral forms due to poor bioavailability
after p.o admin
Adverse effect – headache, fever, pruritus, GIT disturbances
thrombophlebitis
Interaction - cyclosporine + caspofungin ↑s plasma conc.
and elevate liver fxn enzymes
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 EXAMPLES OF SOME
ANTIMYCOTIC AGENTS
• A – Griseofulvin
• B – Nystatin
• C – Amphotericin
(R=H) and its methyl
ester (R=CH3)

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 REFERENCES
1. Galbraith, A., Bullock, S. et al. Fundamentals of Pharmacology
( a text book for Nurses & Health Professionals), 1st edition
(1997). Pearson Education Limited, England. Pages 673 - 676
2. Golan, D.G, Tashjian, A. H. Jnr, et al. Principles of
Pharmacology, the Pathophysiologic Basis of Drug Therapy, 2nd
edition (2008). Lippincott Williams & Wilkins, U.S.A. Pages 619
– 630
3. Hugo, W.B, Russell A.D, Pharmaceutical Microbiology 6th edition
(Blackwell, 1998) Page 121
4. Medicine Information Handbook, 2nd edition (2009), National
Drug Information Resource Centre, Accra. Pages 155-162
5. Olson, J. Clinical Pharmacology made simple, 2nd edition (1991)
MedMaster Inc. U.S.A pg118 – 119
6. Katzung, B.G., Basic and Clinical Pharmacology, 7th Edition
(1998). Appleton & Lange, Stanford, U.K . Page 780
7. Rang, H.P, Dale, M.M et al. Rang and Dale’s Pharmacology, 6th
Edition (2007). Churchill Livingstone Elsevier. Pages 692-693
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 THANK YOU

MERCI

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