Antimycotic Agents

8/7/2019 Antimycotic Agents

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ANTIMYCOTIC AGENTSAND THEIR PROPERTIES

BY

MAWULI ATIEMO


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INTRODUCTION

Mycosis is term forinfections caused by fungi

and the study of fungal infectionsis referred to

asmycology.

Antimycotics agents are drugs used to treatfungal infections.

Fungi are free-living micro-organisms that

exist asyeasts (single-cell, round fungi),molds (multicellular filamentous fungi), or a

combination of the two (so-called dimorphic

fungi)


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Maingroups of fungi

Yeast e.g. Cryptococcus neoformans

Yeast like fungi that produces a sture

resembling a mycelium e.g. Candidaalbicans

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 containingchitin as well aspolysaccharides

Cell membrane composed ofergosterol (Cholesterol formammalians)

Phylogenetic similarity with humans - homologousmetabolic pathways for energy production, proteinsynthesis and cell division.

Most fungi have detoxification system that modifiesantifungal agents.

Greater difficulty in developingselective antifungalagents thanin developingselective 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 antibioticsand 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 methodsculture-base method

direct examination ofspecimens under lightmicroscopy

focus of modern mycologypolymerase chain reaction (PCR),

western blot

antigen detection (serology)

identification of fungal metabolites

Because these techniques are still investigational, they must beperformed in parallel with traditional culture-base method.


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Class of Antimycotic Agents

Characteristics ofideal Antimycotic

Agent:

1. broad spectrum of action2. low drug toxicity

3. multiple routes of administration

4. excellent penetrationinto the CSF,

urine and bone


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Cellular Targets of Antimycotic Agents


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Cellular Targets ofAntimycotic Agents

Currently antifungal agents act on distinctmolecular targets.

1. Flucytosine inhibits fungal DNA synthesis

2. Griseofulvin (Penicillium griseofulvum)inhibits

fungal mitosis by disrupting mitotic spindles.3. Allylamines, Benzylamines, imidazoles andtriazolesinhibit the ergosterol synthesispathway in the ER.

4. Polyenes (Amphotericin B) bind to ergosterol

in the fungal membrane and thereby disruptplasma membrane integrity.

5. Echinocandins (caspofungin, micafungin &anidulafungin) inhibit fungal cell wall synthesis.


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Inhibitors ofFungal Nucleic acid

synthesis: Flucytosine

Mechanism

Flucytosine enters the fungal cell via atransmembrane cytosine permease.

Inside the cell, cytosine deaminase convertsflucytosine to 5-fluorouracil (5 FU), which issubsequently converted to 5 fluorodeoxyuridylicacid monophosphate (5 FdUMP).

5 FdUMPinhibits thymidylate synthase andthereby blocks the conversion of deoxythymidylate(dTMP).

In the absence of dTMP, DNA synthesisisinhibited.


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Flucytosine cont.

Clinical App- Limited to candidiasis,cryptococcosis and chromomycosis

Pkinetics Easily penetrate CNS. Renalexcretion

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 reducesthe likelihood of the emergence of resistance toFlucytosine


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Inhibitors of fungal mitosis: Griseofulvin Mechanism - Binds to tubulin and a microtubule

associated protein, thereby disrupting assembly ofthe mitotic spindle thereby disrupting cell division.

Pkinetics -

Absorption Enhanced if drugis taken with fattymeal. Nearly complete but varies with particlesize.

Distribution about 84% bound to plasma

proteins Metabolism Metabolized in the liver .

Elimination t1/2is 9-24hrs

Excretion urine (1%), faeces(36%), sweat


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Cont. Clinical App.- Fungal infection of the skin, hair, ornail

due to Trichophyton, Microsporum, or Epidermophyton.Not effective against yeast & dimorphic fungi.

Contra indications: severe liver ds, lupuserythematosus, 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 FulcininducesC. P450 enzyems1. increases metabolism of anticoagulants e.g warfarin,

2. reduces the efficacy of oral contraceptives


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Inhibitors of 14 Sterol Demethylase:

Imidazoles & Triazoles Mechanism - Inhibit ultimate conversion of lanosterol

to ergosterol by inhibiting 14 sterol demethylase;

the resulting decrease in ergosterol synthesis and

accumulation of 14 methyl sterols disrupt thetightly packed acyl chains of the phospholipidsin 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. ofskin or fingernails, prophylaxis of mycosesin

immunosuppressed patients.

Pkinetics

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 envt of the stomach.

Excretion faeces as metabolites & unchanged drug, urine 13%Contra indication Achlorhydria patients, patients on bicarbonates,

antacids, H2- blockers, orPPI, pregnancy

Interactions Isoniazid, Rifampicin s plasma conc.

Anticoagulant effect enhanced by Ketoconazole.

s plasma conc. Antidiabetics ( sulfonylureas).


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Fluconazole Most widely used antifungal. Hydrophilic azole available in both oral or

i.v. preps

Indication vaginal candidiasis, systemic candidiasis, cryptococcalmeningitis, prophylaxis of fungal inf. inimmunocompromised patients

following cytotoxic chemotherapy or radiotherapy.

Pkinetics

Absorption- Well absorbed p.o. Bioavailability isnearly 100% from oral

route but . Not affected by gastric PH

unlike Ketoconazole. Distribution Concentrationsin the CSF 50 90% of plasma conc.

Protein bindingis 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- Johnsonsyndrome, CNS ( headache, seizures)

Interactions-s levels of Amitriptyline, Cyclosporine, Phenytoin, Warfarin

s levels & effect ofFluconazole by Carbamazipine,

Phenobarbital, Isoniazid.


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Inhibitors of Ergosterol synthesis pathway

( Inhibitors of Squalene Epoxidase)

Mechanism - Inhibit conversion ofsqualene tolanosterol by inhibitingsqualene epoxidase.

E.g. - Allylamines (terbinafine & naftifine) &Benzylamines ( butenafine

TERBINAFINE Indications- Dermatophyte infs. ofskin & nails,

ringworm inf. (Tinea pedis, T. cruris & T. corporis.)

Terbinafine available in both oral & topical preps.

Topically Allylamines and Benzylamines are moreeffective than topical azoles against commonDermatophyte, esp. Tinea pedis. They are however,less effective than topical azoles against Candidaskininfections.


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Terbinafine cont.

PkineticsAbsorption - 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-Johnsonsyndrome,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 fungalmembrane permeability and stability.

E.g. Amphotericin B & Nystatin- natural pdts from streptomycesspps

Amphotericin B used to be most effective drug forsystemic mycoses.

Pkinetics Highly insoluble. Supplied as buffered deoxycholatecolloidal suspension. Poorly absorbed 4m GIT. Admini.v preferred.

90% bound to tissuessites, 10% bound to plasma protein

Distribution- CSF, vitreous humour and amniotic fluid.

Adverse effect- Toxicity of Ampho B limitsit 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 andcyclosporine s plasma levels

Amphotericin B in liposomes or lipid formulations reducesnephrotoxicity.(prevent exposure to proximal tubule)


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Nystatin

Indication- topical candidiasisinvolving the

skin, vaginal mucosa and oral mucosa Pkinetics

Absorption Insignificant orally. Not absorbed

systemically after topical admin Excretion as unchanged drugin faeces.

Adverse effect- Rashes, oral irritation,

nausea, vomiting, diarrhoea at high doses.


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Inhibitors of fungal wall synthesis:

EchinocandinsMechanism - Noncompetitively inhibit synthesis of (1,3)

D glucans (cell wall chitins), which leads to disruption ofcell wall integrity.

They include caspofungin, micafungin and anidulafungin.

Indications- invitro and invivo antifungal activity againstCandida andAspergillus spps.

All 3 Echinocandins are fungicidal against Candida spps. ( C.glabrata & C. krusei) and fungistatic againstAspergillusspps.

Available only in parenteral forms due to poor bioavailabilityafter p.o admin

Adverse effect headache, fever, pruritus, GIT disturbancesthrombophlebitis

Interaction - cyclosporine + caspofungins plasma conc.and elevate liver fxn enzymes


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EXAMPLES OF SOMEANTIMYCOTIC 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 ofPharmacology (a text book forNurses & Health Professionals), 1st edition(1997). Pearson Education Limited, England. Pages 673 - 676

2. Golan, D.G, Tashjian, A. H. Jnr, et al. Principles ofPharmacology, the Pathophysiologic Basis ofDrug 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 InformationHandbook, 2nd edition (2009), NationalDrug Information Resource Centre, Accra. Pages 155-162

5. Olson, J. Clinical Pharmacology made simple, 2nd edition (1991)

MedMaster Inc. U.S.A pg118 1196. 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 DalesPharmacology, 6th

Edition (2007). Churchill Livingstone Elsevier. Pages 692-693


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THANK YOU

MERCI

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Antimycotic Agents