• Fungi are eukaryotic, heterotrophic organisms that live as saprobes or parasites. • Complex organisms in comparison to bacteria . • Have nucleus and well defined nuclear membrane, and chromosomes. • Have rigid cell wall composed of chitin (bacterial cell wall is composed of peptidoglycan) • Fungal cell membrane contains ergosterol , human cell mebmrane is composed of cholesterol • Antibacterial agents are not effective against fungi. • Fungal infections are also called as mycoses Antifungal Agents, also known as an antimycotic Agents ANTIFUNGAL AGENTS 1 Introduction
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Antifungal agents - SAR (Structure Activity Relationship )
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• Fungi are eukaryotic, heterotrophic organisms that live as saprobes or parasites.
• Complex organisms in comparison to bacteria .
• Have nucleus and well defined nuclear membrane, and chromosomes.
• Have rigid cell wall composed of chitin (bacterial cell wall is composed of peptidoglycan)
• Fungal cell membrane contains ergosterol , human cell mebmrane is composed of cholesterol
• Antibacterial agents are not effective against fungi.
• Fungal infections are also called as mycoses
Antifungal Agents, also known as an antimycotic Agents
ANTIFUNGAL AGENTS
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Introduction
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• Systemic fungal infections are a major cause of death in patients whose immune system is compromised
– cancer or its chemotherapy,
– organ transplantation
– HIV-1 infection.
• Superficial infections of the skin and other soft tissue structures.
• Antifungal agents target
– distinctive components of the fungal cell membrane
– others alter cell wall synthesis
– nucleic acid synthesis
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• Superficial : Affect skin – mucous membrane
– Tinea versicolor
– Dermatophytes : affect keratin layer of skin, hair, nail. e.g. tinea pedis, ring worm infection
– Candidiasis : Yeast-like, oral thrush, vulvo-vaginitis , nail infections.
• Deep Infections :
– Affect internal organs as : lung ,heart , brain leading to pneumonia , endocarditis , meningitis.
A polyene is a molecule with multiple conjugated double bonds.
Polyenes are macrocyclic compounds which bear several conjugated double bonds and distinct lipophilic and hydrophilic regions- containing carbonyls, hydroxyls and a sugar
A polyene antifungal is a macrocyclic polyene with a heavily hydroxylated region on the ring opposite the conjugated system. This makes polyene antifungals amphiphilic.
Examples of polyenes include Amphotericin B and Nystatin
Amphotericin B 13
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Polyene antifungals
The polyene antimycotics bind with sterols in the fungal cell membrane (ergosterol)
Polyenes have greater affinity for ergosterol-containig fungal membranes so, in other words, polyenes are more selective for fungal cells
Reduction of the hydrophobic chain may result in it binding to cholesterol, making it toxic to animals.
The lipophilic region of polyenes interacts with sterols via hydrophobic interactions
Polyenes work by inserting themselves into cell membranes
This results a rise in membrane permeability and loss of cytoplasmic constituents which is detrimental to fungal cell viability
15 Amphotericin B
• Antifungal agent with the broadest spectrum of activity
• Produced by Streptomyces nodosus.
• Natural, Amphoteric polyene macrolide –
– Amphoteric = can react as an acid as well as a base
– polyene = many double bonds
– macrolide = containing a large lactone ring
• Heptaene macrolide - large lactone ring with multiple ketone and hydroxyl group)
• Drug of choice for the vast majority of life-threatening systemic fungal infections
• Interacts with ergosterols, forms pores that increase membrane permeability and allow leakage of intracellular ions &
Polyene antibiotics Amphotericin B
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macromolecules from fungal cDer llrs(Bocrkearll death ).
Polyene antibiotics
Lactone ring
Lipophilic part
• Amphotericin B:
– Obtained from Streptomyces Nodosus
– Amphoteric in nature Hydrophilic part
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• Broad range of pathogenic fungi
• Protozoa, Leishmania braziliensis and Naegleria fowleri
– Uses: in combination with AMB in cryptococcal meningitis
– Narrow spectrum of action
5-fluorocytosine (5-FC) 5-FC 5-FU
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• Absorbed rapidly and well from the GI tract, widely distributed
• Minimally bound to plasma proteins. • Penetrates well into CSF. • Mainly excreted unchanged through kidney • Half life drug normally is 3–6 hours but may reach
200 hours in renal failure. • Dose modification is necessary in renal dysfunction
plasma concentrations should be measured periodically
• Flucytosine is cleared by hemodialysis and peritoneal dialysis
Flucytosine - ADME
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• Given orally at 100 mg/kg/day, in 4 divided doses and is used predominantly in combination with amphotericin B.
• Severe deep fungal infections as in meningitis
• Cryptococcal meningitis: begin with amphotericin B plus flucytosine and change to fluconazole after the patient has improved.
• There is the risk of amphotericin induecd azotemia and flucytocine dose has to be reduced in this situation otherwise the combination will cause bone marrow suppression or colitis
Flucytosine – Uses
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• Hematologic : Leukopenia, thrombocytopenia, bone marrow depression
• Allergic: Rash, nausea, vomiting, diarrhea, and enterocolitis
• Hepatic: Elevation in hepatic transaminases but this reverses when therapy is stopped.
• Toxicity is more frequent in patients with AIDS or azotemia.
• Alopecia
Flucytosine – Adverse effects
Advantages of combination: –Entry of 5 FC
–Reduced toxicity
–Rapid culture conversion
–Reduced duration of therapy
–Decreased resistance
• Differences between AMB & 5 FC • AMB = Active drug, broad spectrum, antibiotic,
fungicidal
• Not absorbed, high protein binding, no BBB, metabolized in liver, highly efficacious, IV, Intrathecal, topical
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• Bivalent chemical group composed of five-membered organic rings (Synthetic antifungals)
• Broad spectrum of activity - Antibacterial, antiprotozoal, anthelminthic and antifungal
• Fungistatic or fungicidal depending on conc of drug
• Group of synthetic fungistatic agents
• Classification: according to the number of nitrogen atoms attached to the ring
systemic fungal infections: Disseminated candidiasis, cryptococcal, coccidiodal meningitis 200-400 mg / day 4- 12 weeks or longer
Meningitis: preferred drug
Eye drops for fungal keratitis
Triazoles
Itraconazole
- Varied absorption.
- Metabolized by cyt P450
- less endocrine effects but occur at high doses
- Less penetration in CSF
- Many drug interactions (due to inhibition of CYT P450/ 3A4)
Fluconazole
- Completely absorbed and better tolerated, Renal excretion
- Less endocrine effects
- Penetrates well into CSF
- Drug Interactions
SAR
Varying polar functional groups to vary polarity
A polar functional group could be added to a drug to increase polarity.
For example: Tioconazole (antifungal) is used only for skin infections because it is non-polar and poorly absorbed in blood.
Introducing a polar hydroxyl group and more polar heterocyclic ring led to the orally active antifungal agent Fluconazole.
In contrast, the polarity of an excessively polar drug could be lowered by removing polar functional groups.
It is important not to remove functional groups which are important to the drug's binding interactions with its target.
Strategies to improve absorption
Voriconazole
II generation triazole
High oral bioavailability, low protein binding
Good CSF penetration
Metabolized by CYP2C19
Doesn’t require gastric acidity for absorption
T1/2= 6 hrs
Uses:
DOC for invasive aspergillosis
Most useful for esophageal candidiasis
First line for moulds like fusarium
Useful in resistant candida infections
Dose and Adverse effects
• Dose : 200 mg BD
• Adverse events:
– Transient visual changes like blurred vision , altered color perception & photophobia
– Rashes in 5 -6 %
– Elevated hepatic enzymes
– Prolongation of QT
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• Topical treatment is useful in superficial fungal infections confined to the stratum corneum, squamous mucosa, or cornea, including dermatophytosis (ringworm), candidiasis, tinea versicolor, piedra, tinea nigra, and fungal keratitis.
• Unsuccessful for mycoses of the nails (onychomycosis) and
hair (tinea capitis)
• No place in subcutaneous mycoses, such as sporotrichosis and chromoblastomycosis.
• Efficacy of topical agents depends not only on the type of lesion and the mechanism of drug action, but also on the viscosity,
hydrophobicity, and acidity of the formulation.
Topical Antifungal Agents
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• Regardless of formulation, penetration of topical drugs into
hyperkeratotic lesions often is poor.
• Removal of thick, infected keratin may be a useful adjunct to
therapy.
• Preferred formulations are
– Creams
– Solutions
– Powders, whether applied by shake containers or aerosols, largely are used for the feet and moist lesions of the groin and other intertriginous areas
Topical Antifungal Agents
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1. Topical azole derivatives
2. Nystatin& Amphotericin
3. Terbinafine
4. Tolnaftate
5. Naftifine
6. Griseofulvin
Topical Antifungal Agents
Used in superficial fungal infections:
Dermatophytosis ( ring worm)
Candidiasis
Fungal keratitis.
Not effective in mycoses of the nails & hair or subcutaneous mycoses.
Preferred formulation for cutaneous application is cream or solution.
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• Indications for topical use include
– tinea corporis
– tinea pedis
– tinea cruris
– tinea versicolor
– cutaneous candidiasis.
• Agents for topical use should be selected based on cost and availability.
• They are applied twice daily for 3–6 weeks.
• Preparations for cutaneous use are effective for
Topical Antifungal Agents - Azoles
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• Creams, suppositories, and tablets for vaginal candidiasis
• 5 gm, Used once daily for 1–7 days, preferably at bedtime to facilitate retention.
• Three vaginal formulations—
– clotrimazole tablets,
– miconazole suppositories,
– Terconazole cream
• Come in both low- and high-dose preparations.
• Shorter duration of therapy is recommended for the higher doses.
• The action is local and only little is absorbed
• Most common side effect is vaginal burning or itching.
• A male sexual partner may experience mild penile irritation.
Topical Antifungal Agents – Vaginal Applications
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Antifungal Agents - Allylamine
Terbinafine
Orally & topically effective drug against candida & dermatophytes
• Tolnaftate a synthetic thiocarbamate • The exact mechanism of action is not entirely known, it is
believed to inhibit squalene epoxidase, an important enzyme in the biosynthetic pathway of ergosterol (a key component of the fungal membrane) in a similar way to allylamines
• Over all toxicity: highest for AMB lowest for fluconazole, itraconazole
Important characteristics
Spectrum of action
• Nystatin: Candidiasis only
• Griseofulvin: Dermatophytosis only
• Terbinafine : Dermatophytosis & candidiasis
• Caspofungin: Aspergillosis & candidiasis
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Tioconazole Fluconazole Fosfluconazole
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Echinocandins
Echinocandins (cyclic peptides) may be used for systemic fungal infections in immunocompromised patients
they inhibit the synthesis of glucan in the cell wall via the enzyme 1,3-Beta-glucan synthase:
Anidulafungin
Caspofungin
Micafungin
Echinocandins are poorly absorbed when administered orally.
When administered by injection they will reach most tissues and organs with concentrations sufficient to treat localized and systemic fungal infections